TW200927761A

TW200927761A - Heparin-binding epidermal growth factor-like growth factor antigen binding proteins

Info

Publication number: TW200927761A
Application number: TW097137321A
Authority: TW
Inventors: Mike Rothe; Norbert Prenzel; Eric Borges; Esther Zwick-Wallasch; Thore Hettmann
Original assignee: U3 Pharma Ag; Amgen Inc
Priority date: 2007-09-26
Filing date: 2008-09-26
Publication date: 2009-07-01
Also published as: EP2207809A1; HK1149025A1; MX2010003380A; EP2207809B1; KR101652125B1; AU2008303796B2; KR20100075559A; IL204757A; US8828382B2; EP2497783A3; WO2009040134A8; MY150553A; DK2207809T3; ES2430068T3; CA2700723A1; WO2009040134A1; JP2011501655A; CN101970485A; CL2013000019A1; RU2504551C2

Description

200927761 九、發明說明【發明所屬之技術領域】人類表皮生長因子受體（HER) —族包含四種不同之受體酪胺酸激酶，稱爲HER1(或erbBl)、HER2(或erbB2)、 HER3(或erbB3)及HER4(或erbB4)。HER1亦通稱爲表皮生長因子受體（EGFR)。除了 HER3外’這些受體具有磷酸受體靶的特異性內源蛋白質酪胺酸激酶活性。HER族之成 ^ 員表現在大部分表皮細胞及許多不同之腫瘤細胞類型中。例如：Η E R族之受體表現在源自表皮和間質之腫瘤細胞中。再者，HER受體酪胺酸激酶涉及細胞增殖和血管新生（此與諸如癌症之疾病有關）。例如：EGFR在乳癌、肝癌、腎臟癌、血癌、支氣管癌、胰臟癌及胃腸癌（諸如結腸、直腸或胃癌）中經常過度表現或被異常活化。大量EGF受體亦與不良之預後和對治療之反應有關（Wright et al-,1 992, Br.J. Ca«cer 65 : 1 1 8-1 2 1 )。因此，中斷來自這 φ 些激酶和傳達至這些激酶之信號傳導將對多種癌症和腫瘤細胞類型具有抗增生，及這類治療效果。【先前技術】受體酪胺酸激酶之酶活性可藉由過度表現及/或藉由經配體傳介之二聚體化來刺激（Heldin，1 995，CeH 80.： 213-22 3)。活化受體同型二聚體及雜二聚體可造成受體上之酪胺酸殘質磷酸化’此接著將其他分子（包括胞內蛋白質）之酪胺酸殘質磷酸化（Ullrich，等人，1 995，Ce// 61 : 200927761

2 0 3 - 2 1 2)。接著，胞內傳訊途徑（諸如那些涉及經有絲分裂原活化之蛋白激酶（MAP激酶）（Dhillon，等人，2007， Oncogene 2 6 : 3279-3290)及隣脂醯肌醇-3-激酶（PI3激酶）者）活化。雖然這些途徑之活化顯示出可增加細胞增殖並抑制細胞凋亡，不過以小分子抑制劑或單株抗體抑制由 HER族成員傳介之傳訊作用顯示出可抑制細胞增殖並促進細胞凋亡（Prenzel，等人，2001，Λβ/αί. Cancer L :11-31)° 與肝素結合之似表皮生長因子的生長因子（ηβ-e GF)爲一種22kDa，Ο-糖基化蛋白質（Higahiyama，等人，1 992，

J Biol Chem 267 ： 6205-6212)。其成熟形式中，HB-EGF 結合並活化 EGF受體和 HER4(EleniuS，等人，1 997， EMBO 1 6: 1 268- 1 278)。HB-EGF爲由與 G-蛋白偶合之受體（GPCR)所誘導之細胞增殖的關鍵傳介子，該誘導作用係經由稱爲三層膜通行傳訊（triple-membrane passing signaling)(TMPS)進行（Prenzel et al., 1999, Natrure 402 : 884-888,回顧於 Fischer et al. 2003, Biochem. Soc. Trans. 31: 1203-1208)。HB-EGF顯示出可促進細胞增殖及血管新生（Zushi et al .,1 997，Int J Cancer 73 : 9 1 7-923 ;

Abramo vitch e t al., 1 9 9 8, FEBS letters 425 ： 441-447 )。HB-EGF亦被證實在多種癌症中扮演關鍵角色，即，其與卵巢腫瘤之侵略行爲有關（Tanaka " α/., 2005, C/i«.

Cancer Res. 1 1 : 47 8 3 -4792)。再者，Η B - EGF 對卵巢癌細胞株形成移植瘤而言是必要的。HB-EGF (野生型或分泌型） -6 - 200927761

過度表現可加速SKOV3及RMG-1細胞中形成腫瘤。然而，使用 siRNA壓倒（knockdown)內生性HB-EGF可終止或延遲SKOV3及RMG-1細胞形成腫瘤。Miyamoto，2004， Cawcer ϋ: 5720。如上述事證之建議，抑制HB-EGF 之表現或活性可抑制腫瘤形成。

類似地，HB-EGF爲某些癌症（包括人類膀胱癌）中預後不良的標記（Thogersen ei α/., 2001，Caw iies. 61 : 6227-623 3 )。活體外硏究指出經遺傳工程處理以表現HB-EGF(野生型，可溶或非可分裂的）之人類EJ膀胱癌細胞顯示出增加 VEGF之生長、非固著依賴性生長（anchorage independent growth)及製造並增強移行。當將這些表現 HB-EGF之EJ膀胱癌細胞移植入裸鼠中時，在那些腫瘤中可觀察到腫瘤形成、血管之大小及密度增加。（Ongus aha， 2004, Cancer Res. 64 : 5283-5290) ° φ 【發明內容】摘要本發明提供一種與HB-EGF結合之經分離的抗原結合蛋白。這些抗原結合蛋白中有些包含A)—或多個選自下列之輕鏈互補決定區（CDRLs): (i)選自SEQ ID NOs: 189-217 之 CDRL1 ; (ii)選自 SEQ ID NOs : 2 1 8-233 之 CDRL2 ;(iii)選自 SEQ ID NOs : 234-274 之 CDRL3 ;或（iv)含有 —或多個不超過4個胺基酸的胺基酸取代、缺失或插入之 (i)、（ii)或（iii)的CD RL。或者，該HB-EGF抗原結合蛋白 200927761 可包含B) 一或多個選自下列之重鏈互補決定區（CDRHs): ⑴選自 SEQ ID NOs : 275-299 之 CDRH1 ; (ii)選自 SEQ ID NOs ： 3 00-3 3 1 之 CDRH2 ; (i i i)選自 S E Q ID Ν Ο s : 3 3 2-372之CDRH3;或者（iv)含有一或多個不超過4個胺基酸的胺基酸取代、缺失或插入之（i)、（Η)或（ni)的CDRH。

於一較佳體系中，該經分離之抗原結合蛋白包含一、二或多個前述輕鏈 CDRLs及—、二或多個前述重鏈 CDRHs。於一觀點中，該經分離之抗原結合蛋白包含 CDRH1、CDRH2、CDRH3、CDRL1、CDRL2 及 CDRL3。

於另一觀點中’該前述A)之經分離的抗原結合蛋白係選自：來自 SEQ ID NOs ： 189-217 之 CDRL1 ;來自 SEQ ID NOs ： 2 1 8-233 之 CDRL2 :來自 SEQ ID NOs : 234-274 之 CDRL3 ;及含有一或多個不超過2個胺基酸的胺基酸取代、缺失或插入之前述⑴、（Π)或（iii)的任一 CDRL。另外，該前述B)之重鏈CD RH係選自：來自SEQ ID NOs: 275-299 之 CDRH1 ;來自 SEQ ID NOs ： 3 00-3 3 1 之 CDRH2 ; 來自SEQ ID NOs: 332-372之CDRH3及含有一或多個不超過2個胺基酸的胺基酸取代、缺失或插入之前述CDRH 。再者，該經分離之抗原結合蛋白可包含一或多個前述 A)之輕鏈CDRLs;及一或多個前述B)之重鏈CDRHs。於另一較佳體系中，該抗原結合蛋白包含選自下列之 CDRL:來自 SEQ ID NOs ： 189-217 之 CDRL1;來自 SEQ ID NOs : 2 1 8-233 之 CDRL2 ;來自 SEQ ID NOs ： 234-274 之CDRL3。該抗原結合蛋白亦可包含選自下列之CDRH : -8- 200927761

來自 SEQ ID NOs : 275-299 之 CDRH1 ;來自 SEQ ID NOs :300-3 3 1 之 CDRH2 ;來自 SEQ ID NOs : 3 32-3 72 之 CDRH3。或者，該經分離之抗原結合蛋白可包含一或多個列於前述A)中之輕鏈CDRLs及一或多個前述B)之重鏈 CDRHs。尤其是，該經分離之抗原結合蛋白可包含SEQ ID NOs ： 189-217 之 CD RL1、SEQ ID NOs: 218-233 之 CDRL2 和 SEQ ID NOs : 234-274 之 CDRL3 及/或 SEQ ID o ❹ NOs ： 275-299 之 CDRH1、SEQ ID NOs ： 3 00-3 3 1 之 CDRH2 和 SEQ ID NOs : 332-3 72 之 CDRH3。於一觀點中，該經分離之抗原結合蛋白包含一輕鏈可變區（VL)，此VL與選自SEQ ID NOs: 94-141之胺基酸序列具有至少8 0 %、9 0 %或1 0 0 %序列同一性。於另一觀點中，該經分離之抗原結合蛋白包含一重鏈可變區（VH)，此 VH與選自SEQ ID NOs: 142-186之胺基酸序列具有至少 8 0 %、9 0 %或1 0 0 %序列同一性。於另一較佳體系中，該經分離之抗原結合蛋白特異辨識至少一個含有IHGE之抗原決定部位及/或HB-EGF之似 EGF結構區。另外，本發明提供一種經分離之抗原結合蛋白，其係與如上述之結合ΗΒ-EGF的經分離之抗原結合蛋白競爭結合。本發明亦提供一種與ΗΒ-EGF結合之經分離的抗原結合蛋白，其包含 A)—或多個選自下列之輕鏈 CDRs(CDRLs): (i)與 SEQ ID NOs: 189-217 之序列具有至 200927761

少8 0%、或至少90%序列同一性之CDRLl ; (ii)與SEQ ID NOs: 21 8-233之序列具有至少 80%、或至少 90%序列同一性之 CDRL2 ;及（iii)與 SEQ ID NOs : 234-274 之序列具有至少80%、或至少90%序列同一性之CDRL3。或者，該與HB-EGF結合之經分離的抗原結合蛋白包含B) —或多個選自下列之重鏈 CDRs(CDRHs): (i)與 SEQ ID NOs: Ϊ2 7 5 -299之序列具有至少 80%、或至少 90%序列同一性之 CDRH1 ; (ii)與 SEQ ID NOs : 300-33 1 之序列具有至少 80%、或至少90%序列同一性之CDRH2;及（iii)與SEQ ID NOs : 332-372之序列具有至少80%、或至少90%序列同 —性之CDRH3。該經分離之抗原結合蛋白亦可包含C)一或多個A)之輕鏈CDRLs及一或多個B)之重鏈CDRHs。

於另一較佳體系中，該經分離之抗原結合蛋白與HB-EGF結合且包含：A)選自下列之輕鏈互補決定區（CDRL): (i)選自 SEQ ID NOs : 234-274 之 CDRL3; (Π)與（i)之 CDRL3之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的CDRL3 ;及（iii)選自下列之CDRL3 胺基酸序列： X1QX2X3X4X5PX6X7(SEQ ID NO : 1 089)，其中 Χι爲I或Μ， Χ2 爲 A、G 或 S， X3爲I或T， X4爲Η或Q， Χ5 爲 F、L 或 W， -10- 200927761 Χ6 爲 C、I、H、L 或 Τ， Χ7爲S或τ ; QQX1X2X3X4X5IT(SEQ ID NO : 1 090)，其中 Xi爲I或s， X2爲F或Y， X3 爲 F、I、S 或 Y， X4 爲 A、S 或 T，

X5爲P或S ;

XiX2X3X4X5X6X7X8T(SEQ ID NO : 1091)，其中 Xi爲L或Q， X2 爲 K、N 或 Q， X3 爲 A、H、S 或 Y， X4 爲 Η、N 或 Y， X5 爲 N、S 或 T， X6 爲人、？、1、丁、¥或丫， X7爲P或無胺基酸， . X8 爲 F、L 或 P ; QXiX2DX3LPX4X5(SEQ ID NO ： 1 092)，其中 X!爲H或Q， X2爲c或Y， X3 爲 D、I、N、S 或 Y， X4 爲 F、I 或 L， X5 爲 A、S 或 T ; QQXiX2X3X4PX5X6X7(SEQ ID NO ： 1 09 3 )，其中 -11 - 200927761 Χι爲Η或Υ， Χ2爲G或Ν， Χ3爲Ν或S， X4爲S或W， X5爲P或無胺基酸， X6爲R或W， X7爲S或T ;及

XiQYX2X3X4X5X6X7F(SEQ ID NO : 1 094) ’ 其中 X l爲H或Q， X2爲F或Y， Χ3 爲 G、I 或 S， X4 爲 F、I 或 T， X5 爲 Μ、P、S 或 T， X6 爲 F、L、R 或 W， X7爲S或T。

該經分離之抗原結合蛋白亦可包含B)選自下列之重鏈互補決定區（CDRH): (i)選自 SEQ ID NOs: 3 3 2-3 72 之 CDRH3; (ii)與⑴之CDRH3之胺基酸序歹丨』的差異爲不超過 2個胺基酸之胺基酸加入、缺失或取代的CDRH3 ;及（iii) 選自下列之CDRH3胺基酸序列：

XiX2X3X4X5X6X7X8X9Xi〇XiiDXi2(SEQ ID NO ： 1 03 5) ，其中 X,爲E或S， X2爲D' G或無胺基酸， -12- 200927761 X3爲D、N或無胺基酸， X4爲G或無胺基酸， X5爲G或無胺基酸， X6爲W、Y或無胺基酸， X7 爲 I、N 或 Y， X8爲A或Y， X9 爲 G、V 或 Y，

X10 爲 A、F 或 G， X! !爲 F、L 或 Μ， Χ12爲V或Υ ;

Q X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 1 0 X 1 1 Υ X 1 2 X 1 3 X 1 4 D X 1 5 ( S E Q ID NO :1036)，其中 \!爲G或無胺基酸， X2 爲 K、L 或 Y， X3 爲 A、G 或 S，〇 X4 爲 S、V 或 Y， X5爲A或G， X6爲G或無胺基酸， X7爲T或無胺基酸， X8爲S或無胺基酸， X9爲Y或無胺基酸， X1〇爲W或Y， Χι 1 爲 G、S 或 Y， X12爲F或Y， -13- 200927761 Χΐ3爲G或無胺基酸，

Xm爲Μ或無胺基酸， Χι5爲V或Υ ; X1X2X3X4X5X6X7X8X9Xi〇XiiXi2Xi3Xi4(SEQ ID NO : 1 03 7) ，其中 Χι爲D、G、L、S或無胺基酸， X2爲G、H、W、Y或無胺基酸， X3爲A、F、W、Y或無胺基酸，

X4爲D、G、Q、T或無胺基酸， X5爲G、I、Q、S或無胺基酸， X6爲A、D、N、Q、S或無胺基酸，乂7爲G、Y或無胺基酸，乂8爲D、Y或無胺基酸， X9爲Y或無胺基酸， Χίο 爲 A 、E、 Ν 或 Υ， Xu 爲 G 、P、 Τ 、V 或 Xl2 爲 F 或I， Xl3 爲 D 或Q ， X 1 4 爲 C 、Η、 V 或 Υ ;

XlX2X3X4X5X6X7X8XgXl〇XllXl2Xl3Xl4Xl5Xl6Xl7DXi8(SEQ ID NO : 1 03 8)，其中 \,爲E、D或無胺基酸， X2爲G、R或無胺基酸， X3爲I、V、Y或無胺基酸， -14- 200927761 X4 爲 A、G、L 或 N， X5 爲 A、G、V 或 W， X6 爲 A、N、R 或 T， X7爲G、N、P或無胺基酸，乂8爲G、T或無胺基酸， χ9 爲 A ：或無胺基酸 > Χι 0爲 D 、E 或 4τττ 1IM JWS 胺基酸 Χι I爲 S 、Y 或 -far mi 胺基酸 Χι 2爲 G 、Y 或 te Μ、、胺基酸 Χι 3爲 N 、Υ 或 Μ j\ w 胺基酸 Xi 4爲 Y 或無胺基酸， Xi 5爲 D 、Υ 或 te JWS 胺基酸 Xi 6爲 A 、G 或並 J \ \N 胺基酸 Xi 7爲 F 或Μ， Xi 8爲 I • V ：或 Υ ；

XlX2X3X4X5X6X7X8X9Xl〇XllXl2Xl3Xl4Xl5Xl6Xl7Xl8 X 1 9X2 0X 2 1 X 2 2 X2 3 (SEQ ID NO ·· 1 03 9)，其中又1爲八、0、0、3或丁， X2爲A、E、G、L、N、R、Y或無胺基酸， X3 爲 A、0、1^、1^、11、丁、丫或無胺基酸， X4爲D、G、R、S、V、Y或無胺基酸， X5爲A、G、I、S、V、Y或無胺基酸， X6爲？、0、1^、11、¥或無胺基酸， X7爲L、T、Y或無胺基酸， -15- 200927761 χ8爲γ或無胺基酸， χ9爲Υ或無胺基酸， Χ1()爲D或無胺基酸，乂^爲S或無胺基酸，乂12爲S或無胺基酸，又13爲G或無胺基酸，父14爲D、L、M、S、Υ或無胺基酸，

乂15爲Η、I、Ρ、V、W或無胺基酸，乂16爲F、G、L、R、S、Υ或無胺基酸，乂17爲D、F、V、W、Υ或無胺基酸，乂18爲（：、？、]^、？、8或丫， Χ19 爲 D、F、G 或 Υ， Χ20 爲 A、C、G、P、R、VSY，乂21爲F、L、M、S或無胺基酸， Χ22爲A、D或無胺基酸， Χ23爲I、L、V、Υ或無胺基酸； X1YSSGWX2X3YGX4X5DX6(SEQ ID NO : 1 040)，其中 X]爲Μ或V， Χ2爲S或無胺基酸， Χ3爲F或無胺基酸， Χ4爲V或無胺基酸， Χ5爲F或Μ， Χ6爲V或Υ ;及 RXiX2X3PFX4Y(SEQ ID NO ： 1041)，其中 -16- 200927761 乂1爲0、11、1^、>^或11， X2 爲 E、T 或 W， X3 爲 L、N、T 或 V， X4爲D或E。

一步包 21 7 之不超過 (iii)選，其中於另一觀點中，該經分離之抗原結合蛋白可進含A)選自下列之CDRL: (i)選自SEQ ID NOs: 189 CDRL1 ; (ii)與⑴之CDRL1之胺基酸序列的差異爲 2個胺基酸之胺基酸加入、缺失或取代的CDRL1 ; 自下列之CDRL1胺基酸序列： X, SSQSLX2X3SDGX4TYLX5(SEQ ID NO ： 1106) Xi爲K或R， . X2爲L或V， X3爲H或Y， Χ4爲Κ或Ν， Χ5 爲 Ν、S 或 Υ ; ❹ RASQXiISX2YLN(SEQ ID NO : 1107)，其中 X!爲 R、S 或 T， Χ2爲R或S ; RASQXiIX2X3X4LX5(SEQ ID NO ： 1108) > 其中 Xi 爲 D、G、S 或 T， X2 爲 A、R 或 S， X3 爲 11、1、1^、11、3或7'， X4 爲 D、W 或 Y， X5 爲 A、G 或 Ν ; -17- 200927761 QASQDIXiX2X3LN(SEQ ID NO : 1109)，其中

Xi爲s或τ， X2爲D或N， X3爲S或Y ; RASQX1VX2X3X4X5LA(SEQ ID NO : 1110)，其中 X!爲S或T， x2爲I或s， ◎ X3爲R或S， X4爲S、N或無胺基酸 X5爲Y或無胺基酸；及 KSSQXiX2LX3X4SNNKNYLX5(SEQ ID NO : 1111)，其中

Xi爲N或S， X2爲I或V， X3爲D或Y，

X4 爲 N、R 或 S， X5爲A或V ; (iv)選自 SEQ ID NOs : 2 1 8-233 之 CDRL2 ; (v)與（iv) 之CDRL2之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的CDRL2 ;或（vi)選自下列之 CDRL2胺基酸序列： X】X2SNX3X4S(SEQ ID NO : 1112)，其中 Xi爲E或K， X2爲I或V， -18- 200927761 Χ3爲R或W， X4爲D或F ;

XiX2SX3LQS(SEQ id NO ： 1113)，其中 Xj爲A或T， X2 爲 A、E 或 V， X3爲S或T ;

Xi ASX2LQS(SEQ ID NO ： 1114) > 其中 Xi爲A或V， x2爲s或T ; DASXjLETCSEQ ID NO ： 1115)，其中 Xi爲I或N ; GASSRAT(SEQ ID NO ： 223)；及 WASXiRES(SEQ ID NO ： 1116)，其中 Xi爲A或T ;或該經分離之抗原結合蛋白可進一步包含B)選自下列之 CDRH ： (i)選自 SEQ ID NOs : 275-299 之 CDRH1 ; (Π)與（i)之CDRH1之胺基酸序列的差異爲不超過2 個胺基酸之胺基酸加入、缺失或取代的CDRH1 ; (iii)選自下列之CDRH1胺基酸序列： GYTX1TX2X3X4X5X6(SEQ ID NO : 1 095)，其中 Xi爲F或L， X2 爲 E、G 或 S， X3 爲 Η、L 或 Y， -19- 200927761 X4 爲 G、S 或 Υ， X5爲I或Μ， Χ6爲Η或S ; GYXiFTS YWIG(SEQ ID NO ： 1 096)，其中 Xi爲R或S ; GFTFXiSX2X3MH(SEQ ID NO ： 1 097)，其中

Xi爲R或S， X2爲H或Y，

X3爲D或G ; GFX!FSX2YX3MX4(SEQ ID NO ： 1 098)，其中 Xi爲p或T， X2 爲 A、R 或 S， X3爲A或S， X4爲N或S ;

GX1SX2SX3X4X5X6X7WX8(SEQ ID NO : 1 099)，其中 Xi爲D或G， X2 爲 F、I 或 V， X3爲R、S或無胺基酸， X4爲G、Y或無胺基酸， Χ5爲D、G、S或無胺基酸， X6 爲 A、S 或 Y， X7爲A或Y， Χ8爲Ν或S ; GFSLSNARMGVS(SEQ ID NO ： 279)；及 -20- 200927761 GFSLX, TGGVGVG(SEQ ID NO ： 1100)，其中 Xi爲S或N ; (iv) 選自 SEQ ID NOs : 3 00-33 1 之 CDRH2 ; (v) 與（iv)之CDRH2之胺基酸序列的差異爲不超過2 個胺基酸之胺基酸加入、缺失或取代的CD RH2 ;及 (vi) 選自下列之CDRH2胺基酸序列： XiX2X3X4X5X6GX7TX8X9X10QKXi iX12(SEQ ID NO: 1101) ，其中 Ό ❸ X!爲S或W， X2爲F或I， X3 爲 D、N 或 S， X4爲A或P， X5 爲 E、N 或 S， X6 爲 D、N 或 S， X7 爲 E、G 或 N， X8爲I或N， X9 爲 C、H 或 Y， X10爲A或T，

Xn爲F或L， X12爲D或G ; IIYPXiDSDX2RYSPSFQG(SEQ id no ： 1102)，其中 X,爲D或G， X2 爲 A、I 或 T :

XiIX2X3DGSX4X5X6YX7DSVX8G(SEQ id NO ： 1103)， -21 - 200927761 其中

Xi爲F或V x2爲 S或w， X3爲 D、S 或 Y， X 4爲 I、N 或 T， x5爲 K或Q， x6爲 N、R 或 Y， X7爲 A、T 或 V， x8爲 K或R ;

XiISX2SX3X4X5X6YYADSVKG(SEQ ID NO ： 1104)，其中

Xi 爲 A、H 或 Y， X2爲 G、R 或 S， X3爲 G或S， X4爲 G、R 或 S， x5爲 S、T 或 Y， X6爲 I或T ; Χ,Χ2Χ3Χ4Χ5Χ6Χ7ΧβΧ9Χι〇Χι 1 YXi2Xi3SXMKS(SEQ ID NO :1105)，其中 X!爲 E、R 或 Y， X 2爲 I或τ， x3爲 Η、N 或 Y， X4爲 C、Η、S、Τ 或 Υ， x5爲 S或R， -22 200927761 Χ6爲G或S， X7 爲 G、K、S 或 T， X8爲T或W， X9爲N或Y，

Xio爲N或無胺基酸， Xu爲D或無胺基酸，

Xi2爲A或N，

X13爲P或V， X】4爲L或V ;

XiIFSNDEKS YSTSLKS (SEQ ID NO ： 1 0 3 3 )，其中 Χι爲Η或LI ;及 LIYWNXiX2KRYSPSLX3S(SEQ ID NO ： 1 034)，其中 Xi爲D或V， X2爲D或E， x3爲K或R。

於另一較佳體系中，前述之該經分離的抗原結合蛋白包含第一胺基酸序列和第二胺基酸序列’該二種序列彼此共價結合。第一胺基酸序列亦包含SEQ ID NOs : 234-274 之 CDRL3、SEQ ID NOs ： 21 8-233 之 CDRL2 及 SEQ ID NOs ·· 189-217之CDRL1，且該第二胺基酸序列包含該 SEQ ID NOs : 332-372 之 CDRH3、SEQ ID NOs : 300-33 1 之 CDRH2 及 SEQ ID NOs : 275 -299 之 CDRH1。於一觀點中，該經分離之抗原結合蛋白可爲單株抗體、多株抗體、重組抗體、人抗體、人化抗體、嵌合型抗體 -23- 200927761 、多特異性抗體或彼等之抗體片段。該抗體片段可爲Fab 片段、Fab'片段、F(ab')2片段、Fv片段、雙特異性單鏈抗體（diabody)或單鏈抗體分子。於一較佳體系中，本發明之經分離的抗原結合蛋白爲人抗體。於另一較佳體系中，該經分離之抗原結合蛋白爲單株抗體》

如此處所描述之經分離的抗原結合蛋白可爲任何下列類型：IgGl-、IgG2-、IgG3-或IgG4-型。於一較佳體系中，該抗原結合蛋白爲IgG2-或IgG4-型。再者，該抗原結合蛋白可與標記基團偶合。這些標記基圑可爲，例如：放射性同位素、放射性核素、螢光基團、酶催化性基團、化學發光基團、生物素化基團或預定之多肽基團。

於另一較佳體系中，該經分離之抗原結合蛋白係與效應子基團（諸如放射性同位素、放射性核素、毒素、治療性基團或化療性基團）偶合。該化療性基團可爲，例如：加利車黴素（calicheamicin)、歐利史汀-PE(auristatin-PE) 、苯醌安絲黴素（geldanamycin)、美他納辛（maytanasine) 或彼等之衍生物。再於另一較佳體系中，該經分離之抗原結合蛋白與如此處所描述和主張專利之抗原結合蛋白競爭結合人HB-EGF。此競爭性抗原結合蛋白可爲，例如單株抗體、多株抗體、重組抗體、人抗體、人化抗體、嵌合型抗體、多特異性抗體或彼等之抗體片段。該抗體片段可爲，例如Fab 片段、Fab'片段、F(ab')2片段、Fv片段、雙特異性單鏈抗體或單鏈抗體分子。於一較佳體系中，該經分離之抗原結 -24-

〇 200927761 合蛋白爲人抗體。於另一較佳體系中，該經分離合蛋白爲單株抗體。於另一較佳體系中，該經分結合蛋白爲IgGl-、IgG2-、IgG3-或IgG4-型。於系中，該抗原結合蛋白爲IgG2-或IgG4-型。於吴體系中，如此文所描述之抗原結合蛋白可與標記塞。標記基團之實例爲放射性同位素、放射性核素、團、酶催化性基團、化學發光基團、生物素化基圍之多肽基團。於另一較佳體系中，該經分離之抗握白係與效應子基團（諸如放射性同位素、放射性核素 '治療性基團或化療性基團）偶合。治療性基團性基團之實例包括，例如加利車黴素、歐利史汀. 醌安絲黴素、美他納辛或彼等之衍生物。於一觀點中，本發明提供減少至少部分經HB -介之信號轉導的經分離之抗原結合蛋白。本發明亦提出一種編碼前述該經分離之抗原結的核酸分子，其中該核酸分子係與控制序列操作性於一觀點中’本發明提供包含前述核酸分子之載體一觀點中’本發明提供包含前述核酸分子及/或載主細胞。於一較佳體系中，本發明提供一種製造抗原的方法’其包含自分泌該抗原結合蛋白之宿主細抗原結合蛋白的步驟。於另一較佳體系中，本發明提供一種醫藥組成包含至少一種前述之本發明的抗原結合蛋白和藥學抗原結之抗原較佳體一較佳團偶合螢光基或預定結合蛋素、毒或化療 PE、苯 EGF傳合蛋白連接。。於另體之宿合蛋白製備該物，其上可接 -25- 200927761 受之載體、稀釋劑或佐劑。於一較佳體系中’該醫藥組成物可包含額外之活性劑’諸如抗腫瘤劑。該抗腫瘤劑可爲，例如抗腫瘤抗體。抗腫瘤抗體之實例爲，例如針對受體酪胺酸激酶或EGFR之抗體。於一觀點中，該醫藥組成物係用於診斷、預防或治療過度增生疾病。再於一觀點中，該過度增生疾病係與HB- EGF表現有關。於另一觀點中，該過度增生疾病係與經擾亂（例如病態增強）的生長因子受體活化作用有關或伴隨發生此經擾亂（例如病態增強）的生長因子受體活化作用，其中該病態增強的生長因子受體活化作用係與G蛋白及/或與G蛋白偶合之受體的活性病態增加有關或係由彼等引起〇於一較佳體系中，該醫藥組成物包含至少一種抗原結合蛋白及藥學上可接受之載體、稀釋劑及/或佐劑以用於診斷、預防或治療癌症，諸如，例如乳癌、胃腸癌、胰臟癌、攝護腺癌、卵巢癌、胃癌、內膜癌、唾腺癌、肺癌、腎臟癌、結腸癌、結腸直腸癌、甲狀腺癌、膀胱癌、神經膠質瘤、黑色素瘤、其他HB-EGF表現或過度表現之癌、或腫瘤轉移形成。於另一較佳體系中，此處所描述之抗原結合蛋白係用於製造用於診斷、預防或治療過度增生疾病之醫藥組成物。於另一較佳體系中，該過度增生疾病係與HB-EGF之表現有關。於—較佳體系中係描述用於診斷與HB-EGF表現有關 200927761 之病況的方法，該方法包含將樣本與此處所描述之經分離的抗原結合蛋白接觸及測定該樣本中是否存有HB-EGF之步驟。於另一較佳體系中，該病況爲與HB-EGF表現有關之過度增生疾病。另一觀點中係描述用於預防或治療與患者體內HB-EGF之表現有關的病況之方法，其包含給予有此需要之患者有效量之如此處所描述的抗原結合蛋白。於另一觀點中 0 ，該病況爲與HB-EGF表現有關之過度增生疾病。再於另一觀點中，該患者爲哺乳動物患者。於一較佳體系中，本發明提供一種套組，其包含如上述之抗原結合蛋白、核酸分子或載體。於另一較佳體系中 ’該套組包含至少一種其他活性劑，其中該其他活性劑爲抗腫瘤劑。此文中將更詳細地描述本發明之這些及其他觀點。本發明之各觀點可包含本發明之不同較佳體系。因此，可預 ^ 料涉及一種要素或要素組合之本發明各較佳體系可包括在本發明之各觀點中。本發明之其他特性、目標及益處可從下列詳述之內容明白察知。發明之詳細說明此處所使用之章節標題係僅用於組織目的而不應用於限制此處所描述之內容。除非此處另外定義，本申請案中所使用之相關科學和技術名詞應具有本技藝中一般技術人士所普遍了解之意義 -27- 200927761 。再者，除非內容中另外需要，單數名詞應包括多數且複數名詞應包括單數。

一般而言，與此處所描述之細胞和組織培養、分子生物學、免疫學、微生物學、遺傳學和蛋白質及核酸化學和雜交技術相關的命名學爲本技藝中所熟知及常用者。除非另外指出，本申請案之方法和技術通常係根據本技藝所熟知之傳統方法及本申請案中所列舉和討論之多種不同之一般和較特殊的參考資料中所描述的方法進行。見，如 Sambrook e t al., Molecular Cloning ' A Laboratory

Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. ( 2001 )和 Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates ( 1 9 9 2 )，以及 Harlow 和 Lane Antibodies : A Laboratory Manual Cold Spring Harbor

Laboratory Press, Cold Spring Harbor, N.Y. ( 1990 ) » ( 其倂爲此文之參考資料）。酶催化反應及純化技術係根據製造者之說明書，如本技藝常進行之方法或此文中所描述者進行。與此處所描述之分析化學、合成有機化學及醫療和藥物化學之實驗室程序和技術相關的專門用語爲本技藝中所熟知且常用者。標準技術可用於化學合成法、化學分析、藥物製造、配製和投遞以及治療患者。需了解，本發明不限於此文所描述之特殊方法、草案和試劑，等且可有所變化。此處所使用之專門用語僅用於插述特殊之較佳體系，並不欲限制所揭示之範圍（其僅由 -28- 200927761 申請專利範圍界定）。除了在操作實例中外或另外指明，此處所使用之所有表示成分量或反應條件之數字在所有情況中應被理解爲可以“約”字修飾。當與百分比有關時，“約”字一詞可指 ±1%。 A · —般綜述

本發明提供與HB-EGF蛋白質（尤其是人類HB-EGF (hHB-EGF))結合之抗原結合蛋白。本發明提供之抗原結合蛋白爲其中嵌入及/或連結此處所描述之一或多個互補決定區（CDRs)的多狀。在一些抗原結合蛋白中，CDRs係嵌入“框構”區中，此框構區決定CDR(s)之方向，如此可取得適當之CDR(s)抗原結合性質。—般而言，提供之抗原結合性質可干擾、阻斷、減少或調節HB-EGF與其同源受體（包括EGF-R及HER4)間之交互作用。此處所描述之某些抗原結合蛋白爲抗體或自抗體衍生。於某些較佳體系中’抗原結合蛋白之多狀構造係以抗體爲基礎，這些抗體包括，但不限於：單株抗體 '雙特異性抗體' 微抗體（minibodies)、結構區抗體、合成抗體（此文中有時稱爲“抗體模擬物”）、嵌合型抗體、人化抗體、人抗體、抗體融合物（此文中有時稱爲“抗體結合物”）及彼等之各別片段。以下進一步描述不同構造。此處所提供之抗原結合蛋白顯示出可結合至HB-EGF( 尤其是人HB-EGF)之數種抗原決定部位。如實例中所示， -29- 200927761 HB-EGF結合其同源受體之能力被降低或受抑制。因此，此處所提供之抗原結合蛋白可抑制HB-EGF之活性。尤其是，與這些抗原決定部位結合之抗原結合蛋白可具有一或多種下列活性：抑制（尤其是）EGF-R及HER4自體磷酸化、EGF-R及HER4信號轉導途徑之誘導、經EGF_R及 HER4誘導之細胞生長及其他當EGF-R及HER4與HB-EGF結合時由其誘導之生理作用。

此處所揭示之抗原結合蛋白具有多種用途。例如：一些抗原結合蛋白可用於特殊結合分析、HB-EGF(尤其是 hHB-EGF)之親和力純化作用以及鑑定pof這類受體之篩選分析中。另外’此處所揭示之抗原結合蛋白可用於診斷及 /或治療疾病（諸如增生疾病）。這些包括，但不限於多種不同類型之癌症。〇 B.與肝素結合之似表皮生長因子的生長因子（HB_ EGF) HB-EGF係由多種不同之腫瘤細胞製造且係作爲自體分泌腫瘤生長因子。Davis-Fleischer ei α/·, 1998，Frοwi Biosci.3 ' 288-299 ； Iwamoto & Mekada, 2000,Cytokine Groivi/z Fflcior 1 1 : 3 3 5 -3 44。HB-EGF 對肝素（其可增加HB-EGF之生物活性）具強烈親和力。產生之ηβ-EGF爲跨膜蛋白’其經由金屬蛋白酶以蛋白質水解分式分裂，產生成熟之溶解型生長因子。 HB-EGF最早係以可溶之分泌型從培養之人類巨嗤細 -30- 200927761 胞的上清液中被鑑定出。該先驅物質pr〇HB-EGF在人類細胞上係作爲白喉毒素受體。HB-EGF可由多種不同類型之細胞製造，包括表皮細胞、角質細胞、單核細胞、系膜細胞、淋巴樣細胞及骨骼肌肉細胞。其爲表皮細胞、纖維母細胞、平滑肌細胞及多種不同之人類癌細胞的強有絲分裂原及趨化因子。

跨膜型HB-EGF可由多種細胞類型合成爲具有208個胺基酸之含有EGF、肝素-結合、跨膜及細胞質結構區跨膜先質（tm-HB-EGF)。胞外結構區可透過金屬蛋白酶之作用以12-至22-kDa之可溶型HB-EGF(sol-HB-EGF)的型式釋出，該金屬蛋白酶之作用係由不同之與G蛋白偶合的受體（GPCRs)或腫瘤啓動子（諸如佛波醇十四酸酯 (tetradecanoyl phorbol acetate)(TPA))調節。通常，細胞表面上有大量跨膜HB-EGF先質保持未經裂解。 tm-HB-EGF及 sol-HB-EGF二者均爲生物學上活性。 Q sol-HB-EGF及tm-HB-EGF二者之生物功能皆由EGF受體 (EGFR ; HER1)及ErbB4(HER4)促成。咸信，這些受體之此類型活化作用係因配體誘導受體發生同型二聚體化或雜二聚體化而產生。當活化時，EGF受體顯示出可增加細胞生長、增加細胞能動性、抑制細胞凋亡及增加細胞轉形。 EGFR-倚賴性傳信途徑可在刺激與G蛋白偶合的受體 (GPCR)時被轉活化。藉由與GPCR交互作用而產生之雜三聚體型G蛋白配體活化作用可產生誘導跨膜金屬蛋白酶之胞外活性的胞內信號。活化GPCR通路之配體包括LPA( -31 - 200927761

水解磷脂酸（lysophosphatidic acid)) '凝血酶、氯化甲醯膽鹼（carbachol)、鈴蟾素（bombesin)及內皮素。這類活化作用導致跨膜生長因子先質之胞外加工，釋出成熟因子，此成熟因子直接或透過蛋白多醣基質與EGFR之胞外區 (ectodomain)交互作用並透過酪胺酸磷酸化來活化EGFR。見，Prenzel ei α/.，1 999，Waiwre 402 : 8 84-8 8 8。因此， HB-EGF爲三層膜通行傳信（TMPS)機制的一種成分，藉此，GPCR可活化與膜結合之金屬蛋白酶，此金屬蛋白酶分解proHB-EGF以釋出可溶性生長因子，而此生長因子接著活化EGF受體，EGFR轉活化作用與多種不同疾病有關，這些疾病有，諸如心臟肥大（回顧 Shah BH，Catt

Kj.Trends Pharmacol Sci.2003 May ； 24 ( 5 ) : 239-244)、血管重塑（回顧 Eguchi e t al., 2 0 0 3, Biochem So c Trans. 2003 ,· 3/ (Pi 6) ·· //9S-202)及癌症（回顧 Fischer ei a /.，2 0 0 3 , 5 m r a)。

本技藝之技術熟習人士可取得HB-EGF蛋白質及編碼那些蛋白質之核酸的序列。例如：這類HB-EGF序列可在生物技術資訊國家中心（NCBI)所提供之資料庫中找到（見，http: //www.ncbi.nlm.nih.gov/)。HB-EGF 之序列的—種實例爲 NCBI 編號 NM 00 1 945 及 NP_00 1 936(gi:45034 1 3)

之胺基酸序列。此序列提供於下以供簡易參考（SEQ ID NO ：1 042)： -32- 200927761 MKLLPSWLKLFLAAVLSALVTGESLERLRRGLAAGTSNPDPPTVSTDQLLPLGGGRD RKVRDLQEADLDLLRVTLSSKPQALATPNKEEHGKRKKKGKGLGKKRDPCLRKYKDFCIHGEC KYVKELRAPSCICHPGYHGERCHGLSLPVENRLYTYDHTTILAWAWLSSVCLLVIVG LLMFRYHRRG GYDVENEEKVKLGMTNSH。注意上述所示之HB-EGF序列（SEQ ID NO: 1 042)具有 19 胺基酸信號肽（MKLLPSVVLKLFLAAVLSA ’ SEQ ID NO : 1 043)。此可溶性胞外結構區包含上述HB-EGF序列之胺基酸 1-1 49。此HB-EGF可溶性胞外結構區之序列爲提供於下〇之 SEQ ID NO : 1044 ： MKLLPSWLKLFLAAVLSALVTGESLERLRRGLAAGTSNPDPPTVSTDQLLPLGGGRD RKVRDLQEADLDLLRVTLSSKPQALATPNKEEHGKRKKKGKGLGKKRDPCLR KYKDFCIHGECKYVKELRAPSCICHPGYHGERCHGLSLP · 當分裂時產生包含胺基酸63- 1 49(87個胺基酸）的成熟 HB-EGF。此成熟HB-EGF之序列爲提供於下之SEQ ID NO : 1045 ： DLQEADLDLLRVTLSSKPQALATPNKEEHGKRKKKGKGLGKKRDPCLRKYKDFCIHG ECKYVKELRAPSCICHPGYHGERCHGLSLP。 © HB-EGF與表皮生長因子（EGFR)交互作用並活化之。 EGFR爲一種170kDa跨膜糖蛋白，其包含胞外配體-結合結構區、跨膜區及具酪胺酸激酶活性之胞內結構區。生長因子與EGFR結合可造成配體-受體複合物內化、該受體及其他蛋白質受質之自體磷酸化’最終導致DNA合成及細胞分裂。此外配體結合結構區不僅可被HB-EGF剌激’亦可被EGF、TGFa及雙調蛋白（AR)刺激。 EGFR過度表現時通常伴隨共同表現似EGF生長因子，此暗示控制生長之自分泌途徑在腫瘤惡化中可能扮演主 -33- 200927761 要角色。如今普遍相信此爲腫瘤細胞可跳脫正常生理控制的機制。 C. HB-EGF受體抗原結合蛋白

此處提供多種可用於調節HB-EGF之活性的選擇性結合劑。這些作用劑包括，例如：含有抗原結合結構區之抗原結合蛋白（如：單鏈抗體、結構區抗體、免疫黏附劑及具抗原結合區之多肽）且其特異結合HB-EGF多肽（尤其是人類HB-EGF)。該作用劑中有些可，例如用於抑制HB-EGF與其受體結合，因此，可用於抑制、干擾或調節一或多種與經HB-EGF傳介之傳訊有關的活性。〇一般而言，提供之抗原結合蛋白通常包含一或多個（如：1、2、3、4、5或6)如此處描述之CDRs。在某些情況中，該抗原結合蛋白包含（a)多肽構造及（b) —或多個插入及/或結合多肽構造之CDRs。多肽構造可有多種不同形式。例如：其可爲或包含天然抗體或其片斷或變異體之框構區，或可完全自然合成。下文中進一步描述多種不同多肽構造之實例。於某些較佳體系中，該抗原結合蛋白之多肽構造爲抗體或係從抗體衍生，該抗體包括，但不限於單株抗體、雙特異性抗體、微抗體、結構區抗體、合成抗體（此文中有時稱爲“抗體模擬物”）、嵌合型抗體、人化抗體、抗體融合物（有時稱爲“抗體結合物”）及彼等之各別部分或片段。在某些情況中，該抗原結合蛋白爲抗體之免疫片段（ -34- 200927761 如：Fab、Fab'、F(ab')2或scFv)。此文中進一步描述並定義不同構造。此處提供之某些抗原結合蛋白特異結合人類HB-EGF 。於一特殊之較佳體系中，該抗原結合蛋白特異結合具有 SEQ ID NO : 1042之胺基酸序列的人類HB-EGF蛋白質。於其中該抗原結合蛋白係用於治療應用之較佳體系中 ^抗原結合蛋白可抑制、干擾或調節一或多種HB-EGF之生物活性。在此情況中，抗原結合蛋白特異結合人類HB-EGF及/或當過量之抗體減少至少約20%、40%、60%、 80%、85%或更多量之人類HB-EGF與其受體結合（例如：藉由在活體外競爭性結合分析中測量結合）時，抗原結合蛋白實質上抑制人類HB-EGF與其受體結合（或者，反之亦然）。HB-EGF具有許多不同之生物作用，這些作用可在許多不同分析中在不同細胞類型中測量；此文中提供這類分析之實例。 1.天然抗體構造此處提供之一些抗原結合蛋白具有通常與天然抗體相關之構造。這些抗體之構造單位通常包含一或多個四聚體，其各由二組完全相同之多肽鏈對組成，但某些哺乳動物之物種亦產製僅具單一重鏈之抗體。在典型抗體中，各對或各成雙組包括一全長“輕”鏈（於某些較佳體系中爲約 25kDa)及一全長“重”鏈（於某些較佳體系中爲約 5〇_ 7〇kDa)。各個別免疫球蛋白鏈係由數個“免疫球蛋白結構 -35- 200927761

區”組成，其各包含約90-110個胺基酸並表現特殊之摺疊樣式。這些結構區爲組成抗體多肽之基本單位。各鏈之胺基端部分通常包括負責辨識抗原之可變區。羧基端部分爲較鏈之另一端更屬演化上保存者，稱爲“恆定區”或“ C”區。人類輕鏈通常被分類爲K及λ輕鏈，這些輕鏈各含有一可變區及一恆定區。重鏈通常被分類爲μ、δ、γ、α 或ε鏈，這些將抗體同型分別定義爲IgM、IgD、IgG、 IgA及IgE。IgG具有數種亞型，包括，但不限於：IgGl 、IgG2、IgG3 和 IgG4。IgM 亞型包括 IgM 和 IgM2。IgA 亞型IgAl和IgA2。人類中，IgA和IgD同型包含四個重鏈和四個輕鏈；IgG和IgE同型包含二個重鏈和二個輕鏈 ;IgM同型包含五個重鏈和五個輕鏈。重鏈C區通常包含一或多個負責效應子功能的結構區。重鏈恆定結構區之數目將取決於該同型。例如：IgG重鏈包含三個稱爲CH1、 CH2及CH3之C區結構區。提供之抗體可具有任一種這些同型及亞型。於某些較佳體系中，該HB-EGF抗體爲IgGl 、IgG2 或 IgG4 亞型。在全長之輕和重鏈中，可變區和恆定區係藉由具有約 12或更多個胺基酸之“厂’區連接，重鏈亦包括具有約超過 10個胺基酸的“D”區。見，如：Fundamental Immunology, 2nd ed., Ch.7 ( Paul, W.,ed. ) 1 989, New

York : Raven Press(其全部內容倂爲此文所有目的之參考資料）。各輕/重鏈對之可變區通常形成抗原結合部位。一種示範之HB-EGF單株抗體的κ輕鏈恆定結構區的 -36- 200927761 實例具有下列胺基酸序列： RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 187)。一種示範之HB-EGF單株抗體的IgG2重鏈恆定結構區的實例具有下列胺基酸序列： ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRT PEVTCWVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRWSVLTWHQDWLNGKEyKCKVSNKG IiPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCljVKGFYPSr)工 AVEWESNGQPENNYKTTPPML DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:188)。 ο 免疫球蛋白鏈之可變區通常顯示出相同之總體構造，其包含藉由三個高可變區（較常稱爲“互補決定區”或 CDRs)連接之高度保存的框構區（FR)。來自上述各重鏈/輕鏈對之二種鏈的CDRs通常係靠框構區對位以形成特異結合靶的蛋白質（如：HB-EGF)上之特殊抗原決定部位的構造。從N-端至C-端，天然輕鏈和重鏈可變區通常均符合下列之這些成分的排列順序：FR1、CDR1、FR2、CDR2、 φ FR3、CDR3和FR4。已規劃編號系統來爲佔據這些結構區各區中之位置的胺基酸編號。此編號系統係在具免疫學重要性之蛋白質的 Kabat 序列（Kabat Sequences of Proteins of Immunological Interest)( 1 9 8 7 and 1991,NIH, Bethesda, MD)或 Chothia & Lesk, 1 98 7, J. Mol. Biol .196 ： 901 ： 917 ；Chothia et al. , 1 9 8 9, Na tur e 342 : 878-883 中規定。此處提供之多種不同輕鏈和重鏈可變區分別描述於第 1A-1P及第2A-20圖中。這些可變區可各黏附至上述重鏈和輕鏈恆定區，以分別形成完整之抗體重鏈和輕鏈。再者 -37- 200927761 ，如此產生之各重鏈和輕鏈可組合以形成完整之抗體構造此處提供之一些抗體的全長輕鏈和重鏈的特殊實例及彼等之對應的胺基酸序列分別摘要於第3A-3K及第4A-40 圖中。

再者，列於第3A-3K圖中之各示範的輕鏈（UL-1、UL-2、UL-3，等）可與第4A-40圖中之任何示範的重鏈組合以形成抗體。這類組合之實例包括UL-1與UH-1至UH-58中任一重鏈之組合；UL-2與UH-1至UH-58中任一重鏈之組合；或Ul-3與UH-1至UH-58中任一重鏈之組合，等。在某些情況中，該抗體包含至少一個輕鏈和一個重鏈’且該輕鏈和重鏈係分別選自第3A-3K圖和第4A-40圖中所列者。在其他情況中，該抗體含有二個同等之輕鏈及二個同等之重鏈。例如：抗體或免疫功能片段可包括二個UL-1 輕鏈及二個UH-1重鏈’或二個UL-2輕鏈及二個Uh-2重鏈，或二個UL-3輕鏈及二個UH-3重鏈，及其他分別列於第3A-3K及第4A-40圖中之輕鏈對和重鏈對的類似組合此處提供之其他抗體爲經由組合分別顯示於第3 A- 3 K 及第4Α-4 0圖中之輕鏈和重鏈所形成之抗體的變異體’其包含與這些鏈之胺基酸序列各具有至少70%、75 %、80 % 、8 5 %、9 0 %、9 5 %、9 7 %或9 9 %之序列同一性的輕鏈及/或重鏈。在某些情況中’這類抗體包含至少一個輕鏈和一個重鏈，然而在其他情況中’該變異形含有二個同等之輕鏈 -38- 200927761 及二個同等之重鏈。 2.抗體之可變結構區

此處亦提供抗原結合蛋白，其含有選自顯示於第1A-1P 圖中之下列抗體輕鏈可變區：UA41, U-VL2, U-Vi_3, U-VL4, U-Vj, U-Vj, U-VJ, U-Vl8, U-Vl9, U-Vl10, U-Vl11, U-Vl12, U-Vl13, U-Vl14, U-Vl15, U-Vl16, U-Vu17, U-Vl18, U-

Vl19, U-Vl20, U-Vl21, U-Vu22, U-Vl23, U-Vl24, U-Vu25, U-Vl26, U-Vl27, U-Vl28, U-Vu29, U-

Vl30, U-Vl31, U-Vl32, U-Vl33, U-Vl34, U-Vl35, U-Vl36, U-Vl37, U-Vl38, U-Vl39, U-Vl40, U-

Vl41, U-Vl42, U-Vl43, U-Vl44, U-Vl45, U-Vl46, U-Vl47, U-Vl48, U-Vl49, U-Vl50, U-Vl51, U- \52, U-VL54, U-VL55, U-VL56, U-VL57, U-VL58· U-VL59, U-VL60, U-VL61, U-VL62, U-VL64,和 o U-\65，及/或選自顯示於第2A-20圖中之抗體重鏈可變區： U-VH1, U-Vh2, U-Vh3, U-Vh4, U-Vh5, U-Vh6, U-Vh7, U-Vh8, U-Vh9, U-Vh10, U-Vh11, U-Vh12, U-Vh13, U-Vh14, U-Vh15, U-Vh16, U-Vh17, U-Vh18, U-Vh19, U-Vh20, U-Vh21, U-Vh22, U-Vh23, U-

Vh24, U-Vh25, U-Vh26, U-Vh27, U-Vh28, U-Vh29, U-Vh30, U-Vh31, U-Vh32, U-Vh33, U-Vh34, U-

Vh35, U-Vh36, U-Vh37, U-Vh38, U-Vh39, U-Vh40, U-Vh41, U-Vh42, U-Vh43, U-Vh44, U-Vh45, U-

Vh46, U-Vh47, U-Vh48, U-Vh49, U-Vh50, U-Vh51, U-Vh52, U-Vh53, U-Vh54, U-Vh55, U-Vh56, U-

Vh57,和U-Vh58，以及這些輕鏈和重鏈可變區之免疫功能片段、衍生物、突變蛋白及變異體。第10A和10B圖中以及第1 1A和1 1B圖中分別提供 φ 不同之輕鏈和重鏈可變區之序列比對。此類型之抗原結合蛋白通常可由式“VHx/VLy”定名，其中“ X”相當於重鏈可變區之數目且“ y”相當於輕鏈可變區之數目（一般而言，X和y各爲1或2)。列於第 1A-1P圖中之各輕鏈可變區可與第 2A- 20圖中所示之任何重鏈可變區組合以形成抗原結合蛋白。這類組合之實例包括U-Vtl與U_Vh1, u_Vh2, & -39- 200927761

Vh3, U-Vh4, U-Vh5, U-Vh6, U-Vh7, U-Vh8, U-Vh9, U-Vh10, U-Vh11, U-Vh12, U-Vh13, U-Vh14, U-Vh15, U-Vh16, U-Vh17, U-Vh18, U-Vh19, U-Vh20, U-Vh21, U-Vh22. U-Vh23, U-Vh24, U-Vh25, U-Vh26, U-Vh27, U-Vh28, U-Vh29, U-Vh30, U-Vh31, U-Vh32, U-Vh33, U-Vh34, U-Vh35, U-Vh36, U-Vh37, U-Vh38, U-Vh39, U-Vh40, U-Vh41, U-Vh42, U-Vh43, U-Vh44, U-Vh45, U-Vh46, U-Vh47, U-Vh48, U-Vh49, U-Vh50, U-Vh51, U-Vh52, U-Vh53, U-Vh54, U-Vh55, U-Vh56, U-Vh57,或U-Vh58, 中任一重鏈之組合或U-Vl2與 U-VH1, U-Vh2, U-Vh3, U-Vh4, U-Vh5, U-Vh6, U-Vh7, U-Vh8, U-

Vh9, U-Vh1〇, U-Vh11, U-Vh12, U-Vh13, U-Vh14, U-Vh15, U-Vh16, U-Vh17, U-Vh18, U-Vh19, U-Vh20, U-Vh21, U-Vh22, U-Vh23, U-Vh24, U-Vh25, U-Vh26, U-Vh27, U-Vh28, U-Vh29, U-Vh30, U-Vh31, U-Vh32, U-Vh33, U-Vh34, U-Vh35, U-Vh36, U-Vh37, U-Vh38, U-Vh39, U-Vh40, U-Vh41, U-Vh42, U-Vh43, U-Vh44, U-Vh45, U-Vh46, U-Vh47, U-Vh48, U-Vh49, U-Vh50, U-Vh51, U-Vh52, U-Vh53, U-Vh54, U-Vh55, U-Vh56, U-Vh57,或U-Vh58 中任一重鏈之組合，等。在某些情況中，該抗原結合蛋白包含至少一列於第 2A-20圖中之重鏈可變區及/或一列於第1A-1P圖中之輕鏈可變區。在某些情況中’該抗原結合蛋白包含至少二個不同之列於第 2A-20圖中的重鏈可變區及/或列於第 1A-1P圖中之輕鏈可變區。這類抗原結合蛋白之實例包含（a)— 個 U-VL1，及（1>)仏\2.士\^3，1).%4,1^%5,1^\6，1^%7,1}-

Vl8, U-Vl9, U-Vl10, U-V..11, U-VL12, U-VL13, U-Vu14, U-VL15, U-VL16, U-VL17, U-VL18, U-Vu19, U-Vl20, U-Vl21, U-Vl22, U-Vl23, U-Vl24, U-Vl25, U-Vl26, U-Vl27, U-Vl28, U-Vl29, U-Vl30, U-Vl31, U-Vl32, U-Vl33, U-Vl34, U-Vu35, U-Vl36, U-Vl37, U-Vl38, U-Vl39, U-Vl40, U-Vu41, U-

Vl42, U-Vl43, U-Vl44, U-Vl45, U-Vu46, U-Vl47, U-Vl48, U-Vl49, U-Vl50. U-Vl51, U.Vl52, U-

Vl54, U-Vl55, U-Vl56, U-Vl57, U-Vl58, U-Vl59, U-Vl60, U-Vl61, U-Vl62, U-Vl64,等 U-Vl65 的其中之一。再者，這類抗原結合蛋白之另一實例包含（a) —個 U-VL2，及（b) U-Vu1, U-Vl3, U-Vl4, U-Vl5, U-Vu6, U-Vl7, U-Vl8, U-Vl9, U-Vl10, U-Vl11, U-Vu12, U-Vl13, U-Vl14, U-Vu15, U-Vl16, U-Vl17, U-Vl18, U-Vl19, U-Vl20, U-Vl21, U-Vl22, U-Vu23, U-Vl24, U-

Vu25, U-Vl26, U-Vl27, U-Vl28, U-Vl29, U-Vl30, U-Vl31, U-Vl32, U-Vl33, U-Vl34, U-Vl35, U-

Vl36, U-Vl37, U-Vl38, U-Vl39, U-Vl40, U-Vl41, U-Vl42, U-Vl43, U-Vl44, U-Vl45, U-Vl46, U-

Vl47, U-Vl48, U-Vl49, U-Vl50, U-Vl51, U-Vl52, U-Vl54, U-Vu55, U-Vl56, U-Vu57, U-Vl58, U-

Vl59, U-Vl60, U-Vl61, U-Vl62, D-Vl64,等 U-Vl65 -40- 200927761 的其中之一。再者，這類抗原結合蛋白之另一實例包含（a)—個 U-VL3，及（1>)1^/1_1,1^1_2,1^^4.1^|_5,1^/1_6,11-

Vl7, U-Vl8, U-Vu9, U-Vl10, U-Vl11, U-Vl12, U-Vl13, U-Vl14, U-Vl15, U-Vl16, U-Vl17, U-Vl18, U-Vl19, U-Vl20, U-Vl21, U-Vl22, U-Vl23, U-Vl24, U-Vl25, U-Vl26, U-Vl27, U-Vl28, U-Vl29, U-Vl30, U-Vl31, U-Vu32, U-Vl33, U-Vl34, U-Vl35, U-Vl36, U-Vl37, U-Vl38, U-Vl39, U-Vl40, U-Vl41, U-Vl42, U-Vl43, U-Vl44, U-Vl45, U-Vl46, U-Vl47, U-Vl48, U-Vl49, U-Vl50, U-Vl51, U-Vl52, U-V 54, U-Vl55, U-Vl56, U-Vl57, U-Vl58, U-Vl59, U-Vl60, U-Vl61, U-Vl62, U-Vl64,和 U-VL65,等的其中之一。再者，這類抗原結合蛋白之另一實例包含（a)—個U-VH1，

及（b ) U-Vh2, U-Vh3, U-Vh4, U-Vh5, U-Vh6, U-Vh7, U-Vh8, U-Vh9, U-Vh1〇, U-Vh11, U-Vh12, U-Vh13, U-Vh14, U-Vh15, U-Vh16, U-Vh17, U-Vh18, U-Vh19, U-Vh20, U-Vh21, U-Vh22, U-

Vh23, U-Vh24, U-Vh25, U-Vh26, U-Vh27, U-Vh28, U-Vh29, U-Vh30, U-Vh31, U-Vh32, U-Vh33, U-

Vh34, U-Vh35, U-Vh36, U-Vh37, U-Vh38, U-Vh39, U-Vh40, U-Vh41. U-Vh42, U-Vh43, U-Vh44, U-

Vh45, U-Vh46, U-Vh47, U-Vh48, U-Vh49, U-Vh50, U-Vh51, U-Vh52, U-Vh53, U-Vh54, U-Vh55, U-

Vh56, U-Vh57,和U-Vh58的其中之一。另一實例包含（a)—個 U- VH2，及（b) U-VH1, U-Vh3, U-Vh4, U-Vh5, U-Vh6, U-Vh7, U-Vh8, U-Vh9, U-Vh10, U-Vh11, U-Vh12, U-Vh13, U-Vh14, U-Vh15, U-Vh16, U-Vh17, U-Vh18, U-Vh19, U-Vh20, U-Vh21, U-Vh22, U-Vh23, U-Vh24, U-Vh25, U-Vh26, U-Vh27, U-Vh28, U-Vh29, U-Vh30, U-Vh31, U-Vh32, U-Vh33, U-Vh34, U-Vh35, U-Vh36, U-Vh37, U-Vh38, U-Vh39, U-Vh40, U-Vh41 , U-Vh42, U-Vh43, U-Vh44, U-Vh45, U-Vh46, U-Vh47, U-Vh4，U-Vh49, U-Vh50, U-Vh51, U-Vh52, U-Vh53, U-Vh54, U-Vh55, U-Vh56, U-Vh57,和 U- VH58的其中之一。再者，另一實例包含（a)—個U-VH3，及 (b) U-VH1, U-Vh2, U-Vh4, U-Vh5, U-Vh6, U-Vh7, U-Vh8, U-Vh9, U-Vh10, U-Vh11, U-Vh12, U-Vh13, U-Vh14, U-Vh15, U-Vh16, U-Vh17, U-Vh18, U-Vh19, U-Vh20, U-Vh21, U-Vh22, U-Vh23, U-Vh24, U-Vh25, U-Vh26, U-,

Vh27, U-Vh28, U-Vh29, U-Vh30, U-Vh31, U-Vh32, U-Vh33, U-Vh34, U-Vh35, U-Vh36, U-Vh37, U-

Vh38, U-Vh39, U-Vh40, U-Vh41, U-Vh42, U-Vh43, U-Vh44, U-Vh45, U-Vh46, U-Vh47, U-Vh48, U-

Vh49, U-Vh50, UA/h51, U-Vh52, U-Vh53, U-Vh54, U-Vh55, U-Vh56, U-Vh57,和 U-Vh58,等的其中之一。重鏈可變區之不同組合可與任一種輕鏈可變區之不同組合組合在一起。 -41 - 200927761 在其他情況中，該抗原結合蛋白包含二個同等之輕鏈可變區及/或二個完全相同之重鏈可變區。例如：該抗原結合蛋白可爲包含二個輕鏈可變區和二個重鏈可變區加上成對之輕鏈可變區和成對之重鏈可變區的抗體或免疫功能片段，且該成對之輕鏈可變區和成對之重鏈可變區係如分別列於第1A-1P圖及第2A-20圖中者。此處提供之一些抗原結合蛋白包含一個輕鏈可變結構區，該輕鏈可變結構區包含之胺基酸序列僅在1、2、3、4 、5、6、7、8、9、10、11、12、13、14 或 15 個胺基酸殘基處與選自下列之輕鏈可變結構區的序列不同： U-VL1, U-Vl2, U-Vl3, U-Vl4, U-Vl5, U-Vl6, U-Vl7, U-Vl8, U-Vl9, U-Vl10, U-VL11, U-Vl12, U-Vu13, U-Vl14, U-Vl15, U-Vl16, U-Vl17, U-Vl18, U-Vl19, U-Vl20, U-Vl21, U-Vl22, U-Vl23, U-Vl24, U-Vl25, U-Vl26, U-Vl27, U-Vl28, U-Vl29, U-Vl30, U-Vl31, U-Vu32, U-

Vl33, U-Vl34, U-Vl35, U-Vl36, U-Vu37, U-Vl38, U-Vl39, U-Vl40, U-Vl41, U-Vl42, U-Vl43, U-

Vl44, U-Vl45, U-Vl46, U-Vl47, U-Vl48, U-Vl49, U-Vu50, U-Vl51, U-Vl52, U-Vl54, U-Vl55, U-

Vl56, U-Vl57, U-Vl58, U-Vl59, U-Vl60, U-Vl61; U-Vl62, U-Vl64 或 U-Vl65 ，其中這類序列之各差異係獨立地爲缺失、插入或取代一個胺基酸。一些抗原結合蛋白中之輕鏈可變區包含與下列輕鏈可變區之胺基酸序列具有至少70%、75%、80%、85°/。、90%、95%、97%或99%之序列同一性的胺基酸序列： U-VL1, U-Vl2, U-Vl3, U-Vl4, U-Vl5, U-Vl6, U-Vl7, U-Vl8, U-Vl9, U-Vl10, U-Vl11, U-Vl12, U-Vl13, U-Vl14, U-Vl15, U-Vl16, U-Vl17, U-Vl18, U-

Vl19, U-Vl20, U-Vl21, U-Vl22, U-Vl23, U-Vl24, U-Vl25, U-Vl26, U-Vl27, U-Vl28, U-Vu29, U-

Vl41, U-Vl42, U-Vl43, U-Vl44, U-Vl45, U-Vl46, U-Vl47, U-Vl48, U-Vl49, U-Vl50, U-Vl51, U-

Vl52, U-Vl54, U-Vl55, U-Vl56, U-Vt57, U-VL58, U-VL59, U-VL60, U-VL61, U-VL62, U-Vu64, or U*

Vl65 〇某些抗體包含一個重鏈可變結構區，該重鏈可變結構區包含之胺基酸序列僅在1、2、3、4、5、6、7、8、9、 -42- 200927761 10、11、12、13、14或15個胺基酸殘基處與選自下列之重鏈可變結構區的序列不同： U-VH1, U-Vh2, U-Vh3, U-Vh4, U-Vh5, U-Vh6, U-Vh7, U-Vh8, U-Vh9, U-Vh10, U-Vh11, U-Vh12, U-Vh13, U-Vh14, U-Vh15, U-Vh16, U-Vh17, U-Vh18, U-Vh19, U-Vh20, U-Vh21, U-Vh22, U-Vh23, U-

Vh46. U-Vh47, U-Vh48, U-Vh49, U-Vh50, U-Vh51, U-Vh52, U-Vh53, U-Vh54, U-Vh55, U-Vh56, U-

Vh57,或 U-Vh58

，其中這類序列之各差異係獨立地爲缺失、插入或取代一個胺基酸。某些抗原結合蛋白中之重鏈可變區包含與下列重鏈可變區之胺基酸序列具有至少70%、75%、80%、85% 、9 0 %、9 5 %、9 7 %或9 9 %之序列同一性的胺基酸序歹[J : U-VH1, U-Vh2, U-Vh3, U-Vh4, U-Vh5, U-Vh6, U-Vh7, U-Vh8, U-Vh9, U-Vh10, U-Vh11, U-Vh12, U-Vh13, U-Vh14, U-Vh15, U-Vh16, U-Vh17, U-Vh18, U-Vh19, U-Vh20, U-Vh21, U-Vh22, U-

Vh34, U-Vh35, U-Vh36, U-Vh37, U-Vh38, U-Vh39, U-Vh40, U-Vh41, U-Vh42, U-Vh43, U-Vh44, U-

Vh45, U-Vh46, U-Vh47, U-Vh48, U-Vh49. U-Vh50, U-Vh51, U-Vh52, U-Vh53, U-Vh54, U-Vh55, U-

Vh56, U-Vh57,或U-Vh58 〇其他抗原結合蛋白（如：抗體或免疫功能片段）包括如前述之變異體輕鏈和變異體重鏈的變異形式。 ❹ 3. C D R s 此處揭示之抗原結合蛋白爲其中移植、插入及/或連結一或多個CDRs之多狀。抗原結合蛋白可具有1、2、3 、4、5或6個CDRs。因此，抗原結合蛋白可具有，如： —個輕鏈 CDR1(“CDRL1” ），及/或一個輕鏈 CDR2(“ CDRL2”），及 / 或一個輕鏈 CDR3( “ CDRL3” ），及 / 或— 個重鏈 CDR1( “ CDRH1 ” ），及/或一個重鏈 C D R2 ( “ CDRH2”），及/或一個重鏈CDR3( “ CDRH3”）。某些抗原 -43- 200927761 結合蛋白同時包括CDRL3及CDRH3。第6A-6F圖及第 7A-7E圖中驗明特殊之CDRs。指定抗體之互補決定區（CDRs)及框構區（FR)(輕鏈和重鏈FR胺基酸序列之實例分別顯示於第8A-8H圖及第 9A-9F 圖中）可利用 Kabat 等人在 Sequences of Proteins of Immunological Interest, 5th Ed.,US Dept, of Health and

Human Services, PHS, NIH, NIH Publication No. 9 1 -3242, 1991中所描述之系統中驗明。此處所揭示之某些抗體包含一或多種與第6A-6F圖（CDRLs)及第7A-7E圖（CDRHs)中呈現之一或多個CDRs的胺基酸序列相一致或具實質之序列同一性的胺基酸序列。

在天然抗體中之CDRs的構造及性質已描述於上。簡單地說，在傳統抗體中，該CDRs係嵌入重鏈和輕鏈可變區中之框構區且其在該處構成負責抗原結合及辨識的區。可變區之一個框構區（由Kabat，等人，1991(同上）定名爲框構區 1-4，FR1、FR2、FR3 和 FR4;亦見 Chothia and Lesk，1 987，同上）內包含至少三個重鏈或輕鏈CDRs，見，上述者（Kabat et al·，1991，Seqrwences· 〇/ 〇/

Immunological Interest, Public Health Service N.I.H., Bethesda, MD ；亦見 Chothia and Lesk, 1 9 8 7, J. Mol. Biol. 196 ： 901-917 ； Chothia et al., 1 989, Nature 3 42: 877- 8 83)。然而，此處所提供之CDRs可不只用於界定傳統抗體構造之抗原結合結構區亦可嵌入多種不同之其他多肽構造中（此文所描述者）。 -44- 200927761 於一觀點中，此處所提供之CDRs爲（a)選自下列之 CDRL : (i)選自 SEQ ID NOs : 1 89-217 之 CDRL1 ; (ii)選自 SEQ ID NOs: 2 1 8-23 3 之 CDRL2; (iii)選自 SEQ ID NOs: 234-274之CDRL3;及（iv)含有一或多個不超過5、 4'3、2或1個胺基酸的胺基酸取代、缺失或插入之（i)、 (ii)或（iii)的 CDRL ; (B)選自下列之 CDRH: (i)選自 SEQ ID NOs : 275 -299 之 CDRH1 ; (i i)選自 S E Q ID Ν Ο s : 3 0 0-0 331 之 CDRH2 ; (iii)選自 SEQ ID NOs : 3 3 2-3 72 之 CDRH3 :或者（iv)含有一或多個不超過5、4、3、2或1個胺基酸的胺基酸取代、缺失或插入之⑴、（ii)或（iii)的CDRH。於另一觀點中係提供與第6A-6F圖及第7A-7E圖中所列之C D R序列具有至少8 0 %、8 5 %、9 0 %或9 5 %序列同一性之CDRs的變異體形式。於另一觀點中，此處所揭示之CDRs包括衍生自相關之單株抗體群的一致序列。如此處所描述之“一致序列” φ 係指具有普遍保存在多種序列間之胺基酸及在指定之胺基酸序列內變化之可變胺基酸的胺基酸序列。此處所提供之 CDR —致序列包括對應於各 CDRL1、CDRL2、CDRL3、 CDRH1、CDRH2 及 CDRH3 之 CDRs。利用標準親緣分析法分析對應於抗HB-EGF抗體之U-Vl和U-VH之CDRs來測定一致序列。此方法中，首先將對應於U-VL或U-VH之整個可變結構區的胺基酸序列轉化成FASTA版式以易於處理比較性比對及系譜推論。根據此比較，將各輕鏈和重鏈可變區分別分割成親緣相關組， -45- 200927761 即，將輕鏈可變區分割成A、B、C、D、E和F六組（見第 12A及第12B圖），將重鏈可變區分割成A、B、C、D、E 、？和G七組（見第12C圖）。然後，在這些各組內，使用各 CDRL1、CDRL2、CDRL3、CDRH1、CDRH2 及 CDRH3 區之比較來定義一致性集合（consensus collections)。輕鏈C D R s之A組包括下列一致性集合： a. 具通式 X1SSQSLX2X3SDGX4TYLX5(SEQ ID NO:

1 106)之 CDRL1，其中 Xi爲κ或R· ’ X2爲L或V ’ X3爲H或Y ’ Χ4爲Κ或Ν ’ Χ5 爲 Ν、S 或 Υ。 b. 具通式 XlX2SNX3X4S(SEQ ID NO: 1112)之 CDRL2 ，其中 Ο

Xi爲E或K ’ X2爲I或V ’ X3爲R或W ’ X4爲D或F ° c.具通式 XlQX2X3X4X5PX6X7(SEQ ID NO: 1 089)之 CDRL3，其中

X!爲I或M ’ χ2爲A、G或S X3爲I或T ’ -46 - 200927761 X4爲Η或Q， X5 爲 F、L 或 W， X6 爲 C、I、H、L 或 T， X7爲S或T。輕鏈CDRs之B組包括下列一致性集合： a.具通式 RASQXilSXzYLNCSEQ ID NO ： 1107)之 CDRL1，其中

X2爲R或S。 b.具通式 XiX2SX3LQS(SEQ ID NO : 1113)之 CDRL2，其中 X!爲A或T， X2 爲 A、E 或 V， X3爲S或T。 c.具通式 QQXiXsXsXAXsIT^SEQ ID NO : 1 090)之

CDRL3，其中

Xi爲I或s， x2爲F或Y， X3 爲 F 、 I 、 S 或 Y ， X4 爲 A、S 或 T， X5爲P或S。輕鏈CDRs之C組包括下列一致性集合： a.具通式 RASQX1IX2X3X4LX5(SEQ ID NO: 1108)之 CDRL1 ，其中 -47- 200927761 X!爲 D、G、S 或 Τ， X2 爲 A、R 或 S， X3 爲 H、I、N、R、S 或 T， X4 爲 D、W 或 Y， X5 爲 A、G 或 N。 b.具通式 XiASX2LQS(SEQ ID NO: 1114)之其中 Xi爲A或V， X2爲S或T。 C.具通式 XiX2X3X4X5X6X7X8T(SEQ ID NO CDRL3 ，其中 Xi爲L或Q， X2 爲 K、N 或 Q， X3 爲 A、H、S 或 Y， X4 爲 Η、N 或 Y， X5 爲 N、S 或 T， X6 爲 A、F、I、T、V*Y， X7爲P或無胺基酸， X8 爲 F、L 或 P。輕鏈CDRs之D組包括下列一致性集合： a.具通式 QASQDIX1X2X3LN(SEQ ID NO: CDRL1 ，其中 X!爲s或τ， X2爲D或N， CDRL2， :1091)之 1109)之

❹ -48- 200927761 x3爲s或Y。 b.具通式 DASX!LET(SEQ ID NO: 1115)之 CDRL2, 其中

Xi爲I或N。 C.具通式 QX1X2DX3LPX4X5(SEQ ID NO ： 1 092)之 CDRL3 ，其中 X!爲H或Q，

X3 爲 D、I、N'S 或 Y， X4 爲 F、I 或 L， X5 爲 A、S 或 T。輕鏈CDRs之E組包括下列一致性集合： a.具通式 RASQXJXzXsXAXsLAiSEQ ID NO: 1110) 之CDRL1 ，其中

Xi爲s或τ， χ2爲I或s， X3爲R或S， X4爲S、N或無胺基酸， X5爲γ或無胺基酸。 b. 具通式 GASSRAT(SEQ ID NO : 223 )之 CDRL2。 c. 具通式 QQXiX2X3X4PX5X6X7(SEQ ID NO: 1 093 )之 CDRL3 ，其中

Xi爲Η或Y， Χ2爲G或Ν， -49 - 200927761 X3爲N或S， X4爲S或W， X5爲P或無胺基酸， X6爲R或W， X7爲S或T。輕鏈CDRs之F組包括下列一致性集合： a. 具通式 KSSQXiXzLXsXjSNNKNYLX^SEQ 1 1 1 1)之 CDRL1，其中 Χι爲N或S， X2爲I或V， X3爲D或Y， X4 爲 N、R 或 S， X5爲A或V。 b. 具通式 WASXiRESCSEQ ID NO: 1116)之其中

Xi爲A或T。 C.具通式 XiQYX2X3X4X5X6X7F(SEQ ID NO CDRL3，其中 Χι爲Η或Q， X2爲F或Y， Χ3 爲 G、I 或 S， X4 爲 F、I 或 T， X5 爲 Μ、P、S 或 T， X6 爲 F、L、R 或 W， ID NO : ❹ CDRL2，〇 :1094)之 -50- 200927761 x7爲S或T。重鏈CDRs之Α組包括下列一致性集合： a.具通式 GYTXJXzXsXaXsXJSEQ ID NO: 1 095 )之 CDRH1 ，其中

Xi爲F或L， X2 爲 E、G 或 S， X3 爲 H、L 或 Y，

X5爲I或M， X6爲H或S。 b.具通式 X1X2X3X4X5X6GX7TX8X9X1〇QKX11X12(SEQ IDNO: 1101)之 CDRH2，其中 Xj爲s或w， x2爲F或I， X3 爲 D、N 或 S，

X4爲A或P， X5 爲 E、N 或 S， X6 爲 D、N 或 S， X7 爲 E、G 或 N， X8爲I或N， X9 爲 C、H 或 Y， X1〇爲A或T，

Xh爲F或L， X12爲D或G。 -51 - 200927761 C.具通式 X1X2X3X4X5X6X7X8X9Xi〇XiiDX12(SEQ ID NO: 1 03 5 )之 CDRH3，其中 Xi爲E或S， X2爲D、G或無胺基酸， X3爲D、N或無胺基酸， X4爲G或無胺基酸， X5爲G或無胺基酸，

X6爲W、Y或無胺基酸， Χ7 爲 I、Ν 或 Υ， Χ8爲Α或Υ， Χ9 爲 G、V 或 Υ， Χ10 爲 A、F 或 G， X!,爲 F、L 或 Μ，

Xi2爲V或Y。

重鏈CDRs之Β組包括下列一致性集合： a.具通式 GYXiFTS YWIG(SEQ ID NO ： 1 096)之 CDRH1 ，其中 b.具通式 IIYPXjDSDXaRYSPSFQGCSEQ ID NO : 1102) 之CDRH2，其中 Χι爲D或G， X2 爲 A、I 或 T。 c.具通式

QX1X2X3X4X5X6X7X8X9Xi〇Xi 1 YXiiXisXmDX] 5(SEQ ID NO -52- 200927761 ：1 03 6)之 CDRH3，其中 Χι爲G或無胺基酸， X2 爲 K、L 或 Y， X3 爲 A、G 或 S， X4 爲 S、V 或 Y， X5爲A或G， X6爲G或無胺基酸，

X7爲T或無胺基酸， X8爲S或無胺基酸， X9爲Y或無胺基酸， Χίο爲W或Y， X! i 爲 G、S 或 Υ， X12爲F或Y，乂13爲G或無胺基酸， X!4爲Μ或無胺基酸， Χι5爲V或Υ。重鏈CD Rs之C組包括下列一致性集合： a.具通式 GFTFXi SX2X3MH(SEQ ID NO ： 1 097)之 CDRH1，其中

Xj爲R或S， X2爲H或Y， Χ3爲D或G。 b.具通式 XiIX2X3DGSX4X5X6YX7DSVX8G(SEQ ID NO :1 1 03)之 CDRH2，其中 -53- 200927761

Xi爲F或V， X2爲S或W， X3 爲 D、S 或 Y， X4 爲 I、N 或 T， X5爲K或Q， X6 爲 N、R 或 Y， X7 爲 A、T 或 V，

Χ8爲Κ或R。

c.具通式 X1X2X3X4X5X6X7X8X9Xl〇Xl1Xl2Xl3Xl4(SEQ ID NO ： 1037)之 CDRH3，其中乂,爲D、G、L、S或無胺基酸， X2爲G、H、W、Y或無胺基酸， Χ3爲A、F、W、Υ或無胺基酸， Χ4爲D、G、Q、Τ或無胺基酸， Χ5爲G、I、Q、S或無胺基酸，

X6爲A、D、N、Q、S或無胺基酸， X7爲G、Y或無胺基酸， Χ8爲D、Υ或無胺基酸， Χ9爲Υ或無胺基酸，乂10爲八、£、>1或丫，乂11爲0、？、1'、¥或丫， Χΐ2爲F或I， Χΐ3爲D或Q， Χ14 爲 C、Η、V 或 Υ。 -54- 200927761 重鏈CDRs之D組包括下列一致性集合： a.具通式 GFXiFSXzYXgMX^SEQ ID NO: 1 098)之 CDRH1 ，其中 Χι爲P或τ， Χ2 爲 A、R 或 S， X3爲A或S， X4爲N或S。 ❹ b.具通式 XiISX2SX3X4X5X6YYADSVKG(SEQ ID NO: 1 1 04)之 CDRH2，其中 X!爲 A、H 或 Y， Χ2 爲 G、R 或 S， X3爲G或S， X4 爲 G、R 或 S， X5 爲 S、T 或 Y， X6爲I或T。

X,X2X3X4X5X6X7X8X9Xi〇Xi 1X12X13X1 4Xl5Xl6Xl7DX18(SEQ ID NO : 1 03 8)之 CDRH3，其中乂1爲E、D或無胺基酸， X2爲G、R或無胺基酸， X3爲I、V、Y或無胺基酸， Χ4 爲 A、G、L 或 Ν， X5 爲 A、G、V 或 W， X6 爲 A、N、R 或 T， -55- 200927761 X7爲G、N、P或無胺基酸， X8爲G、T或無胺基酸， Χ9爲Α或無胺基酸，

Χίο 爲 D 、E 或無胺基酸， Xu 爲 S 、Y 或無胺基酸， Xl2 爲 G 、Y 或無胺基酸， X13 爲 N 、Y 或無胺基酸， Xl4 爲 Y 或無胺基酸， Xl5 爲 D 、Y 或無胺基酸， Xl6 爲 A 、G 或無胺基酸， Xl7 爲 F 或Ϊ Λ > Xl8 爲 I 、V 或Υ 〇重鏈CDRs之E組包括下列一致性集合： a.具通式 GXi SX2SX3X4X5X6X7WX8(SEQ ID NO ·· 1 099)之 CDRH1，其中 Xj爲D或G， X2 爲 F、I 或 V， X3爲R、S或無胺基酸， X4爲G、Y或無胺基酸， Χ5爲D、G、S或無胺基酸， X6 爲 A、S 或 Y， X7爲A或Y， Χ8爲Ν或S。 b.具通式 -56- 200927761 X1X2X3X4X5X6X7X8X9X10X1 1 YXi2Xi3SX]4KS(SEQ ID NO 1105)之 CDRH2，其中

Xi 爲 E、R 或 Y， x2爲I或τ， X3 爲 Η、N 或 Y， Χ4 爲（：、11、8、1'或丫， Χ5爲S或R，

X6爲G或S， X7 爲 G、K、S 或 Τ， X8爲T或W， X9爲N或Y， X1()爲N或無胺基酸，乂^爲D或無胺基酸， X12爲A或N， X13爲P或V， X14爲L或V。 c.具通式 X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X2 X2iX 2 2 X 2 3 (SEQ ID NO : 1 03 9)之 CDRH3，其中 Χι 爲 A、D、G、S 或 T， X2爲A、E、G、L、N、R、Y或無胺基酸， X3爲A、G、L' N、R、Τ、Y或無胺基酸， X4爲D、G、R、S、V、Y或無胺基酸， X5爲A、G、I、S' V、Y或無胺基酸， -57- 200927761 X6爲F、G、L、R、V或無胺基酸， X7爲L、T、Y或無胺基酸， Xs 爲 Y或無胺基酸， χ9 爲 Y或無胺基酸， Xl 0爲 D或無胺: 基酸 Xl 1爲 S或無, 胺基酸 5 Xl 2爲 S或無, 胺基酸， Xl 3爲 G或無胺: 基酸 Xi 4爲 D、 L、 Μ 、S、 Υ或無胺基酸， Xl 5爲 Η、 I ' Ρ、 V、 W或無胺基酸， Xl 6爲 F、 G、 L 、R、 S、Υ或無胺基酸， Xi 7爲 D、 F、 V 、W ' Υ或無胺基酸， Xi 8爲 C、 F、 L 、Ρ、 S或Υ， Xi 9爲 D、 F、 G 或Υ 5 x2 0爲 A、 C、 G 、Ρ、 R、V 或 Υ， x2 1爲 F、 L、 Μ 、S或無胺基酸， x2 2爲 A、 D或無胺基酸， x2 3爲 I ' L、 V 、Υ或無胺基酸。重鏈CDRs之F組包括下列一致性集合： a.具通式 GFSLSN ARMGVS(SEQ ID NO ： 279)之

CDRH1。 b.具通式 XiIFSNDEKSYSTSLKS(SEQ ID NO: 1 03 3 ) 之CDRH2，其中

Xi爲H或L。 -58- 200927761 C.具通式 XJSSGWXsXsYGXJsDXdSEQ ID NO: 1040)之 CDRH3，其中 Xi爲M或V， Χ2爲S或無胺基酸， X3爲F或無胺基酸， X4爲V或無胺基酸， X5爲F或Μ，

Χ6爲V或Υ。重鏈CDRs之G組包括下列一致性集合： a. 具通式 GFSLX1TGGVGVG(SEQ ID NO ： 1100)之 CDRH1 ，其中 X!爲S或N。 b. 具通式 liywnx1x2kryspslx3s(seq id no ： 1 034)之 CDRH2，其中 Xi爲D或V，

X3爲K或R。 c.具通式 RXiX2X3PFX4Y(SEQ ID NO : 1041)之 CDRH3 ，其中

Xi 爲 G、H、L、N 或 R， x2 爲 E、T 或 W， X3 爲 L、N、T 或 V， X4爲D或E。在另—方法中，一致性序列可經由將連續CDRs保持 -59- 200927761 在對應於U-VL或U-VH之相同序列內來測定。簡單地說，此方法中係將對應於整個U-VL* U-VH可變結構區的胺基酸序列轉化成FASTA版式以易於處理比較性比對及系譜推論。接著，以人工連接子序列取代這些序列之框構區，如此’可單獨檢査CDRs’不會因巧合情況（諸如意外共有一共通之種系框構遺留序列的不相關抗體）而引入任何胺基酸位置之權偏誤，但仍將連續CDRs保持在對應於U-VL 或 U-VH之相同序列內。然後，利用使用標準之似 ClutalW對數的程式將此版式之U-Vl或U-VH序列進行序列類似性比對審査（見，Thompson ei α/.,1994, iVuc/efc

Jc/心 4673-4680)。此程式利用UPGMA(不加權算術平均組對）或鄰接法（Neighbor-Joining method)(見，

Saitou and Nei，1987， Molecular Biology and Evolution 4 '

4 0 6-425)根據序列類似性比對同樣地產生種系發生圖（種系樹之說明），以經由分支長度比較和分組來建構及說明序列組間之類似性和差別。二種方法產生類似結果以決定個別組內之一致序列集合。在某些情況中，該抗原結合蛋白包含至少一 CDRL1、 CDRL2或CDRL3(其具有上述一致性序列中之一）。在某些情況中，該抗原結合蛋白包含至少一CDRH1、CDRH2或。。11^13(其具有上述一致性序列中之一）。於其他情況中，該抗原結合蛋白包含至少二個根據上述之一致性序列的 CDRLs，及/或至少二個根據上述之一致性序歹(1的CDRHs 。於一觀點中，該CDRLs/ CDRHs係衍生自不同組。於其 -60- 200927761 他情況中，該抗原結合蛋白包含至少二個來自相同之A、 B、C、D、E或F組的CDRLs及/或至少二個來自相同之 A、B、C、D、E 、F或G組的CDRHs。於其他觀點中，該抗原結合蛋白包含所有三個來自相同之上述A、B、C、 D、E或F組的CDRL1、CDRL2及CDRL3序列及/或所有三個來自相同之人、8、（：、0、£、？或0組的001^1、 CDRH2 及 CDRH3 序歹[J。 ❹ D.示範之抗原結合蛋白根據一種觀點，本發明提供與HB-EGF結合之經分離的抗原結合蛋白，其包含（A) —或多個選自下列之輕鏈互補決定區（CDRLs) : (i)選自 SEQ ID NOs : 189-217 之 CDRL1 ; (ii)選自 SEQ ID NOs : 2 1 8-23 3 之 CDRL2 ; (iii) 選自 SEQ ID NOs: 234-274 之 CDRL3;及（iv)含有一或多個不超過5、4、3、2或1個胺基酸的胺基酸取代、缺失 0 或插入之（0、（Π)及（iii)的CD RL; B)—或多個選自下列之重鏈互補決定區（CDRHs): (i)選自SEQ ID NO: 275 -299 之 CDRH1 ; (ii)選自 SEQ ID NO : 3 00- 3 3 1 之 C DRH2 ; (iii)選自 SEQ ID NO : 3 3 2-3 72 之 CDRH3 ;及（iv)含有一或多個不超過5、4、3、2或1個胺基酸的胺基酸取代、缺失或插入之（i)、（Π)及（iii)的CDRH;或（C)—或多個 (A)之輕鏈CDRLs;及（D) —或多個（B)之重鏈CDRHs。於另一較佳體系中，該經分離之抗原結合蛋白可包含 :(A)選自下列之 CDRL: (i)選自 SEQ ID NO: 189-217 之 -61 - 200927761

CDRLl ; (ii)選自 SEQ ID NO : 2 1 8-23 3 之 CDRL2 ; (iii)選自 SEQ ID NO : 234-274 之 CDRL3 ; B)選自下列之 CDRH : (i)選自 SEQ ID NO : 275-299 之 CDRH1 ; (ii)選自 SEQ ID NO : 3 00-33 1 之 CDRH2 ;及（iii)選自 SEQ ID NO :3 3 2-3 72 之 CDRH3;或（C) 一或多個（A)之輕鏈 CDRLs :及（D)—或多個（B)之重鏈CDRHs。於一較佳體系中，該經分離之抗原結合蛋白可包括（A) SEQ ID NO: 189-217 之 CDRLl、SEQ ID NO : 218-233 之 CDRL2 和 SEQ ID NO :234-274 之 CDRL3 ;及（B) SEQ ID NO : 275-299 之 CDRH1、SEQ ID NO : 3 00-3 3 1 之 CDRH2 和 SEQ ID NO : 332-372 之 CDRH3。

於另一較佳體系中，該抗原結合蛋白包含一可變輕鏈 (VL)，此VL與選自SEQ ID NO : 94-141之胺基酸序列具有至少 8 0 %、8 5 %、9 0 %或 9 5 %序列同一性，及/或一可變重鏈（Vh)，此VH與選自SEQ ID NO: 142-186之胺基酸序列具有至少 8 0 %、8 5 %、9 0 %或 9 5 %序列同一性。於另一較佳體系中，該VL係選自SEQ ID NO: 94-141及/或該 VH 係選自 SEQ ID NO: 142-186。於另一觀點中，本發明亦提供一種經分離之抗原結合蛋白’其特異結合包含至少一個含有IHGE之抗原決定部位及/或HB-EGF之似EGF結構區的抗原決定部位。於另一觀點中，本發明提供一種與HB-EGF結合之經分離的抗原結合蛋白，其包含（A)選自下列之輕鏈互補決定區（CDRL): (i)選自 SEQ ID NO ： 234-274 之 CDRL3, -62- 200927761 (ii)與（i)之CDRL3之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的CDRL3 ;及（iii)選自下列之 CDRL3 胺基酸序列：XWXaXJdsPXJWSEQ ID NO: 108 9)，其中X】係選自I或M，X2係選自A、G或S，X3 係選自I或T，X4係選自Η或Q，X5係選自F、L或W， X6係選自 C、I、H、L或 τ，Χ7係選自 S或 T; QQXiXzXsXdsITiSEQ ID NO: 1090)，其中 Xi 係選自 I 0 或s，X2係選自F或Y，X3係選自F、I、S或Y，X4係選自 A、S 或 T，X5 係選自 P 或 S; ΧππππαβνΧυΤ (SEQ ID NO: 1091)，其中X,係選自L或Q，X2係選自K 、>^或（^’又3係選自八、11、8或¥，乂4係選自^1、>4或丫，乂5係選自>^、8或1'，乂6係選自入、？、1、1'、¥或丫， X7係選自 P或無胺基酸，X8係選自 F、L或 P; QXiXJXsLPXiX^SEQ ID NO: 1092)，其中 X!係選自 Η 或Q，X2係選自c或Y，x3係選自D、I、N、S或Y，X4 φ 係選自 F、I或 L，X5係選自 A、S或 T; QQXiXzXsXJXsXeX^SEQ ID NO: 1 093)，其中 Xi 係選自 H或Y，X2係選自G或N，X3係選自N或S，X4係選自s 或W ’ X5係選自P或無胺基酸，χ6係選自R或w，χ7係選自 S 或 Τ ;及 XAYXzXgXAXsXdJCSEQ ID NO : 1 094) ’其中Xi係選自H或Q’ X2係選自F或Y，X3係選自〇、1或S，X4係選自F、I或T，X5係選自M、P、s或T ，Χ6係選自F、L、R或W，Χ7係選自S或Τ ;及/或（Β) 選自下列之重鏈互補決定區（CDRH): (i)選自SEQ ID N〇s -63- 200927761 :332-372之CDRH3 ; (ii)與⑴之CDRH3之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的 CDRH3 ；及（iii)選自下列之 CDRH3 胺基酸序列： XAXAXsXeXTXsXgXioXiiDXdSEQ ID NO : 1 03 5)，其中Xi係選自E或S，X2係選自D、G或無胺基酸，X3係選自D、N或無胺基酸，X4係選自G或無胺基酸，X5係選自G或無胺基酸，X6係選自W、Y或無胺基酸，X7係選自I、N或Y，X8係選自A或Y，X9係選自G、V或Y ，Χίο係選自A、F或G，Xh係選自F、L或Μ，X12係選

自 V 或 Y; QXAJsXdsXeXjsXQXioXiiYXuXuXMDXH (SEQ ID NO: 1036)，其中Xi係選自G或無胺基酸，X2 係選自K、L或Y，X3係選自A、G或S，X4係選自S、V 或Y，X5係選自A或G，X6係選自G或無胺基酸，X7係選自T或無胺基酸，X8係選自S或無胺基酸，X9係選自 Y或無胺基酸，X1()係選自W或Y’ Xm係選自G、S或Y ，X12係選自F或Y，X13係選自G或無胺基酸，X14係選自 Μ 或無胺基酸，X15係選自 V 或 Y;

XJX2X3X4X5X6X7X8X9X10X1 lXl2Xl3Xl4(SEQ ID NO： 1 03 7) ，其中X!係選自D、G、L、S或無胺基酸，X2係選自G 、11、琛、丫或無胺基酸，又3係選自八、？、1^、丫或無胺基酸，X4係選自D、G、Q、T或無胺基酸，X5係選自G 、1、（5、8或無胺基酸，又6係選自八、0、\、（5、8或無胺基酸，X7係選自G、Y或無胺基酸’ X8係選自D、Y或無胺基酸，X9係選自Y或無胺基酸’ Χίο係選自A、E、N -64 - 200927761 或Υ，Χη係選自G、P、T、V或Υ，Χ12係選自F或I， X13係選自 D或 Q，X14係選自 C、Η、V或 Υ ;

ΧιΧ2Χ3Χ4Χ5Χ6Χ7Χ8Χ9Χι〇Χι 1X12X13X14X15Xl6Xl7DX18(SEQ ID NO: 1038)，其中X!係選自E、D或無胺基酸，Χ2係選自G、R或無胺基酸，Χ3係選自I、V、Υ或無胺基酸， Χ4係選自 A、G、L或Ν，Χ5係選自 A、G、V或W，X6 係選自A、N、R或T，X7係選自G、N、P或無胺基酸， X8係選自G、T或無胺基酸，X9係選自A或無胺基酸， Χϊο係選自D、E或無胺基酸，係選自S、Y或無胺基酸，X12係選自G、Y或無胺基酸，X13係選自N、Y或無胺基酸，X14係選自Y或無胺基酸，X15係選自D、Y或無胺基酸，X16係選自A、G或無胺基酸，X17係選自F或Μ ，Χΐ8 係選自 I、V 或 Υ ; ΧιΧ2Χ3Χ4Χ5Χ6Χ7Χ8Χ9Χι〇Χι ιΧ12

X 1 3 X 1 4 X 1 5 X 1 6 X 1 7 X 1 8 X 1 9X2 0 X 2 1 X2 2 X2 3 (SEQ ID NO : 1 03 9)，其中Xi係選自A、D、G、S或T，X2係選自A、E、G、L 、N、R、Y或無胺基酸，X3係選自 A、G、L、N、R、T 、Y或無胺基酸，X4係選自D、G、R、S、V、Y或無胺基酸，X5係選自 A、G、I、S、V、Y或無胺基酸，X6係選自？、0、1^、尺、乂或無胺基酸，乂7係選自1^、1'、丫或無胺基酸，X8係選自Y或無胺基酸，X9係選自Y或無胺基酸，X1G係選自D或無胺基酸，Xh係選自S或無胺基酸，X12係選自S或無胺基酸，X13係選自G或無胺基酸，X14係選自D、L、M、S、Y或無胺基酸，X15係選自Η 、I、P、V、W或無胺基酸，Χ16係選自F、G、L、R、S -65- 200927761 、Υ或無胺基酸，Χ17係選自D、F、V、W、Y或無胺基酸，x18係選自C、F、L、P、S或Y，x19係選自D、F、

G或Y，X2G係選自A、C、G、P、R、V或Y，X21係選自 F、L、M、S或無胺基酸，X22係選自A、D或無胺基酸， X23 係選自 I、 L、 V、 Y 或無胺基酸； Xi YSSGWX2X3 YGX4X5DX6(SEQ ID NO ： 1 040)，其中 X! 係選自M或V，X2係選自S或無胺基酸，x3係選自F或無胺基酸，X4係選自V或無胺基酸，X5係選自F或Μ， Χ6 係選自 V 或 Υ ;及 RX 丨 X2X3PFX4Y(SEQ ID NO : 1041) ，其中X!係選自G、H、L、N或R，X2係選自E、T或评，又3係選自1^、：^、1'或¥，乂4係選自〇或£。

於一較佳體系中，該經分離之抗原結合蛋白進一步包含：（A)選自下列之 CDRL : (i)選自 SEQ ID NOs : 189-217 之CDRL1 ; (ii)與（i)之CDRL1之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的CDRL1 ; (iii) 選自下列之 CDRL1 胺基酸序列： X1SSQSLX2X3SDGX4TYLX5(SEQ ID NO: 1106)，其中 X! 係選自K或R，X2係選自L或V，X3係選自η或Y，X4

係選自 κ 或 Ν，χ5 係選自 N、s 或 Y RASQXiISX2YLN(SEQ ID NO ： 1107)，其中 Χι 係選自 R、

S 或 T，X2 係選自 R 或 S; RASQX1IX2X3X4LX5(SEQ id NO:1108)，其中X1係選自D、G、S或T，X2係選自A 、11或8，又3係選自11、1、：^、11、8或1'，乂4係選自0、 W 或 Y，X5 係選自 A、G 或 N; QASQDIXiXsXsL^KSEQ ID 66 - 200927761 NO: 1109)，其中X,係選自S或Τ，Χ2係選自D或N， X3 係選自 S 或 Y ; RASQXjVXaXsXjXsLAiSEQ ID NO : I 1 10)，其丰X1係選自S或T，X2係選自I或s，x3係選自R或S，X4係選自S、N或無胺基酸，X5係選自Y或無胺基酸：及 KSSQX,X2LX3X4SNNKNYLX5(SEQ id no ：

II 1 1)，其中Xl係選自N或S，X2係選自I或V，X3係選自D或Y，X4係選自N、R或S，X5係選自A或V;或 (iv)選自 SEQ ID NO : 2 1 8-23 3 之 CDRL2 ; (v)與（iv)之 CDRL2之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的CDRL2 ;或（vi)選自下列之CDRL2胺基酸序列：XiX2SNX3X4S(SEQ ID NO: 1112)，其中又】係選自E或K，X2係選自I或V，X3係選自R或W，X4係選自 D 或 F; X,X2SX3LQS(SEQ ID NO: 1113)，其中 X, 係選自A或T，X2係選自A、E或V，X3係選自S或T; XiASX2LQS(SEQ ID NO: 1114)，其中 Xi 係選自 A 或 V， X2 係選自 S 或 T; DASXAET^SEQ ID NO: 1115)，其中 Xi 係選自 I 或 N ; GASSRAT(SEQ ID NO : 223)；及 WASXiRES(SEQ ID NO: 1116)，其中 X,係選自 A 或 T; 或（B)選自下列之CDRH : (i)選自SEQ ID NO : 275-299之 CDRH1 ; (ii)與（i)之CDRH1之胺基酸序列的差異爲不超過 2個胺基酸之胺基酸加入、缺失或取代的CDRH 1 ; (iii)選

自下列之 CDRH1胺基酸序列：GYTXJXzXsXjXsXdSEQ ID NO: 1095)，其中Χι係選自F或L，X2係選自E、G 或S，X3係選自Η、L或Y，X4係選自G、S或Y，X5係 -67- 200927761 選自 I 或 M，X6 係選自 Η 或 S; GYXJTSYWIGCSEQ ID NO : 1 096)，其中 X! 係選自 R 或 S; GFTFXiSX2X3MH(SEQ id NO: 1 097)，其中 Xi 係選自 R 或 S，x2係選自 H或 Y，X3係選自 D或 G; GFXiFSX2YX3MX4(SEQ ID NO : 1 098)，其中 Xi 係選自 P 或T，x2係選自A、R或S，x3係選自A或S，X4係選自 N 或 S ; GXiSX2SX3X4X5X6X7WX8(SEQ ID NO : 1 099)，其中Xi係選自D或G，X2係選自F、I或V，X3係選自R、 S或無胺基酸，X4係選自G、Y或無胺基酸，X5係選自D 、G、S或無胺基酸，X6係選自A、S或Y，X7係選自A 或 γ，X8 係選自 N 或 S ; GFSLSNARMGVS(SEQ ID NO : 279)；及 GFSLXiTGGVGVG(SEQ ID NO: 1100)，其中 Xi 係選自 S 或 N ; (iv)選自 SEQ ID NO : 3 00-3 3 1 之 CDRH2 ;(v)與（iv)之CDRH2之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的CDRH2 ;或（vi)選自下列之 CDRH2 胺基酸序列：XiXaXsXeXsXeGXJXs XsXmQKXhXuCSEQ ID NO: 1101)，其中 Xi 係選自 S 或 w，X2係選自F或I，X3係選自D、N或S，X4係選自A 或P，X5係選自E、N或S，X6係選自D、N或S，X7係選自E、G或N，X8係選自I或N，X9係選自C、H或Y ，Χίο係選自A或T，Xh係選自F或L，X12係選自D或 G ； IIYPX,DSDX2RYSPSFQG(SEQ id NO ： 1102)，其中 x!係選自 D 或 G，X2係選自 A、I 或 T ; X1IX2X3DGSX4X5X6YX7DSVX8G(SEQ ID NO : 1103)，其中 200927761 Χι係選自F或V’X2係選自S或W，X3係選自D、S或 Y，X4係選自ϊ、N或T，X5係選自K或Q，X6係選自N 、11或Y，X7係選自Α'Τ或V，X8係選自K或R; x1isx2sx3x4x5x6yyadsvkg(seq ID NO : 1 104) ’ 其中 X!係選自A、H或Y，x2係選自G、R或S’x3係選自G 或S，X4係選自G、R或S’X5係選自S、T或Y，X6係

選自 I 或 T ; X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 1。X 1 1 YX I 2 X 1 3 S X 1 4 K S (SEQ ID NO: 1105)，其中X,係選自E、R或Y，X2係選自I或T，X3係選自H、N或Y，X4係選自C、H、S、T 或Y，X5係選自S或R，X6係選自G或S，X7係選自G 、K、S或T，X8係選自T或W，X9係選自N或Y，X10 係選自Ν或無胺基酸，Χη係選自D或無胺基酸’父12係選自 A或N，X13係選自P或V，X14係選自L或V; X,IFSNDEKSYSTSLKS(SEQ ID NO ： 1 03 3)，其中 Χι 係選自 Η 或 LI ;及 LIYWNXiX2KRYSPSLX3S(SEQ ID NO ： 103 4)，其中乂1係選自〇或¥，又2係選自〇或£，乂3係選自K或R。於某些較佳體系中，至少二個或全部三個CDRL1、 CDRL2及CDRL3序列係衍生自相同之A、B、C、D、E或 F組的一致性序列及/或至少二個或全部三個 CDRH 1、 CDRH2及CDRH3序列係衍生自相同之 A、B、C、D、E 、F或G組。於其他情況中，係將來自不同一致性序列組的CDRs相混合及配合。再於另一較佳體系中，上述之經分離的抗原結合蛋白 -69- 200927761 包含第一胺基酸序列和第二胺基酸序列’此二序列係彼此共價結合。於另一較佳體系中，該經分離的抗原結合蛋白的第一胺基酸序列包含SEQ ID NO : 23 4-274之CDRL3、 SEQ ID NOs : 2 1 8 -23 3 之 CDRL2 及 SEQ ID NO ： 189-2 17 之CDRL1。另一方面，該經分離之抗原結合蛋白的第二胺基酸序列包含 SEQ ID NO: 3 32-3 72 之 CDRH3、SEQ ID NOs : 300-3 3 1 之 CDRH2 及 SEQ ID NO ： 275-299 之 CDRH1。於一觀點中，此處提供之經分離的抗原結合蛋白可爲單株抗體、多株抗體、重組抗體、人抗體、人化抗體、嵌合型抗體、多特異性抗體或彼等之抗體片段。於另一較佳體系中，此處提供之經分離的抗原結合蛋白的抗體片段可爲Fab片段、Fab’片段、F(ab')2片段、Fv 片段、雙特異性單鏈抗體或單鏈抗體分子。

於另一較佳體系中，此處提供之該經分離的抗原結合蛋白爲人抗體且可爲IgGl-、IgG2-、IgG3-或IgG4-型。於另一觀點中，此處提供之經分離的抗原結合蛋白可與標記基團偶合，此標記基團係，諸如放射性同位素、放射性核素、螢光基團、酶性基團、化學發光基團、生物素化基團或預定之多肽基團，或效應子基團，諸如放射性同位素、放射性核素、毒素、治療性基團或化療性基團。治療性基團或化療性基團之實例有加利車黴素、歐利史汀-PE、苯醌安絲黴素、美他納辛或彼等之衍生物。於其他觀點中，本發明包括與上述之抗原結合蛋白競 -70- 200927761 爭結合之抗原結合蛋白。本技藝之人士可察知’在具有超過一個前述序列之 CDR的任何抗原結合蛋白方面，可使用獨立選自前述序列之CDRs的任何組合。因此，可產生具有1、2、3、4、5 或6個獨立選擇之CDRs的抗原結合蛋白。然而，如本技藝之人士所知，特殊之較佳體系通常係利用非競爭性 CDRs之組合（如：抗原結合蛋白通常不是以二個CDRH2 0 區，等製成）。以下更詳細地討論此處提供之一些抗原結合蛋白。 1-抗原結合蛋白及結合抗原決定部位當抗原結合蛋白係結合多肽（諸如HB-EGF)之特定殘基內的抗原決定部位時，此意指該抗原結合蛋白特異結合由特定殘基組成之多肽（如：HB-EGF之特定節段）。這類抗原結合蛋白通常不會接觸HB-EGF內之每一殘基。並非 0 每一 HB-EGF內或HB-EGF之胞外結構區內之單一胺基酸取代或缺失一定明顯影響結合親和力。例如：一種方法係涉及測試具有約15個胺基酸之重疊肽的集合，該重疊肽橫跨抗原之序列且差別在增加小量之胺基酸（例如：三個胺基酸）。將該肽固定在微量滴定盤之槽內。固定時可藉由將肽之一端生物素化來實現。相同肽之不同樣本可選擇性地在胺基-及羧基端生物素化並在分開之槽中固定以供比較。此可用於鑑定端-特異性抗原結合蛋白。藉由終止在所欲之特殊胺基酸處可選擇性地包含入額外之肽。此方 -71 - 200927761 法可用於鑑定HB-EGF之內片段的端-特異性抗原結合蛋白。篩檢可特異結合各個不同肽之抗原結合蛋白或免疫功能性片段。抗原決定部位之定義爲顯示出與抗原結合蛋白特異結合之所有肽所共有的胺基酸片段。實例23中列出關於用於界定抗原決定部位之特殊方法的細節。如實例23中所示’此處所提供之抗原結合蛋白可與至至少一個含有IHGE之抗原決定部位及/或HB-EGF之似 EGF結構區結合。 2. 競爭性抗原結合蛋白於另一觀點中’本發明提供抗原結合蛋白，其可與該結合上述抗原決定部位之示範抗體或功能性片段之一互相競爭特異結合HB-EGF。這類抗原結合蛋白亦可結合與此處示範之一種抗原結合蛋白所結合者相同的抗原決定部位或重疊之抗原決定部位。與示範之抗原結合蛋白競爭或結合至相同之抗原決定部位的抗原結合蛋白及片段預料可顯示出類似之功能性質。示範之抗原結合蛋白及片段包括上述者（包括那些具有重鏈和輕鏈、可變結構區以及第1、2 、3、4、6和7圖中所包含之CDRs)。 3. 人抗體及抗體之人化於一較佳體系中，該HB-EGF抗原結合蛋白爲人或人化抗體。人抗體可避免許多與擁有鼠科或大鼠可變區及/ 或恆定區之抗體有關的問題。存在這類源自鼠科或大鼠之 -72- 200927761 蛋白質可導致該抗體被快速清除或可使患者產生對抗該抗體之免疫反應。爲了避免使用源自鼠科或大鼠之抗體，經由將人功能性抗體基因位引入齧齒類、其他哺乳類或動物中可產生純人抗體，如此，齧齒類、其他哺乳類或動物可製造純人抗體。一種用於製造純人抗體的方法係透過使用 XenoMouse®品種老鼠來進行，此品種已經過遺傳工程處 0 理，其含有至高，但小於lOOOkb大小之人重鏈基因位和K 輕鏈基因位的種系配置片段（germline configured fragments)。見，Mendez e t al., 19 9 7, Nature Genetics 15 :1 4 6- 1 56, and Green and Jakobo vits, 1 998, J. Exp. Med. 188: 483-495。XenoMouse® 品種老鼠可自 Abgenix 公司（加州，F r e m ο n t)取得。

XenoMouse®品種老鼠之製造方法討論及描述於下：美國專利申請案序號07/466,008( 1 990年1月12日提出）、07/610,515(1990 年 11 月 8 日提出）、07/919,297(1992 年7月24曰提出）、07/922,649(1992年7月30日提出）、 08/031,801(1993 年 3 月 15 日提出）、08/112,848(1993 年 8 月27日提出）、0 8/23 4，1 45( 1 994年4月28日提出）、 08/3 76,279( 1 99 5 年 1 月 20 日提出）、08/430,93 8(1 995 年 4 月 27日提出）、08/464,584( 1 995年6月5日提出）、 08/464,582( 1 995 年 6 月 5 日提出）、〇8/463，1 91 (1 995 年 6 月5日提出）、08/462,837( 1 995年 6月5日提出）、 08/486,8 53 ( 1 995 年 6 月 5 日提出）、08/486,8 5 7( 1 995 年 6 -73- 200927761

月5日提出）、08/486,8 59( 1 995年 6月5日提出）、 08/4 62,513(1995 年 6 月 5 日提出）、08/7 24,752(199 6 年 10 月2曰提出）、08/759,620(1996年12月3日提出）、美國刊物第2003/0093820號（200 1年11月30日提出）及美國專利案第 6,1 62,963、6，1 50,5 84、6，1 1 4,598、6,075，181 和 5,93 9,5 98 號以及日本專利第 3 068 1 80 B2、3 06 8 5 06 B2 和3 068 507 B2號。亦見，歐州專利案第EP 0 463 1 5 1 B1號（1 996年6月12日准予出版）、國際專利申請案第 WO 94/02602號（1994年2月3日出版）、國際專利申請案第 WO 96/34096 號（ 1 996 年 10 月 31 日出版）、WO 98/24893 號（ 1 998 年 6 月 11 日出版）、WO 00/763 1 0 號 (2000年12月21日出版）。上述專利案、申請案和參考資料之全文各倂爲此文之參考資料。

於一替換之方法中，其他技藝中人（包括GenPharm國際公司）係使用“微小基因位（minilocus) “方法。在微小基因位方法中，外生性Ig基因位係透過包涵入來自Ig基因位之小片（個別基因）來模擬。因此，在構造物中形成一或多個VH基因、一或多個DH基因、一或多個JH基因、mu 恆定區以及通常一個第二恆定區（宜爲γ恆定區）以供插入動物體內。此方法描述於授與Surani等人之美國專利第 5,545,807號及各授與Lonberg和Kay之美國專利案號 5,545,806 ' 5,625,825 ' 5,625,126 ' 5,633,425 、 5,661,016 、5,770,429 、 5,789,650 > 5,814,318 ' 5,877,397 ' 5,874,299 和 6,25 5,45 8、授與 Krimpenfort 和 Berns 之美 -74- 200927761

國專利第5,591，669和6,023,01 0號、授與Berns等人之美國專利第 5,612,205、5,721,367 和 5,789,215 號、和授與 Choi和Dunn等人之美國專利第5,643,763號、以及 GenPh arm國際公司美國專利申請序號第〇7/574,748號 (1 990 年 8 月 29 日提出）、〇7/575,962 號（ 1990 年 8 月 31 日提出）、07/8 1 0,279號（1991年 12月17曰提出）、 07/8 5 3,408 號（ 1 992 年 3 月 18 日提出）、07/904,068 號 (1992 年 6 月 23 日提出）、07/990,860 號（1992 年 12 月 16 日提出）、〇8/05 3，131號（ 1 993年 4月 26日提出）、 08/096,762 號（ 1 993 年 7 月 22 日提出）、0 8/ 1 5 5,3 0 1 號 (1993 年 11 月 18 日提出）、08/161，739 號（1993 年 12 月 3 曰提出）、〇8/ 1 65,699號（1 993年 12月 10日提出）、 08/209,741號（ 1 994年3月9日提出）（其揭示內容倂爲此文之參考資料）。亦見，歐州專利案第0 546 073 B1號、國際專利申請案號 WO 92/0391 8、WO 92/22645、WO 92/22647。WO 92/22670、WO 93/1 2227、WO 94/00569、 WO 94/25 5 8 5 、 W0 96/14436 、 WO 97/1 3 852 和 WO 98/24884和美國專利案號5,98 1,1 75 (其揭示內容倂爲此文之參考資料）。

KiHn亦證明從老鼠製造人抗體，其中，大片之染色體或整個染色體係透過微小細胞融合引入。見’歐州專利申請案第773 288和843 961號（其揭示內容倂爲此文之參考資料）。另外，已製造出KMtm小鼠’其爲Kirin之Tc 鼠與Medarex微小基因位（Humab)小鼠交叉飼育之結果。 -75- 200927761 這些小鼠擁有 Kirin 小鼠之人 IgH 轉染色體 (transchromosome)及 Genpharm 小鼠之 κ 鏈轉基因（Ishida et al. ,2002, Cloning Stem Cells 4 ： 91-102)。人抗體亦可經由活體外方法衍生出。合適之實例包括，但不限於：睡菌體展不技術（CAT, Morphosys，Dyax， Biosite/Medarex, Xoma， Symphogen, Alexion ( formerly Proliferon)，Affimed)、核糖體展示技術（CAT)、酵母菌展示技術，等。 E.抗體之製備方法此處所描述之抗體係利用此處所描述之XenoMouse® 技術製備。這類小鼠可製造人免疫球蛋白分子和抗體且實質上不製造老鼠免疫球蛋白分子和抗體。用於製造人抗體之技術揭示於此處所揭示之專利、申請案和參考資料中。於某些較佳體系中，基因轉殖製造小鼠及人抗體係依美國專利申請案序號08/75入620(1 996年12月3日提出）及國際專利申請案第WO 98/24893號（1998年6月11曰出版）和WO 0 0/7 6310號（2 00 0年12月21日出版）之揭示內容（其倂爲此文之參考資料）進行。亦見，Mendez ei 1997 ，iVfliwre Geweiics 15: 146-156(其揭示內容國倂爲此文之參考資料）。透過使用這類技術已製造針對多種不同之抗原的純人類單株抗體。基本上，以所欲之抗原（如：HB-EGF)將小鼠之XenoMouse®株免疫化，自經高度免化之小鼠回收淋巴 -76- 200927761 Ο ❹ 細胞（諸如Β-細胞），將回收之淋巴球與骨髓型細胞株融合，以製備永生性雜交瘤細胞株。篩檢這些雜交瘤細胞株並加以選擇，以鑑定製造特異於所欲抗原之抗體的雜交瘤細胞株。亦可篩檢上清液中對抗HB-EGF片段之免疫反應性，以進一步測定結合HB-EGF上之所欲功能結構區的不同抗體。亦可篩檢抗體是否結合其他EGFR配體或其族群成員、其他相關之人類趨化素並對抗大鼠、小鼠科和非人類靈長類（諸如彌猴），HB-EGF之垂直同源物（後者係測定物種之交叉反應性）。此處提供用於製造可產製特異於HB-EGF之抗體的多種雜交瘤細胞株之方法。再者，此處提供用於決定由這類細胞株製造之抗體特徵的方法，其包括這類抗體之重鏈和輕鏈的核苷酸和胺基酸序列分析。或者，可直接分析B細胞而不與骨髓瘤細胞融合以產生雜交株。例如：可自高度免疫之XenoMouse®小鼠分離出B細胞並使其增殖和分化成抗體分泌型血漿細胞。然後，藉ELISA篩檢來自細胞上清液之抗體對抗HB-EGF免疫原的反應性。亦可篩檢上清液中對抗HB-EGF片段之免疫反應性，以進一步偵測結合HB-EGF上所欲功能結構區的不同抗體。亦可篩檢抗體是否結合其他EGF受體之配體或其族群成員、其他相關之人類趨化素並對抗大鼠、小鼠和非人類靈長類（諸如彌猴）、HB-EGF之垂直同源物（後者係測定物種之交叉反應性）。來自含有所欲抗體之槽內的B 細胞可藉由多種不同方法永生化，包括自個別或累積之槽中經由融合來製造雜交瘤，或以EBV感染或以已知之永 -77- 200927761 生化基因轉染，再將其平皿接種於合適之介質中。或者，利用HB-EGF-特異性溶血斑試驗將分泌具有所需之特異性的抗體之單一血漿細胞分離出。（Babco〇k ei β/·，1 996, Proc.iVai/. Jcad. Sci. 93: 7843-48)。被作爲溶解目標之細胞宜爲覆蓋HB-EGF抗原之綿羊紅血球（SRBCs)。

如上述討論者，抗體之同型有多種’包括，但不限於人IgGl、IgG2、IgG3及IgG4。吾人可察知，產生之抗體初始時不需要擁有這類同型，而是產生之抗體可擁有任何同型，且該抗體可進行同型變更，此係利用本技藝熟知之習知分子生物技術，使用在合適之表現載體中經分子選殖之V區基因或經選殖之恆定區基因或cDNAs進行，再利用本技藝已知之技術令抗體表現在宿主細胞中。

一般而言，藉由融合雜交瘤製造之抗體爲具有純人類 κ鏈之人IgG2重鏈或人IgG4重鏈。抗體亦可具有其他人類同型（包括IgGl或IgG3 )。該抗體擁有高親和力，當藉由固相及溶液相技術測量時，其通常具有約1CT6至約 1(Γ12Μ或更低之KD。宜使用其Kd至少爲10_9M之抗體來抑制HB-EGF之活性。其KD至少爲1〇_1()Μ之抗體亦較適宜用來抑制HB-EGF之活性。其KD至少爲1(ΓΜΜ之抗體亦較適宜用來抑制Η Β - E G F之活性。吾人可察知，抗HB-EGF可表現在除了雜交瘤細胞株外之細胞株。編碼特殊抗體之序列可用來轉染合適之哺乳動物宿主細胞。在建構用於轉染之合適載體及接下去表現抗體之期間，該抗體可經由類型轉變從一種同型變成另一 -78- 200927761 種同型，如：IgG4抗體可藉本技藝已知之技術經過類型轉變成IgG2。轉染可藉任何已知之用於將多核苷酸引入宿主細胞的方法進行，這些方法包括，例如：將多核苷酸包裝在病毒內（或引入病毒載體內）並以該病毒（或載體）轉導宿主細胞或係藉由本技藝已知之轉染技術（如：美國專利案第 4,399,2 1 6、4,912,040、4,740,461 和 4,959,455 號中所示範者，這些專利案倂爲此文之參考資料）。所使用 0 之轉形程序係取決於欲轉形之宿主。用於將異源多核苷酸引入哺乳動物細胞之方法爲本技藝所熟知，包括由葡聚糖促成之轉染作用、磷酸耗沈澱作用、由聚凝胺（P〇lybrene) 促成之轉染作用、原生質體融合、電穿孔法、將多核苷酸封入脂質體中及直接將DNA顯微注射入細胞核。可作爲用於表現之宿主的哺乳動物細胞株爲本技藝所熟知，包括多種可自美國典型菌種保藏庫（ATCC)取得之永生化細胞株，包括，但不限於：中國倉鼠卵巢（CHO)細胞 φ 、HeLa細胞、幼年倉鼠腎臟（BHK)細胞、猴子腎臟細胞 (COS)、人類肝細胞性癌細胞（如：Hep G2)、人類表皮腎臟2 9 3細胞及多種其他細胞株。特佳之細胞株係透過測定何種細胞株具有高表現水準且製造大量抗HB-EGF抗體來選擇。或者，可從經過遺傳工程處理以製造純人抗體之動物製備這些抗體或從在噬菌體、酵母菌 '核糖體或大腸桿菌中製造之抗體呈現庫製備。見’如：Clacks0n α/·, 19 9 1 ,Nature 3 52： 624-628, Marks et al., 1 99 1, J. Mol. Biol. -79- 200927761 222 : 58 1-597， Feldhaus and Siegel, 2004， J· Immunol·

Methods. 290 : 69-80， Groves and Osbourn, 2005， Expert Op in Biol The r. 5 : 125-135 以及 Jostock and Dubel, 2005,

Comb Che m High Throughput Screen, 8 : 127-133 。

本發明之另一觀點係關於經分離之編碼HB-EGF抗原結合蛋白（諸如抗體）的核酸分子。此文中，此處所使用之 “經分離之核酸分子”意指基因組cDNA或合成來源之多核苷酸、或彼等之一些組合，由於其來源，該“經分離之核酸分子”（1)不與多核苷酸之全部或一部分相連結，其中該“經分離之多核苷酸”可在自然中找到，（2)操作性連接一並非與其天然連結之多核苷酸係，或（3)不會天然以較大序列之一部分的形式出現。再者，此文所指之“核酸分子”意指至少爲10個鹼基長之聚合型核苷酸（爲核糖核苷酸或去氧核苷酸或任一形式之核苷酸的修改型，諸如具有經修改或經取代之糖基，等的核苷酸）。此一詞亦包括單股及雙股型之DNA。下文中更詳細地描述示範之編碼抗原結合蛋白的核酸或彼等之部分。於一較佳體系中，核酸分子係與控制序列操作性連接。此處所使用之“控制序列”係指使編碼序列的表現生效及運作時所必須之與編碼序列相連接的多核苷酸序列。這類控制序列之性質差別取決於該宿主有機體。在原核細胞中，這類控制序列通常包括啓動因子、核糖體結合部位及轉錄終止序列。在真核細胞中，這類控制序列通常包括啓動因子及轉錄終止序列。“控制序列”一詞欲包含（最起 -80- 〇 200927761 碼）對表現及運作而言爲必要之所有成分，亦可存在時可提供益處之額外成分，例如：領導序列伴序列。再者，此處所使用之“操作性連接” 成分所處之位置關係使彼等可以其所欲之方式作，此處所提供之表現控制序列與編碼序列之操作式係使編碼序列可在與表現控制序列相容的條件本發明之另一觀點爲包含編碼此處提供之HB 原結合蛋白的核酸分子之載體。該核酸分子可與ΐ 操作性連接。再者，載體可額外包含複製源或選_ 因。可使用之載體實例有，如：質體、黏質體、电病毒，等。 F.以基本抗體構造爲基礎的抗原結合蛋白如上述討論者，已知基本抗體構造包含四聚髏 Q 聚體係由二對完全相同之多肽鏈組成，各對具有一鏈（約25kDa)及一“重”鏈（約 5 0-70kDa)。各鏈；$ 部分包含一具有約100至11〇或更多胺基酸之可變主要負責抗原辨識。各鏈之羧基端部分係界定一；i 體化效應子功能、循環半生期和其他功能的恆定區輕鏈係分類爲κ和λ輕鏈。重鏈係分類爲//、6、或ε，其將抗體同型分別界定爲IgM、IgD、IgG、 IgE。在輕鏈和重鏈之內，可變區和恆定區係藉由 12或更多個胺基酸之“厂’區連接’該重鏈亦包启含當其融合夥詞係指。再者連接方表現出 EGF抗制序列標記基菌體、。各四 “輕” 胺基端區，其責二聚。人類 7 、 a IgA及具有約具有約 -81 - 200927761 10多個fl女基酸之 D 區。大致上，見Fundamental Immunology 第 7 章（Paul，W.,ed., 2nd ed. Raven Press, Ν·Υ·( 1989))(其全部內容併爲此文所有目的之參考資料）。各輕鏈/重鏈對之可變區形成該抗體之抗原結合部位因此’完整之IgG抗體具有二個結合部位。除了在雙功能或雙特異性抗體中外，該二個結合部位相同。

各鏈之可變區均顯示出相同之總體構造，此總體構造具有由三個高可變區（亦稱爲互補決定區或CDRs)連接之被高度保存的框構區（FR)。來自各對之二個可變區的 CDRs通常係靠框構區對位以結合抗原上之特殊抗原決定部位。從N -端至C -端，輕鏈和重鏈二者之可變區包含 FR1、CDR1、FR2、CDR2、FR3、CDR3 及 FR4。各結構區之胺基酸編派係根據具免疫學重要性之蛋白質的Kabat序歹(1 (National Institutes of Health, Bethesda, Md. ( 1987 和 19 9 1))或 Chothia & Lesk, 1 8 97，J. Mol. Biol. 1 96 : 90 1 -9 17； Chothia et al., 1989，Nature 342 ： 878-883 中之定義。因此，此處提供之抗體可包含至少一具下式之可變區多肽：FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4，其中 FR1 爲第一個人類框構區、CDR1爲第一個互補決定區、FR2爲第二個人類框構區、CDR2爲第二個互補決定區、FR3爲第三個人類框構區、CDR3爲第三個互補決定區且FR4爲第四個人類框構區。一般而言，CDR3爲抗體可變區最多 -82- 200927761 變之區域。於某些較佳體系中，FR1區包括’但不限於胺基酸序列 SEQ ID Nos: 373-393、1066、1067 及 / 或 452-468 中之任一項；CDR1區包括，但不限於胺基酸序列SEQ ID Nos :189-217及/或275-299中之任一項；FR2區包括，但不限於胺基酸序列SEQ ID Nos: 394-413、1068-1074及/ 或469-480中之任一項；CDR2區包括，但不限於胺基酸 0 序列 SEQ ID Nos : 2 1 8-233 及/或 3 00-3 3 1 中之任一項： FR3區包括，但不限於胺基酸序列SEQ ID Nos: 414-439 及/或481-510、1 075中之任一項；CDR3區包括，但不限於胺基酸序列SEQ ID Nos: 234-274及/或332-372中之任 —項；且FR4區包括，但不限於胺基酸序列SEQ ID Nos :440-45 1及/或511-516中之任一項。因此，於某些較佳體系中，此處提供之人抗體具有一或多種此處提供之胺基酸序列。需了解的是，此處提供之抗體的胺基酸序列並不限於該 20 種習知之胺基酸（見，5少 Λί/ΐθίί··ϊ(2η<ι Edition，E.S. Golub and D. R. Gren, Eds.,Sinauer Associates，Sunderland，Mass· ( 1991))其倂爲此文之參考資料）。例如：該胺基酸可包括該20種習知之胺基酸的立體異構物（如：D-胺基酸）、非天然胺基酸，諸如α，α-二經取代之胺基酸、Ν-烷基胺基酸、乳酸及其他非習知之胺基酸。非習知之胺基酸的實例（其亦爲此處提供之抗體的合適成分）包括：4-羥基脯胺酸、γ-羧基麩胺酸酯、ε- -83 - 200927761 N,N，N-三甲基離胺酸、ε-Ν-乙醯基離胺酸、Ο-磷酸絲胺酸、Ν-乙醯基絲胺酸、Ν-甲醯基甲硫胺酸、3-甲基組胺酸、 5-羥基離胺酸、σ-Ν-甲基精胺酸及其他類似之胺基酸和亞胺基酸，如：4-羥基脯胺酸。再者，SEQ ID Nos: 1-516、1 065- 1 075 及 1 033- 1 04 1

、1089-1 1 1 6中所顯示之胺基酸序列的微小變化亦被考慮包含在內，惟其在該胺基酸序列中之變化保持至少75%、宜爲至少8 0 %、9 0 %、9 5 % ’最宜爲9 9 %之S E Q ID Ν 〇 s : 1-516、 1065-1075 及 1033-1041、 1089-1116 中所示的序

列。顯示於 SEQ ID Nos: 1-516、1065-1075 及 1033-1041 、1 089- 1 1 1 6中之胺基酸序列中的較佳變化（即，缺失、插入及/或置換至少一個胺基酸）出現在接近功能結構區之邊界。構造性及功能性結構區可經由將該核苷酸與胺基酸序列資料與公開或專利序列資料庫相比較來鑑定。電腦化比較法可用來鑑定出現在其他具有已知構造及/或功能之抗體中的序列模體（motifs)或預測之蛋白質構造結構區。用於鑑定摺疊成已知之三次元構造的蛋白質序列的方法爲已知方法。見，如：Bowie et α /., 19 91 , Science 253: 164; Proteins, Structures and Molecular Principles ( Creighton, Ed.,W.H. Freeman and Company, New York ( 1984)); Introduction to Protein Structure ( C. Branden and J.

Tooze, eds., Garland Publishing, New York, N.Y. ( 1991 ) )；及 Thornton et al., 1991, Nature 3 54 ： 105，其全部併爲此文之參考資料。因此，熟習本技藝之人士可辨識可用 -84- 200927761 於界定構造及功能結構區之序列模體及構造性結構。顯示於 SEQ ID Nos: 1-516、1 065- 1 075 及 1 033- 1 04 1 、1 089-1 1 1 6中之胺基酸序列中的特佳變化爲那些造成對蛋白質水解或氧化作用之感受性降低、改變糖基化樣式或改變結合親和力或提供或修改抗體之其他物化或功能性質的變化。尤其是，保存性胺基酸置換爲所考量者。保存性置換爲在胺基酸族群（其側鏈彼此關聯）中發生之置換。較 0 佳之胺基酸族群如下：酸性族群=天門冬胺酸化物、麩胺酸化物；鹼性族群=離胺酸、精胺酸、組胺酸；非極性族群=丙胺酸、纈胺酸、白胺酸、異白胺酸、脯胺酸、苯丙胺酸、甲硫胺酸、色胺酸；及不帶電之極性族群=甘胺酸 '天門冬醯胺、麩醯胺、半胱胺酸、絲胺酸、蘇胺酸、酪胺酸。更佳之族群爲：脂族-羥基族群=絲胺酸和蘇胺酸；含醯胺族群=天門冬醯胺和麩醯胺；脂族群=丙胺酸、纈胺酸' 白胺酸和異白胺酸；以及芳香族群=苯丙胺酸、色胺 Q 酸和酪胺酸。例如：吾人可合理期待獨立以異白胺酸或纈月安酸取代白胺酸、以麩胺酸化物取代天門冬胺酸化物、以絲胺酸取代蘇胺酸，或者，以構造上相關之胺基酸進行類似之胺基酸取代對所產生之抗體的結合或性質將不會有重大影響，尤其是若取代並不涉及框構區位置內之胺基酸時 °然而，所有其他可能之胺基酸取代亦包含在內。胺基酸變化是否產生功能性抗體（即，產生結合HB-EGF並減少、中和或實質上抑制HB-EGF之功能的抗體）可輕易地藉由在ELISA或FACS中分析所產生之抗體結合HB-EGF的 -85- 200927761 特殊活性或在活體外或活體內功能分析中測定之。減低、中和或實質上抑制由HB-EGF傳介之信號轉導可經由影響（如：減少或抑制）HB-EGF與其受體（如：EGFR 或HER4)結合來產生。此處所使用之“抗體”或“抗HB-EGF抗體” 一詞意指單株抗體、多株抗體、重組抗體、人抗體（Jones ei α/., 1 986, Nature 321 ： 522-525 ； Riechmann et a/.,1 988,

Nature 3 32 ： 323-329 ；及 Presta, 1 992, Curr. Op. Struct. 5 ζ·ο/_ 2 : 593 : 596)、嵌合型抗體（Morrison " a/·，1984,

Proc. Wa，/· Scf. t/.ϋ 8 1: 685 1 -685 5)、從至少二種抗體形成之多特異性抗體（如：雙特異性抗體）或彼等之抗體片段。“抗體片段”一詞包含前述抗體之任何部分，較佳地，至少爲其抗原結合區或可變區之一。抗體片段爲 Fab片段、Fab1片段、F(ab’）2片段、Fv片段、雙特異性單鏈抗體（Hollinger ei α/., 1993，Proc. Τ/αί/· Jcad. Sc i. 〇 (7.H90: 6444-6448)、單鏈抗體分子（Pltickthun in: The Pharmacology of Monoclonal Antibodies 113，Rosenburg and Moore, EDS, Springer Verlag, N.Y. ( 1 994 ) 269-315 ) 以及其他片段，只要其顯示出所需之結合HB-EGF之能力另外，此處所使用之“抗體”或“抗HB-EGF抗體” 一詞可包括含有經遺傳工程處理之抗體次結構區或天然抗體變異體的似抗體分子。這些似抗體分子可爲單—結構區抗體，諸如那些衍生自天然來源（諸如駱駝抗體 -86- 200927761 (camelids))(Muyldermans et al. ,200 1, Reviesw in A/o / e c m / a r 少 74，277-302)或透過活體外展示源自人類、駱駝或其他物種之集合庫（Holt ei α/.，2003, 2 1 : 484-90)的僅含 VH 或僅含 VL 的結構區。

“ Fv片段”爲含有完整之抗原辨識及結合部位的最小抗體片段。此區係由一二聚體所組成，其包含彼此緊密且爲非共價連結之一重鏈和一輕鏈。此結構中各可變區之三個CDR交互反應以界定Vh-Vl二聚體之表面上的抗原結合部位。總體而言，該6個CDR提供抗體抗原結合特異性。然而，即使是單一可變區（或者僅包含三個特異於抗原之CDR的一半Fv)亦具有辨識及結合抗原之能力，雖然其通常係以較整個結合部位爲低之親和力結合。“ Fab 片段”亦含有輕鏈之恆定區及重鏈之第一恆定區（CH1)。 “Fab片段”與“Fab'片段”之相異處在於重鏈CH1結構區之羧基端有=些殘基加入，包括一或多個來自抗體絞鏈區的半胱胺酸。“F(ab')2片段”最初係以一對“Fab·片段 ”之形式製成，該二個Fab'片段之間具有絞鏈半胱胺酸。製備這類抗體片段之方法（諸如木瓜蛋白酶或胃蛋白酶分解）爲熟習本技藝之人士所已知之方法。此處提供之抗體可固定補體（CDC)或活化抗體-倚賴性細胞毒性（ADCC)，尤其是IgGl抗體、藉由分子生物學從人類或哺乳動物來源之IgG2或IgG4或另一同型轉換之 IgGl變異體或從製造人類IgGl之老鼠全新製造。亦可使 -87- 200927761 用其他方法。此處提供之抗體有時可與標記基團或效應子基團偶合（例如：毒素、化療劑、報告子分子或造影劑）。 G.其他HB-EGF結合蛋白之類型於另一觀點中，此處提供之HB-EGF抗原結合蛋白爲一種具有似抗體結合活性（即，結合HB-EGF)之支架蛋白

在本發明之內容中，此處所使用之“支架蛋白”一詞意指對其修改摺疊作用（諸如多重插入、缺失或取代）具有高耐受性的多肽框構區。此內生性構造穩定性可使蛋白質在界定之區域內發生定點隨機化和激烈變化。如此，其可取得某些新穎性質，但其整體構造之完整性和原始之物化作用仍被保留。此重新採用之特性（大部分但並非絕對）包含對預先界定之標靶分子的結合特異性。

目前，使用之支架蛋白有非常多種，其係不同程度地模仿習知抗體之結合原則（Hey et al.，2005,7>e«心in 23: 514-2 2)。可根據本發明使用之支架蛋白的實例可次分爲不同組別。與抗體相關之支架蛋白係界定爲天然上尺寸較小或構造上較簡單之抗體衍生物或爲已以此方式經遺傳工程處理者。此組包括例如：稱爲奈米抗體者（回顧 Hey et al·，Trends in Biotechnol. 2005 ; 2 3 ( 10) ;514-522)，結構區抗體（Holt et al.，2003,7>e«心 21 : 484-489)或鯊魚抗原反應蛋白（Holt et al.， Trends in Biotechnol. 2003 ; 21 ; 484-489)。第二組支架 -88- 200927761 蛋白爲緊密之蛋白質摺疊物，其可容許單一環形多肽（如 Kunitz 型結構區）（Dennis et α /., 1 9 9 5 ； J. Biol. Cell. 270： 254 1 1 -254 1 7)、人類轉鐵蛋白（Ali ei a/.,1 999 ;«/.

Ce//. 274: 24066-24074)或半胱胺酸結結構模體（cystein- knot structural motives)(Ali et al. , 1999 ； J. Biol. Cell. 〇

274: 24066-24074)之插入或隨機化。類似於抗體之共享在嚴密保存之框構區上的數個高度可變環之構造的蛋白質之代表爲人 CTL A-4(Hufton et α/., 2 0 0 0 FEBS Lett. 475 : 225 -23 1 )、人纖維黏蛋白第HI型結構區（Koide ei ^/.,1998 ;«/.Mo/.以〇/· 284: 1 1 4 1 - 1 1 5 1 )、C型似凝集素結構區或脂質運載蛋白（lip〇calins)(Skerra，2001，*7. 5/oiec/i«o/· 74 : 25 7-27 5)。具有透過胺基酸殘基（其部分位於或完全位於蛋白質之緊密的二級構造中）而取得結合特異性之支架蛋白有，例如錨定蛋白（ankyrin)重覆蛋白質（Binz，2003,·/. Mo/. 5io/.3 3 2 : 489-503 ) ' 蛋白 A 之 Z 結構區（Nord ei ίζ/·，1995,Proie/» 五8 : 601-608)或 γ-結晶型（Fiedler and Rudolph, 2002, International Patent Application WO 0 1 /04 1 44)。支架蛋白和肽類以及其應用可在 Hey H «/.,2 0 0 5, Trends in Biot echnol. 23 : 5 1 4-5 22 ； Binz et a 1.,200 5， Nature Biotechnol. 23 : 1257-1268 )及 Holliger et aZ.,2005, Nature Biotechnol. 23 : 11261136 中檢；視。支架蛋白之遺傳工程處理可被視爲將親和力功能移植或整合至對於其摺疊修改具高度耐受性的多肽結構區之構造框構區上或構造框構區內。親和官能意指根據本發明之 -89- 200927761 蛋白結合親和力。支架蛋白可與提供結合特異性之胺基酸序列在構造上分開。一般而言，顯示出適合用於硏發這類人工親和試劑之蛋白質可藉由合理的，或最普遍之組合蛋白質遺傳工程處理技術來取得，諸如利用本技藝已知之技術，於活體外，在展示之人工支架蛋白庫中對抗原（如： HB-EGF，純蛋白質或顯示在細胞表面上之蛋白質）進行結合作用劑之淘選（Skerra, 2000，J.Mo/. 容· Jul-Aug; 13

(4 ) : 1 67-87 ; Binz and Pluckthun, 2005, Aug ； 16(4)

:45 9-69)。另外，具有似抗體結合活性之支架蛋白可自含有支架蛋白結構區之接受者多肽（如：前述蛋白質之一）衍生，其可移植一供給者多肽的結合結構區以將供給者多肽的結合特異性提供至含有該接受者多肽的支架蛋白結構區上。該插入之結合結構區可爲，如：抗體（尤其是HB-EGF 抗體）之一或多個互補決定區（CDR)。較佳地，該CDR爲 CD R3。插入時可藉由多種熟習本技藝之人士已知的方法（例如：多肽合成法、，編碼胺基酸之核酸合成法）以及熟習本技藝之人士熟知的不同形式之重組方法完成。 H. HB-EGF抗原結合蛋白結合物於另一較佳體系中，HB-EGF抗原結合蛋白（如：此處所提供之抗體）係與標記基團偶合。這類經標示之抗原結合蛋白特別適合用於診斷。此處所使用之“標記基團” 一詞係指可偵測之標記’如：經放射標示之胺基酸或可被經標示之抗生物素蛋白偵測之生物素部分（如：結合螢光 -90- 200927761 標記之抗生蛋白鏈菌素或可藉由光學或色度學方法偵測之酶活性）。本技藝已知多種不同用於標示多肽和糖蛋白（諸如抗體）之方法且可使用之。合適之標記基團包括，但不限於下列：放射同位素或放射核素（如：3H，14c，15N， 35s，9βγ’ 99Tc，^Ιη，1251，1311)、螢光基團（如：FITC 、若丹明、鑭系燐光體）、酶性基團（如：辣根過氧化酶、 β -半乳糖苷酶、螢光素酶、鹼性磷酸酶）、化學發光基團、 0 生物素基團或可被二級回報子（如：白胺酸拉鏈對序列、二級抗體之結合部位、金屬結合結構區、抗原決定部位標籤）辨識之預定的多肽抗原決定部位。於某些觀點中，將標記基團經由具不同長度之間隔子臂黏附以減少可能之立體遮蔽是較有利的。或者’此處提供之HB-EGF抗原結合蛋白（諸如抗體）可與效應子基團偶合。這類經效應子修改之抗原結合蛋白特別適合用於治療。此處所使用之“效應子基團” 一詞係 Q 指細胞毒性基團，諸如放射同位素或放射核素、毒素、治療基團或其他本技藝已知之效應子基團。合適之效應子基團的實例爲放射同位素或放射核素（如：3Η，14C，15Ν， 35S，9°Y，99Tc，，125Ι，131Ι)、加利車黴素、海兔毒素（dolastatin)類似物（諸如歐利史汀和化療劑（諸如苯醌安絲黴素和美他納辛衍生物，包括DM1)。於某些觀點中，將效應子基團經由具不同長度之間隔子臂黏附以減少可能之立體遮蔽是較有利的。亦如此處之描述，許多極有用的HB-EGF抗原結合蛋 200927761 白，如：此處提供之抗體製劑可辨識在HB-EGF之似EGF 結構區內的抗原決定部位，其包括，例如具下列序列之蛋白質殘基106-149 :

PCLRKYKDFCIHGECKYVKELRAPSCICHPGY HGERCHGLSLP (SEQ ID NO: 1 04 6)。於某些較佳體系中，可被此處提供之抗原結合蛋白辨識之表皮生長因子抗原決定部位包括胺基酸序列IHGE。因此，本發明提供可結合及辨識含有 IHGE之抗原決定部位及/或ΗΒ-EGF之似EGF結構區的抗體製劑，例如SEQ ID NO: 1046。〇抗HB-EGF抗原結合蛋白可用於偵測患者樣本中之 ΗΒ-EGF，因此，可作爲此文所描述之疾病狀態的診斷劑。另外，基於其顯著抑制HB-EGF及/或EGF受體活性之能力（如下列實例中所證明者），HB-EGF抗原結合蛋白於治療由HB-EGF之表現及/或HB-EGF之活性所造成的症狀及病況中具有療效。在特殊之較佳體系中，本發明之抗原結合蛋白和方法係關於因HB-EGF相關疾病、HER4相關疾病或EGF受體相關疾病狀態（例如：癌症病況）所產生之症狀的治療方法。其他較佳體系涉及使用此處所描述之抗原結合蛋白和方法來治療不欲有之血管新生、腫瘤疾病，諸如黑色素瘤、非小細胞肺癌、神經膠質瘤、肝細胞（肝）癌、甲狀腺癌、胃癌、攝護腺癌、乳癌、卵巢癌、膀胱癌、肺癌、膠質母細胞瘤、內膜癌、腎臟癌、結腸癌及胰臟癌。 -92- 200927761 I.編碼HB-EGF抗原結合蛋白之核酸本發明亦提供編碼此處所描述之抗原結合蛋白之核酸或其部分，包括編碼抗體之一或二種鏈或片段、衍生物、突變蛋白、或其變異體的核酸、編碼重鏈可變區或僅 CDRs之多核苷酸、足夠作爲雜合探針之多核苷酸、用於鑑定、分析、致突變或擴增編碼多肽之多核苷酸的PCR引物或定序引物、用於抑制多核苷酸之表現的反義核酸及前 0 述之互補序列。該核酸可爲任何長度。其長度可爲，例如 1 5 ， 10 ， 15 ， 20 ， 25 ， 30 ， 35 ， 40 ， 45 ， 50 ， 75 ， 100 ， 125 ， 150 ， 175 ， 200 ， 250 ， 300 ， 350 > 400 ， 450 ， 500 ， 750’ 1，000，1，500，3,000，5,000 或更多核苷酸，及 /或可包含一或多種額外序列，例如：調節序列及/或較大核酸（例如：載體）之一部分。該核酸可爲單股或雙股且可包含RNA及/或DNA核苷酸，及彼等之人工變異體（如：肽核酸）。第15A-15V圖描述多種不同抗原結合蛋白之輕鏈 ◎ 的核苷酸序列。第 16A-16AC圖描述多種不同抗原結合蛋白之重鏈的核苷酸序列。第13A-13M圖描述多種不同抗原結合蛋白之輕鏈可變區的核苷酸序列。第14A-14L圖描述多種不同抗原結合蛋白之重鏈可變區的核苷酸序列。第 18A-18F圖描述多種不同抗原結合蛋白之輕鏈可變區的 CDR區之核苷酸序列。第19A-19G圖描述多種不同抗原結合蛋白之重鏈可變區的CDR區之核苷酸序列。第20A-20K圖描述多種不同抗原結合蛋白之輕鏈可變區的FR區之核苷酸序列。第21 A-2 1K圖描述多種不同抗原結合蛋白 -93- 200927761 之重鏈可變區的FR區之核苷酸序列。第17A圖描述抗原結合蛋白之輕鏈恆定區的核苷酸序列。最後，第17B圖描述抗原結合蛋白之重鏈恆定區的核苷酸序列。編碼某些抗原結合蛋白或其部分（如：全長抗體、重鏈或輕鏈可變結構區或 CDRH1、CDRH2、CDRH3、 CDRL1、CDRL2或CDRL3)之核酸可自曾以HB-EGF或其致免疫片段免疫化之小鼠的B細胞分離出。該核酸可藉由習知程序（諸如聚合酶鏈反應（PCR))分離出。噬菌體展示爲另一種已知技術之實例，藉此可製備抗體衍生物及其他抗原結合蛋白。在一種方法中係將爲所欲之抗原結合蛋白的成分之多肽表現在任何合適之重組表現系統中且令表現之多肽可組合形成抗原結合蛋白分子。於另一觀點中係提供在特殊之雜合條件下與其他核酸 (如：包含第13至21圖中所描述之核酸序列的核酸）雜合之核酸。用於雜合核酸之方法爲本技藝所熟知。見，如：

Current Protocol in Molecular Biology, John Wiley & Sons，Ν·Υ. ( 1989) ,6.3.1-6.3.6。如此處所定義，中度嚴格之雜合條件係使用含有5x氯化鈉/檸檬酸鈉（SSC)、 0.5%SDS、l.OmM EDTA之預先清洗溶液（ρΗ8·0)、具約 5 0%甲醯胺、6xSSC之雜合緩衝劑和5 5 °C之雜合溫度（或其他類似之雜合溶液’諸如含有約50 %甲醯胺者及42。(：之雜合溫度）’以及在60°C，0.5xSSC、0.1%SDS中之清洗條件。嚴格之雜合條件係在45°C、6xSSC中雜合，再在68°C， 0-lxSSC、0.2%SDS中清洗一或多次。再者’熟習本技藝 -94- 200927761 之人士可操控雜合及/或清洗條件以增加或減少雜合嚴格性，如此，該包含彼此至少具有6 5 %、7 0 %、7 5 %、8 0 %、 8 5 %、9 0 %、9 5 %、9 8 %或9 9 %同一性之核苷酸序列的核酸通常會保持彼此雜合。影響雜合條件之選擇的基礎參數和設計合適條件之指導原貝II 列舉於，例如：Sambrook，Fristsch，and Maniatis ( 2001 ^Molecular Cloning : A Laboratory Manual， Cold

Spring Harbor Laboratory Press, Cold Spring Harbor， Ν·Υ·，同上及 Current Protocols in Molecular Biology， 1 995， Ausube 1 e t a/.?eds.,John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4中，且可輕易地由本技藝之一般技術人士根據，如核酸之長度及/或鹼基組成決定。藉由突變可將改變引入核酸中，以藉此造成其編碼之多肽（如：抗體或抗體衍生物）的胺基酸序列改變。突變可利用本技藝之任何已知技術引入。於一較佳體系中係利用，例如：定點突變計劃來改變一或多個特殊胺基酸殘基。於另一較佳體系中係利用，例如：隨機突變計劃來改變一或多個隨機選擇之殘基。然而，可表現出製作之突變種多肽並篩檢所需性之性質。突變可引入核酸中而不會顯著改變其編碼之多肽的生物活性。例如：個人可製造造成在非必須胺基酸殘基處之胺基酸取代的核苷酸取代。或者，可將一或多種選擇性改變由核酸編碼之多肽的生物活性的突變引入核酸中。例如 :突變可定量或定性地改變生物活性。定量變化之實例包 -95- 200927761 括增加、減少或排除活性。定性變化之實例包括改變抗體之抗原特異性。本發明之另一觀點提供適合作爲引物或雜合探針以供偵測核酸序列的核酸分子。核酸分子可僅包含一部分編碼全長多肽之核酸序列，例如：可作爲探針或引物之片段或編碼多肽之活性部分（如：HB-EGF結合部分）之片段。

以核酸序列爲基礎之探針可用於偵測該核酸或類似之核酸，例如：編碼多肽之轉錄子。探針可包含標記基團，例如：放射性同位素、螢光化合物、或酶、或酶輔助因子。這類探針可用來鑑定表現多肽之細胞。

本發明之另一觀點提供包含編碼多肽或其部分（如：含有一或多個CDRs或一或多個可變結構區之片段）之核酸的載體。載體之實例包括，但不限於：質體、病毒載體、非游離基因型（episomal)哺乳動物載體及表現載體，例如 :重組表現載體。重組表現載體中可包含爲適合在宿主細胞中表現該核酸之形式的核酸。重組表現載體包含一或多種調節序列，此調節序列係根據欲用於表現之宿主細胞選擇（此調節序列與欲表現之核酸序列係操作性連接）。調節序列包括那些可在多種類型之宿主細胞中直接組成性表現核苷酸序列者（如：SV40早期基因增强子、勞氏肉瘤（R0US Sarcoma)病毒啓動因子及巨細胞病毒啓動因子）、那些僅在某些宿主細胞中直接表現核苷酸序列者（如：組織特異性調節序列，見：Voss ei α/·，1986 Sc/. 11 :287,Maniatis et a/., 1 9 8 7, Science 236 : 1237，其全部內 -96- 200927761 容倂爲此文之參考資料）及那些於回應特殊之治療或病況時直接誘導性表現核苷酸序列者（如：哺乳動物細胞中之金屬硫蛋白啓動因子及在原核及真核系統中之tet-反應性及/或鏈黴素反應性啓動因子）（見，同上述）。熟習本技藝之人士可察知表現載體之設計可取決於欲轉形之宿主細胞的選擇、所需蛋白質之表現水準，等。表現載體可被引入宿主細胞中以藉此製造此處所描述之由核酸所編碼的蛋白 0 質或肽類（包括融合蛋白質或肽類）。本發明之另一種觀點係提供其中已引入重組表現載體之宿主細胞。宿主細胞可爲任何原核細胞（如：大腸桿菌）或真核細胞（例如：酵母、昆蟲或哺乳動物細胞（如CHO細胞））。載體DNA可經由習知之轉形或轉染技術被引入原核或真核細胞中。爲了穩定轉染哺乳動物細胞，已知根據所使用之表現載體及轉染技術，僅有小部分之細胞能將外來 DNA整合入其基因組中。爲了鑑定及選擇這些整合株，通 Q 常係將編碼可選擇之標記（如：對抗生素之抗性）的基因與所欲基因一起引入宿主細胞中。較佳之可選擇的標記包括那些提供對藥物（諸如G418、勻黴素和甲氨喋呤）之抗性者。在其他方法中，經引入之核酸穩定轉染之細胞可藉由藥物選擇進行鑑定（如：已倂入可選擇之標記基因的細胞可存活，但其他細胞死亡）。 J.用於診斷及治療目的之HB-EGF抗原結合蛋白的用途 -97- 200927761 1.指徵

此處所描述之HB-EGF抗原結合蛋白可用於偵測或治療多種疾病和病症，包括那些涉及過度細胞增生、不欲有之細胞移行及/或異常血管新生之疾病和病症。例如：這些HB-EGF抗原結合蛋白可抑制癌性細胞中由HB-EGF誘導之EGFR及/或HER4酪胺酸磷酸化的（第22-29圖）。這類抑制可中斷驅動細胞增生和移行以及血管新生之傳信的串連反應。再者，HB-EGF抗原結合蛋白可干擾EGFR之轉活化作用。另外，這些抗原結合蛋白抑制基礎HUVEC 〇細胞增殖（第3 2B圖）、內皮細胞脈管形成（第33圖）及活體內基質膠栓子分析中由HB-EGF誘導之血管形成（第36圖）。這些結果指出此處所描述之HB-EGF抗原結合蛋白在活體外及活體內抑制血管新生。再者，這些抗原結合蛋白亦抑制非固著依賴性細胞生長（第34圖及第35圖）和老鼠異體移植腫瘤之生長（第37圖及第38圖）。値得注意的， HB-EGF抗原結合蛋白亦抑制MCF-7和MDA-MB231癌細胞移行（見第27圖）。因此，此處所描述之HB-EGF抗原結合蛋白攻擊腫瘤及其他癌性病況進展中的數個步驟，包括控制細胞增殖、血管新生及與轉移癌之散佈及進展相關的細胞移行。這類多方面之介入治療對控制及抑制癌症之發展過程非常有利。再者，可治療在任何惡化階段之癌症（如：初期、轉移和復發之癌症）。 HB-EGF抗原結合蛋白除了可用於偵測及治療不同惡化階段之癌症中外’這些抗原結合蛋白亦可用於偵測數種 -98- 200927761 類型之癌症。例如：HB-EGF在正常乳房及胰臟組織中的表現水準很低。然而，HB-EGF在約55%之胰臟癌細胞和約70%之乳癌細胞中之表現水準高。再者，如實例中所描述者，在不同癌細胞株中可偵測到HB-EGF之表現，此表示此處所描述之HB-EGF抗原結合蛋白可用於偵測多種癌症類型。〇

例如：可藉由主張專利之抗原結合蛋白偵測或治療之癌症包括固態哺乳動物腫瘤以及血液學惡性疾病。固態哺乳動物腫瘤包括兒童癌症，諸如，例如：生殖細胞腫瘤、軟組織肉瘤、原發性腦瘤、神經母細胞瘤、腎母細胞瘤及癌症，尤其是鱗狀細胞癌及上皮癌。固態哺乳動物腫瘤亦可包括成人癌症，諸如，例如：未知來源之腫瘤、成人之原發性腦瘤、腦下垂體、唇、口腔、鼻咽、喉、上顎寶、篩竇、唾腺、甲狀腺（包括副甲狀腺及類癌）、食道、胃、胰臟、小腸、結腸、直腸、肛管、肝臟、膀胱、肝外膽管之腫瘤、瓦特壺腹之腫瘤、類癌、胃-腸-肝系統之內分泌腫瘤、嗜鉻細胞瘤及副神經節瘤、腎上腺、肺、胸膜、縱隔、胸腺之腫瘤、骨骼及軟組織之腫瘤、唇、眼皮、外耳、其他未具體指明之臉部部分之皮膚腫瘤、頭皮和頸、軀幹、上肢和肩、下肢和臀、外陰、龜頭、陰囊之腫瘤、乳房腫瘤、外陰、陰道、子宮頸、子宮體、卵巢、輸卵管之腫瘤、妊娠和滋養層腫瘤、龜頭、攝護腺、睪九、腎臟、腎盂及輸尿管、膀胱、尿道之腫瘤、眼皮、結膜、葡萄膜、視網膜、眼球和淚腺之眼科腫瘤。血液學惡性疾病包括 -99- 200927761 兒童期之疾病，例如：白血病和淋巴瘤、急性和慢性白血病（AML、ANLL、ALL、CML、MDS)、何杰金氏症、B-細胞、T-細胞、大細胞、濾泡性、淋巴來源及皮膚來源之無痛/低度惡性、侵襲性/高度惡性淋巴瘤、漿細胞惡性腫瘤和與AIDS相關之癌症。 o

另外，此處所描述之HB-EGF抗原結合蛋白亦可用來偵測或治療癌性病況或腫瘤疾病，其包括，例如：腺瘤、管狀絨毛腺瘤、絨毛腺瘤、血管纖維瘤、非典型增生性黏液瘤、勃勒納（Brenner)腫瘤、類癌、海綿狀血管瘤、細胞性平滑肌瘤、絨毛膜血管瘤、先天性中胚層腎瘤、黏液性囊腺瘤、漿液性囊腺瘤、皮樣囊腫、硬纖維瘤、纖維腺瘤、纖維瘤、纖維卵巢膜瘤、瀘泡腺瘤、神經節細胞瘤、巨細胞瘤、顆粒細胞瘤、粒細胞瘤、血管瘤、乳腺導管內乳頭瘤、島狀細胞瘤、平滑肌瘤、脂肪瘤、黃體瘤、腦膜瘤、痣、髓質脂肪瘤、黏液瘤、神經纖維瘤、痣、骨軟骨瘤、嗜鉻細胞瘤、息肉症、神經鞘瘤、漿液性囊腺癌、卵巢甲狀腺腫、滑膜骨軟骨瘤、良性胸腺瘤。其他可藉由此處所描述之HB-EGF蛋白質偵測或治療之癌症類型的實例可從，例如：Am erican Cancer Society (WWW.cancer.org )或從 Wilson et al. ( 1991 ) H a r r i s ο n s P r i n c i p 1 e s 〇 f I n t e r n a 1 M e d i c i n e，1 21h E d i t i ο n，

McGraw-Hill，Inc 找到。因此’此處所描述之HB-EGF抗原結合蛋白可用於治療及/或預防癌症、癌性病況、腫瘤生長、癌細胞轉移、 -100- 200927761 血管新生過程及/或腫瘤疾病。因此，這些抗原結合蛋白提供治療或預防個體內癌症之方法，其涉及投給個體有效量之含有一種如此處所描述之人及/或單株HB-EGF抗原結合蛋白製劑或其組合的組成物。 Ο

很高比例之固態腫瘤疾病通常具有腫瘤血管新生（此爲腫瘤組織中由生長因子（即，VEGF)和其他因子（即，HB-EGF)促成之（異常）血管過度生長）的特徵。透過HB-EGF特異性抗原結合蛋白來瞄準HB-EGF可預防新血管形成，因此可限制現存之腫瘤的擴增及新腫瘤之發展（即，轉移）。除了其作爲促有絲分裂及前入侵配體的角色外，數種硏究證實HB-EGF爲癌症之血管新生過程中的重要調節子。如實例中之說明，HB-EGF顯示出具有在活體中調節血管新生之功能。因此，此處所描述之抗原結合蛋白可用於治療與血管新生相關或由其引起之疾病，如：癌性或非癌性疾病。例如：此處所描述之HB-EGF抗原結合蛋白可干擾平滑肌細胞（SMCs)和內皮細胞間之聯繫（此爲血管新生（如：腫瘤血管新生）過程中血管發展及作用的基礎過程）。再者，這些抗原結合蛋白可至少部分抑制由HB-EGF 誘導之VEGF表現及VEGF自SMCs釋出，此接著可作爲有效之內皮有絲分裂原。類似地，VEGF增加內皮細胞中 HB-EGF之產製，如此，可構成由這二種重要配體所組成之促血管新生反饋環，而此環可經由投服此處所描述之 HB-EGF抗原結合蛋白分裂。最近，除了 VEGF外，另外 -101 - 200927761 〇鑑定出其他關鍵之促血管新生組成分，諸如促血管新生素 1和2(Ang-l和2)和其受體TIE-2以及強力平滑肌細胞 GPCR刺激劑血管緊張素II (AT Π )。有趣的是，HB-EGF爲由 ΑΤΠ誘導之EGFR轉活化以及內皮細胞中 VEGF和 Ang-2下游上調作用的關鍵傳介子。活體中，ΑΤΠ以HB-EGF倚賴性方式誘導血管新生並增強VEGF之血管新生活性。這些發現支持HB-EGF與VEGF同樣可活化經由Ang2 之其他血管新生途徑。因此，哺乳動物中異常之血管新生或癌症可藉由投服有效量之此處所描述的HB-EGF抗原結合蛋白來治療。除了其作爲癌症中血管新生過程之重要調節成分外， HB-EGF抗原結合蛋白療法之推定疾病領域爲具有活化之血管新生途徑的不同非癌症指徵以及側支血流之需求。

慢性發炎疾病（如：腎炎、COPD、發炎性腸病），包括由免疫系統傳介之“發炎反應”（如：移植物對抗宿主之疾病、移植排斥、再狹窄）、代謝疾病（如：糖尿病）或慢性缺氧性病況的特徵通常爲高度-及/或新生血管化（如：慢性潰瘍）。此處所描述之HB-EGF抗原結合蛋白可至少部分抑制血管新生之必要過程-藉由HB-EGF(其係由發炎細胞產製或由低氧來上調）誘導內皮細胞來補充血管平滑肌細胞-因此’其代表一種用於過度/病態血管化之具吸引力的介入療法。在肥胖之個體中，由累積之脂肪（其造成肥胖個體中血管疾病之發病率較高）導致的HB-EGF水準增加可藉由 -102- 200927761 此處所描述之HB-EGF抗原結合蛋白中和。因此，以HB-EGF抗原結合蛋白進行之治療性介入可直接作爲中斷脂質血管軸中的抗脂肪細胞因子。 HB-EGF在纖維母細胞中經由活化表皮生長因子受體可顯著向下調節彈力蛋白mRNA。此作用提供在肺部纖維化進展中之介入途徑。

再者，HB-EGF爲涉及發炎疾病病變之角質細胞的有絲分裂原。另外，HB-EGF之表現及與EGFR共位可能在牛皮癬之早期病變中扮演重要角色，此開啓了治療皮膚發炎疾病的可能治療窗，特別是可以主張專利之抗原結合蛋白來早期治療牛皮癖。以此處所描述之之抗原結合蛋白瞄準HB-EGF亦可產生一種用於治療罹患增生性玻璃視網膜病變（PVR)之患者的治療選擇，因PVR之形成亦伴隨著PVR視網膜中HB-EGF明顯上調。另外，HB-EGF表現在纖維增殖組織中以及其對神經膠細胞之增殖、趨化現象和VEGF分泌的刺激效果指出HB-EGF可能爲PVR期間促成神經膠細胞反應的因子。這些原理亦可應用至其他血管新生倚賴性之眼疾中，諸如老年性和非老年性黃斑部病變、糖尿病性視網膜病變、虹膜新生血管性青光眼、角膜間質炎、早熟及角膜移植失敗之視網膜病變。 GPCRs，諸如腎上腺素受體和血管緊張素受體與高血壓之致病性有關，因其有血管收縮及生長促進力。由於 HB-EGF爲這些通路之關鍵傳介子，中和性抗原結合蛋白 -103- 200927761 適合用於高血壓病（諸如心臟肥大和充血性心臟衰竭、腎衰竭或中風）的瞄準介入。 HB-EGF (此爲平滑肌細胞（SMCs)之強力有絲分裂原和趨化因子）可在動脈內膜增厚之冠狀動脈的動脈粥狀硬化斑塊中偵測到且可由SMCs及巨噬細胞製造。殘餘之脂蛋白（其爲已知之動脈粥狀硬化的產生原因）進一步顯示出可經由HB-EGF所促成之EGFR轉活化來誘導SMC增殖。因此，此處所描述之HB-EGF抗原結合蛋白代表藉由阻斷關鍵之平滑肌細胞功能來瞄準動脈粥狀硬化症之可選擇且有效的作用劑。另外，亦可藉由HB-EGF功能之特殊中和作用來預防在經皮冠狀動脈介入治療干預後發生的再狹窄（其特徵爲平滑肌細胞增殖）。因此，此處所描述之HB-EGF抗原結合蛋白可用於用於治療多種不同疾病，包括非惡性增生疾病，諸如異常之血管新生、肌瘤（子宮纖維化）、良性平滑肌細胞腫瘤、腎絲球硬化症（系膜細胞之過度增生）、平滑肌細胞肥大、動脈粥狀硬化症（血管平滑肌細胞之過度增生）、虹膜紅變；新生血管性青光眼、糖尿病性視網膜病變、糖尿病性眼盲、黃斑部病變、類風濕性關節炎、心臟肥大、牛皮癬，等〇於另一觀點中，HB-EGF抗原結合蛋白可用於治療與經擾亂（如：病態增強）之生長因子受體活化有關或伴隨經擾亂（如：病態增強）之生長因子受體活化的病症。於另一觀點中，此增強之生長因子受體活化作用可能 -104- 200927761

Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn 565 570 575

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala 625 630 635 640

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr -824- 200927761 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly 725 730 735

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765 ❹

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815 〇

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860 -825 - 200927761

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala 865 870 875 880

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala 930 935 940

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala 980 985 990

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn -826- 200927761 1010 1015 1020

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1025 1030 1035

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1040 1045 1050

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1055 1060 1065

O

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1070 1075 1080

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1085 1090 1095

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1100 1105 1110 〇

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1115 1120 1125

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1130 1135 1140

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1145 1150 1155 -827- 200927761

Ala Ala 1160

Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1165 1170

Cys Cys 1175

Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1180 1185

Trp Ser 1190

Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1195 1200

Thr Thr 1205

Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1210 1215

Met Thr 1220

Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1225 1230

Trp Ser 1235

Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1240 1245

Gly Gly 1250

Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1255 1260

Thr Gly 1265

Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1270 1275

Gly Ala 1280

Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1285 1290

Cys Ala

Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg -828 - 200927761 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330

<210〉 585 <211> 1323 <212〉 PRT <213〉現代人 <400〉 585

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80 829- 200927761

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Trp Ser Asn Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240 -830- 200927761

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285 ❹

Gly Cys Asn Met Gly Asn Ala Ala Tyr Met Thr Asn Cys Cys Asn Thr 290 295 300

Thr Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala 305 310 315 320

Arg Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn 325 330 335

Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala 340 345 350

Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr 355 360 365

Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn 370 375 380 -831 - 200927761

Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp 385 390 395 400

Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys 405 410 415

Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 420 425 430

Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly 435 440 445

Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser 450 455 460

Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn 465 470 475 480

Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys 485 490 495

Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr 500 505 510

Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn 515 520 525

Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540 ' -832- 200927761

Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys 545 550 555 560

Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn 565 570 575

Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr 580 585 590 〇

Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala 595 600 605

Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg 610 615 620

Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly 625 630 635 640

Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr 645 650 655

Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr 660 665 670

Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly 675 680 685 - 833 - 200927761

與G蛋白及/或與G蛋白偶合之受體的活性病態增加有關或係由彼等引起。應注意的是，與經擾亂（如：病態增強）之生長因子受體活化有關或伴隨經擾亂（如：病態增強）之生長因子受體活化，且可能與G蛋白及/或與G蛋白偶合之受體的活性病態增加有關或係由彼等引起的病症可與其他那些其特徵爲在經由與G蛋白偶合之受體發生的生長因子受體轉活化作用中生長因子受體活化作用之活性增強的病症區分清楚。 2.診斷方法此處所描述之HB-EGF抗原結合分子可用於用來偵測試驗樣本中之癌細胞的方法中，此方法包含將試驗樣本與抗原結合分子接觸並測定該抗體是否結合樣本中表現 proHB-EGF或Η B - E G F分子之細胞。結合程度可利用對照樣本評估。試驗和對照樣本可爲，如：血液、血清、腹水 Q 、肋膜積液、腦脊髓液、組織、細胞、尿、淋巴、唾液、乳汁或其他樣本。這類對照樣本可爲流體或組織或細胞類型之非癌性樣本。於某些較佳體系中，該對照樣本可爲取自與試驗樣本相同之個體的非癌性樣本。“個體”或“患者”係指需要治療或偵測病況、病症或疾病之哺乳動物，宜爲人。抗體與試驗樣本之成分的結合情形可藉由偵測經結合之報告分子、造影劑或標示來測得或可選擇性地結合此處所描述之抗原結合蛋白來進行偵測。這些HB-EGF抗原結 -105- 200927761

Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr 690 695 700

Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg 705 710 715 720

Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala 725 730 735

Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys 740 745 750

Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn 755 760 765

Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys 770 775 780

Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr 785 790 795 800

Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr 805 810 815

Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly 820 825 830

Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys 835 840 845 - 834- 200927761

Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 850 855 860

Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr 865 870 875 880

Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr 885 890 895 ❹

Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr 900 905 910

Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly 915 920 925

Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly 930 935 940

Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg 945 950 955 960

Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala 965 970 975

Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser 980 985 990 -835 200927761

Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 995 1000 1005

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1010 1015 1020

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1025 1030 1035

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1040 1045 1050

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1055 1060 1065

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1070 1075 1080

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1085 1090 1095

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1100 1105 1110

Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1115 1120 1125

Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1130 1135 1140 -836- 200927761

Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr 1145 1150 1155

Ala Ala Arg

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn 1160 1165 1170

Ala Thr Gly

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr 1175 1180 1185

Gly Gly Asn 0 Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn 1190 1195 1200

Thr Ala Tyr

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn 1205 1210 1215

Gly Thr Asn

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn 1220 1225 1230

Thr Gly Gly

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr 1235 1240 1245

Gly Thr Asn

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn 1250 1255 1260

Met Thr Asn

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn 1265 1270 1275 -837- 200927761

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1280 1285 1290

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1295 1300 1305

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1310 1315 1320 <210〉 586 <211> 1347 <212> PRT <213〉現代人 <400> 586

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80 - 838 - 200927761

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Gly Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Cys Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Ala Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn O 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Gly 195 200 205

Thr Asn Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Thr Tyr -839- 200927761 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Trp Ser Asn Cys Ala Tyr Thr Ala Tyr Gly 290 295 300

Gly Asn Gly Gly Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 325 330 335

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala 340 345 350

Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser 355 360 365

Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn 370 375 380 -840- 200927761

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met 385 390 395 400

Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly 405 410 415

Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn 420 425 430

Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr 435 440 445

Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala 450 455 460

Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn 465 470 475 480

Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp 485 490 495

Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser 500 505 510

Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr 515 520 525

Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp -841 - 200927761 530 535 540

Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser 545 550 555 560

Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn 565 570 575

Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala 580 585 590

Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys 595 600 605

Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn 610 615 620

Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala 625 630 635 640

Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala 645 650 655

Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg 660 665 670

Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys 675 680 685 -842- 200927761

Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys 690 695 700

Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn 705 710 715 720

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys 725 730 735

Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala 740 745 750

Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn 755 760 765

Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala 770 775 780

Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala 785 790 795 800

Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr 805 810 815

Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala 820 825 830

Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly -843 - 200927761 合蛋白可具有一或多個報告子分子、標示或造影劑。報告子分子之定義爲可利用分析偵測之任何部分。曾用於與抗體結合之報告子分子的非限制性實例包括酶、放射標示、半抗原、螢光標示、磷光分子、化學發光分子、發色團、發光分子、光親和分子、染色粒或配體（諸如生物素）。報告分子可提供可偵測之信號。例如：該可偵測之信號可爲螢光、磷光、化學發光、電化學發光、電化學、顏色變化或酶性信號。如第39圖所示，此處所提供之抗HB-EGF 抗體可作爲用於組織樣本之以ELISA爲基礎的生長因子偵測法或免疫化學分析中的捕捉抗體。於某些較佳體系中，該報告分子係與此處所描述之抗原結合蛋白共價結合。於其他較佳體系中，報告分子可選擇性地結合此處所描述之HB-EGF抗原結合蛋白。這類報告分子與此處所描述之抗原結合蛋白的選擇性結合可藉由 —帶有與其共價結合之標示的二級抗體達成，其中該二級抗體選擇性地結合此處所描述之HB-EGF抗原結合蛋白。 3.治療方法：藥學配方，投服途徑癌症之治療或治療癌症係欲包含緩和或消除至少一種通常與該疾病有關之症狀。該治療法亦包括緩和或消除超過一種該相關之症狀。該治療法可治癒癌症，如：其可實質上排除癌症細胞及/或遏制癌性腫瘤之生長。或者，治療可減緩癌症惡化。抗癌活性可利用熟習本技藝之人士可用之方法對多種 -106- 200927761 835 840 845

Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr 850 855 860

Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met 865 870 875 880

Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala 885 890 895

Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn 900 905 910

Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly 915 920 925

Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly 930 935 940

Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg 945 950 955 960

Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp 965 970 975

Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys 980 985 990 -844- 200927761

Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg 995 1000 1005

Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 1010 1015 1020

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1025 1030 1035

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1040 1045 1050

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1055 1060 1065

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1070 1075 1080

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 〇 1085 1090 1095

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1100 1105 1110

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1115 1120 1125

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn -845 - 200927761 1130 1135 1140

Gly Ala 1145

Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1150 1155

Gly Gly 1160

Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1165 1170

Ala Ala 1175

Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1180 1185

Cys Cys 1190

Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1195 1200

Trp Ser 1205

Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1210 1215

Thr Thr 1220

Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1225 1230

Met Thr 1235

Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1240 1245

Trp Ser 1250

Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1255 1260

Gly Gly 1265

Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1270 1275 -846- 200927761

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1280 1285 1290

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1295 1300 1305

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1310 1315 1320

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345 <210> 587 <211> 1338 <212〉 PRT <213〉現代人 <400〉 587

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45 -847- 200927761

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120' 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Met Gly 165 170 175

Asn Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190 -848 - 200927761

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Tyr Gly Gly Asn Thr Gly Gly Cys 290 295 300 ❹

Ala Arg Cys Ala Arg Cys Ala Arg Gly Cys Asn Cys Cys Asn Thr Thr 305 310 315 320

Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly 340 345 350 -849- 200927761

Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys 355 360 365

Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn 370 375 380

Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr 385 390 395 400

Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser 405 410 415

Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn 420 425 430

Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala 435 440 445

Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala 450 455 460

Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn 465 470 475 480

Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met 485 490 495 -850- 200927761

Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala 500 505 510

Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn 515 520 525

Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met 530 535 540

Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser 0 545 550 555 560

Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn 565 570 575

Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala 580 585 590

Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly 595 600 605

Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg 610 615 620

Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly 625 630 635 640

Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala 645 650 655 -851 - 200927761

Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn 660 665 670

Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys 675 680 685

Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys 690 695 700

Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr 705 710 715 720

Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys 725 730 735

Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr 740 745 750

Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn 755 760 765

Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly 770 775 780

Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala 785 790 795 800 -852 200927761

Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn 805 810 815

Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly 820 825 830

Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr 835 840 845

Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn 850 855 860

Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys 865 870 875 880

Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr 885 890 895

Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn 900 905 910

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys 915 920 925

Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly 930 935 940

Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr 945 950 955 960 - 853 - 200927761 不同之癌症或癌細胞進行評估。例如：抗癌活性可經由鑑定此處所描述之預防癌症生長的抗原結合蛋白製劑之 LD1Q()或ED5Q來測定。於一較佳體系中，抗癌活性爲當利用標準劑量反應法測量時殺死50%或100%癌細胞時所使用之抗體量。此處所描述之HB-EGF抗原結合蛋白可單獨投服或與抗體、化療藥物或放射療法一起投給。根據本發明之醫藥 0 組成物可以單一療法之形式或與另一醫藥組成物（宜包含另一抗腫瘤劑，尤其是順鈿或癌思停）組合投服。例如：此處所描述之HB-EGF抗原結合蛋白可與抗腫瘤抗體（如 :嵌合型、人化或人抗腫瘤抗體）一起投服、與特異結合 VEGF以進一步抑制腫瘤血管新生之抗體一起投服、或與特異結合受體酪胺酸激酶（諸如HER2、HER4或EGFR)以進一步抑制腫瘤細胞增殖之抗體一起投服。在第38圖中，抗EGFR抗體與抗HB-EGF抗體均顯示出對二種測試之 Q 治療性抗HB-EGF抗體的協同效果。再者，此處所描述之 HB-EGF抗原結合蛋白可與其他抗腫瘤劑共同投服。可與此處提供之抗體共同投服之抗腫瘤劑的特殊實例包括，例如：傑非提尼（gefitinib)、拉巴提尼（lapatinib)、速尼提尼 (sunitinib)、派美特西（pemetrexed)、貝華西適美 (bevacisumab)、塞突西美（cetuximab)、伊美提尼 (imatinib)、特托如美（trastuzumab)、艾倫托如美 (alemtuzumab)、利托西美（rituximab)、爾洛提尼 (erlotinib)、玻柔美（bortezomib)，等。可抑制癌症或腫瘤 -107- 200927761

Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly 965 970 975

Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr 980 985 990

His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 995 1000 1005

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1010 1015 1020

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1025 1030 1035

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1040 1045 1050

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1055 1060 1065

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1070 1075 1080

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1085 1090 1095 -854- 200927761

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1100 1105 1110

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1115 1120 1125

Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1130 1135 1140

Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1145 1150 1155

Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1160 1165 1170

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1175 1180 1185

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1190 1195 1200

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1205 1210 1215

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1220 1225 1230

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1235 1240 1245 - 855 - 200927761

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1250 1255 1260

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1265 1270 1275

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1280 1285 1290

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1295 1300 1305

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 1335 <210〉 588 <211> 1332 <212> PRT <213〉現代人 <400> 588

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr -856- 200927761 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

O

Tyr Ala Cys Asn Thr Thr Tyr Met Gly Asn Trp Ser Asn Cys Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125 〇

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Ala Ala 165 170 175 -857- 200927761

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Met Gly Asn Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Gly Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Thr Gly Gly Gly Gly Asn Ala Thr His Trp 290 295 300

Ser Asn Gly Cys Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Gly 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn - 858- 200927761 325 330 335

Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380 〇

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn 420 425 430 〇

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480 -859- 200927761

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560

Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn 565 570 575

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala -860- 200927761 625 630 635 640

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685 o

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly 725 730 735 ❹

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780 -861 - 200927761

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala 865 870 875 880

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala -862- 200927761 930 935 940

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala 980 985 990

O

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1010 1015 1020

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1025 1030 1035 ❹

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1040 1045 1050

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1055 1060 1065

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1070 1075 1080 - 863 - 200927761

細胞增殖之任何其他抗癌劑或藥物亦可用於此處所描述和主張專利之組成物中。例如：主張專利之組成物可包含化療劑，諸如截瘤達（capecitabine)、柔紅黴素 (daunorubicin)、柔毛黴素（daunomycin)、更生黴素 (dactinomycin)、多柔比星（doxorubicin)、泛艾比星 (epirubicin)、依達比星（idarubicin)、衣索比星 (esorubicin)、博來黴素（bleomycin)、馬磷酿胺 (mafosfamide)、異環磷醯胺（ifosfamide)、胞喃陡阿拉伯糖苷、雙-氯乙基亞硝基脲、白消安（busulfan)、絲裂黴素 C(mitomycin C)、放線菌素 D、光輝黴素（mithramycin)、潑的尼松、經基黃體素、睪固酮、它莫西芬（tamoxifen)、達卡巴嗪（dacarbazine)、甲基干肼（procarbazine)、六甲基三聚氰胺（hexamethylmelamine)、五甲基三聚氰胺 (pentamethylmelamine)、米托恵醌（mitoxantrone)、'安吖陡 (amsacrine)、苯丁酸氮芥（chlorambucil)、甲基環己基亞硝基脲、氮芥、美法侖（melphalan)、環磷醯胺 (cyclophosphamide)、6-锍基嘌呤、6-硫鳥嘌呤、阿糖胞苷 (CA)、5_氮雜胞苷、羥基脲、去氧助間型黴素 (deoxycoformycin)、4-羥基過氧基環磷醯胺、5-氟尿嘧啶 (5-FU)、5-氟去氧尿嘧啶（5-FUdR)、氨甲喋呤（MTX)、秋水仙素、紫杉醇、長春新鹼、長春花鹼、依托泊苷 (etoposide)、三甲曲沙（trimetrexate)、替尼泊苷 (teniposide)、順鉑、癌思停及己烯雌酚 (diethylstilbestrol)(DES)。大致上，見 The Merck Manual -108- 200927761

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1085 1090 1095

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1100 1105 1110

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1115 1120 1125

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1130 1135 1140

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1145 1150 1155

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1160 1165 1170

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1175 1180 1185

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1190 1195 1200

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1205 1210 1215

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg -864- 200927761 1220 1225 1230

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1235 1240 1245

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1250 1255 1260

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1265 1270 1275

O

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1280 1285 1290

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320 ❹

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 <210〉 589 <211> 1323 <212> PRT <213>現代人 <400> 589 -865 - 200927761

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Gly Cys Asn Thr Ala Tyr 85 90 95

Trp Ser Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Thr Ala Tyr Ala Thr His Trp Ser Asn Trp Ser Asn Trp 145 150 155 160 -866- 200927761

Ser Asn Gly Gly Asn Met Gly Asn Ala Cys Asn Ala Thr His Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

O

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Trp Ser Asn Met Thr Asn Thr Thr Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Ala Tyr Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Thr Asn Thr Gly Gly Gly Cys Asn Cys Cys Asn Thr 290 295 300 -867 - 200927761

Thr Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala 305 310 315 320

Arg Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn 325 330 335

Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala 340 345 350

Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr 355 360 365

Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn 370 375 380

Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp 385 390 395 400

Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys 405 410 415

Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 420 425 430

Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly 435 440 445

Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser 450 455 460 - 868 - 200927761

Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn 465 470 475 480

Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys 485 490 495

Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr 500 505 510

Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn 515 520 525

Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540

Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys 545 550 555 560

Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn 565 570 575

Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr 580 585 590

Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala 595 600 605 -869 - 200927761

Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg 610 615 620

Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly 625 630 635 640

Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr 645 650 655

Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr 660 665 670

Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly 675 680 685

Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr 690 695 700

Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg 705 710 715 720

Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala 725 730 735

Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys 740 745 750

Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn 755 760 765 -870- 200927761

Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys 770 775 780

Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr 785 790 795 800

Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr 805 810 815 ❹

Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly 820 825 830

Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys 835 840 845

Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 850 855 860

Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr 865 870 875 880

Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr 885 890 895

Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr 900 905 910 871 - 200927761

Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly 915 920 925

Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly 930 935 940

Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg 945 950 955 960

Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala 965 970 975

Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser 980 985 990

Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 995 1000 1005

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1010 1015 1020

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1025 1030 1035

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1040 1045 1050

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1055 1060 1065 -872- 200927761

Gly Thr 1070

Met Thr 1085

Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1075 1080

Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1090 1095

Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1105 1110

Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1120 1125

Thr Ala 1100 〇 Gly Cys 1115

Trp Ser 1130

Gly Ala 1145 Ala Cys 1160

Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1135 1140

Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1150 1155

Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1165 1170

Met Thr 1175

Trp Ser 1190

Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1180 1185

Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1195 1200 -873 - 200927761 of Diagnosis and Therapy, 15 th Ed· 1 9 8 7, pp. 1 206- 1228,Berkow er αΛ,Rahway，N.J。當與此處所描述之 HB-EGF抗原結合蛋白（諸如化療劑）一起使用時，可將其個別使用（如：5-FU及一種抗體）、依序使用（如：使用5-FU和一種抗體一段時間後再使用MTX和一種抗體），或與一或多種其他這類化療劑（如：5-FU、MTX和一種抗體，或5-FU、放射療法和一種抗體）組合使用。

本發明亦提供評估具有此處所揭示之胺基酸序列的抗體於治療癌症之治療上有效劑量的方法，其包含在活體內或活體外測定HB-EGF抗原結合蛋白製劑之LD1G()或ED50 。這類方法可計算抑制約1 0 %至1 0 0 %、或約2 0 %至1 0 0 % 、或約 25%至 100%、或約 30%至 100%、或約 40%至 100%、或約50%至100%癌症細胞生長或轉移時每一體積需要之抗原結合蛋白的約略量。於某些較佳體系中可觀察到癌症細胞之生長或轉移少於 1 0 0 %。例如：可抑制約 90%、8 0%、70%、60%或50%之癌症細胞生長及/或轉移。抑制百分比可’例如：經由將抗原結合蛋白製劑投至本技藝中可取得之SCID或nu/nu小鼠（其中已引入腫瘤細胞）中及/或藉由標準方法利用培養之癌細胞來進行測定（見，第38B圖）。實例中描述數種方法。本發明亦包括含有此處所描述之可用於治療疾病（包括’例如：癌症及7或異常血管新生）的HB-EGF抗原結合蛋白之無菌醫藥組成物。這類配方可抑制HB-EGF與其受體（如：EGFR或HER4)結合，以藉此有效地抑制其中，如 -109- 200927761

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1205 1210 1215

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1220 1225 1230

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1235 1240 1245

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1250 1255 1260

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1265 1270 1275

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1280 1285 1290

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1295 1300 1305

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1310 1315 1320 <210〉 590 <211> 1353 <212〉 PRT <213〉現代人 <400〉 590 -874- 200927761

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Trp Ser Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Cys Ala Tyr Ala Thr His Trp Ser Asn Trp Ser Asn Trp - 875- 200927761 145 150 155 160

Ser Asn Trp Ser Asn Met Gly Asn Ala Cys Asn Ala Thr His Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Trp Ser Asn Gly Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Ala Tyr Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Ala 290 295 300 -876 - 200927761

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Gly Asn Gly Gly Asn Gly Gly 305 310 315 320

Asn Ala Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 325 330 335

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Ala Cys Asn Ala Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn 370 375 380

Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr 385 390 395 400

Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly 405 410 415

Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn 420 425 430

Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met 435 440 445

Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala -877- 200927761 450 455 460

Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg 465 470 475 480

Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr 485 490 495

Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr 500 505 510

Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr 515 520 525

Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met 530 535 540

Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr 545 550 555 560

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 565 570 575

Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp 580 585 590

Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys 595 600 605 878- 200927761

Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr 610 615 620

Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys 625 630 635 640

Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr 645 650 655

Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg 660 665 670

Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly 675 680 685

Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys 690 695 700

Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn 705 710 715 720

Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met 725 730 735

Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys 740 745 750

Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly -879- 200927761 755 760 765

Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly 770 775 780

Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr 785 790 795 800

Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr 805 810 815

Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys 820 825 830

Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr 835 840 845

Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn 850 855 860

Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala 865 870 875 880

Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala 885 890 895

Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr 900 905 910 880 200927761

Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met 915 920 925

Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala 930 935 940

Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn 945 950 955 960

Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala 965 970 975

Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly 980 985 990

Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His 995 1000 1005

Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 1010 1015 1020

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1025 1030 1035

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1040 1045 1050

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn -881 - 200927761 1055 1060 1065

Cys Cys 1070

Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1075 1080

Ala Thr 1085

Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1090 1095

Gly Thr 1100

Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1105 1110

Met Thr 1115

Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1120 1125

Thr Ala 1130

Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1135 1140

Gly Cys 1145

Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1150 1155

Trp Ser 1160

Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1165 1170

Gly Ala 1175

Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1180 1185

Ala Cys 1190

Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1195 1200 -882- 200927761

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1205 1210 1215

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1220 1225 1230

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1235 1240 1245

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1250 1255 1260

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1265 1270 1275

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1280 1285 1290

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1295 1300 1305

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1310 1315 1320

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg - 883 - 200927761 :血清、細胞性或組織ηβ-egf異常升高或其中其受體（如：EGFR或HER4)異常活躍之病況。如此處所說明，HB-EGF抗原結合蛋白擁有適當之親和力以強力中和HB-EGF 並調節與ΗΒ-EGF受體相關之傳信。

此處所描述之ΗΒ-EGF抗原結合蛋白宜爲人化之抗原結合蛋白。投服這些人化抗原結合蛋白可降低負面副作用之可能性。再者，這些抗原結合蛋白因爲，例如：被視爲正常人類產物而在活體中穩定，因此，可將免疫系統反應之風險降至最低。再者，這些抗原結合蛋白並不容易被蛋白質水解破壞，因而可改良其循環半生期。因此，此處所描述之ΗΒ-EGF製劑在活體中具有優秀之半生期因此可較不必如此頻繁地投給人們。這類延長之作用期可經由改換腸胃道外途徑（諸如皮下或肌肉內注射）投服而容許較不頻繁且更方便之給藥時間表。

在將抗體凍乾前或重構成後經由，如：通過無菌濾膜過濾可製造無菌配方.。此處所描述之抗原結合蛋白通常係以凍乾形式或在溶液中貯存。治療性抗體組成物通常係置於具有無菌出入口之容器中，例如：置於具有可供取回配方之接合器（諸如可以皮下注射針穿破之塞子）的靜脈內溶液袋或小玻璃瓶中。 ΗΒ-EGF抗原結合蛋白之投服途徑係根據已知方法，如：藉由靜脈內、皮下、皮內、腹膜內、腦內、肌肉內、眼內、動脈內、鞘內、膀胱內、孔內、吸入、疾病部位內等途徑注射或注入’或藉由如下述之持續釋出系統投服。 200927761 1340 1345 1350 <210> 591 <211> 1353 <212〉 PRT <213>現代人 <400〉 591

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Trp Ser Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110 -884- 200927761

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Cys Ala Tyr Ala Thr His Trp Ser Asn Met Gly Asn Trp 145 150 155 160

Ser Asn Trp Ser Asn Met Gly Asn Ala Cys Asn Ala Thr His Thr Ala © 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Trp Ser Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Ala Tyr Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270 - 885 - 200927761

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Ala 290 295 300

Ala Tyr Thr Gly Gly Ala Ala Tyr Ala Ala Tyr Gly Gly Asn Gly Gly 305 310 315 320

Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 325 330 335

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Ala Cys Asn Ala Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn 370 375 380

Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr 385 390 395 400

Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly 405 410 415 -886 200927761

Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn 420 425 430

Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met 435 440 445

Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala 450 455 460

Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg 0 465 470 475 480

Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr 485 490 495

Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr 500 505 510

Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr 515 520 525

Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met 530 535 540

Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr 545 550 555 560

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 565 570 575 -887- 200927761

Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp 580 585 590

Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys 595 600 605

Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr 610 615 620

Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys 625 630 635 640

Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr 645 650 655

Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg 660 665 670

Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly 675 680 685

Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys 690 695 700

Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn 705 710 715 720 888 200927761

Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met 725 730 735

Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys 740 745 750

Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly 755 760 765

Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly 0 770 775 780

Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr 785 790 795 800

Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr 805 810 815

Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys 820 825 830

Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr 835 840 845

Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn 850 855 860

Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala 865 870 875 880 - 889- 200927761

Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala 885 890 895

Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr 900 905 910

Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met 915 920 925

Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala 930 935 940

Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn 945 950 955 960

Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala 965 970 975

Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly 980 985 990

Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His 995 1000 1005

Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 1010 1015 1020 -890 200927761

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1025 1030 1035

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1040 1045 1050

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1055 1060 1065

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg ❹ 1070 1075 1080

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1085 1090 1095

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1100 1105 1110

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1115 1120 1125

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1130 1135 1140

Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1145 1150 1155

Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1160 1165 1170 -891 - 200927761

Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1175 1180 1185

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1190 1195 1200

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1205 1210 1215

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1220 1225 1230

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1235 1240 1245

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1250 1255 1260

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1265 1270 1275

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1280 1285 1290

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1295 1300 1305 - 892- 200927761

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1310 1315 1320

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345 1350 <210> 592 〇 <211> 1332 <212> PRT <213〉現代人 <400> 592

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30 〇

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80 -893 - 200927761 於某些較佳體系中，此處所描述之抗原結合蛋白係藉由注入或大九藥注射而持續投服。此處所描述之HB-EGF抗原結合蛋白可與藥學上可接受之載體製成混合物。此治療組成物可經由靜脈內途徑或通過鼻或肺投服，宜爲液體或粉末霧狀滴（凍乾的）形式。本發明之組成物亦可依需要經由腸胃道外途徑或皮下途徑投服。當經由系統途徑投服時，該治療組成物應爲無菌、 ^ 不含病原且爲腸胃道外途徑可接受之溶液（考量何者爲生理上可接受之pH値、等張性及穩定性）中。這些條件爲熟習本技藝之人士所知。簡單地說，此處所描述之化合物的劑量配方係經由將具有所需純度之化合物與生理上可接受之載體、賦形劑或安定劑混合來製備，以供貯存或投服。這類物質在使用之劑量和濃度下對接受者不具毒性，且其包含緩衝劑’諸如 TRIS HCL、磷酸鹽、檸檬酸鹽、醋酸鹽及其他有機酸鹽；抗氧化劑’諸如抗壞血酸；低分子量 0 (少於約10個殘基）肽類’諸如聚精胺酸 '蛋白質，諸如血清白蛋白、明膠或免疫球蛋白；親水性聚合物，諸如聚乙烯耻咯烷酮；胺基酸（諸如甘胺酸、麩胺酸、天門冬胺酸或精胺酸）；單醣類、雙醣類及其他碳水化合物，包括纖維素或其衍生物、葡萄糖、甘露糖或糊精；螯合劑，諸如 EDTA ;糖醇類’諸如甘露糖醇或山梨糖醇；抗衡離子，諸如鈉及/或非離子性界面活性劑，諸如TWEEN、 PLURONICS或聚乙二醇。用於注射之無菌組成物可根據習知之製藥操作（如 -111 - 200927761

Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr -894- 200927761 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Tyr Met Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285 ❹

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Gly Asn Cys Cys Asn Thr 290 295 300

Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr 305 310 315 320

Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn 325 330 335 ❹

Ala Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380 -895 - 200927761

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn 420 425 430

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp -896- 200927761 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560

Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn 565 570 575

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590 ❹

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala 625 630 635 640 〇

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685 -897- 200927761

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly 725 730 735

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala -898 - 200927761 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala 865 870 875 880

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895 ❹

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala 930 935 940 ❹

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala 980 985 990 -899- 200927761

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1010 1015 1020

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1025 1030 1035

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1040 1045 1050

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1055 1060 1065

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1070 1075 1080

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1085 1090 1095

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1100 1105 1110

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1115 1120 1125

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr -900- 200927761 1130 1135 1140

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1145 1150 1155

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1160 1165 1170

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1175 1180 1185 〇

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1190 1195 1200

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1205 1210 1215

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1220 1225 1230 ❹

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1235 1240 1245

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1250 1255 1260

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1265 1270 1275 -901 - 200927761

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1280 1285 1290

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 <210> 593 <211> 1359 <212〉 PRT <213〉現代人 <400> 593

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60 -902- 200927761

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Met Gly Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110 〇

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Cys Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Ala 195 200 205 -903 - 200927761

Remington · The Science and Practice of Pharmacy ( 20th de，Lippinco11 Wi 1Πams & Wi 1 kens Pub 1 ishers ( 2003 )中所描述者）配製。例如：可能需要將活性化合物溶解或懸浮在載劑中’諸如水或天然蔬菜油（如：芝麻油、花生油或棉花籽油）或合成之脂肪載劑（如油酸乙酯，等）。緩衝劑、防腐劑、抗氧化劑，等可根據可接受之藥學操作倂入其中〇合適之持續釋出製劑包括含有多肽之固態疏水性聚合物的半滲透性基質，該基質爲成形物品、薄膜或微膠囊之形式。持續釋出之基質的實例包括聚酯類、水凝膠（如： L anger et α/.,1981, J. Biomed Mater. Re s . 15 ·· 1 6 7-277 and Langer，1 982，Ckw. rec/i. 1 2 : 98- 1 05 所描述之聚（2-羥乙基-甲基丙烯酸酯）或聚（乙烯醇））、聚乳酸（美國專利案第 3,773,9 1 9號、EP5 8,48 1號）、L-麩胺酸與γί-麩胺酸乙酯之共聚物（Sidman e t α/.,1983, Biopolymers 22 ： 547-556 )、非可降解之乙烯-醋酸乙酯（Langer 同上）、可降解之乳酸-甘醇酸共聚物，諸如LUPRON DepotTM(由乳酸-甘醇酸共聚物和醋酸柳菩林（leuprolide)所組成之注射微球 )及聚-D-(-)3-羥基丁酸（EP 1 3 3,988)。雖然聚合物（諸如乙烯-醋酸乙酯及乳酸-甘醇酸）可使分子釋出超過100天’但某些水凝膠釋出蛋白質之期間較短。當包囊之蛋白質長期保持在體內時’其可能因暴露於 37 °C、濕氣中而變性或聚集’造成生物活性損失且致免疫性可能改變。根據涉及之機制可設計合理之策略來穩定蛋 -112- 200927761

Ala Tyr Ala Thr Gly Trp Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Cys Asn Met Thr Asn Met 290 295 300

Gly Asn Gly Gly Asn Ala Thr His Gly Thr Asn Met Thr Asn Ala Thr 305 310 315 320

Gly Gly Thr Asn Thr Ala Tyr Gly Thr Asn Met Thr Asn Gly Gly Asn 325 330 335

Gly Cys Asn Met Thr Asn Gly Ala Tyr Ala Thr His Thr Gly Gly Gly 340 345 350

Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Ala Arg Gly Thr 355 360 365 -904- 200927761

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn 370 375 380

Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp 385 390 395 400

Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys 405 410 415 〇

Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn 420 425 430

Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly 435 440 445

Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr 450 455 460

Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr 465 470 475 480

Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly 485 490 495

Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly 500 505 510 -905 - 200927761

Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn 515 520 525

Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly 530 535 540

Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser 545 550 555 560

Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn 565 570 575

Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly 580 585 590

Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr 595 600 605

Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr 610 615 620

Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys 625 630 635 640

Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys 645 650 655

Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn 660 665 670 -906- 200927761

Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr 675 680 685

Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys 690 695 700

Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn 705 710 715 720 〇

Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly 725 730 735

Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys 740 745 750

Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn 755 760 765

Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala 770 775 780

Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly 785 790 795 800

Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn 805 810 815 -907- 200927761

Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly 820 825 830

Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly 835 840 845

Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn 850 855 860

Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala 865 870 875 880

Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala 885 890 895

Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn 900 905 910

Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp 915 920 925

Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr 930 935 940

Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn 945 950 955 960

Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala 965 970 975 -908- 200927761

Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala 980 985 990

Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn 995 1000 1005

Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn 1010 1015 1020 ❹

Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 1025 1030 1035

Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1040 1045 1050

Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1055 1060 1065

Met Thr Asn Cys Cys Asn Cys Cys 'Asn Trp Ser Asn Met Gly Asn 1070 1075 1080

Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1085 1090 1095

Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn 1100 1105 1110 -909- 200927761

Ala Cys 1115

Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1120 1125

Gly Gly 1130

Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1135 1140

Gly Ala 1145

Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1150 1155

Thr Gly 1160

Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn 1165 1170

Cys Ala 1175

Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr 1180 1185

Thr Ala 1190

Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1195 1200

Cys Cys 1205

Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn 1210 1215

Gly Ala 1220

Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr 1225 1230

Met Thr 1235

Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1240 1245

Ala Cys 1250

Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1255 1260 -910- 200927761

Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1265 1270 1275

Gly Gly Asn

Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1280 1285 1290

Thr Gly Tyr

Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1295 1300 1305

Gly Ala Arg 〇 Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1310 1315 1320

Cys Ala Tyr

Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1325 1330 1335

Trp Ser Asn

Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1340 1345 1350

Cys Cys Asn

Gly Gly Asn Ala Ala Arg 1355 <210〉 594 <211> 1359 <212> PRT <213>現代人 <400> 594 Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys

Ala Arg Gly -911 - 200927761 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160 -912- 200927761

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala G 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Ala Tyr Gly Ala Arg Ala 290 295 300

Cys Asn Gly Thr Asn Gly Thr Asn Met Gly Asn Gly Gly Asn Met Thr -913 - 200927761 白質。例如：若發現聚集機制爲透過二硫化物交換而形成分子間之S-S鍵時可經由改良氫硫殘基、自酸性溶液凍乾、控制濕度含量、使用合適之添加劑及硏發特殊之聚合物基質組成物來達到穩定效果。

持續釋出之組成物亦包括懸浮在合適配方中（此配方可將結晶保持在懸浮液中）之抗原結合蛋白晶體的製劑。當將這些製劑經由皮下或腹膜內途徑注射時可產生持續釋出之效果。其他組成物亦包含以脂粒捕捉之抗體。含有這類抗體之脂粒係藉由本技藝本身已知之方法製備：美國專利案第 DE 3,218，121 號 Epstein βί α/·，1 98 5，Proc. Wa".

Acad. Sc ί. USA 82 : 3688-3692 ； Hwang et a/.,1 980, Proc. Natl. Acad. Sci. USA 77 : 4030-4034 ； EP 52, 322 ； EP 36,676 ； EP 88,046 ； EP 1 43, 949 ； 142，641;日本專利申請案第 83 - 1 1 8008號；美國專利案第 4,485,045 and 4,544,545 和 EP 1 02,324 號。用於指定之患者的抗原結合蛋白配方之劑量可由主治醫師考慮已知之用來修改藥物作用的不同因子來測定，這些因子包括：疾病之嚴重性和類型、體重、性別、飮食、投服時間和途徑、其他用藥及其他相關之臨床因子。治療上有效之劑量可藉由玻管中或活體內方法測定。欲用於治療之此處所描述的抗原結合蛋白之有效量將取決於’例如：治療目標、投服途徑及患者病況。因此，治療師宜依需要滴定劑量及修改投服途徑，以取得理想之療效。根據上述因子’典型之日劑量係在約0.001毫克/公 -113- 200927761 305 310 315 320

Asn Ala Thr His Met Gly Asn Thr Ala Tyr Thr Gly Tyr Thr Ala Tyr 325 330 335

Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly 340 345 350

Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Cys Asn Gly Thr 355 360 365

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn 370 375 380

Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp 385 390 395 400

Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys 405 410 415

Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn 420 425 430

Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly 435 440 445

Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr 450 455 460 -914- 200927761

Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr 465 470 475 480

Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly 485 490 495

Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly 500 505 510

Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn 515 520 525

Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly 530 535 540

Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser 545 550 555 560

Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn 565 570 575

Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly 580 585 590

Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr 595 600 605

Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr -915 - 200927761 610 615 620

Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys 625 630 635 640

Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys 645 650 655

Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn 660 665 670

Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr 675 680 685

Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys 690 695 700

Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn 705 710 715 720

Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly 725 730 735

Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys 740 745 750

Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn 755 760 765 -916- 200927761

Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala 770 775 780

Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly 785 790 795 800

Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn 805 810 815

Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly 820 825 830

Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly 835 840 845

Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn 850 855 860

Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala 865 870 875 880

Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala 885 890 895

Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn 900 905 910

Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp -917- 200927761 915 920 925

Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr 930 935 940

Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn 945 950 955 960

Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala 965 970 975

Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala 980 985 990

Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn 995 1000 1005

Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn 1010 1015 1020

Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 1025 1030 1035

Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1040 1045 1050

Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1055 1060 1065 -918- 200927761

Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn 1070 1075 1080

Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1085 1090 1095

Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn 1100 1105 1110

Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1115 1120 1125

Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1130 1135 1140

Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1145 1150 1155

Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn 1160 1165 1170

Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr 1175 1180 1185

Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1190 1195 1200

Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn -919- 200927761 1205 1210 1215

Gly Ala 1220

Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr 1225 1230

Met Thr 1235

Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1240 1245

Ala Cys 1250

Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1255 1260

Met Gly 1265

Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn 1270 1275

Ala Ala 1280

Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr 1285 1290

Trp Ser 1295

Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg 1300 1305

Gly Cys 1310

Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr 1315 1320

Thr Ala 1325

Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn 1330 1335

Met Thr 1340

Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn 1345 1350 -920- 200927761

Gly Gly Asn Ala Ala Arg 1355 <210> 595 <211> 1344 <212〉 PRT <213〉現代人 <400> 595

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Ala Tyr Thr 50 55 60 〇

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110 -921 - 200927761

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Ala Thr His Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Ala Ala Tyr Trp 245 250 255 -922- 200927761

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Ala Tyr Met Gly Asn Gly 290 295 300

Gly Asn Gly Gly Asn Gly Gly Asn Gly Ala Tyr Thr Ala Tyr Gly Gly 〇 305 310 315 320

Asn Met Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly 325 330 335

Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Cys Asn Gly 340 345 350

Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys 355 360 365

Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn 370 375 380

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly 385 390 395 400

Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser 405 410 415 -923 - 200927761 斤至100毫克/公斤或更高之範圍內。通常，臨床醫師將給予治療性抗原結合蛋白直到取得所需效果。本療法之進度可輕易地藉由習知分析或依此處之描述監控。吾人可察知根據本發明之組成物及方法的治療性實體在投服時係與合適之載體、賦形劑及其他倂入配方中之作用劑一起投服，以提供改良之轉運、投遞、耐受性’等。這些配方包括，例如：粉末、糊狀物、油膏、膠凍、蠟、油、含囊泡之脂質（陽離子或陰離子性）（諸如Lip〇feCtinTM) 、DNA結合物、無水吸附性糊狀物、水包油及油包水乳劑、乳劑碳蠟（具不同分子量之聚乙二醇）、半固體凝膠及含碳蠟之半固體混合物。前述之任何混合物均適合用於涉及此處所描述之HB-EGF抗原結合蛋白的治療劑及療法中，惟其配方中之活性成分不會被配方去活化且該配方爲生理上相容並可被投服途徑耐受。亦見，

Baldrick P. "Pharmaceutical excipient development: the need for preclinical guidance/1 2000, Regul. Toxicol Pharmacol. 32:210-218; Wang, *'Lyophilization and development of solid protein pharmaceuticals,n 2000, Irit J. Pharm. 203:1-60: Charman WN “Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts," J. Pharm. Sc/.89:967-978; Powell et a/., 1998, wCompendium of excipients for parenteral formulationsIw PDA J. Pharm. Sci. Technol. 52:238-311 以及其中引用之關於製藥化學家所熟知的配方、賦形劑及載體之額外資料。下列實例，包括進行之實驗和取得之結果係僅用於說明而不欲被解釋爲對此文之教示內容的限制。【實施方式】 K.實例1:免疫原之產生方法 -114- 200927761

Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn 420 425 430

Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met 435 440 445

Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr 450 455 460

Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn 465 470 475 480

Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly 485 490 495

Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly 500 505 510

Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn 515 520 525

Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp 530 535 540

Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr 545 550 555 560 924 200927761

Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn 565 570 575

Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr 580 585 590

Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala 595 600 605

Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr 0 610 615 620

Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala 625 630 635 640

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys 645 650 655

Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr 660 665 670

Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys 675 680 685

Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys 690 695 700

Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn 705 710 715 720 -925 - 200927761

Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys 725 730 735

Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 740 745 750

Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn 755 760 765

Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr 770 775 780

Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr 785 790 795 800

Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn 805 810 815

Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr 820 825 830

Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr 835 840 845

Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn 850 855 860 -926- 200927761

Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly 865 870 875 880

Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser 885 890 895

Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn 900 905 910

Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly ¢) 915 920 925

Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr 930 935 940

Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr 945 950 955 960

Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala 965 970 975

Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys 980 985 990

Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 1010 1015 1020 -927- 200927761

Gly Gly 1025

Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1030 1035

Cys Cys 1040

Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1045 1050

Met Thr 1055

Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn 1060 1065

Gly Ala 1070

Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1075 1080

Ala Ala 1085

Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn 1090 1095

Ala Cys 1100

Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1105 1110

Gly Gly 1115

Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1120 1125

Gly Ala 1130

Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1135 1140

Thr Gly 1145

Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn 1150 1155 -928 - 200927761

Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr 1160 1165 1170

Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1175 1180 1185

Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn 1190 1195 1200

Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr ❹ 1205 1210 1215

Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1220 1225 1230

Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1235 1240 1245

Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn 1250 1255 1260

Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr 1265 1270 1275

Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg 1280 1285 1290

Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr 1295 1300 1305 -929- 200927761

Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn 1310 1315 1320

Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn 1325 1330 1335

Gly Gly Asn Ala Ala Arg 1340 <210> 596 <211> 1344 <212〉 PRT <213〉現代人 <400〉 596

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Ala Tyr Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly -930- 200927761 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125 〇

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys 165 170 175 ❹

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Ala Thr His Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Ala Cys 210 215 220 -931 200927761

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Ala Ala Tyr Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Ala Tyr Met Gly Asn Gly 290 295 300

Gly Asn Gly Gly Asn Gly Gly Asn Gly Ala Tyr Thr Ala Tyr Gly Gly 305 310 315 320

Asn Met Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly 325 330 335

Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Cys Asn Gly 340 345 350

Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys 355 360 365

Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn -932- 200927761 370 375 380

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly 385 390 395 400

Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser 405 410 415

Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn 420 425 430 〇

Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met 435 440 445

Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr 450 455 460

Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn 465 470 475 480 ❹

Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly 485 490 495

Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly 500 505 510

Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn 515 520 525 -933 - 200927761

自pcDNA3-VSV-HB-EGF表現構造物擴增包含似EGF 結構區（aa 1-149)的 HB-EGF(Prenzel et al·, 1 999,同上）並將其選殖入一在羧基端提供框構內6His標籤的表現載體內（pcDNA 3.1 myc-his，因維特金（InVitrogen))。在 HEK293細胞中表現此具C端myc(HIS)6標籤之HB-EGF 免疫原並在 Ni-NTA瓊脂糖凝膠（sepharose)(Amersham Pharmacia)和肝素瓊脂糖凝膠（Sigma)上藉二步驟純化作用 Q 進行純化。免疫原之 ΗΒ-EGF部分具下列序列（SEQ ID NO: 1 047)°

1 MKLLPSWLK LFLAAVLSAL VTGESLERLR RGLAAGTSNP 41 DPPTVSTDQL LPLGGGRDRK VRDLQEADLD LLRVTLSSKP 81 QALATPNKEE HGKRKKKGKG LGKKRDPCLR KYKDFCIHGE 121 CKYVKELRAP SCICHPGYHG ERCHGLSLP L.實例2: Xenomouse小鼠之免疫化及觀察到之力價藉由依序將 Xen〇Mouse® 小鼠（XenoMouse品種： XMG2(製造人 IgG2)及 XM3C-1(製造人 IgG4) ’ Abgenix 公司，加州Fremont公司）免疫化來發展抗ΗΒ-EGF之單株抗體。 1.免疫化經由腳掌進行所有注射將XenoMouse動物免疫化。各次注射之總體積爲每一隻老鼠50微升，每隻腳掌25微升〇在第1群（10 XMG2小鼠）和第2群（1〇 XM3C-1)方面 -115- 200927761

Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp 530 535 540

Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn 565 570 575

Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr 580 585 590

Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala 595 600 605

Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr 610 615 620

Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala 625 630 635 640

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys 645 650 655

Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr 660 665 670

Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys -934- 200927761 675 680 685

Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys 690 695 700

Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn 705 710 715 720

Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys 725 730 735 ❹

Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 740 745 750

Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn 755 760 765

Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr 770 775 780 ❹

Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr 785 790 795 800

Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn 805 810 815

Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr 820 825 830 -935 - 200927761

Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr 835 840 845

Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn 850 855 860

Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly 865 870 875 880

Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser 885 890 895

Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn 900 905 910

Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly 915 920 925

Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr 930 935 940

Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr 945 950 955 960

Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala 965 970 975

Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys -936- 200927761 980 985 990

Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 1010 1015 1020

Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1025 1030 1035 〇

Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1040 1045 1050

Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn 1055 1060 1065

Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1070 1075 1080 〇

Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn 1085 1090 1095

Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1100 1105 1110

Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1115 1120 1125 -937- 200927761

Gly Ala 1130

Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1135 1140

Thr Gly 1145

Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn 1150 1155

Cys Ala 1160

Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr 1165 1170

Thr Ala 1175

Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1180 1185

Cys Cys 1190

Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn 1195 1200

Gly Ala 1205

Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr 1210 1215

Met Thr 1220

Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1225 1230

Ala Cys 1235

Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1240 1245

Met Gly 1250

Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn 1255 1260

Ala Ala

Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr -938 - 200927761 1265 1270 1275

Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg 1280 1285 1290

Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr 1295 1300 1305

Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn 1310 1315 1320

O

Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn 1325 1330 1335

Gly Gly Asn Ala Ala Arg 1340

<210〉597 <211> 1335 <212〉 PRT <213〉現代人 <400> 597

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30 -939- 200927761

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190 -940- 200927761

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Ala Thr His Ala 195 200 205

Cys Asn Ala Ala Arg Trp Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

O

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Trp Ser Asn Ala Ala Tyr Ala 290 295 300

Ala Tyr Thr Ala Tyr Gly Gly Asn Thr Gly Tyr Thr Thr Tyr Gly Cys 305 310 315 320

Asn Met Thr Asn Thr Gly Gly Gly Gly Asn Met Gly Asn Gly Gly Asn 325 330 335 -941 - 200927761

Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp 340 345 350

Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala 355 360 365

Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr 370 375 380

Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp 385 390 395 400

Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala 405 410 415

Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn 420 425 430

Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly 435 440 445

Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys 450 455 460

Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly 465 470 475 480

Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala 485 490 495 -942- 200927761

Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys 500 505 510

Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn 515 520 525

Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr 530 535 540 〇

Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr 545 550 555 560

Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn 565 570 575

Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys 580 585 590

Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala 595 600 605

Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn 610 615 620

Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly 625 630 635 640 -943 - 200927761 ，每隻老鼠使用1〇微克之HB-EGF蛋白與TITERMAX GOLD® (Sigma，安大略Oakville)的混合物（1 : 1)(體積/體積）來進行初次免疫化。接著，以在不含病原菌之D-PBS 中的1〇微克HB-EGF蛋白與100微克明礬凝膠（Sigma，安大略Oakville)混合物（1: 1)(體積/體積）進行接下去之四次加強免疫注射。第5次加強免疫之注射包含1〇微克 HB-EGF蛋白與TITERMAX GOLD®之混合物（1 : 1)(體積/ 體積）。第6次和第7次注射包含10微克HB-EGF蛋白與 100微克明礬凝膠之混合物（1: 1)(體積/體積）。最後一次加強免疫注射係以在不含病原菌之D-PBS中的10微克 HB-EGF蛋白（不含佐劑）進行。此實驗計劃係在第0、4、8 、14、18、21、25及28天將Xeno Mouse免疫化並在第32 天進行融合。在第四次加強免疫化後之第16天，第六次加強免疫化後之第23天透過眼後採血程序採取二次血。 2.以力價選擇供收成之動物藉ELISA測定來自經免疫化之XenoMouse®小鼠的血清中的抗HB-EGF抗體力價。簡單地說，將在抗原塗覆緩衝劑（Antigen Coating Buffer)(0.1M 碳酸鹽緩衝劑、 pH9.6 NaHC03(MW84)8.4 克/升）中之 HB-EGF 蛋白質（2 微克/毫升）塗覆在 Costar Labcoat 普遍結合性（Universal Binding)聚苯乙嫌96-槽盤（康寧公司，麻州 Acton)上，置於4°C 一整夜。第二天，利用Biotek盤清洗器，以清洗緩衝劑（在1乂？88中之0.05%吐溫（丁评661〇20)清洗盤一次。然 -116- 200927761

Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly 645 650 655

Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg 660 665 670

Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly 675 680 685

Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly 690 695 700

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn 705 710 715 720

Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala 725 730 735

Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr 740 745 750

His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg 755 760 765

Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly 770 775 780

Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala 785 790 795 800 -944- 200927761

Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg 805 810 815

Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly 820 825 830

Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala 835 840 845

O

Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 850 855 860

Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr 865 870 875 880

Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly 885 890 895

Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn 900 905 910

Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly 915 920 925

Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala 930 935 940 -945- 200927761

Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg 945 950 955 960

Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met 965 970 975

Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala 980 985 990

Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg 995 1000 1005

Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn 1010 1015 1020

Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn 1025 1030 1035

Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn 1040 1045 1050

Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly 1055 1060 1065

Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 1070 1075 1080

Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn 1085 1090 1095 -946- 200927761

Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr 1100 1105 1110

Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn 1115 1120 1125

Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn 1130 1135 1140 ❾

Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg 1145 1150 1155

Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn 1160 1165 1170

Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn 1175 1180 1185

Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn 1190 1195 1200

Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn 1205 1210 1215

Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr 1220 1225 1230 -947- 200927761

Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg 1235 1240 1245

Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr 1250 1255 1260

Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly 1265 1270 1275

Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr 1280 1285 1290

Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg 1295 1300 1305

Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn 1310 1315 1320

Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 1335 <210> 598 <211〉 1335 <212> PRT <213〉現代人 <400〉 598

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15 -948 - 200927761

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys -949- 200927761 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Ala Thr His Ala 195 200 205

Cys Asn Ala Ala Arg Trp Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Trp Ser Asn Ala Ala Tyr Ala 290 295 300

Ala Tyr Thr Ala Tyr Gly Gly Asn Thr Gly Tyr Thr Thr Tyr Gly Cys 305 310 315 320 -950- 200927761

Asn Met Thr Asn Thr Gly Gly Gly Gly Asn Met Gly Asn Gly Gly Asn 325 330 335

Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp 340 345 350

Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala 355 360 365 ❹

Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr 370 375 380

Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp 385 390 395 400

Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala 405 410 415

Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn G 420 425 430

Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly 435 440 445

Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys 450 455 460

Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly -951 - 200927761 465 470 475 480

Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala 485 490 495

Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys 500 505 510

Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn 515 520 525

Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr 530 535 540

Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr 545 550 555 560

Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn 565 570 575

Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys 580 585 590

Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala 595 600 605

Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn 610 615 620 -952- 200927761

Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly 625 630 635 640

Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly 645 650 655

Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg 660 665 670

Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly 675 680 685

Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly 690 695 700

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn 705 710 715 720

Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala 725 730 735

Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr 740 745 750

His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg 755 760 765

Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly -953 - 200927761 後’以200微升/槽封閉緩衝劑（〇.5%BS A、0.1 %吐溫20、 0.01%乙汞硫柳酸鈉（Thimerosal)，在lxPBS中）將盤封閉，在室溫下培育1小時。封閉1小時後，利用Biotek盤清洗器’以清洗緩衝劑清洗盤一次。將取自經HB-EGF蛋白免疫化之 XenoMouse® 小鼠或天然未經處理之 XenoMouse®動物的血清在〇.5%BSA/PSB緩衝劑（1 : 3稀釋）中滴定（複製二份），滴定時係從1 : 100之初始稀釋倍 0 數開始滴定。最後一槽爲空白槽。將這些盤在室溫下培育 2小時，利用Biotek盤清洗器，以清洗緩衝劑清洗盤三次。將在封閉緩衝劑中，最終濃度爲1 : 2000之與山羊抗人 IgG Fc-特異性辣根過氧化酶（目錄編號H 1 0 5 07)結合的抗體加入其中，並在室溫中培育1小時。利用Biotek盤清洗器，以清洗緩衝劑清洗盤三次。清洗後，在盤中加入TMB 呈色介質（BioFxBSTP-0100-01)，使其發展10-20分鐘或直至陰性對照槽開始顯現顏色。加入終止溶液（6 5 OnM TMB 〇之終止作用劑（BioFxBSTP-0100-01)，每瓶以 100毫升水重構之）。從650nm處之光學密度測定各XenoMouse®動物之特殊力價並顯示於下列表1中。力價値爲其OD讀値爲背景値之二倍的血清最大稀釋倍數的倒數。因此，數値愈高，則對HB-EGF之體液免疫反應愈強。 -117- 200927761 770 775 780

Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala 785 790 795 800

Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg 805 810 815

Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly 820 825 830

Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala 835 840 845

Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 850 855 860

Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr 865 870 875 880

Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly 885 890 895

Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn 900 905 910

Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly 915 920 925 954- 200927761

Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala 930 935 940

Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg 945 950 955 960

Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met 965 970 975

Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala 980 985 990

Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg 995 1000 1005

Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn 1010 1015 1020

Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn 1025 1030 1035

Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn 1040 1045 1050

Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly 1055 1060 1065

Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn -955 - 200927761 1070 1075 1080

Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn 1085 1090 1095

Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr 1100 1105 1110

Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn 1115 1120 1125

Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn 1130 1135 1140

Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg 1145 1150 1155

Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn 1160 1165 1170

Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn 1175 1180 1185

Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn 1190 1195 1200

Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn 1205 1210 1215 956- 200927761

Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr 1220 1225 1230

Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg 1235 1240 1245

Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr 1250 1255 1260

Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly 1265 1270 1275

Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr 1280 1285 1290

Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg 1295 1300 1305

Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn © 1310 1315 1320

Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 1335 <210〉 599 <211> 1377 <212〉 PRT <213〉現代人 -957 - 200927761 <400〉 599

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140 -958 - 200927761

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Trp Ser Asn Trp 赢 245 250 255 ❹

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Ala Tyr Ala 290 295 300 -959 - 200927761

Ala Tyr Thr Ala Tyr Gly Gly Asn Met Thr Asn Thr Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Gly Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn 325 330 335

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Thr 340 345 350

Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly 355 360 365

Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Cys Asn 370 375 380

Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly 385 390 395 400

Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys 405 410 415

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn 420 425 430

Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp 435 440 445 -960 200927761

Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys 450 455 460

Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr 465 470 475 480

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr 485 490 495

Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys 0 500 505 510

Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn 515 520 525

Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly 530 535 540

Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys 545 550 555 560

Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn 565 570 575

Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met 580 585 590

Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys 595 600 605 -961 - 200927761

Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr 610 615 620

Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr 625 630 635 640

Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala 645 650 655

Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr 660 665 670

Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala 675 680 685

Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly 690 695 700

Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn 705 710 715 720

Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys 725 730 735

Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser 740 745 750 -962- 200927761

Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn 755 760 765

Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala 770 775 780

Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly 785 790 795 800

Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn 0 805 810 815

Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys 835 840 845

Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr 850 855 860

Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly 865 870 875 880

Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys 885 890 895

Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn 900 905 910 -963 - 200927761 表1 第1組,fp，X MG2，10小鼠注射4次後注射6次後 Mouse ID Reactivity to HB-EGF P4721 3,800 59,000 P4722 6,500 68,000 P4723 2,500 43,000 P4724 2?400 22,000 P4725 2,400 71,000 P4726 450 58,000 P4727 1,600 20,000 P4728 2,700 61,000 P4729 800 61,000 P47210 5J00 78,000 NC <100 <100 PC <100 <100 第 2 組，fp，XM3C-l，10 小鼠，注射4次後注射6次後 Mouse ID Reactivity to HB-EGF P2664 35 2,300 P2666 20 750 P2669 30 850 P26610 75 1,900 P2892 60 550 P2894 60 1,400 P2895 95 2,600 P2896 45 2,500 P3672 50 2,000 P3678 60 1,800 NC <100 <100 PC 35 20 Μ .實例3 :雜交瘤之產生方法及結合劑之初級篩檢將經免疫化之小鼠殺死並收成和累積來自各組的淋巴結。將淋巴細胞在DMEM中硏磨分離自組織釋出之細胞，將細胞懸浮在DMEM中。計算細胞，且對細胞小九加入 0.9毫升DMEM 1億個淋巴細胞以溫和且完全令該細胞懸浮。利用1〇〇微升CD 90 +磁珠/1億個細胞，藉由將該細胞與磁珠一起在4 °C中培育15分鐘以標記該細胞。將該含有至多1〇8個陽性細胞（或至多全部2xl09細胞）之經磁石標示的細胞懸浮液塡至LS +分析柱上，以DMEM清洗該分析柱。收集全部洗提液作爲CD90-陰性分液（預料這些細胞大部分爲B細胞）。

將清洗過之來自上述之增濃的B細胞與自ATCC購得之非分泌性骨髓瘤 P3X63Ag 8.65 3細胞（目錄編號 CRL -118- 200927761

Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp 915 920 925

Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr 930 935 940

Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn 945 950 955 960

Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met 965 970 975

Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala 980 985 990

Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn 995 1000 1005

Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn 1010 1015 1020

Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg 1025 1030 1035

Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 1040 1045 1050 -964- 200927761

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1055 1060 1065

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1070 1075 1080

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1085 1090 1095

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn ❹ 1100 1105 1110

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1115 1120 1125

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1130 1135 1140

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1145 1150 1155

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1160 1165 1170

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1175 1180 1185

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1190 1195 1200 -965 - 200927761

Ala Ala 1205

Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1210 1215

Cys Cys 1220

Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1225 1230

Trp Ser 1235

Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1240 1245

Thr Thr 1250

Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1255 1260

Met Thr 1265

Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1270 1275

Trp Ser 1280

Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1285 1290

Gly Gly 1295

Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1300 1305

Thr Gly 1310

Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1315 1320

Gly Ala 1325

Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1330 1335 -966- 200927761

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1340 1345 1350

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1355 1360 1365

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1370 1375 <210〉 600 O <211〉 1353 <212〉 PRT <213>現代人 <400〉 600

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30 ❹

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80 -967 200927761

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Ala Ala Tyr Thr 100 105 110

Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Gly Gly Asn Ala Cys 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr -968 - 200927761 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Thr Thr Tyr Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Thr Tyr 275 280 285 ❹

Thr Gly Tyr Gly Cys Asn Met Gly Asn Ala Cys Asn Thr Ala Tyr Thr 290 295 300

Ala Tyr Gly Ala Tyr Ala Thr His Met Thr Asn Ala Cys Asn Gly Gly 305 310 315 320

Asn Thr Ala Tyr Cys Cys Asn Thr Thr Tyr Thr Ala Tyr Thr Thr Tyr 325 330 335 ❹

Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn 370 375 380 -969- 200927761

Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr 385 390 395 400

Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly 405 410 415

Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn 420 425 430

Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met 435 440 445

Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala 450 455 460

Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg 465 470 475 480

Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr 485 490 495

Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr 500 505 510

Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr 515 520 525

Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met -970- 200927761 530 535 540

Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr 545 550 555 560

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 565 570 575

Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp 580 585 590 〇

Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys 595 600 605

Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr 610 615 620

Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys 625 630 635 640 〇

Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr 645 650 655

Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg 660 665 670

Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly 675 680 685 -971 - 200927761

Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys 690 695 700

Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn 705 710 715 720

Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met 725 730 735

Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys 740 745 750

Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly 755 760 765

Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly 770 775 780

Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr 785 790 795 800

Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr 805 810 815

Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys 820 825 830

Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr -972- 200927761 835 840 845

Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn 850 855 860

Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala 865 870 875 880

Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala 885 890 895 ❹

Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr 900 905 910

Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met 915 920 925

Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala 930 935 940 〇

Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn 945 950 955 960

Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala 965 970 975

Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly 980 985 990 -973 200927761 1 580)(Kearney ei α/，1 979, «/. 1 23 : 1 548- 1 5 5 0)以 1 : 1之比例混合’以進行融合。將細胞混合物在8 0 0 g輕輕地離心。將上清液完全移除後，以2 - 4毫升鏈蛋白酶溶液（CalBiochem，目錄編號53702，0.5毫克/毫升，在PBS 中）處理細胞小九不超過2分鐘。然後，加入3 -5毫升FBS 以終止酶活性，以電細胞融合溶液ECFS(0.3M蔗糖， Sigma目錄編號S7903，O.lmM醋酸鎂，Sigma目錄編號 0 M2545，O.lmM醋酸鈣’ Sigma目錄編號C4705)將懸浮液之總體積調整爲40毫升。離心後，移除上清液，將細胞再懸浮於40毫升ECFS中。重複此清洗步驟，將細胞再懸浮於ECFS中，使濃度成爲2xl06細胞/毫升。利用融合產生器ECM200 1型（Genetronic公司，加州聖地牙哥）進行電細胞融合。所使用之融合室大小爲2.0毫升，使用下列儀器設定：調準條件：電壓：50V，時間： 50秒；膜破裂點：電壓：3 00 0V，時間：30微秒；融合後 Q 保持時間：3秒。電細胞融合後，在無菌條件下將細胞懸浮液自融合室小心移除，並轉移入含有相同體積之雜交瘤培養介質 (DMEM(JRH Biosciences)、15 % FBS(Hyclone)，其中補充以L-麩醯胺、pen/strep、OPI(草醯醋酸鹽、丙酮酸鹽、牛胰島素）（均來自 Sigma)及 IL-6(Boehringer Mannheim))之無菌管中。將細胞在37°C培育15-30分鐘，再在400g離心5分鐘。將細胞輕輕地懸浮在小體積雜交瘤選擇介質（補充以0.5xHA(Sigma，目錄編號A 9 6 6 6)之雜交瘤培養介 -119- 200927761

Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His 995 1000 1005

Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 1010 1015 1020

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1025 1030 1035

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1040 1045 1050

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1055 1060 1065

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1070 1075 1080

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1085 1090 1095

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1100 1105 1110

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1115 1120 1125

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His -974- 200927761 1130 1135 1140

Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1145 1150 1155

Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1160 1165 1170

Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1175 1180 1185 ❹

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1190 1195 1200

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1205 1210 1215

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1220 1225 1230 〇

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1235 1240 1245

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1250 1255 1260

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1265 1270 1275 -975 200927761

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1280 1285 1290

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1295 1300 1305

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1310 1315 1320

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345 1350 <210〉 601 <211> 1353 <212> PRT <213〉現代人 <400〉 601

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45 200927761

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95 ❹

Gly Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Ala Ala Tyr Thr 100 105 110

Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Gly Gly Asn Ala Cys 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190 -977 - 200927761

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Thr Thr Tyr Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Thr Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Ala Cys Asn Thr Ala Tyr Thr 290 295 300

Ala Tyr Gly Ala Tyr Ala Thr His Met Thr Asn Ala Cys Asn Gly Gly 305 310 315 320

Asn Thr Ala Tyr Cys Cys Asn Thr Thr Tyr Thr Ala Tyr Thr Thr Tyr 325 330 335

Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350 -978 - 200927761

Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn 370 375 380

Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr 385 390 395 400

O

Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly 405 410 415

Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn 420 425 430

Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met 435 440 445

Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala 450 455 460

Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg 465 470 475 480

Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr 485 490 495 -979- 200927761

Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr 500 505 510

Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr 515 520 525

Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met 530 535 540

Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr 545 550 555 560

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 565 570 575

Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp 580 585 590

Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys 595 600 605

Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr 610 615 620

Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys 625 630 635 640

Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr 645 650 655 -980- 200927761

Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg 660 665 670

Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly 675 680 685

Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys 690 695 700 ❹

Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn 705 710 715 720

Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met 725 730 735

Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys 740 745 750

Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly 755 760 765

Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly 770 775 780

Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr 785 790 795 800 981 - 200927761

Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr 805 810 815

Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys 820 825 830

Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr 835 840 845

Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn 850 855 860

Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala 865 870 875 880

Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala 885 890 895

Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr 900 905 910

Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met 915 920 925

Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala 930 935 940

Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn 945 950 955 960 -982- 200927761

Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala 965 970 975

Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly 980 985 990

Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His 995 1000 1005 〇

Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 1010 1015 1020

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1025 1030 1035

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1040 1045 1050

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1055 1060 1065

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1070 1075 1080

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1085 1090 1095 -983 - 200927761 質）中，並根據最終在每一 96槽盤中接種5xl06B細胞及每槽200微升來以更多之雜交瘤選擇介質將體積做適當調整。將細胞輕輕混合，以移液管移至96槽盤中，使細胞在其中生長。在第7或10天去除一半介質，重新以雜交瘤選擇介質餵食細胞。培養14天後藉由ELISA篩檢來自第1群及第2群之雜交瘤上清液中的HB-EGF-特異性單株抗體。在初級篩檢中’以50微升/槽之在塗覆緩衝劑（〇·ΐΜ碳酸鹽緩衝劑， pH9.6，NaHC03 8_4克/升）中的HB-EGF蛋白質（2微克/毫升）塗覆ELISA盤，再將其在4°C下培育一整夜。培育後，以清洗緩衝劑（在PBS中之0.05%吐溫20)清洗盤一次。加入200微升/槽封閉緩衝劑（〇.5%BS A、0.1 %吐溫20、 0.01%乙汞硫柳酸鈉，在lxPBS中）並將盤在室溫下培育1 小時。培育後，以清洗緩衝劑清洗盤一次。將一份份（5 〇微升/槽）雜交瘤上清液及陽性和陰性對照組加入其中，並將盤在室溫下培育2小等。全程使用之陽性對照組爲來自經相關之HB-EGF蛋白免疫化的XenoMouse®小鼠的血清，陰性對照組爲來自經KLH免疫化之相關XenoMouse® 小鼠品種的血清。培育後，以清洗緩衝劑清洗盤三次。加入100微升/槽之偵測抗體山羊抗-huIgG Fc-HRP(Caltag公司，目錄編號H10507，使用濃度爲1: 2000稀釋液）並將盤在室溫中培育1小時。培育後，以清洗緩衝劑清洗盤三次，在盤中加入100微升/槽之TMB(Bi〇Fx實驗室，目錄編號TMSK-0100-01)。令盤發展約10分鐘（直至陰性對照 -120- 200927761

Gly Thr 1100

Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1105 1110

Met Thr 1115

Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1120 1125

Thr Ala 1130

Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1135 1140

Gly Cys 1145

Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1150 1155

Trp Ser 1160

Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1165 1170

Gly Ala 1175

Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1180 1185

Ala Cys 1190

Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1195 1200

Met Thr 1205

Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1210 1215

Trp Ser 1220

Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1225 1230

Trp Ser 1235

Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1240 1245 -984- 200927761

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1250 1255 1260

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1265 1270 1275

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1280 1285 1290 〇

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1295 1300 1305

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1310 1315 1320

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345 1350 <210> 602 <211> 1338 <212〉 PRT <213〉現代人 <400> 602

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Cys -985 - 200927761 15 10 15

Ala Arg Thr Gly Gly Gly Gly Asn Gly Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Met Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Ala Tyr 85 90 95

Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr Gly Gly Ala Thr His Met 100 105 110

Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr His 130 135 140

Gly Gly Asn Gly Ala Arg Ala Thr His Ala Ala Tyr Cys Ala Tyr Trp 145 150 155 160 -986- 200927761

Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys Asn Ala Ala Tyr Thr Ala 165 170 175

Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn Met Thr Asn Ala Ala Arg 180 185 190

Trp Ser Asn Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Trp 195 200 205

Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys Asn Trp Ser Asn Ala Ala 210 215 220

Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Met Thr Asn 225 230 235 240

Ala Ala Arg Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Ala 245 250 255

Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala Tyr Ala Cys Asn Gly Cys 260 265 270

Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn 275 280 285

Met Gly Asn Gly Gly Asn Gly Gly Asn Thr Ala Tyr Trp Ser Asn Trp 290 295 300

Ser Asn Trp Ser Asn Thr Gly Gly Thr Ala Tyr Thr Gly Gly Thr Thr -987- 200927761 305 310 315 320

Tyr Gly Ala Tyr Cys Cys Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys 355 360 365

Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn 370 375 380

Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr 385 390 395 400

Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser 405 410 415

Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn 420 425 430

Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala 435 440 445

Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala 450 455 460 -988 - 200927761

Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn 465 470 475 480

Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met 485 490 495

Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala 500 505 510

Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn 515 520 525

Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met 530 535 540

Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser 545 550 555 560

Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn 565 570 575

Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala 580 585 590

Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly 595 600 605

Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg -989- 200927761 610 615 620

Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly 625 630 635 640

Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala 645 650 655

Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn 660 665 670

Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys 675 680 685

Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys 690 695 700

Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr 705 710 715 720

Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys 725 730 735

Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr 740 745 750

Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn 755 760 765 -990- 200927761

Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly 770 775 780

Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala 785 790 795 800

Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn 805 810 815 Q Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly 820 825 830

Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr 835 840 845

Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn 850 855 860

Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys 865 870 875 880

Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr 885 890 895

Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn 900 905 910

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys -991 - 200927761 915 920 925

Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly 930 935 940

Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr 945 950 955 960

Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly 965 970 975

Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr 980 985 990

His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 995 1000 1005

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1010 1015 1020

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1025 1030 1035

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1040 1045 1050

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1055 1060 1065 -992- 200927761

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr 1070 1075 1080

Cys Ala Arg

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn 1085 1090 1095

Thr Gly Tyr

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn 1100 1105 1110

Thr Thr Tyr

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr 1115 1120 1125

Ala Thr His

Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly 1130 1135 1140

Gly Ala Arg

Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg 1145 1150 1155

Cys Cys Asn

Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr 1160 1165 1170

Ala Ala Arg

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn 1175 1180 1185

Ala Thr Gly

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr 1190 1195 1200

Gly Gly Asn

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn

Thr Ala Tyr -993 - 200927761 槽勉強開始顯現顏色）。加入50微升/槽之終止溶液（ΤΜΒ 終止溶液（BioFx實驗室，目錄編號STPR-0100-01))，在 ELISA分析儀上於450 nm波長處讀取96槽盤之數値。自根據初級篩檢之陽性雜交瘤細胞生長槽中去除舊培養上清液，將HB-EGF陽性雜交瘤細胞懸浮在新鮮雜交瘤培養介質中並轉移至24槽盤中。培養2天後，這些上清液已可進行第二次確認篩檢。在第二次確認篩檢中，以二 0 組偵測抗體：用於偵測人類 γ鏈之山羊抗-huIgGFc-HRP(Caltag公司，目錄編號H10507，使用濃度爲稀釋1 :2000)及用於偵測人類κ輕鏈之山羊抗-hIgK-HRP(南方生物技術公司，目錄編號2060-05)，藉由ELISA(如上述）來篩檢在第一次篩檢中之陽性上清液，以證明該抗體製劑爲 HB-EGF特異性且其組成爲純人類之組成。此二套ELISA 程序與上述程序完全相同，但分別使用二種不同之偵測抗體。 ❹ 在第二次確認篩檢之同時，進行計數器ELISA篩檢以排除那些對myC(his)6標籤有反應之抗體。ELISA程序與上述者完全相同，但以不相關之myc(his)6標籤蛋白（ML- myc(his)6蛋白）塗覆來取代以HB-EGFmyc(his)6蛋白塗覆〇在第二次確認及計數器ELISA篩檢後可自第1群和第 2群鑑定出49種純人IgG/KHB-EGF特異性單株抗體。 N.實例4 :在功能性分析中按比例提高及試驗抗體 -121 - 200927761 1205 1210 1215

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1220 1225 1230

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1235 1240 1245

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1250 1255 1260

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1265 1270 1275

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1280 1285 1290

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1295 1300 1305

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 1335

<210〉 603 <211> 1338 <212〉 PRT 994- 200927761 <213〉現代人 <400〉 603

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Cys 15 10 15

Ala Arg Thr Gly Gly Gly Gly Asn Gly Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Met Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 〇 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Ala Tyr 85 90 95

Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr Gly Gly Ala Thr His Met 100 105 110

Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr His 130 135 140 -995 - 200927761

Gly Gly Asn Gly Ala Arg Ala Thr His Ala Ala Tyr Cys Ala Tyr Trp 145 150 155 160

Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys Asn Ala Ala Tyr Thr Ala 165 170 175

Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn Met Thr Asn Ala Ala Arg 180 185 190

Trp Ser Asn Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Trp 195 200 205

Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys Asn Trp Ser Asn Ala Ala 210 215 220

Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Met Thr Asn 225 230 235 240

Ala Ala Arg Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Ala 245 250 255

Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala Tyr Ala Cys Asn Gly Cys 260 265 270

Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn 275 280 285 -996- 200927761

Met Gly Asn Gly Gly Asn Gly Gly Asn Thr Ala Tyr Trp Ser Asn Trp 290 295 300

Ser Asn Trp Ser Asn Thr Gly Gly Thr Thr Tyr Thr Gly Gly Thr Thr 305 310 315 320

Tyr Gly Ala Tyr Cys Cys Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly 〇 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys 355 360 365

Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn 370 375 380

Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr 385 390 395 400

Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser 405 410 415

Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn 420 425 430

Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala 435 440 445 -997 - 200927761

Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala 450 455 460

Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn 465 470 475 480

Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met 485 490 495

Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala 500 505 510

Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn 515 520 525

Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met 530 535 540

Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser 545 550 555 560

Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn 565 570 575

Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala 580 585 590 -998 - 200927761

Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly 595 600 605

Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg 610 615 620

Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly 625 630 635 640

Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala ¢) 645 650 655

Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn 660 665 670

Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys 675 680 685

Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys 690 695 700

Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr 705 710 715 720

Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys 725 730 735

Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr 740 745 750 -999- 200927761

Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn 755 760 765

Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly 770 775 780

Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala 785 790 795 800

Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn 805 810 815

Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly 820 825 830

Th| Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr, 835 840 ； 845 1

Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn 850 855 860

Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys 865 870 875 880

Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr 885 890 895 -1000 200927761

Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn 900 905 910

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys 915 920 925

Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly 930 935 940

Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr 945 950 955 960

Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly 965 970 975

Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr 980 985 990

His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 赢 995 1000 1005 ❹

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1010 1015 1020

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1025 1030 1035

Gly Thr' Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1040 1045 1050 -1001 - 200927761

Cys Cys 1055

Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1060 1065

Ala Thr 1070

Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1075 1080

Gly Thr 1085

Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1090 1095

Met Thr 1100

Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1105 1110

Thr Ala 1115

Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1120 1125

Gly Cys 1130

Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1135 1140

Trp Ser 1145

Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1150 1155

Gly Ala 1160

Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1165 1170

Ala Cys 1175

Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1180 1185 1002 200927761

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1190 1195 1200

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1205 1210 1215

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1220 1225 1230

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1235 1240 1245

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1250 1255 1260

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1265 1270 1275

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn ^ 1280 1285 1290 ❹

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1295 1300 1305

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 1335 -1003 - 200927761 此實例描述該產製對HB-EGF具親和力之抗HB_EGF 抗體的雜交瘤細胞株的鑑定方法。 1.由雜交瘤製造之可結合表現HB-EGF之細胞株的抗HB-EGF抗體之FACS偵測法藉由FACS分析測定細胞株上之HB-EGF表現。爲了進行此分析，以在PBS中之1 〇mM EDTA來收成2xl05個選出之表現HB-EGF的細胞，將其再懸浮於FACS緩衝劑 (PBS，3%FCS，0.4%疊氮化物）中並接種在96-槽圓底盤上。在lOOOrpm離心3分鐘以去除上清液，將細胞再懸浮於自雜交瘤衍生之抗HB-EGF抗體稀釋液（100微升/槽）中並在下培育45分鐘。以FACS緩衝劑清洗細胞二次，將其與在FACS緩衝劑中稀釋100倍之二級抗體（100微升/ 槽）驢-抗-人PE(Jackson)—起再懸浮。將細胞懸浮液在4°C 、黑暗中培育30分鐘，以FACS緩衝劑清洗二次並分析之（FACS，Beckman Coulter)。這些分析結果提供於下列表2和3中，其提供各 FACS分析之螢光平均値。如表3和4中之說明，在不會表現HB-EGF之CHO對照組細胞中實質上未偵測到HB-EGF之表現。然而，當HB-EGF以重組方式過度表現於 CHO細胞中時，數種單株抗體製劑顯示出強力結合那些表現HB-EGF之細胞。與MDA-MB231結合時，SCC-9和 COS-7細胞有些不同，但結合一種表現HB-EGF之細胞類型的抗體通常亦與另一種細胞類型結合。如表2中所示， -122- 200927761 <210> 604 <211〉 1347 <212> PRT <213>現代人 <400〉 604

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr Gly Gly Ala Thr His Met 100 105 110

Gly Asn Cys Ala Arg Cys Cys Asn Gly Cys Asn Gly Gly Asn Ala Ala -1004 - 200927761 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr His 130 135 140

Gly Gly Asn Met Gly Asn Ala Thr His Thr Ala Tyr Ala Cys Asn Trp 145 150 155 160

Ser Asn Gly Gly Asn Ala Cys Asn Ala Cys Asn Ala Ala Tyr Thr Ala 165 170 175 〇

Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn Met Thr Asn Ala Ala Arg 180 185 190

Trp Ser Asn Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr Gly Trp 195 200 205

Ser Asn Gly Thr Asn Gly Ala Tyr Ala Cys Asn Trp Ser Asn Ala Ala 210 215 220 ❹

Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Met Thr Asn 225 230 235 240

Ala Ala Arg Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Ala 245 250 255

Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala Tyr Ala Cys Asn Gly Cys 260 265 270 -1005 200927761

Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn 275 280 285

Met Gly Asn Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Trp Ser Asn Thr 290 295 300

Ala Tyr Gly Gly Asn Cys Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 325 330 335

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala 340 345 350

Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser 355 360 365

Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn 370 375 380

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met 385 390 395 400

Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly 405 410 415

Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn -1006- 200927761 420 425 430

Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr 435 440 445

Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala 450 455 460

Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn 465 470 475 480 ❹

Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp 485 490 495

Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser 500 505 510

Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr 515 520 525 ❹

Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp 530 535 540

Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser 545 550 555 560

Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn 565 570 575 -1007 200927761

Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala 580 585 590

Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys 595 600 605

Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn 610 615 620

Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala 625 630 635 640

Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala 645 650 655

Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg 660 665 670

Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys 675 680 685

Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys 690 695 700

Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn 705 710 715 720

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys -1008 - 200927761 725 730 735

Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala 740 745 750

Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn 755 760 765

Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala 770 775 780 ❹

Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala 785 790 795 800

Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr 805 810 815

Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala 820 825 830 ❹

Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly 835 840 845

Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr 850 855 860

Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met 865 870 875 880 -1009- 200927761

Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala 885 890 895

Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn 900 905 910

Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly 915 920 925

Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly 930 935 940

Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg 945 950 955 960

Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp 965 970 975

Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys 980 985 990

Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg 995 1000 1005

Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 1010 1015 1020

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn -1010- 200927761 1025 1030 1035

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1040 1045 1050

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1055 1060 1065

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1070 1075 1080 ❹

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1085 1090 1095

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1100 1105 1110

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1115 1120 1125 ❹

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1130 1135 1140

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1145 1150 1155

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1160 1165 1170 -1011 - 200927761

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1175 1180 1185

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1190 1195 1200

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1205 1210 1215

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1220 1225 1230

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1235 1240 1245

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1250 1255 1260

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1265 1270 1275

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1280 1285 1290

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1295 1300 1305

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg -1012- 200927761 1310 1315 1320

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345

<210〉 605 <211> 1356 <212> PRT <213〉現代人 <400〉 605

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80 1013- 200927761 數種抗體製劑（包括’如：U2_24、U2_5、U2_19、U2·21、 U2-15和U2-4 2抗體製劑）顯示出強力結合表現HB-EGF之 CHO細胞。類似地’抗體製劑U2-39、U2-26、U2-44、 U2-4 5和U2-48亦顯示出與表現HB-EGF之CHO細胞良好結合。表2 抗HB-EGF抗體上清液之FACS分析(第1群)

CHO對照組細胞對表現 HB-EGF之CH0細胞內生性表現HB-EGF之細胞株抗體 CHO-K1 CHO-HB- EGF MDA-MB231 SCC-9 COS:7 KLH 0.2 0.3 0.4 0.2 0.4 U2-18 0.3 154 3.1 1.2 1.6 U2-68 0.2 238 1.7 0.6 1.1 U2-24 0.2 360 2 0.6 6.7 U2-14 0.3 132 2.8 0.8 1.1 U2-1 0.2 64 1.8 0.7 3.1 U2-32 0.2 76 1.7 1.2 1.8 U2-40 0.2 137 2.1 1.3 1.1 U2-5 0.3 371 6.9 1.7 2.2 U2-8 0.3 148 3.7 1.4 1.4 U2-13 0.2 136 0.4(2.6) 0.5 0.8 U2-17 0.2 170 1.6 0.6 1.4 U2-19 0.4 347 5.5 1.8 6.1 U2-38 0.3 30 3.9 0.9 1.4 U2-21 0.2 344 3.9 3.4 2.1 U2-15 0.2 370 3 0.6 0.9 U2-16 0.2 197 1.5 0.4 0.9 U2-30 0.3 273 3.5 1 3,4 U2-44 0.3 5.6 0.8 0.2 5.2 U2-42 1.2 277 3.3 0.5 6.7 U2-36 0.9 112 1.6 0.3 4.9 U2-22 0.3 221 1.1 0.2 4.9 U2-56 0.2 38 0.5 0.2 1.8 Neg 0.2 0.2 0.3 Pos (山羊 aHB) 0.2 80 3 -123- 200927761

Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Trp Ser Asn Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Ala Cys 165 170 175

Asn Ala Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Ala Thr His Gly Thr Asn Ala Cys 210 215 220

Asn Trp Ser Asn Met Gly Asn Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240 -1014- 200927761

Trp Ser Asn Met Thr Asn Ala Ala Arg Met Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285 ❹

Thr Gly Tyr Gly Cys Asn Met Gly Asn Trp Ser Asn Gly Cys Asn Met 290 295 300

Thr Asn Met Gly Asn Thr Ala Tyr Thr Thr Tyr Gly Ala Tyr Thr Gly 305 310 315 320

Gly Met Thr Asn Thr Thr Tyr Trp Ser Asn Gly Ala Tyr Gly Thr Asn 325 330 335

Trp Ser Asn Gly Ala Tyr Ala Thr His Thr Gly Gly Gly Gly Asn Cys 340 345 350

Ala Arg Gly Gly Asn Ala Cys Asn Ala Thr Gly Gly Thr Asn Ala Cys 355 360 365

Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn 370 375 380 -1015- 200927761

Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly 385 390 395 400

Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys 405 410 415

Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn 420 425 430

Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly 435 440 445

Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr 450 455 460

Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn 465 470 475 480

Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp 485 490 495

Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys 500 505 510

Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn 515 520 525

Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly 530 535 540 -1016- 200927761

Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly 545 550 555 560

Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 565 570 575

Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys 580 585 590 〇

Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly 595 600 605

Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn 610 615 620

Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala 625 630 635 640

Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala 645 650 655

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn 660 665 670

Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly 675 680 685 -1017- 200927761

Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly 690 695 700

Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn 705 710 715 720

Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr 725 730 735

Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala 740 745 750

Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn 755 760 765

Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys 770 775 780

Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr 785 790 795 800

Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn 805 810 815

Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly 820 825 830

Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala 835 840 845 -1018- 200927761

Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg 850 855 860

Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala 865 870 875 880

Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala 885 890 895 〇

Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn 900 905 910

Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly 915 920 925

Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala 930 935 940

Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr 945 950 955 960

Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr 965 970 975

Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala 980 985 990 -1019- 200927761

Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn 995 1000 1005

Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His 1010 1015 1020

Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn 1025 1030 1035

Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn 1040 1045 1050

Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn 1055 1060 1065

Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg 1070 1075 1080

Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr 1085 1090 1095

Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn 1100 1105 1110

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn 1115 1120 1125

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr 1130 1135 1140 -1020- 200927761

Ala Thr 1145

Gly Ala 1160

His Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly 1150 1155

Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg 1165 1170

Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr 1180 1185

Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn 1195 1200

Cys Cys 1175 ❹ Ala Ala 1190

Ala Thr 1205

Gly Gly 1220 Thr Ala 1235

Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr 1210 1215

Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn 1225 1230

Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn 1240 1245

Gly Thr 1250

Thr Gly 1265

Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn 1255 1260

Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr 1270 1275 -1021 - 200927761

Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn 1280 1285 1290

Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn 1295 1300 1305

Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr 1310 1315 1320

Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn 1325 1330 1335

Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 1340 1345 1350

Ala Ala Arg 1355 <210〉 606 <211> 1338 <212〉 PRT <213〉現代人 <400〉 606

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Met Thr 20 25 30 -1022 - 200927761

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Ala Arg 35 40 45

Trp Ser Asn Met Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Gly Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Met Gly Asn Thr Thr Tyr Ala Cys Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Ala Thr Gly Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 〇 130 135 140

Gly Gly Asn Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly 145 150 155 160

Ala Tyr Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Ala Cys Asn Met Gly 165 170 175

Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr -1023 - 200927761 表3 抗HB-EGF抗體上清液;mCS分析(第2群) CH0對照_胞對表現 HB_EGF之CHO細胞內生性表細B-EGF之細胞株抗體 CHO-K1 CHO-HB- EGF MDA-MB231 SCC-9 COS-7 U2-63 0.2 36(0.4) 0.5 0.2 0.6 U2-54 0.3 49 0.6 0.2 2.4 U2-65 0.2 1.9 0.4 0.2 0.3 U2-10 0.2 2.3 0.5 0.2 1.2 _ U2-53 0.2 144 0.5 0.2 0.6 U2-66 0.2 149 0.5 0.2 0.5 U2-61 0.4 28 0.4 0.2 1.4 U2-67 0.2 82 0.5 0.2 0.6 U2-28 0.3 198 1 0.2 3.2 U2-2 0.2 127 0.5 0.2 0.5 U2-62 0.2 47 0.5 0.2 0.6 U2-39 0.2 205 2.6 0.6 8.3 U2-3 0.2 168 0.9 0.2 2.5 U2-43 0.4 185 0.8 0.2 1.7 U2-34 0.7 125 1.2 0.3 6.4 U2-26 0.2 242 1.5 0.3 4.7 U2-41 0.3 186 1.2 0.2 3.3 U2-44 0.4 248 1.2 0.2 2.2 U2-45 0.6 248 1.4 0.2 6.4 U2-57 0.2 ^201 0.7 0.2 0.5 U2-12 0.6 1.2 1.2 0.5 1.6 U2-46 0.4 129 1 0.2 2.5 U2-48 0.4 273 1.3 0.3 2.1 U2-6 0.5 108 3.9 1.5 5.9 U2-58 0.2 277 0.9 0.2 0,4 U2-51 0.5 176 1.1 6.2 3.6 U2-60 0.2 3.6 0.4 0.2 0.3 Neg 0.2 0.2 0.3 Pos (山孝 aHB) 0.2 80 3 2.對經HB-EGF誘導之EGFR酪胺酸憐酸化的抑制作用 -124- 200927761 180 185 190

Cys Ala Arg Gly Gly Asn Cys Ala Arg Gly Thr Asn Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Ala Ala Arg Trp Ser 210 215 220

Asn Ala Thr His Trp Ser Asn Ala Cys Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Thr Gly Gly Trp Ser Asn Trp Ser Asn Met 245 250 255

Thr Asn Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Ala Thr Gly Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn Thr 290 295 300

Ala Tyr Gly Gly Asn Thr Ala Tyr Trp Ser Asn Thr Ala Tyr Thr Thr 305 310 315 320

Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335 -1024- 200927761

Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys 355 360 365

Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn 370 375 380

Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr 385 390 395 400

Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser 405 410 415

Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn 420 425 430

Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala 〇 435 440 445

Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala 450 455 460

Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn 465 470 475 480

Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met -1025 - 200927761 485 490 495

Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala 500 505 510

Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn 515 520 525

Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met 530 535 540

Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser 545 550 555 560

Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn 565 570 575

Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala 580 585 590

Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly 595 600 605

Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg 610 615 620

Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly 625 630 635 640 -1026 - 200927761

Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala 645 650 655

Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn 660 665 670

Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys 675 680 685

Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys 690 695 700

Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr 705 710 715 720

Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys 725 730 735

Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr 〇 740 745 750

Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn 755 760 765

Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly 770 775 780

Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala -1027 - 200927761 785 790 795 800

Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn 805 810 815

Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly 820 825 830

Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr 835 840 845

Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn 850 855 860

Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys 865 870 875 880

Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr 885 890 895

Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn 900 905 910

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys 915 920 925

Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly 930 935 940 -1028 - 200927761

Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr 945 950 955 960

Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly 965 970 975

Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr 980 985 990

His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 995 1000 1005

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1010 1015 1020

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1025 1030 1035

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 〇 1040 1045 1050

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1055 1060 1065

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1070 1075 1080

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr -1029- 200927761 1085 1090 1095

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1100 1105 1110

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1115 1120 1125

Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1130 1135 1140

Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1145 1150 1155

Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1160 1165 1170

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1175 1180 1185

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1190 1195 1200

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1205 1210 1215

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1220 1225 1230 -1030- 200927761

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1235 1240 1245

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1250 1255 1260

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1265 1270 1275

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1280 1285 1290

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1295 1300 1305

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 〇 1325 1330 1335 <210〉 607 <211〉 1341 <212〉 PRT <213〉現代人 <400> 607

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Cys 15 10 15 -1031 - 200927761

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Ala Arg 35 40 45

Trp Ser Asn Met Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Gly Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Trp Ser Asn Thr Thr Tyr Ala Cys Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Ala Thr Gly Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly 145 150 155 160 -1032 - 200927761

Ala Tyr Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Cys Asn Met Gly 165 170 175

Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr 180 185 190

Cys Ala Arg Gly Gly Asn Cys Ala Arg Gly Thr Asn Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Ala Ala Arg Trp Ser 210 215 220

Asn Ala Thr His Ala Ala Tyr Ala Cys Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Thr Gly Gly Trp Ser Asn Trp Ser Asn Met 245 250 255

Thr Asn Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Ala Thr Gly Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Cys Ala Arg Gly Gly Asn Thr Ala Tyr Gly 290 295 300

Gly Asn Trp Ser Asn Gly Gly Asn Thr Gly Gly Gly Gly Asn Thr Ala 305 310 315 320 -1033 - 200927761 使用下列實驗計劃來鑑定何種抗hb-egf抗體製劑可抑制經HB-EGF誘導之表皮生長因子受體酪胺酸磷酸化作用。這類實驗進一步決定該抗體之特徵並協助鑑定何種雜交瘤細胞株可製造抑制HB-EGF活性之抗體而應加以選殖及擴增。

將40000個SCC9人類鱗狀細胞癌之細胞接種在96-槽盤中之100微升介質中。令細胞在60微升不含血清之介質中飢餓24小時。在4°C，以100微升抗EGFR抗體（2 微克/毫升）塗覆黑色Maxisorp 96槽盤一整夜。不需清洗，以3 00微升封閉溶液（PBS + 0.5%BSA)取代塗覆溶液並留在室溫中培育2小時。將10微克/毫升之IgG2對照組 (Sigma)或自雜交瘤衍生之抗HB-EGF抗體加入20奈克/毫升HB-EGF(R&D系統）中，並在37°C預先培育30分鐘（體積：40微升）。在37t，以單獨之介質處理細胞或以抗體/ 配體處理溶液細胞3分鐘。去除介質，在冰上，以100微升之以Triton-X-100爲底質的含ImM PMSF、10微克/毫升抑肽酶（Aprotinin)、10mM NaF及2mM原釩酸鈉的溶胞緩衝劑將細胞溶解。以PBS + 0.05%吐溫20清洗封閉之 Maxisorp盤。將80微升細胞溶胞化物直接轉移至經清洗之Maxisorp盤，並在4 °C培育一整夜且一邊輕輕地攪動。以PBS + 0.05%吐溫20清洗盤6次，再在各槽中加入100 微升在稀釋緩衝劑（PBS + 0.5%BSA + 0.05%吐溫 20 + 5mM EDTA)中稀釋4000倍的4G10-生物素（UBI)，並在室溫下培育2小時。以PBS+0.05 %吐溫20清洗盤6次’再在各 -125- 200927761

Tyr Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn 325 330 335

Cys Ala Arg Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala 340 345 350

Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser 355 360 365

Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn 370 375 380

Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys 385 390 395 400

Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys 405 410 415

Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn 420 425 430

Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly 435 440 445

Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys 450 455 460 -1034- 200927761

Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn 465 470 475 480

Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly 485 490 495

Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr 500 505 510

Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn 515 520 525

Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly 530 535 540

Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser 545 550 555 560

Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn 565 570 575

Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly 580 585 590

Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys 595 600 605

Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr 610 615 620 -1035 - 200927761

Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala 625 630 635 640

Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr 645 650 655

Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr 660 665 670

Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr 675 680 685

Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr 690 695 700

Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn 705 710 715 720

Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala 725 730 735

Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr 740 745 750

Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn 755 760 765 -1036 200927761

Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly 770 775 780

Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser 785 790 795 800

Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg 805 810 815

Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr 820 825 830

Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala 835 840 845

Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg 850 855 860

Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 865 870 875 880

Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys 885 890 895

Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn 900 905 910

Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys 915 920 925 -1037- 200927761

Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala 930 935 940

Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg 945 950 955 960

Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala 965 970 975

Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys 980 985 990

Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His 995 1000 1005

Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn 1010 1015 1020

Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn 1025 1030 1035

Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn 1040 1045 1050

Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg 1055 1060 1065 -1038 - 200927761

Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr 1070 1075 1080

Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn 1085 1090 1095

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn 1100 1105 1110

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr 1115 1120 1125

Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly 1130 1135 1140

Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg 1145 1150 1155

Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr ▲ 1160 1165 1170 ❹

Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn 1175 1180 1185

Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr 1190 1195 1200

Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn 1205 1210 1215 -1039- 200927761

Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn 1220 1225 1230

Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn 1235 1240 1245

Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr 1250 1255 1260

Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn 1265 1270 1275

Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn 1280 1285 1290

Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr 1295 1300 1305

Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn 1310 1315 1320

Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 1325 1330 1335

Ala Ala Arg 1340 -1040- 200927761 <210〉 608 <211〉 1359 <212〉 PRT <213〉現代人 <400> 608

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30 ❹

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Ala Arg 35 40 45

Trp Ser Asn Met Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Gly Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80 ❹

Tyr Trp Ser Asn Thr Thr Tyr Ala Cys Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Ala Thr Gly Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125 -1041 - 200927761

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly 145 150 155 160

Gly Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Ala Thr His Met Gly 165 170 175

Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr 180 185 190

Cys Ala Arg Gly Gly Asn Cys Ala Arg Gly Thr Asn Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Ala Ala Arg Trp Ser 210 215 220

Asn Ala Thr His Trp Ser Asn Ala Cys Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Thr Gly Gly Trp Ser Asn Trp Ser Asn Met 245 250 255

Thr Asn Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Ala Thr Gly Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr -1042 - 200927761 275 280 285

Gly Cys Asn Met Gly Asn Cys Ala Arg Gly Gly Asn Met Thr Asn Gly 290 295 300

Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Ala Cys Asn Trp Ser 305 310 315 320

Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr 325 330 335 ❹

Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly 340 345 350

Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Cys Asn Gly Thr 355 360 365

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn 370 375 380 〇

Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp 385 390 395 400

Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys 405 410 415

Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn 420 425 430 1043 200927761 槽中加入100微升在稀釋緩衝劑（PBS + 0.5%BSA + 0.05%吐溫20 + 5mM EDTA)中稀釋20000倍之與AP結合的抗生蛋白鏈菌素（UBI)並在室溫下培育30分鐘。以PBS + 0.05%吐溫20清洗盤6次，再在各槽中加入100微升之AttoPhos 受質。將盤在室溫、黑暗中培育3小時，在30、90和180 分鐘時監測逐漸形成之螢光（激發：43 0nm，發射：5 80nm) 〇藉由觀察到之由各種自雜交瘤衍生之抗HB-EGF抗體製劑所造成之IgG2對照組（Sigma)磷酸化減少的量來計算經HB-EGF誘導之EGFR酪胺酸磷酸化受抑制的百分比。各不同之抗HB-EGF抗體製劑的結果提供在第23A和 23B圖中。如所說明者，單株抗體製劑U2-18、U2-24、 U2-19、U2-42、U2-39、U2-34、U2-45 和 U2-6 顯示出強力抑制EGFR酪胺酸磷酸化。 3.抗HB-EGF抗體製劑抑制經LPA誘導之EGFR磷酸化作用

EGFR倚賴性傳訊途徑可在刺激與G蛋白偶合之受體 (GPCR)時被活化。經由與GPCR交互作用而造成之雜三聚體G蛋白配體活化作用可產生誘導跨膜金屬蛋白酶之胞外活性的胞內細胞信號。可活化GPCR途徑之配體包括： LPA(溶血磷脂酸）、凝血酶、碳醯膽鹼、鈴蟾素及內皮素。這類活化作用導致跨膜生長因子先質之胞外處置並釋出成熟因子，此成熟因子直接或透過蛋白多糖母質與EGFR -126- 200927761

Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly 435 440 445

Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr 450 455 460

Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr 465 470 475 480

Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly 485 490 495

Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly 500 505 510

Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn 515 520 525

Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly 530 535 540

Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser 545 550 555 560

Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn 565 570 575

Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly -1044 - 200927761 580 585 590

Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr 595 600 605

Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr 610 615 620

Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys 625 630 635 640 〇

Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys 645 650 655

Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn 660 665 670

Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr 675 680 685 〇

Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys 690 695 700

Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn 705 710 715 720

Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly 725 730 735 1045 200927761

Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys 740 745 750

Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn 755 760 765

Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala 770 775 780

Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly 785 790 795 800

Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn 805 810 815

Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly 820 825 830

Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly 835 840 845

Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn 850 855 860

Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala 865 870 875 880

Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala -1046 - 200927761 885 890 895

Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn 900 905 910

Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp 915 920 925

Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr 930 935 940 ❹

Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn 945 950 955 960

Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala 965 970 975

Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala 980 985 990 〇

Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn 995 1000 1005

Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn 1010 1015 1020

Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 1025 1030 1035 -1047- 200927761

Gly Gly 1040

Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1045 1050

Cys Cys 1055

Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1060 1065

Met Thr 1070

Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn 1075 1080

Gly Ala 1085

Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1090 1095

Ala Ala 1100

Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn 1105 1110

Ala Cys 1115

Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1120 1125

Gly Gly 1130

Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1135 1140

Gly Ala 1145

Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1150 1155

Thr Gly 1160

Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn 1165 1170

Cys Ala

Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr -1048 - 200927761 1175 1180 1185

Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1190 1195 1200

Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn 1205 1210 1215

Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr 1220 1225 1230 〇

Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1235 1240 1245

Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1250 1255 1260

Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn 1265 1270 1275 〇

Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr 1280 1285 1290

Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg 1295 1300 1305

Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr 1310 1315 1320 -1049 - 200927761

Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn 1325 1330 1335

Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn 1340 1345 1350

Gly Gly Asn Ala Ala Arg 1355 <210> 609 <211> 1353 <212〉 PRT <213〉現代人 <400> 609

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Cys Ala Arg Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Gly Ala 65 70 75 80 -1050- 200927761

Tyr Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Trp Ser Asn Gly Cys Asn Gly Cys Asn Thr Gly Gly Ala Ala Tyr Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Trp Ser Asn Cys Cys 115 120 125 ❹

Asn Trp Ser Asn Met Gly Asn Gly Gly Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Met Thr Asn Gly Gly Asn Met Gly Asn Ala Cys Asn Thr 145 150 155 160

Ala Tyr Thr Gly Tyr Met Gly Asn Trp Ser Asn Ala Ala Arg Thr Gly 165 170 175

Gly Thr Ala Tyr Ala Ala Tyr Gly Ala Tyr Thr Ala Tyr Gly Cys Asn 180 185 190

Gly Thr Asn Trp Ser Asn Gly Thr Asn Ala Ala Arg Trp Ser Asn Met 195 200 205

Gly Asn Ala Thr His Ala Cys Asn Ala Thr His Ala Ala Tyr Cys Cys 210 215 220 -1051 - 200927761

Asn Gly Ala Tyr Ala Cys Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr 225 230 235 240

Cys Ala Arg Thr Thr Tyr Trp Ser Asn Met Thr Asn Cys Ala Arg Met 245 250 255

Thr Asn Ala Ala Tyr Trp Ser Asn Gly Thr Asn Ala Cys Asn Cys Cys 260 265 270

Asn Gly Ala Arg Gly Ala Tyr Ala Cys Asn Gly Cys Asn Gly Thr Asn 275 280 285

Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly 290 295 300

Ala Tyr Met Gly Asn Gly Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly 305 310 315 320

Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 325 330 335

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Ala Cys Asn Ala Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn 370 375 380 -1052- 200927761

Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr 385 390 395 400

Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly 405 410 415

Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn 420 425 430 ❹

Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met 435 440 445

Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala 450 455 460

Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg 465 470 475 480

Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr 485 490 495

Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr 500 505 510

Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr 515 520 525 -1053 - 200927761 之外域（ectodomain)交互作用並透過磷酸化作用活化之。見，Prenzel et al1 999, Nature 402 ： 884-888 〇利用下列程序測試此處提供之抗HB-EGF抗體製劑以確認其是否可抑制COS-7細胞中由GPCR配體LPA誘導之EGFR酪胺酸磷酸化。

將250.000個COS-7細胞接種在6槽盤中之2毫升介質中並培養一整夜。令細胞在1毫升不含血清之介質中飢餓24小時。與抗體預先培育後（37°C，1小時），以ΙΟμιη LPA刺激細胞（37 °C，3分鐘），再在冰上，以400微升之以Triton-X-100爲底質的含有ImM PMSF、10微克/毫升抑肽酶、l〇mM NaF及2mM原釩酸鈉的溶胞緩衝劑將細胞溶解。在低溫室將EGFR免疫沈澱（340微升溶胞化物， 340微升HNTG，30微升蛋白A瓊脂糖凝膠（Sepharose)， 1.5 微升 aEGFR ( 108.1，Prenzel 等人，1 999，同上））4 小時後，以500微升HNTG緩衝劑清洗沈澱物3次，再將 φ 其在 7.5%SDS PAGE上移行。轉移至硝基纖維素膜 (Schleicher&Schuell)上後，以辨識磷酸酪胺酸殘基之抗體 (初級抗體4G10(1:2000，Upstate生物技術）；二級抗老鼠抗體1 : 1 0000，Jackson實驗室）探測墨跡。剝除後重新以綿羊抗EGFR(Upstate生物技術）進行點墨顯示出等量受體沈澱在各道中。第24圖提供西方點墨之結果，其說明何種抗HB-EGF 抗體製劑可抑制經LPA誘導之EGFR酪胺酸磷酸化。如第 24圖所示，U2-19和U2-42抗HB-EGF抗體製劑強力抑制 -127- 200927761

Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met 530 535 540

Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr 545 550 555 560

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 565 570 575

Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp 580 585 590

Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys 595 600 605

Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr 610 615 620

Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys 625 630 635 640

Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr 645 650 655

Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg 660 665 670

Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly 675 680 685 -1054 - 200927761

Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys 690 695 700

Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn 705 710 715 720

Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met 725 730 735

O

Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys 740 745 750

Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly 755 760 765

Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly 770 775 780

Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr 785 790 795 800

Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr 805 810 815

Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys 820 825 830 -1055 - 200927761

Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr 835 840 845

Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn 850 855 860

Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala 865 870 875 880

Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala 885 890 895

Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr 900 905 910

Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met 915 920 925

Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala 930 935 940

Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn 945 950 955 960

Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala 965 970 975

Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly 980 985 990 -1056- 200927761

Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His 995 1000 1005

Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 1010 1015 1020

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1025 1030 1035

O

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1040 1045 1050

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1055 1060 1065

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1070 1075 1080

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1085 1090 1095

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1100 1105 1110

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1115 1120 1125 -1057 - 200927761

Thr Ala 1130

Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1135 1140

Gly Cys 1145

Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1150 1155

Trp Ser 1160

Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1165 1170

Gly Ala 1175

Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1180 1185

Ala Cys 1190

Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1195 1200

Met Thr 1205

Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1210 1215

Trp Ser 1220

Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1225 1230

Trp Ser 1235

Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1240 1245

Gly Ala 1250

Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1255 1260

Cys Ala 1265

Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1270 1275 1058 200927761

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1280 1285 1290

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1295 1300 1305

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1310 1315 1320 〇

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345 1350

<210> 610 <211> 336 <212> PRT <213>現代人 <400〉 610

Gly Ala Tyr Gly Thr Asn Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn -1059- 200927761 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Tyr Thr Asn Gly Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Cys Ala Asn Thr Ala Tyr Tyr 100 105 110

Thr Asn Ala Ala Tyr Thr Gly Gly Thr Thr Tyr Cys Ala Arg Cys Ala 115 120 125

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Trp Ser Asn 130 135 140

Cys Cys Asn Met Gly Asn Met Gly Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Thr Gly 165 170 175

Gly Gly Ala Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190 1060- 200927761

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Ala Ala Tyr Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Trp Ser Asn 275 280 285

Cys Ala Asn Cys Ala Tyr Thr Gly Gly Cys Cys Asn Ala Thr His Cys 〇 290 295 300

Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala 305 310 315 320

Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335 <210〉 611 -1061 200927761 <211〉 336 <212〉 PRT <213〉現代人 <400〉 611

Gly Ala Tyr Gly Thr Asn Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 1 5 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Tyr Thr Asn Gly Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Cys Ala Asn Thr Ala Tyr Tyr 100 105 110

Thr Asn Ala Ala Tyr Thr Gly Gly Thr Thr Tyr Cys Ala Arg Cys Ala 115 120 125 -1062 - 200927761

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Trp Ser Asn 130 135 140

Cys Cys Asn Met Gly Asn Met Gly Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Thr Gly 165 170 175

Gly Gly Ala Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr His Cys Ala Arg Gly Gly Asn 275 280 285 -1063 - 200927761 由LPA誘導之EGFR磷酸化。U2-24抗HB-EGF抗體製劑以較輕微之程度抑制經LPA誘導之EGFR酪胺酸磷酸化。〇.實例5:用來產生單株抗體之雜交瘤選殖法根據從前述實例中描述之實驗觀察到之試驗結果，藉由限制性稀釋從49個原始分離物中選出43個雜交瘤細胞株以供選殖並進一步決定其單株抗體之特性。藉由FACS 分析顯示出所選出之用於選殖的細胞株可結合表現HB-EGF之細胞株並抑制經HB-EGF刺激之EGF受體酪胺酸磷酸化。某些雜交瘤所產生之抗體不夠用於運作所有初級篩檢分析。將此雜交瘤子集合再進一步進行雜交瘤選殖。 P.實例6:進一步描述與抗體相關之對經GPCR誘導之EGFR酪胺酸磷酸化的抑制作用之特性本實例提供其他資料證明此處提供之數種抗HB-EGF 抗體製劑顯示出以劑量倚賴之方式抑制經GPCR誘導之 EGF受體酪胺酸磷酸化。利用不同濃度之候選抗體製劑U2-42、U2-39和U2-45及下列程序檢査這些抗體製劑之抑制作用。將 1 50,000 個細胞（MDA-MB231，PPC1)接種在 12 槽盤中之1毫升介質中。令細胞在500微升不含血清之介質中飢餓24小時。在4°C，以100微升抗EGFR抗體（2微克 /毫升）塗覆黑色Maxisorp 96槽盤一整夜。不需清洗，以 3 00微升封閉溶液（？88 + 0.5%88八）取代塗覆溶液並留在室 -128- 200927761

Cys Ala Asn Cys Ala Tyr Thr Gly Gly Cys Cys Asn Cys Ala Asn Cys 290 295 300

Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala 305 310 315 320

Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335 <210〉 612 <211〉 336 <212〉 PRT <213〉現代人 <400〉 612

Gly Ala Tyr Gly Thr Asn Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala -1064 - 200927761 65 70 75 80

Arg Trp Ser Asn Tyr Thr Asn Gly Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Cys Ala Asn Thr Ala Tyr Tyr 100 105 110

Thr Asn Ala Ala Tyr Thr Gly Gly Tyr Thr Asn Cys Ala Arg Cys Ala 115 120 125 ©

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Trp Ser Asn 130 135 140

Cys Cys Asn Met Gly Asn Met Gly Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Thr Gly 165 170 175 〇

Gly Gly Ala Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly Ala 210 215 220 -1065 - 200927761

Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Gly Gly Asn 275 280 285

Cys Ala Asn Cys Ala Tyr Thr Gly Gly Cys Cys Asn Ala Thr His Cys 290 295 300

Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala 305 310 315 320

Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335 <210〉 613 <211> 336 <212〉 PRT <213〉現代人 <400> 613

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15 -1066- 200927761

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Cys Cys Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60 ❹

Ser Asn Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Tyr Thr Asn Tyr Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Arg Cys Ala Asn Thr Ala Tyr Tyr 100 105 110

Thr Asn Thr Ala Tyr Thr Gly Gly Thr Ala Tyr Tyr Thr Asn Cys Ala 115 120 125

Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Cys Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160 -1067 - 200927761

Ala Tyr Gly Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Gly Gly Asn 275 280 285

Ala Thr His Cys Ala Arg Tyr Thr Asn Cys Cys Asn Thr Gly Tyr Trp 290 295 300

Ser Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala 305 310 315 320 -1068 - 200927761

Asn Ala Ala Arg Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335 <210〉 614 <211〉 336 <212> PRT <213>現代人 <400〉 614

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Cys Cys Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 〇 50 55 60

Ser Asn Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Tyr Thr Asn Tyr Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Arg Cys Ala Asn Thr Ala Tyr Tyr -1069- 200927761 100 105 110

Thr Asn Thr Ala Tyr Thr Gly Gly Thr Ala Tyr Tyr Thr Asn Cys Ala 115 120 125

Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Cys Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Gly Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255 -1070- 200927761

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Trp Ser Asn 275 280 285

Ala Thr His Cys Ala Arg Tyr Thr Asn Cys Cys Asn Tyr Thr Asn Cys 290 295 300

Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys Ala 305 310 315 320

Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335 <210〉 615 <211> 336 <212〉 PRT <213〉現代人 <400> 615

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Cys Cys Asn Gly Gly Asn 35 40 45 -1071 - 200927761

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Tyr Thr Asn Tyr Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Arg Cys Ala Asn Thr Ala Tyr Tyr 100 105 110

Thr Asn Thr Ala Tyr Thr Gly Gly Thr Thr Tyr Tyr Thr Asn Cys Ala 115 120 125

Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Cys Ala Arg Cys Cys Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Gly Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190 -1072 200927761

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Trp Ser Asn 275 280 285

Ala Thr His Cys Ala Arg Tyr Thr Asn Cys Cys Asn Ala Thr His Cys 290 295 300

Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Tyr Gly Gly Asn Cys Ala 305 310 315 320

Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335 <210〉 616 <211〉 321 -1073 200927761

溫中培育2小時。將細胞與10微克/毫升抗HB-EGF抗體在37°C下預先培育30分鐘，再在37°C，以GPCR配體 LPA(10pm，PPC1 細胞）或凝血酶（1 U/毫升，MD Α-ΜΒ23 1 細胞）處理3分鐘。去除介質，在冰上，以200微升之以 Triton-X-100爲底質之含 ImM PMSF、10微克/毫升抑肽酶、10mM NaF及2mM原釩酸鈉的溶胞緩衝劑將細胞溶解。以PBS + 0.05%吐溫20清洗封閉之Maxisorp盤6次。將細胞溶胞化物直接轉移至清洗過之Maxisorp盤，再在4°C 下培育一整夜，並輕輕攪動。以PBS + 0.05%吐溫20清洗盤6次，再在各槽中加入 100微升在稀釋緩衝劑（PBS + 0.5%BSA + 0.05%吐溫20 + 5mM EDTA)中稀釋4000倍的4G10-生物素（UBI)並在室溫下培育2小時。以PBS + 0.05%吐溫20清洗盤6次，再在各槽中加入1〇〇微升在稀釋緩衝劑（PBS + 0.5%BSA + 0.05%吐溫 20 + 5mM EDTA)中稀釋20000倍之與AP結合的抗生蛋白鏈菌素（UBI)並在室溫下培育30分鐘。以PBS + 0.05%吐溫 20清洗盤6次，再在各槽中加入1〇〇微升之AttoPhos受質。將盤在室溫、黑暗中培育3小時，在30、90和180 分鐘時監測逐漸形成之螢光（激發：430ηιη，發射：5 80nm) 如第26圖所示，對經LPA誘導之EGFR酪胺酸磷酸化的抑制作用爲劑量倚賴性-當抗ΗΒ-EG抗體之量增加時可觀察到較強之對EGFR酪胺酸磷酸化的抑制作用。第25圖說明候選抗體製劑U2-42、U2-39和U2-45亦 -129- 200927761 <212> PRT <213〉現代人 <400> 616

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Gly Asn Ala Thr His Gly Cys Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Thr 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His -1074- 200927761 130 135 140

Thr Ala Tyr Gly Thr Asn Gly Cys Asn Trp Ser Asn Cys Ala Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190 ❹

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240 〇

Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Ala Ala Tyr Thr Ala 260 265 270

Tyr Ala Ala Tyr Trp Ser Asn Gly Cys Asn Cys Cys Asn Thr Thr Tyr 275 280 285 -1075- 200927761

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320

Arg <210> 617 <211〉 321 <212> PRT <213〉現代人 <400> 617

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Thr His Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -1076- 200927761

Arg Gly Gly Asn Ala Thr His Trp Ser Asn Ala Ala Tyr Gly Ala Tyr 85 90 95

Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Thr 115 120 125 〇

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Cys Ala Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr

210 215 220 -1077 - 200927761

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Ala Ala Arg Thr Ala 260 265 270

Tyr Ala Ala Tyr Trp Ser Asn Gly Thr Asn Cys Cys Asn Tyr Thr Asn 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210〉 618 <211〉 336 <212> PRT <213〉現代人 <400〉 618

Ala Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15 -1078 - 200927761

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Tyr Thr Asn Gly Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Cys Ala Asn Thr Ala Tyr Tyr 100 105 110

Thr Asn Trp Ser Asn Thr Gly Gly Tyr Thr Asn Cys Ala Arg Cys Ala 115 120 125

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Met Gly Asn Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Ala Thr His Trp Ser Asn Ala Ala Tyr Met Gly -1079 - 200927761 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Gly Cys Asn Gly Gly Asn Cys Ala Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Gly Cys Asn 275 280 285

Cys Ala Asn Cys Ala Arg Thr Thr Tyr Cys Cys Asn Cys Ala Tyr Cys 290 295 300

Ala Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala 305 310 315 320 -1080- 200927761

Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala Arg 325 330 335 <210> 619 <211〉 336 <212〉 PRT <213〉現代人 <400> 619 ·

Gly Ala Arg Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 0 15 10 15

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Tyr Thr Asn Gly Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Cys Ala Asn Thr Ala Tyr Tyr 100 105 110 -1081 - 200927761

Thr Asn Trp Ser Asn Thr Gly Gly Tyr Thr Asn Cys Ala Arg Cys Ala 115 120 125

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Met Gly Asn Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Ala Thr His Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Cys 195 200 205

Ala Asn Gly Gly Asn Gly Cys Asn Gly Gly Asn Cys Ala Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255 -1082 200927761

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Gly Cys Asn 275 280 285

Cys Ala Asn Cys Ala Arg Thr Thr Tyr Cys Cys Asn Cys Ala Tyr Cys 290 295 300

Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys Ala 305 310 315 320

Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335 <210> 620 <211> 324 <212〉 PRT <213〉現代人 <400〉 620

Gly Ala Arg Ala Thr His Gly Thr Asn Tyr Thr Asn Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Gly Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45 -1083 - 200927761 可有效抑制MDA-MB231細胞中經凝血酶誘導之EGFR磷酸化。當加入之抗HB-EGF抗體增加時，抑制作用亦增加，因而可觀察到劑量倚賴性抑制作用。第26圖說明藉由此處所提供之抗HB-EGF抗體製劑對PPC-1細胞中由LPA 誘導之EGFR酪胺酸磷酸化的抑制作用爲劑量倚賴性。如圖所示：當抗HB-EGF抗體製劑增加時可偵測到較強之對 EGFR酪胺酸磷酸化的抑制作用。 Q.實例7 :藉人抗HB-EGF抗體抑制經GPCR誘導之 MDA-MB231細胞移行進行轉移實驗以檢査此處提供之抗體是否阻斷經 GPCR配體神經鞘氨醇-1-磷酸酯誘導之細胞移行。將血清-飢餓之人類乳癌MDA-MB 231細胞與指出之對抗該細胞懸浮液的抗體在37 °C預先培育45分鐘。然後，將500毫升細胞懸浮液（50,000個細胞）置於以膠原蛋白I 塗覆之轉移槽（tranSwell)(BD Falcon，8微米小孔）的頂端小室中。在底部小室中使用750毫升單獨或含有GPCR配體神經鞘氨醇-卜磷酸酯（R&D系統）之介質（MEM、胺基酸、丙酮酸鈉、Pen-Strep、0· 1 %BSA)。在 37°C移行 8小時後，固定細胞，以DAPI染色，計算細胞核以供統計學評估。第27圖中提供使用候選之抗HB-EGF抗體製劑U2-42 、U2-39和U2-45進行之這些MDA-MB231細胞移行分析的結果。如圖中所示，抗HB-EGF抗體製劑U2-42抑制約 -130- 200927761

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Tyr Thr Asn Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Cys Ala Asn Gly Thr Asn Ala Thr His Trp Ser Asn Trp Ser Asn 85 90 95

Thr Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys 100 105 110

Ala Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala 115 120 125

Arg Gly Cys Asn Cys Cys Asn Met Gly Asn Tyr Thr Asn Tyr Thr Asn 130 135 140

Ala Thr His Trp Ser Asn Gly Gly Asn Gly Cys Asn Trp Ser Asn Trp 145 150 155 160

Ser Asn Met Gly Asn Gly Cys Asn Cys Ala Asn Gly Gly Asn Ala Thr 165 170 175

His Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn 180 185 190

Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys -1084 - 200927761 195 200 205

Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala 210 215 220

Asn Ala Thr His Trp Ser Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg 225 230 235 240

Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Gly 245 250 255 〇

Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala 260 265 270

Arg Thr Ala Tyr Gly Gly Asn Trp Ser Asn Trp Ser Asn Cys Cys Asn 275 280 285

Met Gly Asn Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly 290 295 300 ❹

Gly Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr 305 310 315 320

His Ala Ala Arg

<210> 621 <211> 318 <212> PRT -1085 - 200927761 <213>現代人 <400> 621

Gly Ala Arg Ala Thr His Gly Thr Asn Tyr Thr Asn Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Gly Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Tyr Thr Asn Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Trp Ser Asn Met Gly Asn Tyr Thr Asn 85 90 95

Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala 100 105 110

Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys 115 120 125

Asn Met Gly Asn Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 130 135 140 -1086- 200927761

Gly Gly Asn Gly Cys Asn Trp Ser Asn Met Gly Asn Met Gly Asn Gly 145 150 155 160

Cys Asn Cys Ala Asn Gly Gly Asn Ala Thr His Cys Cys Asn Gly Ala 165 170 175

Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn 180 185 190

Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr 195 200 205

Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser 210 215 220

Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Cys Cys Asn Gly Ala Arg 225 230 235 240

Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr 245 250 255

Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala Tyr Gly Gly 260 265 270

Asn Trp Ser Asn Trp Ser Asn Cys Cys Asn Met Gly Asn Trp Ser Asn 275 280 285 -1087- 200927761

Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Ala 290 295 300

Ala Arg Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 305 310 315 <210> 622 <211> 321 <212> PRT <213〉現代人 <400〉 622

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Gly Asn Ala Thr His Met Gly Asn Ala Ala Tyr Gly Ala Tyr 85 90 95 -1088- 200927761

Tyr Thr Asn Gly Gly Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Gly Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly © 195 200 205

Ala Arg Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr -1089 - 200927761 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Tyr Thr Asn Cys Ala Arg Cys Ala 260 265 270

Tyr Ala Ala Tyr Trp Ser Asn Thr Ala Tyr Cys Cys Asn Cys Cys Asn 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210〉 623 <211> 339 <212〉 PRT <213〉現代人 <400> 623

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30 1090 200927761

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Tyr Thr Asn Gly Thr Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Thr Thr Tyr Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190 -1091 - 200927761

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Cys Ala Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Thr Thr Tyr Cys Cys Asn Thr 290 295 300

Gly Gly Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335 -1092 200927761

Ala Ala Arg <210〉 624 <211> 339 <212〉 PRT <213〉現代人 <400〉 624

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15 ❹

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60 ❾

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110 -1093 - 200927761 70%之MDA-MB231細胞移行；抗HB-EGF抗體製劑U2-45 抑制約100%之MDA-MB231細胞移行；而抗HB-EGF抗體製劑U2-39抑制約100%之MDA-MB231細胞移行。因此，這些抗HB-EGF抗體抑制MDA-MB23 1細胞移行之能力是堅實的。〇

R.實例8 :藉人抗HB-EGF抗體抑制經HB-EGF誘導之MCF-7細胞移行進行轉移實驗以檢查此處提供之抗體是否阻斷經HB-EGF直接誘導之細胞移行。這些試驗之結果強調何種抗體製劑可用於發展作爲抗轉移癌作用劑。將血清-飢餓之人類乳癌MCF-7細胞（50,000個細胞）的細胞懸浮液置於以膠原蛋白I塗覆之轉移槽（BD Falcon ，8微米小孔）的頂端小室中。在有或無10微克/毫升HB-EGF抗體之存在下，將一份份750毫升單獨或含有20奈克/毫升HB-EGF (R&D系統）之介質（MEM、胺基酸、丙酮酸鈉、Pen-Strep、0.1%BSA)置於底部小室中。在 37°C培育及移行8小時後，固定細胞，以DAPI染色，計算細胞核以供統計學評估。第28圖中提供使用候選之抗HB-EGF抗體製劑U2-42 、U2-3 9和U2-45進行之這些移行分析的結果。如圖中所示，抗HB-EGF抗體製劑U2-42抑制約55%之MCF-7細胞移行；抗HB-EGF抗體製劑U2-45抑制約93%之MCF-7細胞移行；而抗HB-EGF抗體製劑U2-39抑制約 98°/。之 -131 - 200927761

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr -1094 - 200927761 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Cys Ala Asn Cys Ala Asn Thr 290 295 300

Gly Gly Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg

<210> 625 <211> 339 <212> PRT <213〉現代人 <400> 625

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30 -1095 - 200927761

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Ala Ala Tyr Gly Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190 -1096 - 200927761

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240 〇

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Cys Ala Asn Cys Cys Asn Met 290 295 300

Gly Asn Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335 -1097 200927761

Ala Ala Arg <210> 626 <211> 339 <212〉 PRT <213〉現代人 <400> 626

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Ala Ala Tyr Gly Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110 -1098 - 200927761

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 〇 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr -1099 - 200927761 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Cys Ala Asn Cys Cys Asn Met 290 295 300

Gly Asn Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg <210> 627 <211〉 339 <212> PRT <213〉現代人 <400> 627

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30 -1100- 200927761

Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn 0 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190 -1101 - 200927761

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Gly Gly Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Ala Thr His Trp Ser Asn Met 290 295 300

Gly Asn Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335 -1102 200927761

Ala Ala Arg <210> 628 <211〉 339 <212> PRT <213〉現代人 <400〉 628

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15 ❹

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60 〇

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Tyr Thr Asn Thr Ala Tyr Ala Ala Tyr 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110 -1103 - 200927761 MCF-7細胞移行。因此’這些抗HB-EGF抗體抑制MCF-7 細胞移行之能力是堅實的。 S.實例9 :最佳之10種抗HB-EGF抗體的特性下列表4中提供最佳之1〇種自雜交瘤衍生之抗體製劑於經GPCR誘導之三層膜通行傳訊（TMPS)實驗中的結果之摘要。該TMPS實驗涉及SCC9細胞中之LPA刺激、 MDA-MB231細胞中之凝血酶剌激、SkOV-8細胞中之LPA 刺激、MDA-MB231之神經鞘氨醇-1-磷酸酯移行。所提供之數據代表與無抗體存在之相同分析相比較時’於分析中使用抗體製劑時所觀察到之對TMP S轉錄激活信號的抑制百分比。各實驗之最佳之3種抗體以粗體字母強調。表4 TMPS轉錄激活信號的抑制百分比 TMPS mf Ab SCC9.3 MDA-MB231 MDA-MB231 SkoV-8 SkoV-8 MDA-MB231 U2-39 56.9 126.6 131.1 130.7 65.5 115 U2-45 58.5 136.8 95.7 99.4 75.1 104 U2-42 62.8 123.2 125.6 110.7 73.1 69.9 U2-34 50.6 109.5 93.6 95.1 73 99.6 U2-46 36.6 88.1 77.5 80.5 76.1 n.d. U2-19 n_d_ n.d. n.d. n.d. n.d. 85 U2-26 n.d. 143 91.8 106.1 31.4 55.9 U2-51 n.d. n.d. n.d. n.d n.d. 85.3 U2-15 n.d. 121.7 92.6 87 17.6 45.5 U2-22 n.d. 74.2 94.3 64.4 18.2 n.d. T.實例10 :藉人抗HB-EGF抗體抑制經HB-EGF誘導之HER4酪胺酸磷酸化本實例顯示出抗HB-EGF抗體製劑抑制經HB-EGF誘 -132- 200927761

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Tyr Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr -1104- 200927761 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Cys Ala Asn Cys Ala Asn Thr 290 295 300

Gly Gly Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg

<210〉 629 <211> 339 <212〉 PRT <213〉現代人 <400〉 629

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30 -1105 - 200927761

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Tyr Thr Asn Thr Ala Tyr Ala Ala Tyr 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190 -1106- 200927761

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 210 215 220

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Tyr Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Cys Ala Asn Cys Ala Asn Thr 290 295 300

Gly Gly Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335 -1107 200927761

Ala Ala Arg <210> 630 <211〉 339 <212> PRT <213〉現代人 <400〉 630

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110 -1108- 200927761

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Gly Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 〇 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240

Ala Thr His Trp Ser Asn Gly Gly Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Tyr Thr -1109- 200927761 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Cys Ala Asn Ala Thr Gly Thr 290 295 300

Thr Tyr Trp Ser Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Tyr Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg <210〉 631 <211> 339 <212〉 PRT <213〉現代人 <400〉 631

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30 1110 200927761

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Tyr Thr Asn Gly Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190 -1111 - 200927761

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Thr Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Tyr Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Cys Ala Asn Cys Cys Asn Tyr 290 295 300

Thr Asn Cys Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly 305 310 315 320

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Cys Asn Ala Thr His 325 330 335 -1112 200927761

Ala Ala Arg <210〉 632 <211> 339 <212> PRT <213〉現代人 <400〉 632

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15 〇

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60 〇

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Tyr Thr Asn Thr Ala Tyr Met Gly Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110 -1113- 200927761 導之HER4酪胺酸磷酸化。使用下列程序來評估抗HB_ EGF抗體對HE R4酪胺酸磷酸化之效果。將1 25,000個T47D人類乳癌細胞接種在24_槽盤中之 5 00微升介質中。令細胞在200微升不含血清之介質中飢餓24小時。使用R&D系統人類磷酸-ErbB4 ELISA套組來偵測HER4酪胺酸磷酸化。在室溫下，以100微升老鼠抗-人 ErbB4抗體（捕捉抗體 1微克/毫升）塗覆透明之 0 Maxisorp 96槽盤一整夜。以PBS + 0.05%吐溫20清洗經塗覆之 Maxisorp 盤 6 次，以 300 微升封閉溶液 (PBS + 0.5%BSA)取代清洗溶液並在室溫中培育2小時。將 50微升具有5x濃度抗ΗΒ-EGF抗體（10微克/毫升）不含血清之介質與5x濃度HB-EGF(20奈克/毫升）一起在37°C培育30分鐘，再將其加入各槽中（複製二份）。去除介質，在冰上，以 200微升之以 Triton-X-100爲底質之含 ImM PMSF、10微克/毫升抑肽酶、10mM NaF及2mM原釩酸鈉 ^ 的溶胞緩衝劑將細胞溶解。以P B S + 0.0 5 %吐溫2 0清洗經封閉之Maxisorp盤3次。將細胞溶胞化物直接轉移至經過清洗之Maxisorp盤，在4°C培育一整夜並輕輕地攪動之。以PBS + 0.05%吐溫20清洗盤6次，再在各槽中加入 1〇〇微升在稀釋緩衝劑（PBS + 0.5%BSA + 0.05%吐溫20 + 5mM EDTA)中稀釋之抗-磷酸-酪胺酸-HRP(偵測抗體600奈克/ 毫升），並在室溫下培育2小時。以PBS+0.05%吐溫20清洗盤6次，在各槽中加入1〇〇微升之四甲基聯苯胺（TMB ’ Calbiochem)，再將盤在室溫下培育20分鐘。加入50微 -133- 200927761

Ala Tyr Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Gly Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr -1114- 200927761 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Thr Tyr Ala Thr His Cys Ala Asn Cys Cys Asn Tyr 290 295 300

Thr Asn Cys Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly 305 310 315 320 ❹

Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg

<210〉 633 <211〉3.21 <212〉 PRT 〇 <213〉現代人 <400> 633

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30 -1115- 200927761

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Cys Ala Tyr Thr Ala Tyr 85 90 95

Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Thr Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Trp Ser Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Ala Ala Arg Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190 -1116- 200927761

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Cys Cys Asn Thr Thr Tyr 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320

Arg -1117- 200927761 <210〉 634 <211〉 321 <212〉 PRT <213>現代人 <400〉 634

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly Cys Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Tyr Thr Asn Gly Cys Asn Thr Gly Gly Tyr Thr Asn Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125 -1118- 200927761

Asn Cys Cys Asn Ala Ala Arg Trp Ser Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 〇 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Ala Ala Tyr Cys Ala Asn Thr Ala Tyr Cys Cys Asn Thr Thr Tyr -1119- 200927761 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Ala Thr Gly Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320

Arg <210> 635 <211> 324 <212〉 PRT <213>現代人 <400> 635

Gly Ala Arg Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Cys Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Tyr Thr Asn Trp 50 55 60 1120- 200927761

Ser Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr 85 90 95

Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Gly Ala Tyr Cys Cys Asn Gly Gly Asn Cys Ala Arg Gly Cys 〇 115 120 125

Asn Cys Cys Asn Met Gly Asn Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Gly Asn Gly Cys Asn Trp Ser Asn Met Gly Asn Met 145 150 155 160

Gly Asn Gly Cys Asn Cys Ala Asn Gly Gly Asn Ala Thr His Cys Cys 165 170 175

Asn Gly Cys Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Arg Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220 -1121 - 200927761

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Trp Ser Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Gly Thr Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Cys Ala 260 265 270

Tyr Ala Ala Tyr Ala Ala Tyr Thr Gly Gly Cys Cys Asn Cys Cys Asn 275 280 285

Thr Gly Gly Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly 290 295 300

Gly Asn Cys Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr 305 310 315 320

His Ala Ala Arg <210〉 636 <211〉 321 <212〉 PRT <213>現代人 <400> 636

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys -1122- 200927761 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Gly Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60 〇

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Met Gly Asn Thr Gly Gly 85 90 95

Tyr Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110 〇

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160 -1123 - 200927761 升之 1M H2S04以終止反應並在 450run處讀取吸收 (Thermo Lab Systems ELISA 分析儀）。結果顯示於第29圖中。如所說明者，抗-HB-EGF抗體製劑U2-42.1或U2-39.1之濃度增加造成經HB-EGF誘導之HER4酪胺酸磷酸化受抑制的程度增加。 U.實例1 1 :單株抗體交叉反應性此實例提供其他資料來證明抗猿猴HB-EGF、老鼠 HB-EGF及相關之似EGF生長因子雙調蛋白之抗HB-EGF 抗體製劑的交叉反應性。選殖猴子及老鼠型HB-EGF後，以各表現構造物轉染HEK293細胞，在FACS實驗中測試抗體結合這些蛋白質之能力。藉由ELIS A版式分析測試雙調蛋白之交叉反應性。

1.選殖猿猴HB-EGF 本硏究中係製備猿猴HB-EGF質體。藉由聚合酶鏈反應（PCR)，以根據猿猴 HB-EGF序列之引物自猿猴腎臟 cDNA 選殖猿猴 HB-EGF cDNA。用於將猿猴HB-EGF增數之引物如下：前向引物： 5'-GGG TTA ACG CCA CCA TGA AGC TGC TGC CGT CG-3' (SEQ ID NO: 1048) 逆向引物： 5'-CCG CTC GAG GTG GGA ATT AGT CAT GCC C -3' (SEQ ID NO: 1049) 以Hpal和Xhol分解PCR產物並連接入以Hind3分 -134- 200927761

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Gly Cys 260 265 270

Asn Ala Ala Tyr Trp Ser Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Thr Thr Tyr Ala Ala -1124- 200927761 305 310 315 320

Arg <210> 637 <211〉321 <212> PRT <213〉現代人 <400> 637

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Cys Ala Asn Thr Ala Tyr 85 90 95 -1125 - 200927761

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Thr Thr Tyr Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205 ❹

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Gly Cys Asn Thr 245 250 255 -1126- 200927761

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Cys Ala Tyr Trp Ser Asn Gly Cys Asn Cys Cys Asn Thr Thr Tyr 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys 290 295 300 〇

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320

Arg

<210> 638 <211> 318 <212> PRT <213〉現代人 <400〉 638

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn -1127- 200927761 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Cys Ala Asn Ala Thr His Trp Ser Asn Ala Thr His Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190 -1128- 200927761

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Trp Ser Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn 275 280 285

Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys Ala Asn Ala 〇 290 295 300

Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 305 310 315 <210> 639 <211〉 321 <212> PRT <213〉現代人 -1129- 200927761 <400〉 639

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Met Gly Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Ala Ala Tyr Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140 -1130- 200927761

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Met Gly Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 赢 245 250 255 ❹

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Trp Ser Asn Ala Thr His Cys Cys Asn Tyr Thr Asn 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys 290 295 300 -1131 - 200927761

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210> 640 <211> 321 <212> PRT <213>現代人 <400〉 640

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Gly 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Cys Ala Asn Ala Thr His Xrp Ser Asn Met Gly Asn Thr Ala Tyr -1132- 200927761 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140 ❹

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Cys Ala Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190 ❹

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr 210 215 220

Asn Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240 -1133 - 200927761 解之pCDNA3.1中。純化後，將猿猴HB-EGF質體轉 DH5a細菌細胞中，並在安苄青黴素選擇之條件下使增。然後，使用單一之轉形選殖株令質體高度表現於青黴素選擇介質中。利用市售之DNA純化套組純化猿猴HB-EGF質體短暫轉染HEK293T細胞。形入之倍安苄後以〇 2.選殖老鼠HB-EGF 本硏究中係製備老鼠HB-EGF質體。藉由聚合酶應（PCR)，以根據老鼠HB-EGF序列之引物自老鼠 cDNA 選殖老鼠 HB-EGF cDNA。用於將老鼠HB-EGF增數之引物如下：鏈反肺臟前向引物： 5-GGA ATT CGC CAC CAT GAA GCT GCTGCC GTC G-3' (SEQ ID NO: 1050) 逆向引物= 5，-CCG CTC GAG GTG GGA GCT AGC AGC CAC GCC-3. (SEQ ID NO: 1051)

以EcoRl和Xhol分解PCR產物及pCDNA3.1 DNA並連接之。純化後，將老鼠HB-EGF質體轉形入 α細菌細胞中，並在安苄青黴素選擇之條件下使之倍然後，使用單一之轉形選殖株令質體高度表現於安苄素選擇介質中。利用市售之DNA純化套組純化後以載體 DH5 增。青黴老鼠 HB-EGF質體短暫轉染ΗΕΚ293 Τ細胞。 3.猿猴及老鼠HB-EGF之轉染和表現爲了篩檢此處提供之抗體的交叉反應性，利用磷酸鈣 -135- 200927761

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Ala Thr 260 265 270

His Thr Ala Tyr Trp Ser Asn Cys Ala Asn Trp Ser Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210〉 641 <211〉 321 <212〉 PRT <213〉現代人 <400〉 641

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30 -1134- 200927761

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 ❹

Arg Met Gly Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Gly Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Ala Arg Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175 1135- 200927761

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Ala Thr His Cys Ala Asn Cys Cys Asn Ala Thr His 275 280 285

G

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Thr 305 310 315 320

His -1136 200927761 <210〉 642 <211〉 321 <212〉 PRT <213〉現代人 <400〉 642

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Met Gly Asn Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys -1137- 200927761 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Cys Ala Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Ala Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270 -1138- 200927761

Asn Thr Ala Tyr Thr Thr Tyr Cys Ala Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320 ❹ Arg <210> 643 <211> 321 <212〉 PRT <213〉現代人 <400〉 643

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60 -1139- 200927761

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Cys Ala Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205 1140 200927761

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr Thr 210 215 220

Tyr Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Trp Ser Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala ^ 305 310 315 320 〇

Arg <210〉 644 <211〉 321 <212〉 PRT <213>現代人 <4〇〇> 644 -1141 - 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Cys Ala Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr -1142- 200927761 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205 〇

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr 210 215 220

Asn Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Trp Ser Asn Thr 245 250 255 ❹

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Thr Tyr Thr Ala Tyr Cys Ala Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300 -1143 - 200927761 法以猿猴或老鼠HB-EGF質體短暫轉染HEK293T細胞，接著藉由FACS分析來分析之。因此，在轉染前30小時將3X106個HEK293T細胞接種在15公分細胞培養盤中之16毫升介質中，並在7%C02 及37 °C下培育。將在720微升二次蒸餾水中之32微克猿猴或老鼠 HB-EGF DNA或空載體與 2.5M CaCl2和 2xBBS(pH6.96)混合並在室溫中培育10分鐘。培育後，將溶液一滴滴地滴在細胞上並在3%C02及37°C下培育8 小時。在介質中浸泡後，將細胞與新鮮之生長介質在 7%C02及3 7〇C下培育24小時。 4.進行FACS分析以篩檢抗體之交叉反應性因此，以在PBS中之10mM EDTA收成2xl05個經轉染之細胞，將其再懸浮於FACS緩衝劑（PBS，3%FCS， 0.4 %疊氮化物）中並接種在96槽圓底盤中。在lOOOrpm離心3分鐘以去除上清液後，將細胞再懸浮於抗HB-EGF抗體稀釋液（100微升/槽）中並在4°C中培育 45分鐘。以 FACS緩衝劑清洗細胞二次並與在FACS緩衝劑中稀釋100 倍之二級抗體（100微升/槽）驢-抗-人- PE(Jackson) —起再懸浮。將細胞懸浮液在、黑暗中培育30分鐘，以FACS 緩衝劑清洗二次再分析之（FACS，Beckmam Coulter)。第3 0 A圖顯示出三種單株抗體製劑與來自猿猴之pro-HB-EGF交叉反應。第3 0B圖顯示出藉由FACS分析偵測出U2-45單株抗 -136- 200927761

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210> 645 <211> 321 <212> PRT <213>現代人 <400〉 645

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 1 5 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95 -1144- 200927761

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240 -1145- 200927761

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Cys Ala Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210〉 646 <211> 321 <212〉 PRT <213>現代人 <400〉 646

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30 -1146- 200927761

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 〇 130 135 140

Thr Ala Tyr Cys Ala Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn -1147- 200927761 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Trp Ser Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Thr Tyr Thr Ala Tyr Gly Cys Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg -1148- 200927761 <210〉 647 <211〉 321 <212〉 PRT <213>現代人 <400〉 647

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125 -1149- 200927761

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Cys Ala Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270 -1150- 200927761

Asn Thr Ala Tyr Thr Thr Tyr Cys Ala Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210> 648 <211〉 321 <212> PRT <213〉現代人 <400〉 648

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15 ❹

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60 -1151 - 200927761

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr 145 150 155 160

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr -1152- 200927761 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270 ❹

Tyr Gly Ala Tyr Thr Ala Tyr Tyr Thr Asn Cys Cys Asn Thr Thr Tyr 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320 ❹

Arg <210> 649 <211> 321 <212〉PRT <213〉現代人 <400〉 649 -1153 - 200927761 體製劑與老鼠HB-EGF交叉反應。進一步之試驗顯示出抗體U2-46和U2-51亦偵測老鼠HB-EGF。然而，抗體U2-45.1僅非常微弱（5-10%)地中和由老鼠HB-EGF誘導之 EGFR酪胺酸磷酸化。

5.雙調蛋白交叉反應性ELISA分析之議定計劃在4°C下，以不同濃度之雙調蛋白（R&D系統，濃度：在PBS中之1奈克/毫升、10奈克/毫升、1〇〇奈克/毫升）塗覆 96槽盤（Nunc，Maxisorp) —整夜。以清洗緩衝劑 (PBS + 0.05%吐溫20 ; 150微升/槽）清洗盤後（6次），將盤與封閉緩衝劑（PBS + 0.5%BSA，100微升/槽）在室溫下培育 4小時。以清洗緩衝劑清洗盤6次。使用在抗體稀釋緩衝劑（含〇_5%BSA、0.05%吐溫 20、5mM EDTA 之 PBS)中之 5微克/毫升經純化的人抗HB-EGF抗體作爲初級抗體並在室溫下培育90分鐘。以清洗緩衝劑清洗盤6次，加入二級抗人-POD(Dianova)抗體（在含〇.5%BSA、0.05% 吐溫 20 、5mM EDTA之PBS中稀釋10000倍）並在室溫中培育60 分鐘。以清洗緩衝劑清洗盤6次後，在室溫下加入TMB受質（默克生物科技）15分鐘。加入1〇〇微升之25 0mM HC1 以停止藍色形成並以免疫分析儀（Thermo labsystems)在 4 5 0 n m測量吸收。第30C圖顯示出藉由ELISA版式分析測定出抗體U2-45及微弱抗體U2-46結合雙調蛋白。U2-45單株抗體結合 -137- 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Gly Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr 145 150 155 160 -1154- 200927761

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

O

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Gly 260 265 270

Tyr Gly Ala Tyr Gly Ala Tyr Tyr Thr Asn Cys Cys Asn Tyr Thr Asn 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys 290 295 300 -1155- 200927761

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210> 650 <211> 321 <212> PRT <213〉現代人 <400〉 650

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Gly Ala Tyr Thr Ala Tyr 85 90 95 -1156- 200927761

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr 145 150 155 160

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr -1157- 200927761 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Tyr Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Tyr Thr Asn Cys Cys Asn Tyr Thr Asn 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210> 651 <211> 321 <212> PRT <213〉現代人 <400> 651

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30 -1158- 200927761

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly Cys Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr © 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr 145 150 155 160

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190 -1159- 200927761

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Tyr Thr Asn Cys Cys Asn Tyr Thr Asn 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg -1160- 200927761 <210> 652 <211〉 321 <212〉 PRT <213〉現代人 <400> 652

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30 ❹

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 ❹

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125 1161 - 200927761

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Thr His Tyr 145 150 155 160

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Ala Arg Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Gly 260 265 270

Tyr Gly Ala Tyr Ala Thr His Tyr Thr Asn Cys Cys Asn Tyr Thr Asn -1162- 200927761 275 280 285

Trp Ser Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg ❸ <210〉 653 <211> 321 <212〉 PRT <213>現代人 <400〉 653

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60 -1163 - 200927761

雙調蛋白，但U2-45.1對雙調蛋白之KD僅爲8nM(相對於其對HB-EGF之KD爲0.043nM)。U2-45.1單株抗體對AR 亦爲非中和性。 V.實例 12:抗 HB-EGF 單株抗體 U2-42.2、U2-39.1、 U2-45.3、U2-26.2和U2-3 4.1之KD値的動力學排除試驗分析利用KinExA技術測定單株抗體U2-42.2、U2-39.1、 U2-45.3、U2-26.2 和 U2-34.1 結合人 HB-EGF 之 KD 値。爲此，使用KinExA 3000儀器。在所有單株抗體之滴定方面，在4°C下將50毫克之吖內酯珠與在5 OmM碳酸鈉緩衝劑（pH9.0)中之HB-EGF(〜29微克）偶合一整液。將HB-EGF 與小珠結合後，將小珠離心沈下，以封閉緩衝劑（1 M Tris 緩衝劑，pH8.3，10毫克/毫升BSA)清洗1次，再次離心，然後將其在~2 3 °C，封閉緩衝劑中培育1至2小時以封閉任何存於小珠表面之剩餘的反應性吖內酯基團。封閉後，將小珠轉移至標準之KinExA小珠的小玻璃瓶內並將其置於儀器上。單株抗體U2-42.2 :進行雙重曲線分析以測定KD値。在控制KD之滴定曲線方面係以逐漸增加濃度之HB-EGF 來滴定12種含有37pM名義單株抗體結合部位濃度的溶液，在控制單株抗體之滴定曲線方面係滴定111 ΟρΜ結合部位溶液。各溶液之總體積爲10毫升（控制KD)或2毫升（控制單株抗體），使之在〜23°C平衡30-36小時（控制KD)或6 -138- 200927761

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr 145 150 155 160

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220 -1164- 200927761

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270 o

Tyr Gly Ala Tyr Ala Ala Tyr Tyr Thr Asn Cys Cys Asn Tyr Thr Asn 275 280 285

Gly Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys 290 295 300

Ala Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Met Gly 305 310 315 320

<210> 654 <211〉 321 <212> PRT <213〉現代人 <400> 654

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys -1165- 200927761 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Gly Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Cys Ala Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr 145 150 155 160 -1166- 200927761

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Gly Ala Tyr Trp Ser Asn Tyr Thr Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala -1167- 200927761 305 310 315 320

Arg <210〉 655 <211> 321 <212> PRT <213〉現代人 <400〉 655

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr 85 90 95 -1168- 200927761

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Tyr Thr Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Cys Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr ¢) 145 150 155 160

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255 -1169- 200927761

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Tyr Thr Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210〉 656 <211> 321 <212〉 PRT <213〉現代人 <400> 656

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn -1170- 200927761 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Gly Ala Tyr Thr Ala Tyr 85 90 95 〇

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140 ❿

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr 145 150 155 160

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190 -1171 - 200927761

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Tyr Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Tyr Thr Asn Cys Cys Asn Ala Thr His 275 280 285

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg <210> 657 -1172- 200927761 <211〉 321 <212〉 PRT <213〉現代人 <400> 657

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30 ❹

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn 85 90 95

Tyr Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125 -1173 - 200927761 小時（控制單株抗體）。所有用於滴定之溶液係利用玻璃量瓶製備，HB-EGF之濃度在1〇.5ηΜ至205 fM間變化。用於分析這些溶液之儀器方法包含將小珠包裝在玻璃毛細管中的小珠包裝步驟，令經平衡之溶液以0·25毫升/分鐘之速度流過小珠管柱10鐘（2.5毫升，控制KD)或1分鐘 (0.25毫升，控制單株抗體），複製三份。接著，將3.4nM( 控制KD)或l.lnM(控制單株抗體）經螢光標示之cy-5山羊 φ 抗-人（Fc特異性）多株抗體以0.5毫升/分鐘之速度流過小珠包2分鐘，以標示捕捉在小珠上之游離單株抗體結合部位。在670nm處測量在620nm處激發之來自小珠包的螢光發射。依附屬之KinExA軟體包（1.0.3版）的標準做法將所產生之螢光測量値轉化成游離單株抗體結合部位對總抗原濃度之％。利用KinEx A軟體將雙重曲線配合至1: 1平衡等溫模型中（包含漂移修正因子）。

配合數據之最理想的KD値爲53pM，95 %信賴區間之低和高極限値分別爲3 4 p Μ和8 1 p Μ。單株抗體U2 - 3 9.1 :製作控制KD之滴定曲線以測定 KD値。以逐漸增加濃度之HB-EGF來滴定12種含有55PM 名義單株抗體結合部位濃度的溶液。各溶液之總體積爲10 毫升，並使之在〜23 °C平衡3 0-3 6小時。所有用於滴定之溶液係利用玻璃量瓶製備，HB-EGF之濃度係在10.5nM至 205 fM間變化。用於分析這些溶液之儀器方法包含將小珠包裝在玻璃毛細管中的小珠包裝步驟，令經平衡之溶液以 -139- 200927761

Asn Cys Cys Asn Ala Ala Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr 145 150 155 160

Thr Asn Gly Ala Arg Cys Ala Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Cys Ala Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Tyr Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Tyr Thr Asn Cys Cys Asn Ala Thr His 275 280 285 1174- 200927761

Cys Ala Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys 290 295 300

Ala Asn Met Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg ❹ <210〉 658 <211> 360 <212> PRT <213〉現代人 <400〉 658

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Ala -1175- 200927761 80 65 70 75

Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr His Trp Ser Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Cys Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Thr Gly Gly Ala Thr His Trp Ser Asn Gly Cys Asn Trp 145 150 155 160

Ser Asn Ala Ala Tyr Gly Gly Asn Ala Ala Tyr Cys Ala Asn Ala Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Tyr Thr Asn 180 185 190

Cys Ala Arg Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala 195 200 205

Thr Gly Cys Ala Asn Cys Ala Asn Gly Ala Tyr Cys Ala Asn Trp Ser 210 215 220 -1176- 200927761

Asn Cys Ala Asn Trp Ser Asn Cys Ala Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Ala Thr Gly Gly Ala Arg Tyr Thr Asn Met Gly Asn Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Trp Ser Asn Gly Ala Tyr Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Tyr Ala Ala Tyr Thr 290 295 300

Gly Gly Ala Ala Tyr Thr Ala Tyr Gly Gly Asn Thr Thr Tyr Thr Thr 305 310 315 320

Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn 355 360 <210> 659 -1177- 200927761 <211> 351 <212> PRT <213〉現代人 <400> 659

Cys Ala Arg Gly Thr Asn Cys Ala Tyr Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Gly Gly Asn Cys Ala Tyr 85 90 95

Thr Ala Tyr Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Cys Ala 115 120 125 -1178- 200927761

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Thr Gly Gly Ala Thr His Ala Ala Tyr Cys Cys Asn Ala 145 150 155 160

Ala Tyr Trp Ser Asn Gly Gly Asn Gly Gly Asn Cys Ala Asn Ala Ala 165 170 175

Tyr Thr Gly Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr 0 180 185 190

Cys Ala Arg Gly Gly Asn Met Gly Asn Gly Thr Asn Cys Ala Asn Ala 195 200 205

Thr Gly Cys Ala Asn Met Gly Asn Gly Ala Tyr Cys Ala Asn Trp Ser 210 215 220

Asn Ala Thr His Trp Ser Asn Cys Ala Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Ala Thr Gly Gly Ala Arg Tyr Thr Asn Trp Ser Asn Met Gly Asn Tyr 245 250 255

Thr Asn Met Gly Asn Trp Ser Asn Gly Ala Tyr Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285 -1179- 200927761

Gly Cys Asn Met Gly Asn Trp Ser Asn Ala Thr His Gly Cys Asn Gly 290 295 300

Thr Asn Gly Cys Asn Tyr Thr Asn Gly Ala Tyr Thr Ala Tyr Thr Gly 305 310 315 320

Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Tyr Thr Asn 325 330 335

Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 340 345 350 <210> 660 <211> 351 <212> PRT <213〉現代人 <400〉 660

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr -1180- 200927761 50 55 60

Gly Tyr Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Gly Gly Asn Thr Ala Tyr 85 90 95

Thr Ala Tyr Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110 ❹

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Cys Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Thr Gly Gly Ala Thr His Ala Ala Tyr Cys Cys Asn Ala 145 150 155 160

Ala Tyr Trp Ser Asn Gly Gly Asn Gly Gly Asn Cys Ala Asn Ala Ala 165 170 175

Tyr Cys Ala Tyr Cys Ala Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr 180 185 190

Cys Ala Arg Gly Gly Asn Met Gly Asn Gly Thr Asn Cys Ala Asn Ala 195 200 205 -1181 - 200927761

Thr Gly Cys Ala Asn Met Gly Asn Gly Ala Tyr Cys Ala Asn Trp Ser 210 215 220

Asn Ala Thr His Trp Ser Asn Cys Ala Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Ala Thr Gly Gly Ala Arg Tyr Thr Asn Trp Ser Asn Met Gly Asn Tyr 245 250 255

Thr Asn Met Gly Asn Trp Ser Asn Gly Ala Tyr Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Trp Ser Asn Ala Thr His Gly Cys Asn Gly 290 295 300

Thr Asn Gly Cys Asn Tyr Thr Asn Gly Ala Tyr Thr Ala Tyr Thr Gly 305 310 315 320

Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Tyr Thr Asn 325 330 335

Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 340 345 350 <210> 661 -1182- 200927761 <211> 366 <212> PRT <213〉現代人 <400〉 661

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30 ❹

Asn Met Gly Asn Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Gly Ala Arg Tyr Thr Asn 85 90 95

Trp Ser Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125 1183 - 200927761 0.25毫升/分鐘之速度流過小珠管柱10鐘（2.5毫升），複製三份。接著，將3·4ηΜ經螢光標示之cy-5山羊抗·人（Fc 特異性）多株抗體以0.5毫升/分鐘之速度流過小珠包2分鐘，以標示捕捉在小珠上之游離單株抗體結合部位。在 670nm處測量在620nm處激發之來自小珠包的螢光發射。利用附屬之KinExA軟體包（1.0.3版）將所產生之螢光測量値轉化成游離單株抗體結合部位對總抗原濃度之％。由於配體非特異性結合至小珠包，利用KinExA軟體將滴定曲線配合至1: 1平衡等溫模型中（包含配體非特異性結合）。配合數據之最理想的KD値爲7.8pM，95%信賴區間之低和高極限値分別爲5.6pM和1 1 pM。單株抗體U2-45.3 :進行雙重曲線分析以測定KD値。在控制KD之滴定曲線方面係以逐漸增加濃度之HB-EGF 來滴定12種含有40PM名義單株抗體結合部位濃度的溶液，在控制單株抗體之滴定曲線方面係滴定1 060pM結合部位溶液。各溶液之總體積爲10毫升（控制KD)或2毫升（控制單株抗體），使之在〜23t平衡3 0-3 6小時（控制KD)或6 小時（控制單株抗體）。所有用於滴定之溶液係利用玻璃量瓶製備，HB-EGF之濃度在5.25nM至102fM間變化。用於分析這些溶液之儀器方法包含將小珠包裝在玻璃毛細管中的小珠包裝步驟，令經平衡之溶液以0.25毫升/分鐘之速度流過小珠管柱10鐘（2.5毫升，控制KD)或1分鐘 (0.25毫升，控制單株抗體），複製三份。接著，將3.4nM( 控制KD)或l.lnM(控制單株抗體）經螢光標示之cy-5山羊 200927761

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Trp Ser Asn Thr Thr Tyr Gly Ala Tyr Cys Cys Asn Gly 145 150 155 160

Ala Arg Gly Ala Tyr Gly Gly Asn Gly Ala Arg Cys Ala Asn Ala Thr 165 170 175

His Thr Ala Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr 180 185 190

Cys Ala Arg Gly Gly Asn Met Gly Asn Gly Thr Asn Cys Ala Asn Ala 195 200 205

Thr Gly Tyr Thr Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Trp Ser 210 215 220

Asn Cys Ala Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Ala Thr Gly Gly Ala Arg Tyr Thr Asn Trp Ser Asn Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Trp Ser Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285 -1184- 200927761

Gly Cys Asn Cys Ala Asn Gly Ala Arg Gly Gly Asn Gly Ala Tyr Gly 290 295 300

Gly Asn Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala 305 310 315 320

Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly 325 330 335 ❹

Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala Asn Gly 340 345 350

Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 355 360 365

<210> 662 <211> 366 <212> PRT <213>現代人 <400〉 662

Cys Ala Arg Gly Thr Asn Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Thr Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Gly Ala Arg -1185- 200927761 35 40 45

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Ala Ala Tyr Gly Cys Asn 85 90 95

Met Gly Asn Ala Thr Gly Gly Gly Asn Gly Thr Asn Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Tyr Thr Asn Gly Cys Asn Cys Ala Tyr Ala Thr His Thr 145 150 155 160

Thr Tyr Trp Ser Asn Ala Ala Tyr Gly Ala Tyr Gly Ala Arg Ala Ala 165 170 175

Arg Trp Ser Asn Thr Ala Tyr Trp Ser Asn Cys Ala Asn Trp Ser Asn 180 185 190 -1186- 200927761

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Tyr Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Ala Ala Arg Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Trp Ser Asn Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Tyr Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Ala Thr Gly Thr Ala Tyr Trp 290 295 300

Ser Asn Trp Ser Asn Gly Gly Asn Thr Gly Gly Thr Ala Tyr Gly Gly 305 310 315 320

Asn Gly Thr Asn Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly 325 330 335

Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly -1187- 200927761 340 345 350

Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 355 360 365 <210> 663 <211〉 369 <212> PRT <213>現代人 <400〉 663

Cys Ala Arg Gly Thr Asn Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Thr Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Gly Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Ala Ala Tyr Gly Cys Asn S5 90 95 -1188- 200927761

Met Gly Asn Ala Thr Gly Gly Gly Asn Gly Thr Asn Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Tyr Thr Asn Gly Thr Asn Tyr Thr Asn Ala Thr His Thr 0 145 150 155 160

Thr Tyr Trp Ser Asn Ala Ala Tyr Gly Ala Tyr Gly Ala Arg Ala Ala 165 170 175

Arg Trp Ser Asn Thr Ala Tyr Trp Ser Asn Cys Ala Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Tyr Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Ala Ala Arg Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Trp Ser Asn Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Tyr Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Ala 245 250 255 -1189- 200927761

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Thr Asn Thr Ala Tyr Trp 290 295 300

Ser Asn Trp Ser Asn Gly Gly Asn Thr Gly Gly Trp Ser Asn Thr Thr 305 310 315 320

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 325 330 335

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys 340 345 350

Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 355 360 365

Asn <210〉 664 <211〉 354 <212〉 PRT <213>現代人 -1190- 200927761 <400> 664

Cys Ala Arg Ala Thr His Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Cys Ala Arg 35 40 45

O

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Ala Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala Arg 130 135 140 -1191 - 200927761

Thr Gly Gly Tyr Thr Asn Gly Cys Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Tyr Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Cys Ala Asn Ala Ala Arg Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Tyr Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Met Gly Asn Gly -1192- 200927761 290 295 300

Ala Arg Tyr Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn 325 330 335

Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350 ❹

Ser Asn <210> 665 <211> 354 <212〉 PRT <213〉現代人 <400〉 665

Cys Ala Arg Ala Thr His Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Cys Ala Arg 35 40 45 -1193 - 200927761 抗-人（Fc特異性）多株抗體以0.5毫升/分鐘之速度流過小珠包2分鐘，以標示捕捉在小珠上之游離單株抗體結合部位。在670nm處測量在620nm處激發之來自小珠包的螢光發射。依附屬之KinExA軟體包（1 .0·3版）的標準做法將所產生之螢光測量値轉化成游離單株抗體結合部位對總抗原濃度之％。利用KinEx Α軟體將雙重曲線配合至1: 1平衡等溫模型中（包含漂移修正因子）。 0 配合數據之最理想的KD値爲43pM，95%信賴區間之低和高極限値分別爲27pM和65pM。單株抗體U2-26.2 :進行雙重曲線分析以測定KD値。在控制KD之滴定曲線方面係以逐漸增加濃度之HB-EGF 來滴定12種含有41PM名義單株抗體結合部位濃度的溶液，在控制單株抗體之滴定曲線方面係滴定1〇60ρΜ結合部位溶液。各溶液之總體積爲10毫升（控制KD)或2毫升（控制單株抗體），使之在〜23°C平衡3 0-3 6小時（控制KD)或6 0 小時（控制單株抗體）滴定。所有用於滴定之溶液係利用玻璃量瓶製備，HB-EGF之濃度在2.63πΜ至51.4fM間（控制 KD)及5.26nM至103fM間（控制單株抗體）變化。用於分析這些溶液之儀器方法包含將小珠包裝在玻璃毛細管中的小珠包裝步驟，令經平衡之溶液以0.25毫升/分鐘之速度流過小珠管柱10鐘（2.5毫升，控制KD)或1分鐘（0.25毫升，控制單株抗體），複製三份。接著，將3.4nM(控制KD) 或l.lnM(控制單株抗體）經螢光標示之cy-5山羊抗-人（Fc 特異性）多株抗體以0.5毫升/分鐘之速度流過小珠包2分 -141 - 200927761

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Ala Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Tyr Thr Asn Gly Cys Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Tyr Thr Asn Cys 195 200 205 -1194- 200927761

Ala Asn Ala Thr His Cys Ala Asn Ala Ala Arg Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Cys Ala Asn Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Tyr Thr Asn Cys Ala Asn Gly Thr Asn Cys Ala Asn Gly 245 250 255 ❹

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Ala Ala Tyr Thr 290 295 300

Gly Gly Cys Ala Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn 325 330 335

Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350 -1195- 200927761

Ser Asn <210> 666 <211〉 354 <212〉 PRT <213〉現代人 <400> 666

Cys Ala Arg Ala Thr His Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Tyr Cys Ala Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110 -1196- 200927761

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Tyr Thr Asn Gly Cys Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Tyr Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Cys Ala Asn Ala Ala Arg Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Tyr Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala -1197- 200927761 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Tyr Thr Asn Gly 290 295 300

Ala Arg Tyr Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn 325 330 335

Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn <210〉 667 <211〉 354 <212> PRT · <213〉現代人 <400〉 667

Cys Ala Arg Ala Thr His Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15 -1198- 200927761

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 0 65 70 75 80

Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Ala Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Tyr Thr Asn Gly Cys Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175 -1199 - 200927761

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Tyr Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Cys Ala Asn Ala Ala Arg Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Tyr Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Ala 245 250 255

Ala Tyr Tyr Thr Asn Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Met Gly Asn Gly 290 295 300

Ala Arg Gly Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320 -1200 200927761

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn 325 330 335

Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn

<210〉 668 <211> 354 <212〉 PRT <213〉現代人 <400〉 668

Cys Ala Arg Ala Thr His Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Cys Ala Asn Tyr Thr 20 25 30 〇

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80 -1201 - 200927761

Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Ala Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Tyr Thr Asn Gly Cys Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Thr Asn Gly Ala Arg Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Met Gly Asn Trp Ser Asn Met Gly Asn Tyr Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Cys Ala Asn Ala Ala Arg Gly Cys Asn Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn -1202- 200927761 225 230 235 240

Gly Thr Asn Tyr Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr 275 280 285 ❹

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Cys Ala Tyr Cys 290 295 300

Ala Asn Ala Ala Tyr Cys Cys Asn Thr Thr Tyr Gly Ala Arg Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn 325 330 335 ❹

Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn

<210〉 669 <211> 354 <212〉 PRT -1203 - 200927761 鐘，以標示捕捉在小珠上之游離單株抗體結合部位。在 670nm處測量在620nm處激發之來自小珠包的螢光發射。依附屬之KinExA軟體包（1.0.3版）的標準做法將所產生之螢光測量値轉化成游離單株抗體結合部位對總抗原濃度之 %。利用KinEx A軟體將雙重曲線配合至1: 1平衡等溫模型中（包含漂移修正因子）。配合數據之最理想的KD値爲61 pM，95%信賴區間之低和高極限値分別爲37pM和ΙΟΟρΜ。單株抗體U2-34.1:製作控制KD之滴定曲線以測定 KD値。以逐漸增加濃度之HB-EGF來滴定12種含有40PM 名義單株抗體結合部位濃度的溶液。各溶液之總體積爲10 毫升，使之在〜23 t平衡3 0-3 6小時。所有用於滴定之溶液係利用玻璃量瓶製備，HB-EGF之濃度在 5.26nM至 1 03 fM間變化。用於分析這些溶液之儀器方法包含將小珠包裝在玻璃毛細管中的小珠包裝步驟，令經平衡之溶液以 0.25毫升/分鐘之速度流過小珠管柱10鐘（2.5毫升），複製三份。接著，將5.1nM經螢光標示之cy-5山羊抗·人（Fc 特異性）多株抗體以0.5毫升/分鐘之速度流過小珠包2分鐘，以標示捕捉在小珠上之游離單株抗體結合部位。在 670nm處測量在620nm處激發之來自小珠包的營光發射。依附屬之KinExA軟體包（1.0.3版）的標準作法將所產生之螢光測量値轉化成游離單株抗體結合部位對總抗原濃度之 %。由於配體非特異性結合至小珠包，利用KinExA軟體將滴定曲線配合至1: 1平衡等溫模型中（包含配體非特異 -142- 200927761 <213〉現代人 <400〉 669

Cys Ala Arg Ala Thr His Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Ala Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala Arg 130 135 140 -1204 - 200927761

Thr Gly Gly Tyr Thr Asn Gly Cys Asn Tyr Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190 ❹

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Tyr Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Cys Ala Asn Ala Ala Arg Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Tyr Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr 275 280 285 -1205 - 200927761

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Gly Gly Asn Gly 290 295 300

Ala Arg Tyr Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn 325 330 335

Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn <210> 670 <211> 363 <212〉PRT <213〉現代人 <400〉 670

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45 1206- 200927761

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Cys Asn Thr Thr Tyr Trp Ser Asn Met Gly Asn Thr Ala Tyr 85 90 95

Trp Ser Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Gly Cys Asn Ala Thr His Trp Ser Asn Trp Ser Asn Trp Ό 145 150 155 160

Ser Asn Trp Ser Asn Trp Ser Asn Thr Ala Tyr Ala Thr His Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala -1207 - 200927761 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly 290 295 300

Gly Asn Gly Cys Asn Cys Ala Asn Cys Cys Asn Gly Ala Tyr Gly Cys 305 310 315 320

Asn Thr Thr Tyr Gly Ala Tyr Ala Thr His Thr Gly Gly Gly Gly Asn 325 330 335

Cys Ala Arg Gly Gly Asn Cys Ala Asn Ala Thr Gly Gly Thr Asn Cys 340 345 350 -1208 - 200927761

Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 355 360 <210> 671 <211> 384 <212> PRT <213〉現代人 <400〉 671

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Tyr Thr Asn Gly 〇 1 5 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Cys Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110 -1209 - 200927761

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Trp 145 150 155 160

Ser Asn Gly Gly Asn Gly Gly Asn Trp Ser Asn Cys Ala Asn Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255 -1210 200927761

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Ala Ala Arg Gly Ala Arg Gly Gly Asn Ala Thr His Gly 290 295 300

Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Ala Asn Gly Cys ^ 305 310 315 320

Asn Gly Ala Arg Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr 325 330 335

Thr Ala Tyr Gly Cys Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr 340 345 350

Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala 355 360 365

Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 370 375 380 <210> 672 <211> 375 <212〉 PRT <213〉現代人 <400> 672 -1211 - 200927761

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Tyr Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Cys Asn Ala Thr Gly Trp Ser Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Trp -1212- 200927761 145 150 155 160

Ser Asn Gly Gly Asn Gly Gly Asn Trp Ser Asn Cys Ala Asn Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205 〇

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255 ❾

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Ala Ala Arg Gly Ala Arg Gly Gly Asn Ala Thr His Gly 290 295 300 -1213 - 200927761 性結合）。配合數據之最理想的KD値爲59pM，95%信賴區間之低和高極限値分別爲32pM和87PM。 W.實例13:抗體親和力斯卡查德（Scatchard)分析之測定方法藉由間接FACS斯卡查德分析進行此處所提供之抗體 0 的親和力測量。爲了進行此分析，以在PBS中之10mM EDTA收成2x105個所欲細胞，將其再懸浮在FACS緩衝劑（？88，3°/^〇3，0.4%疊氮化物）中並接種在96 -槽圓底盤上。在10 0 Orpm離心3分鐘以去除上清液，將細胞再懸浮於抗HB-EGF抗體稀釋液（100微升/槽），此抗HB-EGF抗體稀釋液係從20微克/毫升開始，以1 : 2稀釋步驟稀釋。將細胞懸浮液在4°C下培育45分鐘，.以FACS緩衝劑清洗二次，將其與在FACS緩衝劑中稀釋100倍之二級抗體 φ (100微升/槽）驢-抗-人PE(Jacks〇n)—起再懸浮。將細胞懸浮液在4°C、黑暗中培育30分鐘，以FACS緩衝劑清洗二次並分析之（FACS ’ Beckman Coulter)。根據FACS斯卡查德分析計算各次測量之螢光平均値。自各螢光平均値減去不含HB-EGF抗體之細胞的背景螢光。製作X値=螢光平均値，y値=螢光平均値/單株抗體濃度（nM)之斯卡査德繪圖。KD値爲線性方程式Ι/m之絕對値。 -143- 200927761

Cys Asn Gly Cys Asn Met Gly Asn Gly Ala Tyr Trp Ser Asn Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Cys Asn Ala Thr Gly 325 330 335

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Cys Ala Asn Cys Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn 370 375 <210> 673 <211> 375 <212〉 PRT <213>現代人 <400> 673

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Tyr Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45 1214 200927761

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95 ❹

Gly Cys Asn Ala Thr Gly Trp Ser Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Trp 145 150 155 160

Ser Asn Gly Gly Asn Gly Gly Asn Trp Ser Asn Cys Ala Asn Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190 -1215- 200927761

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Ala Arg Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Ala Ala Arg Gly Ala Arg Gly Gly Asn Ala Thr His Gly 290 295 300

Cys Asn Gly Gly Asn Met Gly Asn Gly Ala Tyr Trp Ser Asn Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 325 330 335

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350 -1216- 200927761

Gly Asn Cys Ala Asn Cys Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn 370 375

<210〉 674 <211> 369 <212〉 PRT ❹ <213〉現代人 <400〉 674

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr -1217- 200927761 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Thr Thr Tyr Ala Thr His Trp Ser Asn Gly Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Cys Ala Asn Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Thr Gly Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240 -1218- 200927761

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Gly 290 295 300

Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Thr Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Gly Gly Asn Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr 325 330 335

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Tyr 340 345 350

Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 355 360 365

Asn <210> 675 1219- 200927761 <211> 342 <212〉 PRT <213〉現代人 <400〉 675

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr·Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125 -1220 - 200927761

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285 -1221 - 200927761

Gly Cys Asn Met Gly Asn Ala Ala Tyr Gly Thr Asn Ala Thr His Gly 290 295 300

Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn 325 330 335

Trp Ser Asn Trp Ser Asn 340 <210〉 676 <211> 360 <212〉 PRT <213〉現代人 <400〉 676

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr -1222 - 200927761 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Ala Tyr Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110 〇

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160 ❿

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Thr His Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205 -1223 - 200927761 表5 FACS斯卡查德測定之抗體U242和U2-39對三種不同之人類癌細胞株的親和力胞株 DLD-1 NCI-ADR MDA-MB231 U2-42 4,88 5,98 0,41 U2-39 9,05 7,63 6,21 X.實例14 :抗HB-EGF單株抗體U2-4 5.3結合雙調蛋白之KD値的動力學排除試驗分析製作控制KD之滴定曲線以測定KD値。以逐漸增加濃度之雙調蛋白來滴定12種含有4·4ηΜ名義單株抗體結合部位濃度的溶液。各溶液之總體積爲毫升’並使之在〜2 3 °C平衡30-36小時。所有用於滴定之溶液係利用玻璃量瓶製備，雙調蛋白之濃度在1·23 μΜ至24pM間變化。用於分析這些溶液之儀器方法包含將小珠包裝在玻璃毛細管中的小珠包裝步驟，令經平衡之溶液以0.25毫升/分鐘之速度流過小珠管柱1鐘（〇·25毫升），複製三份。接著，將684pM經螢光標示之cy-5山羊抗-人（Fc特異性）多株抗體以0.5毫升/分鐘之速度流過小珠包裝2分鐘，以標示捕捉在小珠上之游離單株抗體結合部位。在670nm處測量在 620nm處激發之來自小珠包的螢光發射。依附屬之 KinExA軟體包（1.0·3版）的標準作法將所產生之螢光測量値轉化成游離單株抗體結合部位對總抗原濃度之％。由於配體非特異性結合至小珠包，在各濃度處收集之複製三組中僅有一組（將前3個2-倍雙調蛋白濃度自分析中排除）可進行分析並利用KinExA軟體配合至1: 1平衡等溫模型中 -144- 200927761

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Gly Asn Gly Gly Asn Gly Cys Asn Cys 290 295 300

Ala Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Thr Ala Tyr Thr Thr 305 310 315 320

Tyr Cys Ala Arg Cys Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn -1224 - 200927761 355 360 <210〉 677 <211〉 354 <212〉 PRT <213>現代人 <400〉 677

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

O

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110 -1225 - 200927761

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270 -1226 - 200927761

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Thr Asn Tyr Thr Asn Tyr Thr Asn Thr Gly Gly Thr Thr Tyr Gly 290 295 300

Gly Asn Gly Ala Arg Cys Ala Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320 〇

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Trp Ser Asn 325 330 335

Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Cys 340 345 350

Cys Asn

<210〉 678 <211> 345 <212〉 PRT <213〉現代人 <400〉 678

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr -1227 - 200927761 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Trp Ser Asn Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Thr Ala 165 170 175 -1228 200927761

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Ala Ala Tyr Tyr Thr Asn Cys Cys Asn Thr 290 295 300

Thr Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala 305 310 315 320

Arg Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn -1229 - 200927761 325 330 335

Gly Thr Asn Trp Ser Asn Trp Ser Asn 340 345 <210> 679 <211〉 369 <212〉 PRT <213〉現代人 <400> 679

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95 -1230- 200927761

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Gly Ala Tyr Gly 〇 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Cys Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Cys Ala Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Gly 195 200 205

Thr Asn Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Thr Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255 -1231 - 200927761

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Trp Ser Asn Cys Ala Tyr Thr Ala Tyr Gly 290 295 300

Gly Asn Gly Gly Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 325 330 335

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys 340 345 350

Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 355 360 365

Asn <210> 680 <211> 360 <212〉 PRT <213〉現代人 -1232- 200927761 <400〉 680

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45 〇

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95 ❹

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140 -1233 - 200927761 配合數據之最理想的KD値爲5·0ηΜ，95%信賴區間之低和高極限値分別爲3·1ηΜ和7.7ηΜ。

Υ.實例15:最佳抗體製劑之選擇標準使用下列標準鑑定最佳抗體製劑：抑制TMPS之效力、藉由觀察抗體抑制EGF受體及HER4酪胺酸磷酸化之程度而測得之直接抑制HB-EGF的效力、抗體對HB-EGF之親和力、抗體對其他分子之交叉反應性及抗原決定部位之特性。 Ζ.實例 16 :抗 HB-EGF抗體抑制 HB-EGF刺激 HUVEC細胞增殖和脈管形成本實例說明雖然HB-EGF刺激人類血管內皮細胞 (HUVEC)增殖，但此處所提供之抗HB-EGF抗體抑制基礎 Q HUVEC細胞增殖。本實例亦顯示，抗HB-EGF抗體抑制 HUVEC脈管形成（此爲新血管新生之玻管內模型）。抑制 HUVEC增殖及/或血管新生不僅可用來治療癌症亦可用來 • 治療涉及不欲有之血管新生的非癌性病況（如：糖尿病性視網膜病變）。 1 ·程序：藉由流式細胞技術測定HUVEC細胞上之 Η B - E G F表現藉由FACS分析測定人類內皮細胞上之HB-EGF表現 -145- 200927761

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Met Gly 165 170 175

Asn Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Tyr Gly Gly Asn Thr Gly Gly Cys -1234 - 200927761 290 295 300

Ala Arg Cys Ala Arg Cys Ala Arg Gly Cys Asn Cys Cys Asn Thr Thr 305 310 315 320

Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly 340 345 350 〇

Thr Asn Trp Ser Asn Trp Ser Asn 355 360 <210> 681 <211> 354 <212〉 PRT <213〉現代人 <400> 681

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45 -1235 - 200927761

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Met Gly Asn Trp Ser Asn Cys Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Ala Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Met Gly Asn Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205 -1236- 200927761

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Cys Ala Asn Tyr Thr Asn Gly Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255 〇

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Thr Gly Gly Gly Gly Asn Ala Thr His Trp 290 295 300

Ser Asn Gly Cys Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Gly 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn 325 330 335

Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350 -1237- 200927761

Ser Asn <210〉 682 <211〉 345 <212〉 PRT <213〉現代人 <400〉 682

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Gly Cys Asn Thr Ala Tyr 85 90 95

Trp Ser Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110 -1238 - 200927761

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Thr Ala Tyr Ala Thr His Trp Ser Asn Trp Ser Asn Trp 145 150 155 160

Ser Asn Gly Gly Asn Met Gly Asn Cys Ala Asn Ala Thr His Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Thr Thr Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Ala -1239- 200927761 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Tyr Thr Asn Thr Gly Gly Gly Cys Asn Cys Cys Asn Thr 290 295 300

Thr Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala 305 310 315 320

Arg Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn 325 330 335

Gly Thr Asn Trp Ser Asn Trp Ser Asn 340 345 <210> 683 <211> 375 <212〉 PRT <213〉現代人 <400> 683

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30 -1240 200927761

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 〇 85 90 95

Trp Ser Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Cys Ala Tyr Ala Thr His Trp Ser Asn Trp Ser Asn Trp 145 150 155 160

Ser Asn Trp Ser Asn Met Gly Asn Cys Ala Asn Ala Thr His Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190 -1241 - 200927761

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Trp Ser Asn Gly Thr Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Ala 290 295 300

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Gly Asn Gly Gly Asn Gly Gly 305 310 315 320

Asn Ala Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 325 330 335 -1242 200927761

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Cys Ala Asn Cys Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn 370 375 <210> 684 0 <211> 375 <212〉PRT <213〉現代人 <400〉 684

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30 ❹

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80 -1243 - 200927761

。因此，以在PBS中之10mM EDTA收成2xl05個所欲細胞，將其再懸浮在卩八€8緩衝劑（？83，3%?€3，0.4%疊氮化物）中並接種在96-槽圓底盤上。在lOOOrpm離心3分鐘以去除上清液，將細胞再懸浮於抗HB-EGF抗體稀釋液 (100微升/槽，10微克/毫升抗HB-EGF抗體）中並在4°C下培育45分鐘。以FACS緩衝劑清洗細胞二次，將其與在 FACS緩衝劑中稀釋100倍之二級抗體（1〇〇微升/槽）抗-人 PE(JackS〇n)—起再懸浮。將細胞懸浮液在4°C、黑暗中培育30分鐘，以FACS緩衝劑清洗二次並分析之（FACS， Beckman Coulter)。

爲了測試抗HB-EGF抗體對HUVEC增殖之效果，將約5 000個HUVEC細胞接種在48個槽中，該槽中含有帶有EGM-2、氫化可的松、抗壞血酸、正大黴素-二性黴素及2%FCS之介質且介質中含有bFGF、VEGF、EGF和 IGF-l(Cambrex)。將細胞在37°C培育一整夜後，以含有 0.5%FCS之PBS清洗細胞2次。令細胞在含有EGM-2、 0.5%FCS，未補充生長因子之介質中飢餓8小時。將在 5 00微升飢餓介質中之HB-EGF或抗HB-EGF抗體製劑加入其中。然後，將細胞再培養6 0小時，以胰蛋白處理後計算之。爲了測試抗HB-EGF抗體對HUVEC脈管形成之效果，將200微升減少生長因子之基質膠（BD生物科學）平板固定於48槽上。在48槽之每一槽中加入2 5 0微升 -146- 200927761

Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Trp Ser Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Cys Ala Tyr Ala Thr His Trp Ser Asn Met Gly Asn Trp 145 150 155 160

Ser Asn Trp Ser Asn Met Gly Asn Cys Ala Asn Ala Thr His Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Thr Ala Tyr -1244 - 200927761 225 230 235 240

Tyr Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr 245 250 255

Thr Asn Met Gly Asn Gly Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285 ❹

Gly Cys Asn Met Gly Asn Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Ala 290 295 300

Ala Tyr Thr Gly Gly Ala Ala Tyr Ala Ala Tyr Gly Gly Asn Gly Gly 305 310 315 320

Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 325 330 335 ❹

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Cys Ala Asn Cys Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn 370 375 -1245 - 200927761 <210> 685 <211> 354 <212> PRT <213〉現代人 <400> 685

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125 -1246 - 200927761

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175 ❹

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Tyr Tyr Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270 -1247 - 200927761

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Gly Asn Cys Cys Asn Thr 290 295 300

Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr 305 310 315 320

Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn 325 330 335

Cys Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn <210> 686 <211〉 381 <212> PRT <213〉現代人 <400〉 686

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30 -1248 - 200927761

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Met Gly Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Cys Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn -1249 - 200927761 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Ala 195 200 205

Ala Tyr Ala Thr Gly Trp Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Cys Asn Tyr Thr Asn Met 290 295 300

Gly Asn Gly Gly Asn Ala Thr His Gly Thr Asn Tyr Thr Asn Ala Thr 305 310 315 320

Gly Gly Thr Asn Thr Ala Tyr Gly Thr Asn Tyr Thr Asn Gly Gly Asn 325 330 335 -1250 200927761

Gly Cys Asn Tyr Thr Asn Gly Ala Tyr Ala Thr His Thr Gly Gly Gly 340 345 350

Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Ala Ala Arg Gly Thr 355 360 365

Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 370 375 380 ¢) <210> 687 <211〉 381 <212〉 PRT <213>現代人 <400> 687

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80 -1251 - 200927761

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala 210 215 220 1252- 200927761

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 0 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Ala Tyr Gly Ala Arg Cys 290 295 300

Ala Asn Gly Thr Asn Gly Thr Asn Met Gly Asn Gly Gly Asn Tyr Thr 305 310 315 320

Asn Ala Thr His Met Gly Asn Thr Ala Tyr Thr Gly Tyr Thr Ala Tyr 325 330 335

Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly 340 345 350

Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala Asn Gly Thr 355 360 365

Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 370 375 380 -1253 - 200927761 HUVEC介質（來自Cambrex之EBM-2 +氫化可的松+抗壞血酸+正大黴素-二性黴素+〇.25%FCS)。預先培育20分鐘後，加入在50微升介質+0.25%FCS(其中含有HB-EGF(10奈克/毫升）或U2-42、U2-39或U2-45抗HB-EGF抗體（10微克/毫升））中之20,000個HUVEC細胞。藉由取得培養槽之代表性區域的顯微照片來監控脈管形成。計算HUVEC管之封閉區域來進行定量分析。 ❿ 2.結果如第 30圖中之FACS分析所示，HB-EGF表現在 HUVEC上。第32A-B圖中提供細胞增殖試驗之結果。如第32A圖中所示，HB-EGF刺激HUVEC細胞增殖約38% 。然而，當加入抗HB-EGF抗體製劑U2-42、U2-39和U2-45時，這類細胞增殖之刺激被抑制約8%至14%(第3 1B圖 )。在此分析中，U2-3 9抗HB-EGF抗體製劑提供最高之抑 Q 制水準。脈管形成試驗之結果提供於第3 3 A-Μ圖中。顯示於第34A-C圖中之不含抗HB-EGF抗體的對照分析顯示出 HUVEC細胞連結形成圓形構造或“脈管”。然而，當加入抗HB-EGF抗體製劑U2-42、U2-39和U2-45時，這類脈管形成受到抑制。觀察到之脈管數目的摘要提供於第 33M圖中。如第33M圖中所示，U2-42抗HB-EGF抗體製劑使脈管退化之速度最快’接著爲U2-3 9抗HB-EGF抗體製劑。 -147- 200927761 <210> 688 <211〉 366 <212〉 PRT <213〉現代人 <400〉 688

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Ala Ala Tyr Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys -1254- 200927761 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175 0

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Ala Thr His Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Cys Ala 210 215 220 ❹

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Ala Ala Tyr Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270 -1255 - 200927761

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Ala Tyr Met Gly Asn Gly 290 295 300

Gly Asn Gly Gly Asn Gly Gly Asn Gly Ala Tyr Thr Ala Tyr Gly Gly 305 310 315 320

Asn Met Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly 325 330 335

Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala Asn Gly 340 345 350

Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 355 360 365 <210〉 689 <211> 366 <212〉 PRT <213>現代人 <400〉 689

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30 -1256- 200927761

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Ala Ala Tyr Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80 〇

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175 -1257 200927761

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Ala Thr His Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Ala Ala Tyr Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Ala Tyr Met Gly Asn Gly 290 295 300

Gly Asn Gly Gly Asn Gly Gly Asn Gly Ala Tyr Thr Ala Tyr Gly Gly 305 310 315 320

Asn Met Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly 325 330 335 -1258 - 200927761

Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala Asn Gly 340 345 350

Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 355 360 365

<210> 690 <211> 357 <212〉 PRT ❹ <213〉現代人 <400〉 690

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn -1259- 200927761 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Ala Thr His Cys 195 200 205

Ala Asn Ala Ala Arg Trp Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240 -1260 - 200927761

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Trp Ser Asn Ala Ala Tyr Ala 290 295 300

Ala Tyr Thr Ala Tyr Gly Gly Asn Thr Gly Tyr Thr Thr Tyr Gly Cys 305 310 315 320

Asn Tyr Thr Asn Thr Gly Gly Gly Gly Asn Met Gly Asn Gly Gly Asn 325 330 335

Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp 340 345 350

Ser Asn Trp Ser Asn 355 <210〉 691 <211> 357 <212> PRT <213〉現代人 -1261 - 200927761 <400〉 691

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140 1262- 200927761

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160

Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Ala Thr His Cys 0 195 200 205

Ala Asn Ala Ala Arg Trp Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Trp Ser Asn Ala Ala Tyr Ala 290 295 300 -1263 - 200927761 八八.實例17:抗118-£0?抗體抑制經1^40?刺激及基礎株落形成進行軟瓊脂分析以檢查此處提供之抗體抑制非固著依賴性細胞生長。軟瓊脂株落形成分析爲標準之活體外分析以測試轉形之細胞，因僅有這類轉形之細胞可在軟瓊脂中生長。

爲了執行此分析’將 OVCAR-8、BM-1 640和 NCI-H226細胞與在IMEM介質（Gibco)中之10奈克/毫升HB-EGF及20微克/毫升之抗HB-EGF抗體或作爲陰性對照組之IgG2(SIGMA)—起培育，然後再懸浮於0.2%Difco瓊脂中。將細胞懸浮液平皿接種在96槽盤中之0.4%軟瓊脂-底層上，其上覆蓋IMDM介質，複製四份。令株落形成約 14天，然後以40微升MTT(Sigma，1毫克/毫升，在PBS

中）染色4小時。藉由HTSBonit(Lemna Tec)株落形成軟體定量HB-EGF之刺激和抗HB-EGF抗體之抑制效果。於另一分析中，在37 °C下，將750或1000個細胞（取決於SkOV-3株落71或74，第34D和F圖）與在IMEM介質（Gibco)中之20微克/毫升之抗HB-EGF抗體或作爲陰性對照組之IgG2(SIGMA)—起培育30分鐘，然後再懸浮於 0.4%Difco瓊脂中（或者，用於株落74者爲0.2%)。將細胞懸浮液平皿接種在96槽盤中之0.75 %軟瓊脂-底層（或者，用於株落74者爲0.4%)上，其上覆蓋IMDM介質，複製四份。在類似之分析中，在37°C下，將2000個BxPC-3細胞 -148- 200927761

Ala Tyr Thr Ala Tyr Gly Gly Asn Thr Gly Tyr Thr Thr Tyr Gly Cys 305 310 315 320

Asn Tyr Thr Asn Thr Gly Gly Gly Gly Asn Met Gly Asn Gly Gly Asn 325 330 335

Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp 340 345 350

Ser Asn Trp Ser Asn 355 <210〉 692 <211> 399 <212〉 PRT <213〉現代人 <400> 692

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr -1264 - 200927761 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

O

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Cys 145 150 155 160 ❹

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Cys 195 200 205 -1265 - 200927761

Ala Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Ala Tyr Ala 290 295 300

Ala Tyr Thr Ala Tyr Gly Gly Asn Tyr Thr Asn Thr Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Gly Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn 325 330 335

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Thr 340 345 350

Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly -1266- 200927761 355 360 365

Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala Asn 370 375 380

Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 385 390 395

<210> 693 <211〉 375 ❹ <212〉 PRT <213〉現代人 <400> 693

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80 -1267 - 200927761

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Ala Ala Tyr Thr 100 105 110

Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Gly Gly Asn Cys Ala 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240 -1268 - 200927761

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Thr Thr Tyr Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Thr Tyr 275 280 285 ❹

Thr Gly Tyr Gly Cys Asn Met Gly Asn Cys Ala Asn Thr Ala Tyr Thr 290 295 300

Ala Tyr Gly Ala Tyr Ala Thr His Tyr Thr Asn Cys Ala Asn Gly Gly 305 310 315 320

Asn Thr Ala Tyr Cys Cys Asn Thr Thr Tyr Thr Ala Tyr Thr Thr Tyr 325 330 335

Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn 370 375 1269 - 200927761 <210〉 694 <211〉 375 <212〉 PRT <213〉現代人 <400> 694

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Ala Ala Tyr Thr 100 105 110

Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys Cys 115 120 125 -1270 - 200927761

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Gly Gly Asn Cys Ala 165 170 175

Asn Thr Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Thr Thr Tyr Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Thr Tyr -1271 - 200927761 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Cys Ala Asn Thr Ala Tyr Thr 290 295 300

Ala Tyr Gly Ala Tyr Ala Thr His Tyr Thr Asn Cys Ala Asn Gly Gly 305 310 315 320

Asn Thr Ala Tyr Cys Cys Asn Thr Thr Tyr Thr Ala Tyr Thr Thr Tyr 325 330 335

Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn 370 375 <210〉 695 <211〉 360 <212> PRT <213〉現代人 <400〉 695

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Cys 1 5 10 15 -1272 - 200927761

Ala Arg Thr Gly Gly Gly Gly Asn Gly Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Tyr Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr Gly Gly Asn Gly Gly © 65 70 75 80

Asn Trp Ser Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Ala Tyr 85 90 95

Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr Gly Gly Ala Thr His Met 100 105 110

Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr His 130 135 140

Gly Gly Asn Gly Ala Arg Ala Thr His Ala Ala Tyr Cys Ala Tyr Trp 145 150 155 160

Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala Asn Ala Ala Tyr Thr Ala 165 170 175 -1273 - 200927761 (第34F圖）與在含有20%FCS之IMEM介質（Gibco)中之20 微克/毫升抗HB-EGF抗體或20微克/毫升作爲陰性對照組之IgG2(SIGMA)—起培育 30分鐘。將細胞再懸浮於 0.4%Difco瓊脂中，再將細胞懸浮液平皿接種在96槽盤中之0.75%軟瓊脂-底層上，複製四份。以IMDM介質覆蓋培養槽。二層均含有20%FCS。

令株落形成約14天，然後以40微升MTT(Sigma，1 毫克/毫升，在PBS中）染色4小時。結果顯示於第34A-F 圖中，其說明經HB-EGF刺激之株落形成（第34A-C圖）和基礎株落形成（第34D-F圖）明顯被抗HB-EGF抗體降低。例如：如第 34A圖所示，與不含 HB-EGF之對照組 OVCAR-8細胞培養相較下，HB-EGF刺激OVCAR-8細胞形成明顯較大之平均株落尺寸。然而，當在HB-EGF之存在下，將OVCAR-8細胞與抗HB-EGF U2-39抗體一·起培養時，平均株落尺寸降至類似於在未以HB-EGF處理之對照組細胞中所觀察到之尺寸（第34A圖）。BM-1640細胞（源自攝護腺癌組織）可觀察到類似之結果（見，第34B圖）。抗HB-EGF U2-45和U2-42抗體亦可抑制BM-1640株落形成0 抗HB-EGF抗體亦抑制經HB-EGF刺激之NCI-H226 肺癌細胞株落形成（第34C圖）。如第36C圖所示，當在 HB-EGF之存在下，將NCI-H226細胞與抗HB-EGF U2-39 抗體一起培養時，平均株落尺寸降至類似於在未以HB-EGF處理之對照組細胞中所觀察到之尺寸。 -149- 200927761

Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg 180 185 190

Trp Ser Asn Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Trp 195 200 205

Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala 210 215 220

Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn 225 230 235 240

Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys 245 250 255

Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys 260 265 270

Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn 275 280 285

Met Gly Asn Gly Gly Asn Gly Gly Asn Thr Ala Tyr Trp Ser Asn Trp 290 295 300

Ser Asn Trp Ser Asn Thr Gly Gly Thr Ala Tyr Thr Gly Gly Thr Thr 305 310 315 320 -1274 200927761

Tyr Gly Ala Tyr Cys Cys Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn 355 360

<210> 696 <211〉 360 <212〉 PRT <213〉現代人 <400〉 696

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Cys 15 10 15

Ala Arg Thr Gly Gly Gly Gly Asn Gly Cys Asn Gly Gly Asn Tyr Thr 20 25 30 ❹

Asn Tyr Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr Gly Gly Asn Gly Gly 65 70 75 80 -1275 - 200927761

Asn Trp Ser Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Ala Tyr 85 90 95

Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr Gly Gly Ala Thr His Met 100 105 110

Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr His 130 135 140

Gly Gly Asn Gly Ala Arg Ala Thr His Ala Ala Tyr Cys Ala Tyr Trp 145 150 155 160

Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala Asn Ala Ala Tyr Thr Ala 165 170 175

Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg 180 185 190

Trp Ser Asn Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Trp 195 200 205

Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala 210 215 220

Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn -1276 - 200927761 225 230 235 240

Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys 245 250 255

Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys 260 265 270

Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn 275 280 285 ❹

Met Gly Asn Gly Gly Asn Gly Gly Asn Thr Ala Tyr Trp Ser Asn Trp 290 295 300

Ser Asn Trp Ser Asn Thr Gly Gly Thr Thr Tyr Thr Gly Gly Thr Thr 305 310 315 320

Tyr Gly Ala Tyr Cys Cys Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335 ❹

Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn 355 360

<210> 697 <211> 369 <212〉 PRT -1277 - 200927761 <213〉現代人 <400〉 697

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr Gly Gly Ala Thr His Met 100 105 110

Gly Asn Cys Ala Arg Cys Cys Asn Gly Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr His 130 135 140 -1278 - 200927761

Gly Gly Asn Met Gly Asn Ala Thr His Thr Ala Tyr Cys Ala Asn Trp 145 150 155 160

Ser Asn Gly Gly Asn Cys Ala Asn Cys Ala Asn Ala Ala Tyr Thr Ala 165 170 175

Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg 180 185 190 〇

Trp Ser Asn Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr Gly Trp 195 200 205

Ser Asn Gly Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala 210 215 220

Arg Ala Ala Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn 225 230 235 240

Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys 245 250 255

Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys 260 265 270

Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn 275 280 285 -1279- 200927761

Met Gly Asn Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Trp Ser Asn Thr 290 295 300

Ala Tyr Gly Gly Asn Cys Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 325 330 335

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys 340 345 350

Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 355 360 365

Asn <210> 698 <211〉 378 <212〉 PRT <213〉現代人 <400> 698

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30 1280 200927761

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Gly Gly 65 70 75 80

Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Gly Asn 85 90 95

Gly Gly Asn Trp Ser Asn Thr Ala Tyr Thr Gly Gly Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Ala Tyr Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Ala Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Cys Ala 165 170 175

Asn Ala Ala Tyr Thr Ala Tyr Ala Ala Tyr Cys Cys Asn Trp Ser Asn -1281 - 200927761 180 185 190

Tyr Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Gly Thr Asn Cys 195 200 205

Ala Asn Ala Thr His Trp Ser Asn Ala Thr His Gly Thr Asn Cys Ala 210 215 220

Asn Trp Ser Asn Met Gly Asn Ala Ala Tyr Cys Ala Arg Thr Thr Tyr 225 230 235 240

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Tyr Thr Asn Trp Ser Asn Trp 245 250 255

Ser Asn Gly Thr Asn Cys Ala Asn Gly Cys Asn Gly Cys Asn Gly Ala 260 265 270

Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Trp Ser Asn Gly Cys Asn Tyr 290 295 300

Thr Asn Met Gly Asn Thr Ala Tyr Thr Thr Tyr Gly Ala Tyr Thr Gly 305 310 315 320

Gly Tyr Thr Asn Thr Thr Tyr Trp Ser Asn Gly Ala Tyr Gly Thr Asn 325 330 335 1282 200927761

Trp Ser Asn Gly Ala Tyr Ala Thr His Thr Gly Gly Gly Gly Asn Cys 340 345 350

Ala Arg Gly Gly Asn Cys Ala Asn Ala Thr Gly Gly Thr Asn Cys Ala 355 360 365

Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 370 375 〇 <21〇> 699 <211> 360 <212> PRT <213〉現代人 <400〉 699

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Tyr Thr

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Ala Arg 35 40 45

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Gly Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80 -1283 - 200927761 經由抗HB-EGF抗體之處理可減少株落之數目及尺寸 (第34D-F圖）。因此’第34D圖說明抗HB-EGF抗體可減少由SkOV-3 HB-EGF選殖株71細胞（源自SkOV-3卵巢癌細胞’此細胞株係經proHB-EGF表現構造物穩定轉染）形成之基礎株落數。如圖所示，過度表現HB-EGF之對照組 SkOV-3細胞形成大量株落。然而，當在HB-EGF之存在下，將SkOV-3 HB-EGF選殖株71細胞與抗HB-EGF U2-42或U2-3 9抗體一起培養時，株落數大幅減少。類似地，抗HB-EGF抗體抑制SkOV-3 (選殖株74)細胞（源自卵巢癌組織）和BxPC3細胞（源自胰臟腺癌組織）株落形成（第 34E-F 圖）。這些數據指出由非常多種不同之癌細胞類型形成之株落和腫瘤可被抗HB-EGF抗體（包括此處所提供之U2-42、 U2-3 9和U2-45抗體製劑）抑制。 BB.實例18 :抗HB-EGF抗體抑制活體內之腫瘤生長第37圖說明在以SCID老鼠進行之異種移植實驗中形成之胰臟BxPC3腫瘤的平均體積。如圖所示，當與載劑對照組相比較時，於抗體製劑U2-42及/或U2-39存在時，已建立之腫瘤生長明顯受抑制。第38A圖顯示出抗HB-EGF抗體U2-42、U2-3 9和U2-45在活體內抑制已建立之 EFO-27 HB-EGF選殖株5 8細胞的生長。腫瘤生長抑制效果顯示出可能爲劑量倚賴性，25毫克/公斤之劑量爲高度有效之治療劑，而較低之劑量（諸如1或5毫克/公斤）較無 -150- 200927761

Tyr Met Gly Asn Thr Thr Tyr Cys Ala Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Ala Thr Gly Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly 145 150 155 160

Ala Tyr Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Cys Ala Asn Met Gly 165 170 175

Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr 180 185 190

Cys Ala Arg Gly Gly Asn Cys Ala Arg Gly Thr Asn Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Ala Ala Arg Trp Ser 210 215 220 1284- 200927761

Asn Ala Thr His Trp Ser Asn Cys Ala Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Thr Gly Gly Trp Ser Asn Trp Ser Asn Tyr 245 250 255

Thr Asn Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Ala Thr Gly Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn Thr 290 295 300

Ala Tyr Gly Gly Asn Thr Ala Tyr Trp Ser Asn Thr Ala Tyr Thr Thr 305 310 315 320

Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys Ala Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn 355 360 <210〉 700 <211> 363 -1285 - 200927761 <212〉 PRT <213〉現代人 <400> 700

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Ala Arg 35 40 45

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Gly Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Trp Ser Asn Thr Thr Tyr Cys Ala Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Ala Thr Gly Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly -1286 - 200927761 130 135 140

Gly Gly Asn Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly 145 150 155 160

Ala Tyr Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Cys Asn Met Gly 165 170 175

Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr 180 185 190 〇

Cys Ala Arg Gly Gly Asn Cys Ala Arg Gly Thr Asn Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Ala Ala Arg Trp Ser 210 215 220

Asn Ala Thr His Ala Ala Tyr Cys Ala Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240 ❹

Tyr Thr Asn Cys Ala Arg Thr Gly Gly Trp Ser Asn Trp Ser Asn Tyr 245 250 255

Thr Asn Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Ala Thr Gly Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285 -1287- 200927761

Gly Cys Asn Met Gly Asn Cys Ala Arg Gly Gly Asn Thr Ala Tyr Gly 290 295 300

Gly Asn Trp Ser Asn Gly Gly Asn Thr Gly Gly Gly Gly Asn Thr Ala 305 310 315 320

Tyr Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn 325 330 335

Cys Ala Arg Gly Gly Asn Cys Ala Asn Tyr Thr Asn Gly Thr Asn Cys 340 345 350

Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 355 360 <210> 701 <211> 381 <212〉 PRT <213>現代人 <400> 701

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Ala Arg 35 40 45 -1288 - 200927761

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Gly Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Trp Ser Asn Thr Thr Tyr Cys Ala Asn Trp Ser Asn Thr Ala Tyr 85 90 95 ❹

Thr Gly Gly Ala Thr His Gly Gly Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Ala Thr Gly Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Tyr Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly 145 150 155 160

Gly Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Ala Thr His Met Gly 165 170 175

Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr 180 185 190 -1289- 200927761

Cys Ala Arg Gly Gly Asn Cys Ala Arg Gly Thr Asn Cys Ala Asn Ala 195 200 205

Thr His Trp Ser Asn Gly Cys Asn Gly Ala Tyr Ala Ala Arg Trp Ser 210 215 220

Asn Ala Thr His Trp Ser Asn Cys Ala Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Tyr Thr Asn Cys Ala Arg Thr Gly Gly Trp Ser Asn Trp Ser Asn Tyr 245 250 255

Thr Asn Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Ala Tyr Cys Ala 260 265 270

Asn Gly Cys Asn Ala Thr Gly Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Cys Ala Arg Gly Gly Asn Tyr Thr Asn Gly 290 295 300

Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Ala Asn Trp Ser 305 310 315 320

Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr 325 330 335

Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly 340 345 350 -1290 - 200927761

Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala Asn Gly Thr 355 360 365

Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 370 375 380

<210> 702 <211> 375 <212〉 PRT 〇 <213>現代人 . <400〉 702

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Gly Ala 65 70 75 80

Tyr Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Thr Ala Tyr -1291 - 200927761 85 90 95

Trp Ser Asn Gly Cys Asn Gly Cys Asn Thr Gly Gly Ala Ala Tyr Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Trp Ser Asn Cys Cys 115 120 125

Asn Trp Ser Asn Met Gly Asn Gly Gly Asn Tyr Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Tyr Thr Asn Gly Gly Asn Met Gly Asn Cys Ala Asn Thr 145 150 155 160

Ala Tyr Thr Gly Tyr Met Gly Asn Trp Ser Asn Ala Ala Arg Thr Gly 165 170 175

Gly Thr Ala Tyr Ala Ala Tyr Gly Ala Tyr Thr Ala Tyr Gly Cys Asn 180 185 190

Gly Thr Asn Trp Ser Asn Gly Thr Asn Ala Ala Arg Trp Ser Asn Met 195 200 205

Gly Asn Ala Thr His Cys Ala Asn Ala Thr His Ala Ala Tyr Cys Cys 210 215 220

Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr 225 230 235 240 -1292 - 200927761

Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Cys Ala Arg Tyr 245 250 255

Thr Asn Ala Ala Tyr Trp Ser Asn Gly Thr Asn Cys Ala Asn Cys Cys 260 265 270

Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr Asn 275 280 285

Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly 290 295 300

Ala Tyr Met Gly Asn Gly Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly 305 310 315 320

Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 325 330 335

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Cys Ala Asn Cys Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn 370 375 <210〉 703 -1293 - 200927761 效（第38B圖）。 CC.實例19 :抗HB-EGF抗體與抗EGFR抗體Erbitux 之組合療法第35圖顯示出可以抗HB-EGF抗體單一作用劑適度至強力抑制EFO-27 HB-EGF選殖株58細胞之生長。然而，抗HB-EGF與抗EGFR抗體之劑量控制組合在抑制株落 0 形成上非常有效。再者，抗HB-EGF與抗EGFR抗體之組合可強力抑制活體內異體移植之生長，使卵巢癌腫瘤生長完全退化（第38C圖）。 DD.實例20 :多種不同之癌細胞類型上之HB-EGF表現藉由FACS分析測定在人類癌細胞株上之HB-EGF表現。爲了進行此分析，以在PBS中之10mM EDTA收成 Q 2xl05個細胞，將其再懸浮在FACS緩衝劑（PBS，3%FCS ’ 〇·4%疊氮化物）中並轉移至96-槽圓底盤上。在l〇〇〇rpm 離心3分鐘以去除上清液，將細胞再懸浮於抗HB-EGF抗體稀釋液（100微升/槽）中並在4°C下培育45分鐘。以 FACS緩衝劑清洗細胞二次，將其與在FACS緩衝劑中稀釋100倍之二級抗體（100微升/槽）驢-抗-人PE(Jackson) — 起再懸浮。將細胞懸浮液在4。(：、黑暗中培育3 0分鐘，以 FACS緩衝劑清洗二次並分析之（FACS，Beckman Coulter) -151 - 200927761 <211> 324 <212〉 DNA <213〉現代人 <400> 703 cgaactgtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60 ggaactgcta gcgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120 tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180 agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240 aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300 agcttcaaca ggggagagtg ttag 324 <210> 704 <211> 981 <212> DNA <213〉現代人 <400〉 704 gcctccacca agggcccatc ggtcttcccc ctggcgccct gctctagaag cacctccgag 60 agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 240 tacacatgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 300 aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 360 ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 420 -1294 - 480 480

200927761 gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac ❹ ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaatg a <210〉 705 <211〉 48 <212> PRT <213〉現代人 <400> 705

Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Tyr 15 10 15

Thr Asn Gly Thr Asn Thr Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly 20 25 30

Asn Ala Ala Tyr Cys Ala Asn Thr Ala Tyr Tyr Thr Asn Ala Ala Tyr 35 40 45 540 600 660 720 780 840 900 960 981 -1295 - 200927761 <210> 706 <211〉 48 <212〉 PRT <213〉現代人 <400> 706

Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Tyr 15 10 15

Thr Asn Tyr Thr Asn Cys Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly 20 25 30

Asn Ala Ala Arg Cys Ala Asn Thr Ala Tyr Tyr Thr Asn Thr Ala Tyr 35 40 45 <210〉 707 <211> 33 <212〉 PRT <213>現代人 <400〉 707

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Gly Asn Ala 15 10 15

Thr His Gly Cys Asn Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn Gly Cys 20 25 30

Asn -1296 200927761 <210〉 708 <211〉 33 <212〉 PRT <213〉現代人 <400> 708

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Gly Asn Ala 15 10 15

Thr His Trp Ser Asn Ala Ala Tyr Gly Ala Tyr Tyr Thr Asn Gly Cys 20 25 30

Asn <210> 709 <211〉 48 <212〉 PRT <213〉現代人

<400> 709

Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Tyr 15 10 15

Thr Asn Gly Thr Asn Cys Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly 20 25 30

Asn Ala Ala Tyr Cys Ala Asn Thr Ala Tyr Tyr Thr Asn Trp Ser Asn 35 40 45 -1297 - 200927761 <210〉 710 <211〉 36 <212〉PRT <213〉現代人 <400> 710

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Cys Ala Asn Gly 15 10 15

Thr Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr Tyr Thr 20 25 30

Asn Gly Cys Asn 35 <210> 711 <211> 30 <212> PRT <213〉現代人 <400> 711

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Gly 15 10 15

Thr Asn Trp Ser Asn Met Gly Asn Tyr Thr Asn Gly Cys Asn 20 25 30 <210> 712 <211> 33 -1298 - 200927761 <212> PRT <213〉現代人 <400> 712

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Gly Asn Ala 15 10 15

Thr His Met Gly Asn Ala Ala Tyr Gly Ala Tyr Tyr Thr Asn Gly Gly 20 25 30 〇 Asn <210〉 713 <211> 51 <212〉 PRT <213〉現代人 <400> 713

Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Gly 15 10 15

Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn Trp Ser Asn Ala Ala 20 25 30

Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn 35 40 45

Gly Thr Asn 50 -1299 - 200927761 <210> 714 <211> 51 <212> PRT <213〉現代人 <400〉 714

Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Gly 15 10 15

Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn Trp Ser Asn Ala Ala 20 25 30

Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn 35 40 45

Gly Cys Asn 50 <210〉 715 <211> 51 <212〉 PRT <213〉現代人 <400> 715

Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala Arg Ala Ala Tyr Gly 15 10 15

Thr Asn Tyr Thr Asn Thr Ala Tyr Trp Ser Asn Trp Ser Asn Ala Ala 20 25 30 -1300- 200927761

Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn 35 40 45

Gly Cys Asn 50

<210〉 716 <211〉 51 <212> PRT ❹ <213〉現代人 <400〉 716

Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Gly 15 10 15

Thr Asn Tyr Thr Asn Thr Ala Tyr Ala Ala Tyr Trp Ser Asn Ala Ala 20 25 30

Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn 35 40 45

Gly Cys Asn 50 <210〉 717 <211> 51 <212〉 PRT <213〉現代人 -1301 - 200927761 <400> 717

Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Gly 15 10 15

Thr Asn Tyr Thr Asn Gly Ala Tyr Trp Ser Asn Trp Ser Asn Ala Ala 20 25 30

Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn 35 40 45

Gly Cys Asn 50 <210> 718 <211> 51 <212> PRT <213〉現代人 <400> 718

Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Ala 15 10 15

Thr His Tyr Thr Asn Thr Ala Tyr Met Gly Asn Trp Ser Asn Ala Ala 20 25 30

Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn 35 40 45

Gly Cys Asn -1302- 200927761 50 <210〉 719 <211〉 33 <212〉PRT <213〉現代人 <400> 719

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Ala Tyr Ala 15 10 15

O

Thr His Trp Ser Asn Cys Ala Tyr Thr Ala Tyr Tyr Thr Asn Gly Cys 20 25 30

Asn

<210> 720 <211> 33 <212〉 PRT <213>現代人 <400> 720

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Ala Tyr Ala 15 10 15

Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn Gly Cys 20 25 30

Asn -1303 - 200927761 這些分析結果顯示於下列表6中。表6 癌細胞中之HB-EGF表現細胞株組織表現水準 MDA-MB231 乳房 ++ NCI-ADR 乳房 +++ ZR75-1 乳房 /+ MKN-1 胃 + MKN-28 胃 +++ PPC1 攝護腺 ++ PC3 攝護腺 ++ HT144 黑色素瘤 -/+ MelGerlach 黑色素瘤 +++ IGROV-1 卵巢 + ES2 卵巢 ++ SkOV-3 卵巢 + SkOV-8 卵巢 + TOV21G 卵巢 ++ OVCAR-8 卵巢 +++ Calu-6 肺 + NCI-H460 肺 ++ MS-751 子宮頸 ++ SIHA 子宮頸 + HelaS3 子宮頸 + U266 骨髓瘤 - SCABER 膀胱 ++ HCT-116 結腸 ++ HCT-15 結腸 + SW620 結腸 ++ EE.實例21 :用於藉由免疫組織化學及ELISA偵測組織及體液中之HB-EGF的抗HB-EGF抗體測試抗HB-EGF抗體U2-42和U2-39爲表現在人類固定樣本中之HB-EGF染色的能力。如第39A圖所示’二種抗體均顯示出明顯爲人類腎小管細胞膜和質染色’而對照 -152- 200927761 <210〉 721 <211> 33 <212> PRT <213〉現代人 <400〉 721

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Gly 15 10 15

Thr Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Tyr Thr Asn Gly Cys 20 25 30

Asn <210> 722 <211> 33 <212〉 PRT <213〉現代人 <400〉 722

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Ala Tyr Ala 1 5 10 15

Thr His Trp Ser Asn Met Gly Asn Thr Gly Gly Tyr Thr Asn Gly Cys 20 25 30

Asn -1304- 200927761 <210> 723 <211〉 33 <212〉 PRT <213〉現代人 <400〉 723

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Ala 15 10 15 〇

Thr His Trp Ser Asn Cys Ala Asn Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr

<210〉 724 <211〉 33 <212〉 PRT <213〉現代人 <400> 724

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Cys Ala Asn Ala 15 10 15

Thr His Trp Ser Asn Ala Thr His Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr -1305 - 200927761 <210> 725 <211> 33 <212〉 PRT <213〉現代人 <400> 725

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Ala 15 10 15

Thr His Met Gly Asn Trp Ser Asn Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr <210> 726 <211> 33 <212> PRT <213〉現代人 <400〉 726

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Cys Ala Asn Ala 15 10 15

Thr His Trp Ser Asn Met Gly Asn Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr -1306- 200927761 <210> 727 <211> 33 <212> PRT <213〉現代人 <400> 727

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Met Gly Asn Ala 15 10 15

O

Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr

<210> 728 <211> 33 <212〉 PRT <213〉現代人 <400> 728

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Ala 15 10 15

Thr His Trp Ser Asn Met Gly Asn Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr -1307 - 200927761 <210> 729 <211> 33 <212〉 PRT <213〉現代人 <400> 729

Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala Arg Trp Ser Asn Ala 15 10 15

Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr <210〉 730 <211> 33 <212> PRT <213〉現代人 <400> 730

Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Ala Tyr Ala 15 10 15

Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr -1308- 200927761 <210〉731 <211> 33 <212〉 PRT <213〉現代人 <400〉 731

Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Ala Tyr Ala 15 10 15 ❹

Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Ala Ala 20 25 30

Tyr

<210〉 732 <211> 33 <212〉 PRT <213〉現代人 <400> 732

Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Ala Tyr Ala 15 10 15

Thr His Trp Ser Asn Gly Ala Tyr Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr -1309 - 200927761 <210〉 733 <211> 33 <212〉 PRT <213〉現代人 <400〉 733

Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala Arg Gly Ala Tyr Ala 1 5 10 15

Thr His Cys Ala Asn Ala Ala Tyr Thr Ala Tyr Tyr Thr Asn Ala Ala 20 25 30

Tyr <210> 734 <211> 21 <212> PRT <213〉現代人 <400> 734

Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Thr Gly Gly Gly 15 10 15

Ala Tyr Trp Ser Asn 20 <210〉 735 -1310- 200927761 <211> 21 <212> PRT <213〉現代人 <400> 735

Gly Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn 20 ❹ <210〉 736 <211> 21 <212〉 PRT <213〉現代人 <400〉 736

Gly Thr Asn Gly Cys Asn Trp Ser Asn Cys Ala Asn Tyr Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn 20 <210> 737 <211> 21 <212> PRT <213〉現代人 <400〉 737

Gly Cys Asn Gly Cys Asn Trp Ser Asn Cys Ala Asn Tyr Thr Asn Cys 15 10 15 -1311 - 200927761

Ala Arg Trp Ser Asn 20 <210〉 738 <211> 21 <212> PRT <213〉現代人 <400> 738

Ala Ala Arg Ala Thr His Trp Ser Asn Ala Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn 20 <210〉 739 <211〉 21 <212〉 PRT <213〉現代人 <400> 739

Gly Gly Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met Gly Asn Gly 15 10 15

Cys Asn Cys Ala Asn 20 <210〉 740 <211> 21 -1312- 200927761 <212> PRT <213〉現代人 <400> 740

Gly Gly Asn Gly Cys Asn Trp Ser Asn Met Gly Asn Met Gly Asn Gly 15 10 15

Cys Asn Cys Ala Asn 20 0 <210〉 741 <211> 21 <212〉 PRT <213〉現代人 <400> 741

Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn 20 <210> 742 <211〉 21 <212〉 PRT <213〉現代人 <400> 742

Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala Asn Met Gly Asn Gly 15 10 15 -1313- 200927761 組未顯示出任何染色。除了在患者組織樣本中以免疫組織化學法偵測HB-EGF外，HB-EGF以生長因子之形式釋入多種不同的體液中。以作爲塗覆劑之人類抗HB-EGF抗體爲基礎來建立ELISA，此ELISA偵測液態樣本中之HB-EGF水準，其偵測濃度可低於40微微克/毫升（第3 9B圖） 0 FF.實例22 :抗體之典範類別編碼最佳抗體之基因係依前一個實例中之描述定序。使用此序列資料將抗體分派至典範類型。

Chothia等人根據抗體構造之“典範類別”來描述各免疫球蛋白鏈之高度可變區（Chothia， et al.,19^7 ,J.Mol.Biol.,\ 96 ( 4 ) : 901-17)。分析多種免疫球蛋白之Fab和VL片段的原子構造以決定其胺基酸序列與其抗原結合部位之三次元構造間的關係。Chothia等人透 Q 過其擠壓、氫鍵鍵結或呈現不常見之Φ、Ψ或ω構造之能力發現主要負責高度可變區之主鏈結構的殘基非常少。這些殘基被發現出現在高度可變區內之部位及保存之α_片框構區中。經由檢查具有未知構造之免疫球蛋白的序列’ Chothia等人證明許多免疫球蛋白具有大小類似於一種已知構造的高度可變區，且在負責該觀察之結構的部位處額外含有完全相同之殘基。他們的發現指出這些高度可變區具有之結構接近那些在已知構造中之結構。在該高度可變區的5個區中’結構 -153- 200927761

Ala Arg Trp Ser Asn 20 <210> 743 <211> 21 <212〉 PRT <213〉現代人 <400〉 743

Thr Gly Gly Gly Cys Asn Trp Ser Asn Cys Ala Asn Met Gly Asn Ala 15 10 15

Ala Arg Trp Ser Asn 20 <210〉744 <211〉 21 <212> PRT <213>現代人 <4〇〇> 744

Thr Gly Gly Gly Cys Asn Trp Ser Asn Gly Cys Asn Met Gly Asn Gly 15 10 15

Ala Arg Trp Ser Asn 20

<210〉 745 <211〉21 <212〉PRT -1314- 200927761 <213〉現代人 <400> 745

Gly Cys Asn Gly Ala Arg Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn 20 <210> 746 〇 <211> 21 <212〉PRT <213〉現代人 <400〉 746

Cys Ala Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn 20 ❹ <210〉 747 <211> 21 <212> PRT <213>現代人 <400〉 747

Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Tyr Thr Asn Cys 15 10 15 -1315 - 200927761

Ala Arg Trp Ser Asn 20 <210> 748 <211> 21 <212〉 PRT <213>現代人 <400〉 748

Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Tyr Thr Asn Gly 15 10 15

Ala Arg Cys Ala Asn 20 <210〉 749 <211> 21 <212〉 PRT <213〉現代人 <400> 749

Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Thr His Tyr Thr Asn Gly 15 10 15

Ala Arg Cys Ala Asn 20 <210〉 750 <211> 27 <212〉 PRT <213〉現代人 -1316- 200927761 <400〉 750

Ala Thr Gly Cys Ala Arg Trp Ser Asn Cys Ala Asn Cys Ala Tyr Thr 15 10 15

Gly Gly Cys Cys Asn Ala Thr His Cys Ala Asn 20 25

<210> 751 <211> 27 <212> PRT <213〉現代人 <400〉 751

Ala Thr His Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala Tyr Thr 15 10 15

Gly Gly Cys Cys Asn Cys Ala Asn Cys Ala Asn 20 25 <210〉 752 <211> 27 <212> PRT <213〉現代人 <400〉 752

Ala Thr Gly Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys Ala Tyr Thr 15 10 15

Gly Gly Cys Cys Asn Ala Thr His Cys Ala Asn -1317- 200927761 20 25 <210> 753 <211> 27 <212> PRT <213>現代人 <400> 753

Ala Thr Gly Cys Ala Arg Gly Gly Asn Ala Thr His Cys Ala Arg Tyr 15 10 15

Thr Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn 20 25 <210> 754 <211> 27 <212> PRT <213〉現代人 <400〉 754

Ala Thr Gly Cys Ala Arg Trp Ser Asn Ala Thr His Cys Ala Arg Tyr 15 10 15

Thr Asn Cys Cys Asn Tyr Thr Asn Cys Ala Asn 20 25 <210> 755 <211> 27 <212> PRT <213>現代人 -1318- 200927761 <400〉 755

Ala Thr Gly Cys Ala Arg Trp Ser Asn Ala Thr His Cys Ala Arg Tyr 15 10 15

Thr Asn Cys Cys Asn Ala Thr His Cys Ala Asn 20 25

<210〉 756 <211〉 27 <212〉 PRT 〇 <213〉現代人 <400〉 756

Cys Ala Arg Ala Ala Tyr Thr Ala Tyr Ala Ala Tyr Trp Ser Asn Gly 15 10 15

Cys Asn Cys Cys Asn Thr Thr Tyr Cys Ala Asn 20 25

<210〉 757 <211〉 27 <212〉 PRT <213〉現代人 <400> 757

Cys Ala Arg Ala Ala Arg Thr Ala Tyr Ala Ala Tyr Trp Ser Asn Gly 15 10 15

Thr Asn Cys Cys Asn Tyr Thr Asn Cys Ala Asn 20 25 -1319- 200927761 <210> 758 <211> 27 <212> PRT <213〉現代人 <400> 758

Ala Thr Gly Cys Ala Arg Gly Cys Asn Cys Ala Asn Cys Ala Arg Thr 15 10 15

Thr Tyr Cys Cys Asn Cys Ala Tyr Cys Ala Asn 20 25 <210> 759 <211> 27 <212〉PRT <213〉現代人 <400〉 759

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Gly Gly Asn Trp Ser Asn Trp 15 10 15

Ser Asn Cys Cys Asn Met Gly Asn Cys Ala Asn 20 25 <210〉 760 <211〉 27 <212〉 PRT <213〉現代人 <400〉 760 -1320- 200927761

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Gly Gly Asn Trp Ser Asn Trp 15 10 15

Ser Asn Cys Cys Asn Met Gly Asn Trp Ser Asn 20 25 <210> 761 <211〉 27 <212〉 PRT <213〉現代人〇 <400> 761

Tyr Thr Asn Cys Ala Arg Cys Ala Tyr Ala Ala Tyr Trp Ser Asn Thr 15 10 15

Ala Tyr Cys Cys Asn Cys Cys Asn Cys Ala Asn 20 25

<210〉 762 <211〉 27 <212〉PRT <213>現代人 <400〉 762

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Thr 15 10 15

Thr Tyr Cys Cys Asn Thr Gly Gly Cys Ala Asn 20 25 -1321 - 200927761 <210〉 763 <211> 27 <212〉PRT <213〉現代人 <400> 763

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Cys 15 10 15

Ala Asn Cys Ala Asn Thr Gly Gly Cys Ala Asn 20 25 <210> 764 <211> 27 <212〉 PRT <213〉現代人 <400〉 764

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Cys 15 10 15

Ala Asn Cys Cys Asn Met Gly Asn Cys Ala Asn 20 25 <210> 765 <211> 27 <212〉 PRT <213〉現代人 <400> 765 -1322 - 200927761

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Ala 15 10 15

Thr His Trp Ser Asn Met Gly Asn Cys Ala Asn 20 25 <210〉 766 <211〉 27 <212> PRT <213〉現代人 0 <400〉 766

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Cys 15 10 15

Ala Asn Ala Thr Gly Thr Thr Tyr Trp Ser Asn 20 25

<210〉 767 <211> 27 <212> PRT <213〉現代人 <400> 767

Cys Ala Tyr Cys Ala Arg Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Cys 15 10 15

Ala Asn Cys Cys Asn Tyr Thr Asn Cys Ala Asn 20 25 -1323 - 200927761 集庫顯示出係侷限在非常少數之分離構造類別。這些常出現之高度可變區的主鏈結構稱爲“典範構造” ° Chothia 等人（Chothia ei α/.,1 989 ; Waiwre 342 : 877- 8 3 )及其他人 (Martin ei a/.,1996 ;«/· Λ/ο/.·βϊ·ο/.263 · 800-15)之其他硏究中確認有一小型主鏈結構集庫爲6個抗體之高度可變區中之至少5個高度可變區所有。分析各抗體製劑之互補決定區（CDRs)以測定其典範類別。如所知者，典範類別僅被分派爲抗體重鏈之CDR 1和 CDR2以及抗體輕鏈之CDR1、CDR2和CDR3。下表中摘要分析之結果。典範類別資料之形式爲HCDR1-HCDR2-LCDR1-LCDR2-LCDR3 ( Η 1-H2-L 1-L2-L3 )，其中 “HCDR ”係指重鏈CDR， “ LCDR”係指輕鏈CDR。因此’例如 :1-3-2-1-1之典範類別係指具有屬於典範類別1之 HCDR1、屬於典範類別3之HCDR2、屬於典範類別2之 LCDR1、屬於典範類別1之LCDR2及屬於典範類別1之 LCDR3。當抗體中之胺基酸符合爲各典範類別所界定之胺基酸時則將其分配至特殊之典範類別。爲各典範類別界定之胺基酸可在，如：前述Chothia等人之文章中找到。表7和表8表示對每一種HB-EGF抗體之規範類型分類’當無符合之典範類別時則以字母s及一個數字標記典範類別之選派，諸如“ si 8” ，意指該CDR尺寸爲18。 -154- 200927761 <210〉 768 <211> 27 <212> PRT <213〉現代人 <400〉 768

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Thr Thr Tyr Ala Thr His Cys 15 10 15

Ala Asn Cys Cys Asn Tyr Thr Asn Cys Ala Asn 20 25 <210〉 769 <211> 27 <212〉 PRT <213〉現代人 <400> 769

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Ala Ala Tyr Ala Ala Tyr Thr 15 10 15

Ala Tyr Cys Cys Asn Thr Thr Tyr Cys Ala Asn 20 25 <210〉 770 <211> 27 <212> PRT <213〉現代人 <400〉 770

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Ala Ala Tyr Cys Ala Asn Thr -1324- 200927761 15 10

Ala Tyr Cys Cys Asn Thr Thr Tyr Cys Ala Asn 20 25 <210> 771 <211〉 30 <212〉 PRT <213>現代人 <400> 771 〇

Cys Ala Arg Cys Ala Arg Cys Ala Tyr Ala Ala Tyr Ala Ala Tyr Thr 15 10 15

Gly Gly Cys Cys Asn Cys Cys Asn Thr Gly Gly Cys Ala Asn 20 25 30

<210> 772 <211> 27 <212〉 PRT <213〉現代人 <400> 772

Cys Ala Arg Cys Ala Arg Gly Cys Asn Ala Ala Tyr Trp Ser Asn Thr 15 10 15

Thr Tyr Cys Cys Asn Cys Cys Asn Cys Ala Asn 20 25 <210> 773 -1325 - 200927761 <211> 27 <212> PRT <213>現代人 <400〉 773

Cys Ala Arg Cys Ala Arg Trp Ser Asn Cys Ala Tyr Trp Ser Asn Gly 15 10 15

Cys Asn Cys Cys Asn Thr Thr Tyr Cys Ala Asn 20 25 <210〉 774 <211〉 24 <212> PRT <213>現代人 <400> 774

Cys Ala Arg Cys Ala Arg Trp Ser Asn Thr Ala Tyr Trp Ser Asn Cys 15 10 15

Ala Asn Tyr Thr Asn Cys Ala Asn 20 <210〉 775 <211〉 27 <212> PRT <213>現代人 <400> 775

Cys Ala Arg Cys Ala Arg Trp Ser Asn Thr Ala Tyr Trp Ser Asn Ala 15 10 15 -1326- 200927761

Thr His Cys Cys Asn Tyr Thr Asn Cys Ala Asn 20 25 <210> 776 <211〉 27 <212> PRT <213〉現代人 <400〉 776

Cys Ala Arg Cys Ala Arg Ala Thr His Thr Ala Tyr Trp Ser Asn Cys 15 10 15

Ala Asn Trp Ser Asn Ala Thr His Cys Ala Asn 20 25 <210〉 777 <211> 27 <212〉 PRT <213〉現代人

<400〉 777

Cys Ala Arg Cys Ala Arg Trp Ser Asn Thr Ala Tyr Ala Thr His Cys 15 10 15

Ala Asn Cys Cys Asn Ala Thr His Cys Ala Asn 20 25 <210〉 778 <211> 27 -1327- 200927761 <212〉 PRT <213〉現代人 <400> 778

Cys Ala Arg Cys Ala Arg Trp Ser Asn Thr Ala Tyr Thr Thr Tyr Cys 15 10 15

Ala Asn Cys Cys Asn Ala Thr His Cys Ala Asn 20 25 <210〉 779 <211> 27 <212> PRT <213〉現代人 <400> 779

Cys Ala Arg Cys Ala Arg Trp Ser Asn Thr Ala Tyr Thr Thr Tyr Trp 15 10 15

Ser Asn Cys Cys Asn Ala Thr His Cys Ala Asn 20 25 <210> 780 <211> 27 <212> PRT <213〉現代人 <400〉 780

Cys Ala Arg Cys Ala Arg Trp Ser Asn Thr Thr Tyr Thr Ala Tyr Cys 15 10 15 -1328 - 200927761

Ala Asn Cys Cys Asn Ala Thr His Cys Ala Asn 20 25 <210> 781 <211> 27 <212〉 PRT <213〉現代人 <400> 781

Cys Ala Arg Cys Ala Arg Trp Ser Asn Thr Thr Tyr Thr Ala Tyr Gly 〇 1 5 10 15

Cys Asn Cys Cys Asn Ala Thr His Cys Ala Asn 20 25 <210> 782 <211〉 27 <212〉 PRT <213〉現代人

<400> 782

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Gly Ala Tyr Thr Ala Tyr Tyr 15 10 15

Thr Asn Cys Cys Asn Thr Thr Tyr Cys Ala Asn 20 25

<210> 783 <211> 27 <212> PRT -1329- 200927761 <213〉現代人 <400〉 783

Cys Ala Arg Cys Ala Arg Thr Gly Tyr Gly Ala Tyr Gly Ala Tyr Tyr 15 10 15

Thr Asn Cys Cys Asn Tyr Thr Asn Cys Ala Asn 20 25 <210〉 784 <211〉 27 <212> PRT <213〉現代人 <400> 784

Cys Ala Arg Cys Ala Tyr Thr Ala Tyr Gly Ala Tyr Ala Ala Tyr Tyr 15 10 15

Thr Asn Cys Cys Asn Tyr Thr Asn Cys Ala Asn 20 25 <210> 785 <211> 27 <212〉 PRT <213〉現代人 <400> 785

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Gly Ala Tyr Ala Ala Tyr Tyr 15 10 15 -1330- 200927761

Thr Asn Cys Cys Asn Tyr Thr Asn Cys Ala Asn 20 25 <210〉 786 <211〉 27 <212〉 PRT <213〉現代人 <400> 786

Cys Ala Arg Cys Ala Arg Thr Gly Tyr Gly Ala Tyr Ala Thr His Tyr 15 10 15

Thr Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn 20 25 <210〉 787 <211〉 27 <212〉 PRT <213>現代人 <400〉 787

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Gly Ala Tyr Ala Ala Tyr Tyr 15 10 15

Thr Asn Cys Cys Asn Tyr Thr Asn Gly Cys Asn 20 25 <210〉 788 <211> 27 <212〉 PRT <213〉現代人 -1331 - 200927761 <400> 788

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Gly Ala Tyr Trp Ser Asn Tyr 15 10 15

Thr Asn Cys Cys Asn Ala Thr His Cys Ala Asn 20 25 <210〉 789 <211> 27 <212〉 PRT <213〉現代人 <400〉 789

Cys Ala Arg Cys Ala Arg Thr Ala Tyr Gly Ala Tyr Ala Ala Tyr Tyr 15 10 15

Thr Asn Cys Cys Asn Ala Thr His Cys Ala Asn 20 25 <210> 790 <211> 27 <212〉 PRT <213>現代人 <400> 790

Cys Ala Arg Cys Ala Tyr Thr Ala Tyr Gly Ala Tyr Ala Ala Tyr Tyr 15 10 15

Thr Asn Cys Cys Asn Ala Thr His Cys Ala Asn -1332- 200927761 20 25 <210> 791 <211> 30 <212〉 PRT <213〉現代人 <400> 791

Gly Gly Asn Thr Ala Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Trp 15 10 15 ❹

Ser Asn Thr Ala Tyr Gly Gly Asn Ala Thr His Trp Ser Asn 20 25 30 <210> 792 <211〉 30 <212〉 PRT <213>現代人 <400> 792

Gly Gly Asn Thr Ala Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Gly 15 10 15

Gly Asn Cys Ala Tyr Thr Ala Tyr Ala Thr Gly Cys Ala Tyr 20 25 30 <210〉 793 <211> 30 <212> PRT <213〉現代人 -1333 - 200927761 表7

抗體(已分類的） H1-H2-L1-L2-L3 H3長度 U2-18.1 3-1-2-1-1 17 U2-13.1 1-3-4-1-1 14 U2-19.1 3-1-3-1-1 13 U2-38.1 3-1-2-1-1 23 U2-21.1 3-1-3-1-s9 8 U2-15.1 1-3-4-M 14 U2-16.1 1-2-8-1-1 11 U2-30.1 1-2-3-1-1 13 U2-42.1 1 -3-2-1 -s9 8 U2-36.1 3-s18-2-1 *s10 13 U2-22.1 1-3-3-1-1 11 U2-56.1 3-1-2-1-1 δ U2-24.1 3-s16-3-1-s9 12 U2-24.2.1 3*s 16-3-1 -s9 12 U2-14.1 1-3-4-1-1 14 U2-1.1 1-3-4-1-1 5 U2-32.1 1-1-3-1-1 15 U2-40.1 1-3-2-1-3 δ U2-5.1 1-3-4-1-1 6 U2-8.1 3-1-4-1-1 17 U2-39.1 1-3-2-1-1 6 U2-3.1 3-1-4-1-1 16 U2-43.1 1-1-2-1-1 12 U2-34.1 1-3-2-1-1 16 U2-26.1 3-1-3-1-s9 9 U2-41.1 1-3-2-1-1 12 U2-45.1 1-3-2-1-1 19 U2-54.1 3-1-2-1-1 15 U2-57.1 3-1-2-M 8 U2-12.1 1-3-2-1-s9 9 U2-46.1 1-3-2-1-1 16 U2-48.2 1-1-2-1-1 12 U2-6.1.1 1-3-4-1-1 11 U2-6.1.2 1-3-2-1-1 16 U2-58.1 3-S16-2-1-1 8 U2-51.1 1-3-2-1-1 16 U2-65.2 3-1-2-1-1 δ U2-53.1 1-1-2-1-1 12 U2-61.1 1-3-2-1-1 9 U2-28.1 3-1-3-1 ~s9 12 -155- 200927761 <400〉 793

Gly Gly Asn Thr Ala Tyr Cys Ala Asn Thr Thr Tyr Cys Ala Asn Gly 15 10 15

Gly Asn Thr Ala Tyr Thr Ala Tyr Ala Thr Gly Cys Ala Tyr 20 25 30 <210> 794 <211〉 30 <212> PRT <213〉現代人 <400〉 794

Gly Gly Asn Thr Ala Tyr Cys Ala Asn Tyr Thr Asn Cys Ala Asn Gly 15 10 15

Ala Arg Tyr Thr Asn Trp Ser Asn Ala Thr Gly Cys Ala Tyr 20 25 30 <210> 795 <211〉 36 <212〉 PRT <213>現代人 <400> 795

Gly Gly Asn Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Ala 15 10 15

Ala Tyr Gly Cys Asn Met Gly Asn Ala Thr Gly Gly Gly Asn Gly Thr 20 25 30 -1334- 200927761

Asn Trp Ser Asn 35 <210> 796 <211〉 36 <212〉 PRT <213>現代人 <400〉 796

Gly Gly Asn Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys 15 10 15

Ala Asn Gly Gly Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Gly Asn 35 <210〉 797 <211> 36 <212〉 PRT <213〉現代人 <400〉 797

Gly Gly Asn Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Tyr Cys 15 10 15

Ala Asn Gly Gly Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr 20 25 30 -1335 - 200927761

Asn Gly Gly Asn 35 <210〉 798 <211> 30 <212〉 PRT <213>現代人 <400〉 798

Gly Gly Asn Thr Thr Tyr Cys Cys Asn Thr Thr Tyr Trp Ser Asn Met 15 10 15

Gly Asn Thr Ala Tyr Trp Ser Asn Ala Thr Gly Ala Ala Tyr 20 25 30 <210〉 799 <211> 30 <212〉PRT <213>現代人 <400> 799

Gly Gly Asn Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp 15 10 15

Ser Asn Thr Ala Tyr Gly Cys Asn Ala Thr Gly Ala Ala Tyr 20 25 30 <210〉 800 <211> 30 -1336- 200927761 <212〉 PRT <213〉現代人 <400> 800

Gly Gly Asn Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp 15 10 15

Ser Asn Thr Ala Tyr Gly Cys Asn Ala Thr Gly Trp Ser Asn 20 25 30 〇 <21〇> 801 <211> 30 <212> PRT <213〉現代人 <400〉 801

Gly Gly Asn Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp 15 10 15

Ser Asn Thr Ala Tyr Gly Gly Asn Ala Thr Gly Cys Ala Tyr

<210〉 802 <211> 30 <212〉 PRT <213〉現代人 <400〉 802

Gly Gly Asn Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp 15 10 15 -1337- 200927761

Ser Asn Thr Ala Tyr Gly Ala Tyr Ala Thr Gly Cys Ala Tyr 20 25 30 <210> 803 <211> 30 <212> PRT <213〉現代人 <400〉 803

Gly Gly Asn Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Met Gly Asn Trp 15 10 15

Ser Asn Cys Ala Tyr Gly Gly Asn Ala Thr Gly Cys Ala Tyr 20 25 30 <210> 804 <211〉 30 <212〉 PRT <213〉現代人 <400〉804

Gly Gly Asn Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Gly 15 10 15

Cys Asn Thr Ala Tyr Trp Ser Asn Ala Thr Gly Ala Ala Tyr 20 25 30

<210〉 805 <211〉 30 <212> PRT -1338 - 200927761 <213〉現代人 <400> 805

Gly Gly Asn Thr Thr Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp 15 10 15

Ser Asn Thr Ala Tyr Trp Ser Asn Ala Thr Gly Ala Ala Tyr 20 25 30 <210〉 806 〇 <211〉 36 <212〉 PRT <213〉現代人 <400〉 806

Gly Gly Asn Gly Gly Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp 15 10 15

Ser Asn Gly Gly Asn Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly 20 25 30 ❹

Gly Trp Ser Asn 35 <210> 807 <211> 36 <212> PRT <213〉現代人 <400〉 807 -1339- 200927761

Gly Gly Asn Gly Gly Asn Trp Ser Asn Ala Thr His Trp Ser Asn Met 15 10 15

Gly Asn Gly Gly Asn Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly 20 25 30

Gly Trp Ser Asn 35 <210> 808 <211〉 36 <212〉 PRT <213〉現代人 <400〉808

Gly Gly Asn Gly Gly Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp 15 10 15

Ser Asn Gly Gly Asn Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly 20 25 30

Gly Trp Ser Asn 35 <210〉 809 <211> 36 <212> PRT <213〉現代人 <400〉 809 -1340- 200927761

Gly Gly Asn Gly Gly Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp 15 10 15

Ser Asn Gly Gly Asn Gly Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Gly 20 25 30

Gly Ala Ala Tyr 35 <210〉 810 0 <211〉 30 <212〉 PRT <213〉現代人 <400> 810

Gly Gly Asn Gly Gly Asn Trp Ser Asn Thr Thr Tyr Trp Ser Asn Gly 1 5 10 15

Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn 20 25 30 ❹ <210> 811 <211〉 30 <212〉 PRT <213>現代人 <400〉 811

Gly Gly Asn Gly Gly Asn Trp Ser Asn Ala Thr His Trp Ser Asn Trp 15 10 15 -1341 - 200927761

Ser Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Gly Trp Ser Asn 20 25 30 <210〉 812 <211> 36 <212〉 PRT <213〉現代人 <400〉 812

Gly Gly Asn Gly Gly Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp 15 10 15

Ser Asn Gly Gly Asn Gly Gly Asn Trp Ser Asn Thr Ala Tyr Thr Gly 20 25 30

Gly Trp Ser Asn 35 <210> 813 <211> 30 <212> PRT <213〉現代人 <400> 813

Gly Gly Asn Thr Ala Tyr Met Gly Asn Thr Thr Tyr Cys Ala Asn Trp 15 10 15

Ser Asn Thr Ala Tyr Thr Gly Gly Ala Thr His Gly Gly Asn 20 25 30 1342- 200927761 <210> 814 <211〉 30 <212〉 PRT <213〉現代人 <400〉 814

Gly Gly Asn Thr Ala Tyr Trp Ser Asn Thr Thr Tyr Cys Ala Asn Trp 15 10 15

Ser Asn Thr Ala Tyr Thr Gly Gly Ala Thr His Gly Gly Asn 20 25 30 ❹ <210〉 815 <211〉 36 <212> PRT <213〉現代人 <400〉 815

Gly Gly Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp 15 10 15

Ser Asn Thr Ala Tyr Trp Ser Asn Gly Cys Asn Gly Cys Asn Thr Gly 20 25 30

Gly Ala Ala Tyr 35 <210〉 816 <211> 51 <212〉 PRT <213〉現代人 -1343 - 200927761 表8 抗體 H1-H2-L1-L2-L3 (已分類的） H3長度 U2-43.1 1-1-2Ϊ-1-1 12 U2-48.2 1-1-2-1-1 12 U2-53.1 1-1-2-1-1 12 U2-32.1 1·1·3·1·1 15 U2-30.1 1-2-3-1-1 13 U2-16.1 1-2-8-1-1 11 U2-39.1 1-3-2-1-1 6 U2-61.1 1-3-2-1-1 9 U2-41.1 1-3-2-1-1 12 U2-34.1 1-3-2-1-1 16 U2-46.1 1-3-2-1-1 16 U2-6.1.2 1-3-2-1-1 16 U2-51.1 1-3-2-1-1 16 U2-45.1 1-3-2-1-1 19 U2-40.1 1-3-2-1-3 8 U2-42.1 1 -3-2-1 ~s9 8 U2-12.1 1-3-2-1-s9 9 U2-22.1 1-3-3-1-1 11 U2-1.1 1-3-4-1-1 5 U2-5.1 1-3-4-1-1 6 U2-6.1.1 1-3-4-1-1 11 U2-13.1 1 -3-4-1 -1 14 U2-15.1 1-3-4-M 14 U2-14.1 1-3-4-1-1 14 U2-56.1 3-1-2-1-1 8 U2-57.1 3-1-2-1-1 8 U2-65.2 3-1-2-1-1 8 U2-54.1 3-1-2-1-1 15 U2-18.1 3-1-2-1-1 17 U2-19.1 3-1-3-1-1 13 U2-21.1 3-1-3-1-S9 8 U2-26.1 3-1-3-1-S9 9 U2-28.1 3-1-3-1-S9 12 U2-3.1 3-1-4-1-1 16 U2-8.1 3-1-4-M 17 U2-58.1 3-s16-2-1-1 8 U2-24.1 3-s16-3-1-s9 12 U2-24.2.1 3-s16-3-1-s9 12 U2-36.1 3-s18-2-1-s10 13 U2-38.1 3-1-2-1-1 23 -156- 200927761 <400〉 816

Thr Gly Gly Ala Thr His Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala 1 5 10 15

Ala Tyr Gly Gly Asn Ala Ala Tyr Cys Ala Asn Ala Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Tyr Thr Asn Cys Ala Arg 35 40 45

Gly Ala Tyr 50 <210〉 817 <211> 51 <212〉PRT <213〉現代人 <400> 817

Thr Gly Gly Ala Thr His Ala Ala Tyr Cys Cys Asn Ala Ala Tyr Trp 15 10 15

Ser Asn Gly Gly Asn Gly Gly Asn Cys Ala Asn Ala Ala Tyr Thr Gly 20 25 30

Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr Cys Ala Arg 35 40 45 1344 200927761

Gly Gly Asn 50 <210〉 818 <211> 51 <212〉PRT <213〉現代人 <400〉 818

Thr Gly Gly Ala Thr His Ala Ala Tyr Cys Cys Asn Ala Ala Tyr Trp 15 10 15 〇

Ser Asn Gly Gly Asn Gly Gly Asn Cys Ala Asn Ala Ala Tyr Cys Ala 20 25 30

Tyr Cys Ala Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr Cys Ala Arg 35 40 45

Gly Gly Asn 50 ❿ <210〉 819 <211〉 51 <212> PRT <213〉現代人 <400〉 819

Trp Ser Asn Thr Thr Tyr Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly 15 10 15 -1345 - 200927761

Ala Tyr Gly Gly Asn Gly Ala Arg Cys Ala Asn Ala Thr His Thr Ala 20 25 30

Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr Cys Ala Arg 35 40 45

Gly Gly Asn 50 <210> 820 <211> 48 <212> PRT <213〉現代人 <400〉 820

Cys Ala Tyr Ala Thr His Thr Thr Tyr Trp Ser Asn Ala Ala Tyr Gly 15 10 15

Ala Tyr Gly Ala Arg Ala Ala Arg Trp Ser Asn Thr Ala Tyr Trp Ser 20 25 30

Asn Cys Ala Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn 35 40 45 <210> 821 <211> 48 <212> PRT <213〉現代人 <400> 821 -1346- 200927761

Tyr Thr Asn Ala Thr His Thr Thr Tyr Trp Ser Asn Ala Ala Tyr Gly 1 5 10 15

Ala Tyr Gly Ala Arg Ala Ala Arg Trp Ser Asn Thr Ala Tyr Trp Ser 20 25 30

Asn Cys Ala Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn 35 40 45 <210〉 822 © <211〉 48 <212〉 PRT <213〉現代人 <400〉 822

Tyr Thr Asn Ala Thr His Thr Ala Tyr Thr Gly Gly Ala Ala Tyr Gly 15 10 15

Ala Tyr Gly Ala Tyr Ala Ala Arg Met Gly Asn Thr Ala Tyr Trp Ser 20 25 30 ❿

Asn Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn 35 40 45 <210〉 823 <211> 48 <212〉 PRT <213〉現代人 <400> 823 -1347 - 200927761

Tyr Thr Asn Ala Thr His Thr Ala Tyr Thr Gly Gly Ala Ala Tyr Gly 15 10 15

Thr Asn Gly Ala Arg Ala Ala Arg Met Gly Asn Thr Ala Tyr Trp Ser 20 25 30

Asn Cys Cys Asn Trp Ser Asn Tyr Thr Asn Met Gly Asn Trp Ser Asn 35 40 45 <210> 824 <211> 51 <212〉 PRT <213〉現代人 <400〉 824

Gly Cys Asn Ala Thr His Trp Ser Asn Trp Ser Asn Trp Ser Asn Trp 15 10 15

Ser Asn Trp Ser Asn Thr Ala Tyr Ala Thr His Thr Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45

Gly Gly Asn 50

<210〉 825 <211〉 51 <212〉 PRT -1348 - 200927761 <213〉現代人 <400〉 825

Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly 15 10 15

Gly Asn Gly Gly Asn Trp Ser Asn Cys Ala Asn Thr Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg

Gly Gly Asn 50 <210〉 826 <211> 51 <212> PRT <213〉現代人 <400> 826

Thr Thr Tyr Ala Thr His Trp Ser Asn Gly Ala Tyr Gly Ala Tyr Gly 15 10 15

Gly Asn Trp Ser Asn Cys Ala Asn Ala Ala Arg Thr Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45 -1349- 200927761

Gly Gly Asn 50 <210〉 827 <211〉 51 <212> PRT <213〉現代人 <400〉 827

Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly Ala Tyr Gly 15 10 15

Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Thr Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45

Gly Gly Asn 50 <210> 828 <211〉 51 <212〉 PRT <213〉現代人 <400〉 828

Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly Ala Tyr Gly 15 10 15 -1350- 200927761

Gly Asn Trp Ser Asn Ala Thr His Ala Ala Arg Thr Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45

Gly Gly Asn 50 0 <210> 829 <211〉 51 <212〉PRT <213〉現代人 <400> 829

Gly Thr Asn Ala Thr His Thr Gly Gly Trp Ser Asn Gly Ala Tyr Gly 15 10 15

Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Thr Ala Tyr Thr Ala

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45

Gly Gly Asn 50 <210〉 830 <211> 51 1351 - 200927761 <212〉 PRT <213〉現代人 <400〉 830

Gly Thr Asn Ala Thr His Thr Gly Gly Gly Ala Tyr Gly Ala Tyr Gly 15 10 15

Gly Asn Trp Ser Asn Ala Ala Tyr Cys Ala Arg Thr Ala Tyr Thr Ala 20 25 30

Tyr Cys Ala Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45

Gly Gly Asn 50 <210〉 831 <211> 51 <212> PRT <213〉現代人 <400〉 831

Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly Ala Tyr Gly 15 10 15

Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Met Gly Asn Thr Ala 20 25 30

Tyr Gly Thr Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45 -1352- 200927761

Gly Gly Asn 50 <210〉 832 <211> 51 <212〉 PRT <213>現代人 <400> 832

Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly Ala Tyr Gly 15 10 15

Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Met Gly Asn 35 40 45

Gly Gly Asn 50 <210> 833 <211> 51 <212> PRT <213〉現代人 <400> 833

Thr Ala Tyr Ala Thr His Trp Ser Asn Trp Ser Asn Trp Ser Asn Gly 15 10 15 - 1353 - 200927761 表9爲每一類別抗體數之分析。該具有指示於左欄中之特殊典範類別的抗體數顯示於右欄中。最常見之構造爲1-3-2-1-1。全部40種單株抗體中有 8種具有此組合。表9 各典範類別組合中之抗HB-EGFjit體數〇 H1-H2-L1-L2-L3 計數 1-1-2-1-1 3 1-1-3-1-1 1 1-2-3-1-1 1 1-2-8-1-1 1 1-3-2-1-1 8 1-3-2-1-3 1 1-3-2-1-S9 2 1-3-3-1-1 1 1-3-4-1-1 6 3-1-2-1-1 5 3-1-3·1·1 1 3_1-3-1-s9 3 Q 3-1-4-1-1 2 3-S16-2-1-1 1 3*s16-3-1-s9 2 3-s 18-2-1 -s 10 1 3-1-2-1-1 1 GG.實例23 :抗HB-EGF抗體之抗原決定部位測定本實例描述測定被抗體製劑辨識之抗原決定部位的測定法。測試之抗體：分析5種可中和HB-EGF活性之源自人類的 XenoMouse 單株抗體製劑：U2-39; U2-42; U2-45; -157- 200927761

Gly Asn Met Gly Asn Cys Ala Asn Ala Thr His Thr Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45

Gly Gly Asn 50 <210〉 834 <211〉 51 <212〉 PRT <213〉現代人 <400〉 834

Cys Ala Tyr Ala Thr His Trp Ser Asn Trp Ser Asn Trp Ser Asn Trp 15 10 15

Ser Asn Met Gly Asn Cys Ala Asn Ala Thr His Thr Ala Tyr Thr Ala 20 25 30

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45

Gly Gly Asn 50 <210〉 835 -1354- 200927761 <211> 51 <212〉 PRT <213〉現代人 <400> 835

Cys Ala Tyr Ala Thr His Trp Ser Asn Met Gly Asn Trp Ser Asn Trp 15 10 15

Ser Asn Met Gly Asn Cys Ala Asn Ala Thr His Thr Ala Tyr Thr Ala 20 25 30 ❹

Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn Ala Ala Arg 35 40 45

Gly Gly Asn 50

<210〉 836 <211〉 48 <212〉 PRT <213〉現代人 <400〉 836

Thr Ala Tyr Ala Thr His Cys Ala Tyr Trp Ser Asn Trp Ser Asn Gly 15 10 15

Gly Asn Trp Ser Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Ala Ala 20 25 30

Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn - 1355 - 200927761 35 40 45 <210〉 837 <211> 48 <212〉PRT <213〉現代人 <400> 837

Thr Ala Tyr Ala Thr His Thr Ala Tyr Cys Ala Tyr Trp Ser Asn Gly 15 10 15

Gly Asn Trp Ser Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Ala Ala 20 25 30

Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn 35 40 45 <210〉 838 <211〉 48 <212〉PRT <213〉現代人 <400〉 838

Thr Ala Tyr Ala Thr His Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Gly 15 10 15

Gly Asn Trp Ser Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Ala Ala 20 25 30

Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn -1356- 200927761 35 40 45 <210> 839 <211〉 48 <212〉 PRT <213〉現代人 <400> 839

Thr Ala Tyr Ala Thr His Cys Ala Tyr Thr Ala Tyr Trp Ser Asn Gly 15 10 15 〇

Gly Asn Trp Ser Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Ala Ala 20 25 30

Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn 35 40 45

<210〉 840 <211> 48 <212〉 PRT <213〉現代人 <400〉 840

Thr Ala Tyr Ala Thr His Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Gly 15 10 15

Gly Asn Gly Gly Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Ala Ala 20 25 30

Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn -1357 - 200927761 35 40 45 <210〉 841 <211〉 48 <212〉 PRT <213〉現代人 <400〉841

Gly Ala Arg Ala Thr His Ala Ala Tyr Cys Ala Tyr Trp Ser Asn Gly 1 5 10 15

Gly Asn Trp Ser Asn Cys Ala Asn Ala Ala Tyr Thr Ala Tyr Ala Ala 20 25 30

Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn 35 40 45 <210〉 842 <211> 48 <212〉 PRT <213〉現代人 <400〉842

Met Gly Asn Ala Thr His Thr Ala Tyr Cys Ala Asn Trp Ser Asn Gly 15 10 15

Gly Asn Cys Ala Asn Cys Ala Asn Ala Ala Tyr Thr Ala Tyr Ala Ala 20 25 30

Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn -1358 - 200927761 35 40 45 <210〉 843 <211〉 48 <212〉 PRT <213>現代人 <400〉 843

Thr Ala Tyr Ala Thr His Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Gly 15 10 15 〇

Gly Asn Trp Ser Asn Cys Ala Asn Ala Ala Tyr Thr Ala Tyr Ala Ala 20 25 30

Tyr Cys Cys Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Trp Ser Asn 35 40 45

<210〉844 <211> 51 <212〉PRT <213〉現代人 <4〇〇> 844

Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly Ala Tyr Gly 15 10 15

Ala Tyr Trp Ser Asn Gly Ala Tyr Cys Ala Asn Met Gly Asn Thr Ala 20 25 30

Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr Cys Ala Arg -1359- 200927761 35 40 45

Gly Gly Asn 50 <210〉845 <211〉 51 <212〉PRT <213〉現代人 <400〉 845

Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly Ala Tyr Gly 15 10 15

Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Cys Asn Met Gly Asn Thr Ala 20 25 30

Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr Cys Ala Arg 35 40 45

Gly Gly Asn 50 <210> 846 <211〉 51 <212〉 PRT <213〉現代人 <400〉 846

Ala Thr His Ala Thr His Thr Ala Tyr Cys Cys Asn Gly Gly Asn Gly -1360- 200927761 10 15

Ala Tyr Trp Ser Asn Gly Ala Tyr Ala Thr His Met Gly Asn Thr Ala 20 25 30

Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn Thr Thr Tyr Cys Ala Arg 35 40 45

Gly Gly Asn 50 〇 <210〉 847 <211〉 54 <212> PRT <213〉現代人 <400〉 847

Met Gly Asn Cys Ala Asn Thr Ala Tyr Thr Gly Tyr Met Gly Asn Trp 15 10 15

Ser Asn Ala Ala Arg Thr Gly Gly Thr Ala Tyr Ala Ala Tyr Gly Ala 20 25 30

Tyr Thr Ala Tyr Gly Cys Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn 35 40 45

Ala Ala Arg Trp Ser Asn 50 -1361 - 200927761 <210> 848 <211> 33 <212> PRT <213>現代人 <400〉 848

Gly Ala Arg Gly Ala Tyr Ala Ala Tyr Thr Gly Gly Ala Ala Tyr Thr 1 5 10 15

Ala Tyr Gly Gly Asn Thr Thr Tyr Thr Thr Tyr Gly Ala Tyr Thr Ala 20 25 30

Tyr <210〉 849 <211〉 24 <212〉 PRT <213>現代人 <400> 849

Trp Ser Asn Ala Thr His Gly Cys Asn Gly Thr Asn Gly Cys Asn Tyr 15 10 15

Thr Asn Gly Ala Tyr Thr Ala Tyr 20 <210> 850 <211> 39 <212〉 PRT <213〉現代人 1362 - 200927761 <400> 850

Gly Ala Arg Gly Gly Asn Gly Ala Tyr Gly Gly Asn Gly Gly Asn Thr 15 10 15

Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr 20 25 30

Gly Gly Ala Tyr Gly Thr Asn 35 〇 <210〉 851 <211> 36 <212> PRT <213〉現代人 <400〉 851

Ala Thr Gly Thr Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Thr 15 10 15

Gly Gly Thr Ala Tyr Gly Gly Asn Gly Thr Asn Thr Thr Tyr Gly Ala 20 25 30

Tyr Thr Ala Tyr 35 <210〉 852 <211〉 39 <212〉 PRT <213〉現代人 -1363 - 200927761 U2-26和U2-19。這些單株抗體製劑中有4種顯示出特異於人HB-EGF，而抗體製劑U2-45顯示出與老鼠HB-EGF 及人雙調蛋白具有一些交叉反應性。所有這些中和抗體製劑配置在MCAB第7&8箱中（見下文）。 1 .抗原決定部位之測定

藉由PCR增數自Hela mRNA分離出人HB-EGF cDNA 並利用IgK信號肽序列將成熟之HB-EGF序列選殖入 pSecTAg載體中（爲myC_His融合蛋白之形式）。成熟HB-EGF多肽表現在293T細胞中並分泌入介質中。藉由定點突變將HB-EGF之白喉毒素結合部位及EGF 受體結合部位進行突變。亦選殖短型 Η B - E G F ( L 〇 u k i a η o v e ί α / ·，G e « e 1 9 5 : 8 1-8 6)(其遺漏似EGF結構區之第三個二硫鍵）。將具有SEQ ID NO: 1052之HB-EGF的似EGF結構區（ DPCLRKYKD FCIHGECKYVKELRAPSCICHPGYHGERCHGLSLP )選殖入pSecTag載體中，以myc-His融合蛋白之形式表現及分泌。 2.結果所有 U2-39 ; U2-42 ; U2-45 ; U2-26 和 U2-19 抗體製劑均辨識不連續之抗原決定部位。這些抗體無一可辨識短型 HB-EGF。所有5種抗體製劑之結合部位係在似EGF結構區內， -158- 200927761 <400〉 852

Gly Thr Asn Thr Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Thr 15 10 15

Gly Gly Trp Ser Asn Thr Thr Tyr Thr Ala Tyr Gly Gly Asn Ala Thr 20 25 30

Gly Gly Ala Tyr Gly Thr Asn 35 <210> 853 <211〉 24 <212〉 PRT <213>現代人 <400〉 853

Met Gly Asn Met Gly Asn Gly Ala Arg Tyr Thr Asn Cys Cys Asn Thr 15 10 15

Thr Tyr Gly Ala Tyr Thr Ala Tyr 20 <210〉 854 <211> 24 <212〉 PRT <213〉現代人 <400〉 854

Met Gly Asn Ala Ala Tyr Thr Gly Gly Cys Ala Asn Cys Cys Asn Thr -1364- 200927761 10 15

Thr Tyr Gly Ala Tyr Thr Ala Tyr 20 <210> 855 <211> 24 <212> PRT <213>現代人 <400> 855 ❹

Met Gly Asn Tyr Thr Asn Gly Ala Arg Tyr Thr Asn Cys Cys Asn Thr 15 10 15

Thr Tyr Gly Ala Tyr Thr Ala Tyr 20

<210〉 856 <211> 24 <212〉 PRT <213〉現代人 <400〉 856

Met Gly Asn Met Gly Asn Gly Ala Arg Gly Thr Asn Cys Cys Asn Thr 15 10 15

Thr Tyr Gly Ala Tyr Thr Ala Tyr 20 <210> 857 -1365 - 200927761 <211> 24 <212〉 PRT <213〉現代人 <400> 857

Met Gly Asn Cys Ala Tyr Cys Ala Asn Ala Ala Tyr Cys Cys Asn Thr 15 10 15

Thr Tyr Gly Ala Arg Thr Ala Tyr 20 <210〉 858 <211〉 24 <212〉 PRT <213〉現代人 <400〉 858

Met Gly Asn Gly Gly Asn Gly Ala Arg Tyr Thr Asn Cys Cys Asn Thr 15 10 15

Thr Tyr Gly Ala Tyr Thr Ala Tyr 20 <210> 859 <211> 36 <212〉 PRT <213〉現代人 <400> 859

Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly Gly Asn Gly Cys Asn Cys 15 10 15 -1366- 200927761

Ala Asn Cys Cys Asn Gly Ala Tyr Gly Cys Asn Thr Thr Tyr Gly Ala 20 25 30

Tyr Ala Thr His 35

<210〉 860 <211> 57 <212> PRT ❹ <213〉現代人 <400〉 860

Gly Ala Arg Gly Gly Asn Ala Thr His Gly Cys Asn Gly Thr Asn Gly 1 5 10 15

Cys Asn Gly Gly Asn Cys Ala Asn Gly Cys Asn Gly Ala Arg Thr Ala 20 25 30

Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Cys Asn 35 40 45

Ala Thr Gly Gly Ala Tyr Gly Thr Asn 50 55 <210〉 861 <211> 48 <212> PRT <213〉現代人 -1367- 200927761 <400〉 861

Gly Ala Arg Gly Gly Asn Ala Thr His Gly Cys Asn Gly Cys Asn Met 15 10 15

Gly Asn Gly Ala Tyr Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Thr Ala 20 25 30

Tyr Thr Ala Tyr Gly Cys Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 35 40 45 <210> 862 <211> 48 <212〉 PRT <213〉現代人 <400〉 862

Gly Ala Arg Gly Gly Asn Ala Thr His Gly Cys Asn Gly Gly Asn Met 1 5 10 15

Gly Asn Gly Ala Tyr Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Thr Ala 20 25 30

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 35 40 45 <210〉 863 <211〉 42 <212〉PRT <213〉現代人 -1368 - 200927761 <400〉 863

Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Gly Ala Tyr Trp Ser Asn Trp 15 10 15

Ser Asn Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly 20 25 30

Asn Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr 35 40 ❹ <210> 864 <211〉 15 <212〉PRT <213〉現代人 <400〉 864

Ala Ala Tyr Gly Thr Asn Ala Thr His Gly Ala Tyr Thr Ala Tyr 15 10 15

<210> 865 <211> 33 <212〉 PRT <213〉現代人 <400〉 865

Gly Gly Asn Gly Gly Asn Gly Cys Asn Cys Ala Asn Gly Gly Asn Gly 15 10 15

Cys Asn Gly Ala Arg Thr Ala Tyr Thr Thr Tyr Cys Ala Arg Cys Ala 20 25 30 -1369- 200927761

Tyr <210> 866 <211> 27 <212〉 PRT <213〉現代人 <400> 866

Tyr Thr Asn Thr Gly Gly Thr Thr Tyr Gly Gly Asn Gly Ala Arg Cys 15 10 15

Ala Asn Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr 20 25 <210> 867 <211> 18 <212〉PRT <213>現代人 <400〉 867

Ala Ala Tyr Tyr Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr 15 10 15

Ala Tyr <210〉 868 <211〉 42 -1370- 200927761 <212〉 PRT <213〉現代人 <400〉 868

Trp Ser Asn Cys Ala Tyr Thr Ala Tyr Gly Gly Asn Gly Gly Asn Gly 15 10 15

Ala Tyr Thr Ala Tyr Gly Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly 20 25 30

Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 35 40 <210> 869 <211> 33 <212〉 PRT <213>現代人 <400〉 869

Gly Ala Tyr Gly Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Cys

Ala Arg Gly Cys Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 20 25 30

Tyr <210> 870 <211> 27 -1371 - 200927761 <212> PRT <213〉現代人 <400〉 870

Thr Gly Gly Gly Gly Asn Ala Thr His Trp Ser Asn Gly Cys Asn Cys 15 10 15

Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Gly Tyr 20 25 <210> 871 <211> 18 <212〉 PRT <213〉現代人 <400> 871

Thr Gly Gly Gly Cys Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr 15 10 15

Ala Tyr <210> 872 <211〉48 <212〉 PRT <213〉現代人 <400〉 872

Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Ala Ala Tyr Thr Gly Gly Ala 1 5 10 15 -1372- 200927761

Ala Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala Ala Tyr Thr Ala 20 25 30

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 35 40 45 <210> 873 <211> 48 <212〉 PRT <213>現代人 ❹ <400〉 873

Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Ala Ala Tyr Thr Gly Gly Ala 15 10 15

Ala Tyr Ala Ala Tyr Gly Gly Asn Gly Gly Asn Thr Ala Tyr Thr Ala 20 25 30

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn

<210> 874 <211〉 24 <212> PRT <213〉現代人 <400> 874

Gly Gly Asn Cys Cys Asn Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala 15 10 15 1373 - 200927761 其包含具有下列序列之成熟蛋白質的殘基44-86 :

DPCLRKYKDFCIHGECKYVKELRAPSCICHPGYHGER CHGLSLP ( SEQ ID NO ： 1052)。在似 EGF 結構區中之第 3個雙硫鍵對於所有U2-39 ; U2-42 ; U2-45 ; U2-26和U2- 19抗體製劑之鍵結是必要的。

3.藉由定點突變進行抗體結合部位之構造-功能分析以通常在老鼠pro-HB-EGF中找到之對應的胺基酸殘基取代人pro-HB-EGF之似EGF結構區內的1至4個殘基來創造ΗΒ-EGF中之12種獨立之突變。假設許多現有之抗體製劑爲物種選擇性，在已知之人 ΗΒ-EGF蛋白和來自不同物種之相關蛋白間的不同處進行定點突變，以鑑定HB-EGF抗原決定部位。尤其是，介於人類和老鼠 ΗΒ-EGF間之胺基酸差異如下：K122R ; V124L ； K125Q ； I133K ；和 H135L。用於測定抗原決定部位之完整ΗΒ-EGF突變多肽序列列表提供於表10中。編碼所需之突變種蛋白質的突變種 ΗΒ-EGF核酸暫時表現於293 T細胞中，藉由ELIS A測量單株抗體結合。因此，以這些突變製造ΗΒ-EGF突變種多肽，並測試這類突變種多肽以確認現有之抗體製劑是否仍結合HB-EGF突變種多肽。若不，則該突變之胺基酸對抗體結合亦同樣重要’因此，其形成抗原決定部位之重要部分。表11摘要所得之結合結果，其中“是”表示僅管有 -159- 200927761

Thr Gly Gly Ala Tyr Gly Thr Asn 20 <210〉 875 <211> 51 <212〉PRT <213〉現代人 <400〉 875

Gly Cys Asn Tyr Thr Asn Met Gly Asn Gly Gly Asn Ala Thr His Gly 15 10 15

Thr Asn Tyr Thr Asn Ala Thr Gly Gly Thr Asn Thr Ala Tyr Gly Thr 20 25 30

Asn Tyr Thr Asn Gly Gly Asn Gly Cys Asn Tyr Thr Asn Gly Ala Tyr 35 40 45

Ala Thr His 50 <210> 876 <211〉 51 <212〉 PRT <213〉現代人 <400〉 876

Gly Ala Tyr Gly Ala Arg Cys Ala Asn Gly Thr Asn Gly Thr Asn Met 15 10 15 -1374- 200927761

Gly Asn Gly Gly Asn Tyr Thr Asn Ala Thr His Met Gly Asn Thr Ala 20 25 30

Tyr Thr Gly Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr 35 40 45

Gly Thr Asn 50 ❹ <210〉 877 <211〉 36 <212> PRT <213〉現代人 <400〉 877

Gly Ala Tyr Met Gly Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly 15 10 15

Ala Tyr Thr Ala Tyr Gly Gly Asn Met Gly Asn Ala Thr Gly Gly Ala

Tyr Gly Thr Asn 35 <210〉 878 <211> 27 <212> PRT <213〉現代人 <400〉 878 1375 - 200927761

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Gly Gly Asn Thr 15 10 15

Gly Tyr Thr Thr Tyr Gly Cys Asn Tyr Thr Asn 20 25 <210〉 879 <211〉 69 <212〉PRT <213〉現代人 <400> 879

Gly Gly Asn Thr Ala Tyr Ala Ala Tyr Thr Ala Tyr Gly Gly Asn Tyr 15 10 15

Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Ala Tyr Trp Ser 20 25 30

Asn Trp Ser Asn Gly Gly Asn Thr Ala Tyr Cys Cys Asn Trp Ser Asn 35 40 45

Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly 50 55 60

Ala Tyr Gly Thr Asn 65 <210> 880 <211> 45 -1376- 200927761 <212〉 PRT <213〉現代人 <400〉 880

Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Gly Ala Tyr Ala Thr His Tyr 15 10 15

Thr Asn Cys Ala Asn Gly Gly Asn Thr Ala Tyr Cys Cys Asn Thr Thr 20 25 30

Tyr Thr Ala Tyr Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr 35 40 45 <210〉 881 <211〉 36 <212〉 PRT <213〉現代人 <400> 881

Gly Gly Asn Gly Gly Asn Thr Ala Tyr Trp Ser Asn Trp Ser Asn Trp 15 10 15

Ser Asn Thr Gly Gly Thr Ala Tyr Thr Gly Gly Thr Thr Tyr Gly Ala 20 25 30

Tyr Cys Cys Asn 35 <210> 882 <211〉 36 -1377- 200927761 <212> PRT <213〉現代人 <400> 882

Gly Gly Asn Gly Gly Asn Thr Ala Tyr Trp Ser Asn Trp Ser Asn Trp 15 10 15

Ser Asn Thr Gly Gly Thr Thr Tyr Thr Gly Gly Thr Thr Tyr Gly Ala 20 25 30

Tyr Cys Cys Asn 35 <210〉 883 <211> 45 <212〉 PRT <213>現代人 <400〉 883

Gly Ala Tyr Gly Gly Asn Thr Ala Tyr Trp Ser Asn Thr Ala Tyr Gly 15 10 15

Gly Asn Cys Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala 20 25 30

Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn 35 40 45 <210〉 884 <211> 48 -1378 - 200927761 <212〉 PRT <213〉現代人 <400> 884

Trp Ser Asn Gly Cys Asn Tyr Thr Asn Met Gly Asn Thr Ala Tyr Thr 15 10 15

Thr Tyr Gly Ala Tyr Thr Gly Gly Tyr Thr Asn Thr Thr Tyr Trp Ser 20 25 30

Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 35 40 45 <210〉 885 <211〉 33 <212> PRT <213>現代人 <400〉 885

Cys Ala Arg Ala Ala Arg Trp Ser Asn Thr Ala Tyr Gly Gly Asn Thr 15 10 15

Ala Tyr Trp Ser Asn Thr Ala Tyr Thr Thr Tyr Gly Ala Tyr Thr Ala 20 25 30

Tyr <210> 886 <211> 36 -1379- 200927761 <212> PRT <213〉現代人 <400〉 886

Cys Ala Arg Gly Gly Asn Thr Ala Tyr Gly Gly Asn Trp Ser Asn Gly 15 10 15

Gly Asn Thr Gly Gly Gly Gly Asn Thr Ala Tyr Thr Thr Tyr Gly Ala 20 25 30

Tyr Thr Ala Tyr 35 <210〉 887 <211〉 54 <212〉 PRT <213〉現代人 <400〉 887

Cys Ala Arg Gly Gly Asn Tyr Thr Asn Gly Cys Asn Gly Thr Asn Gly 15 10 15

Cys Asn Gly Gly Asn Cys Ala Asn Trp Ser Asn Thr Ala Tyr Thr Ala 20 25 30

Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 35 40 45

Gly Ala Tyr Gly Thr Asn 50 -1380- 200927761 <210〉 888 <211〉 39 <212〉 PRT <213〉現代人 <400〉 888

Gly Ala Tyr Met Gly Asn Gly Cys Asn Gly Thr Asn Gly Cys Asn Gly 15 10 15

Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr 20 25 30

Gly Gly Ala Tyr Gly Thr Asn 35 <210〉 889 <211〉 69 <212〉 PRT <213>現代人 <400> 889

Gly Ala Tyr Gly Thr Asn Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn 35 40 45 -1381 - 200927761

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr 65 <210〉 890 <211〉 69 <212〉 PRT <213〉現代人 <400〉 890

Gly Ala Tyr Gly Thr Asn Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr 65 <210〉 891 -1382- 200927761 <211〉 69 <212〉 PRT <213〉現代人 <400> 891

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr 20 25 30 ❹

Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Cys Cys Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr 65

<210> 892 <211〉 69 <212> PRT <213〉現代人 <400〉 892

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Tyr Thr -1383 - 200927761 指出之突變，仍發生結合，“不”表示結合大致上被指出之突變排除，“減少”表示當出現突變時，結合減少。表10 野生型 LGKKRDPCLRKYKDFCIHGE- CKWKELRAPSCICHPGYHGERCHGLSLP SEQ ID NO: F115Y Y 1053 L127F F 1054 E141H ... u_________ 1055 K122R; V124L； K125Q P LQ 1056 F115Y； K122R； V124L； K125Q γ P LQ 1057 K122R； V124L； K125Q； E141H __ ________ . …r_| 〇 μ 1058 I133K; H135L 1/ I 1059 F115Y； I133K; H135L 1060 L127F; I133K; H135L 1061 L148T ________ __________ τ 1062 E141H; L148T Η Τ 1063 117-120 IHGE 改變爲 LHDGV 1064 -160- 200927761 20 25 30

Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Cys Cys Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr 65 <210> 893 <211> 69 <212〉 PRT <213〉現代人 <400> 893

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Ala 50 55 60 -1384- 200927761

Thr His Thr Gly Tyr 65 <210〉 894 <211〉 69 <212〉 PRT <213>現代人 <400> 894

Ala Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15 〇

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60 ❹

Ser Asn Thr Gly Tyr 65 <210> 895 <211> 69 <212〉 PRT <213〉現代人 <400〉 895 -1385 - 200927761

Gly Ala Arg Ala Thr His Gly Thr Asn Tyr Thr Asn Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Gly Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Tyr Thr Asn Trp 50 55 60

Ser Asn Thr Gly Tyr 65 <210〉 896 <211> 69 <212〉 PRT <213>現代人 <400〉 896

Gly Ala Arg Ala Thr His Gly Thr Asn Tyr Thr Asn Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Gly Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Tyr Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45 -1386 200927761

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Tyr Thr Asn Trp 50 55 60

Ser Asn Thr Gly Tyr 65 <210> 897 <211〉 69 <212〉 PRT <213〉現代人 ❹ <400> 897

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210〉 898 <211〉 69 -1387- 200927761 <212〉PRT <213〉現代人 <400> 898

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr 65 <210〉 899 <211〉 69 <212〉 PRT <213〉現代人 <400> 899

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30 -1388- 200927761

Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr 65 ❹ <210> 900 <211〉 69 <212〉 PRT <213〉現代人 <400〉 900

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr -1389- 200927761 65 <210〉 901 <211> 69 <212〉 PRT <213〉現代人 <400> 901

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210> 902 <211> 69 <212〉 PRT <213〉現代人 <400> 902

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys -1390- 200927761 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly Cys Asn Ala Thr His Cys 50 55 60 ❹

Ala Asn Thr Gly Tyr 65 <210〉 903 <211〉 69 <212〉 PRT <213〉現代人 <400〉 903

Gly Ala Arg Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Cys Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45 -1391 - 200927761

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Tyr Thr Asn Trp 50 55 60

Ser Asn Thr Gly Tyr 65 <210〉 904 <211〉 69 <212〉 PRT <213〉現代人 <400> 904

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Gly Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210> 905 <211> 69 <212> PRT -1392- 200927761 <213〉現代人 <400> 905

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 〇 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65

<210〉 906 <211〉 69 <212〉 PRT <213〉現代人 <400〉 906

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30 -1393 - 200927761 表11 結合結果構造物/Mab U2-42.3 U2-39.1 U2-19.3 U2-26.1 U2-45 1 人 proHB-EGF (WT) 是是是是是 2 F115Y 否否是是減少 3 L127F 是否是是是 4 E141H 否是是是是 5 K122R, V124L, K125Q 是是是是是 6 F115Y.K122R, V124L, K125Q 否否是是減少 7 K122R, V124L, K125Q, E141H 否是是是是 8 I133K, H135L 是是否否是 9 F115Y, I133K, H135L 否否否否減少 10 L127F.I133K, H135L, 是否否否是 11 S147T 是是是是是 12 E141H, S147T 否是是是是 13 IHGE (117-120) to LHDGV 是是否否否關鍵殘基 F115&E141 F115 & L127 1133 或 H135 1133 或 H135 F115?

這些結合硏究指出U2-42和U2-39抗體製劑可辨識白喉毒素結合結構區，而F115、L127和E141殘基對白喉毒素之結合作用很重要。 © 再者，當HB-EGF中出現F115Y或E141H突變時， U2-42抗體製劑之結合作用大體上被排除。因此，Phe-1 15 及Glu-141對U2-42抗體結合是重要的。U2-45抗體製劑亦顯示出需要Phe-115，因爲當Phe-115突變時，此抗體製劑之結合作用減少。 U2-39抗體製劑與HB-EGF結合時需要Phe-115及

Leu-1 27，因爲這些殘基中任一種之突變大體上會排除抗體之結合作用。 U2-19、U2-26和U2-45抗體製劑結合介於殘基117- -161 - 200927761

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210> 907 <211> 69 <212> PRT <213>現代人 <400〉 907

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 -1394 - 200927761 <210〉 908 <211> 69 <212〉 PRT <213〉現代人 <400〉 908

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210〉 909 <211> 69 <212〉 PRT <213〉現代人 <400> 909

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15 -1395 - 200927761

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210> 910 <211> 45 <212> PRT <213>現代人 <400〉 910

Thr Gly Gly Tyr Thr Asn Cys Ala Arg Cys Ala Arg Met Gly Asn Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Trp Ser Asn Cys Cys Asn Met Gly 20 25 30

Asn Met Gly Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 911 -1396- 200927761 <211> 45 <212〉 PRT <213〉現代人 <400> 911

Thr Gly Gly Thr Ala Tyr Tyr Thr Asn Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Cys Ala 20 25 30 〇

Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 912 <211〉 45 <212> PRT <213>現代人 <400> 912

Thr Gly Gly Thr Thr Tyr Tyr Thr Asn Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Cys Ala 20 25 30

Arg Cys Cys Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 913 -1397- 200927761 <211> 45 <212〉 PRT <213〉現代人 <400〉 913

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Thr Asn Cys Cys Asn Ala Ala 20 25 30

Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 914 <211> 45 <212〉 PRT <213>現代人 <400〉 914

Thr Gly Gly Tyr Thr Asn Cys Ala Arg Cys Ala Arg Met Gly Asn Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Met Gly 20 25 30

Asn Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 915 -1398 - 200927761 <211〉 45 <212> PRT <213>現代人 <400〉 915

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Met Gly 20 25 30

O

Asn Tyr Thr Asn Tyr Thr Asn Ala Thr His Trp Ser Asn 35 40 45 <210〉 916 <211> 45 <212> PRT <213>現代人 <400〉 916

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Met Gly 20 25 30

Asn Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 917 -1399- 200927761 <211〉 45 <212〉 PRT <213〉現代人 <400> 917

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Met Gly Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 918 <211〉 45 <212〉 PRT <213〉現代人 <400〉 918

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Tyr Thr Asn Thr Thr Tyr Ala Thr His Thr Ala Tyr 35 40 45 <210> 919 -1400 - 200927761 <211〉 45 <212〉 PRT <213〉現代人 <400〉 919

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 920 <211> 45 <212〉 PRT <213〉現代人 <400〉 920

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys ❹ 1 5 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Gly Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 921 -1401 - 200927761 <211> 45 <212> PRT <213〉現代人 <400〉921

Thr Gly Gly Thr Thr Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Trp Ser Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 922 <211> 45 <212〉 PRT <213〉現代人 <400> 922

Thr Gly Gly Tyr Thr Asn Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Trp Ser Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 923 • 1402- 200927761 <211> 45 <212〉PRT <213〉現代人 <400> 923

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Gly Ala Tyr Cys 15 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Met Gly 20 25 30

Asn Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 924 <211〉 45 <212> PRT <213〉現代人 <400〉 924

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 〇 1 5 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 925 -1403 - 200927761 120(IHGE)間之保留區。如表η中所示，抗體製劑U2-19 和U2-26亦辨識在Ile-133及/或His-135處之抗原決定部位’因爲這些殘基中至少有一對其結合具關鍵性。根據其結合性質將抗體置於表1 2中所列之關係“箱 »» 〇裝箱（binning)爲將抗體根據其競爭結合抗原之作用分組的方法（見，Jia ei a/_，2004，288: 91-98)。箱之分配係根據所觀察之所有測試抗體的結合形態的差異有多大而定。因此，箱並非永遠與藉由其他方式測定之抗原決定部位相關，僅可約略界定抗原決定部位。表12 抗體關係箱第1箱第2箱第3箱第4箱第5箱第6箱第7箱第8箱 U2-24.2 U2-1.3 U2-15.3 U2-13.3 U2-16.3 U2-18.3 U2-19.2 U2-3.2 U2-32.3 U2-30.2 U2-14.3 U2-38.1 U2-21.3 U2-5.3 U2-2.1 1.19.2 U2-34.1 U2-17.1 U2-57.1 U2-36.3 U2-26.2 U2-56.3 I U2-58.3 U2-40.3 U2-41.3 U2*61.1 U2-8.3 U2-45.3 U2-22.3 U2-46.3 U2- U2-39.1 48.2.1 U2-54.2 U2-6.1 U2-51.2 U2-53.3 U2-28.2 —般而言，U 2 - 4 5抗體製劑之抗原決定部位測定指出第7箱抗體製劑與老鼠HB-EGF和人類雙調蛋白交叉反應 -162- 200927761 <211> 45 <212〉 PRT <213〉現代人 <400> 925

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Thr Thr Tyr Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 926 <211〉 45 <212〉PRT <213〉現代人 <400> 926

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Met Gly Asn Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Tyr Gly Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 927 -1404 - 200927761 <211> 45 <212〉 PRT <213〉現代人 <400〉 927

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Gly Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 928 <211〉 45 <212> PRT <213〉現代人 <400〉 928

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Cys 〇 1 5 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Cys Cys Asn Gly Ala 20 25 30

Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210〉 929 -1405 - 200927761 <211> 45 <212〉PRT <213〉現代人 <400> 929

Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala Ala Arg Tyr 15 10 15

Thr Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Cys Cys Asn Ala Ala 20 25 30

Arg Tyr Thr Asn Tyr Thr Asn Ala Thr His Cys Ala Tyr 35 40 45 <210> 930 <211> 96 <212> PRT <213>現代人 <400〉 930

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Ala Ala Tyr Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Met Gly Asn Gly -1406 - 200927761 50 55 60

Thr Asn Gly Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Gly Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95

<210〉 931 <211> 96 <212〉 PRT <213〉現代人 <400> 931

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Met Gly Asn Gly 50 55 60

Thr Asn Gly Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80 -1407 - 200927761

Asn Gly Gly Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉 932 <211〉 96 <212〉 PRT <213〉現代人 <400> 932

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95

<210〉 933 <211> 96 <212> PRT -1408 - 200927761 <213〉現代人 <400〉 933

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Gly Cys 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn

Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Met Gly Asn Gly 50 55 60

Thr Asn Gly Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Gly Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 ❹ <210> 934 <211〉 96 <212〉 PRT <213〉現代人 <400〉 934

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 1 5 10 15 -1409 - 200927761

Thr Tyr Trp Ser Asn Gly Gly Asn Cys Ala Asn Gly Gly Asn Gly Cys 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Met Gly Asn Gly 50 55 60

Thr Asn Gly Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Gly Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210> 935 <211> 96 <212〉 PRT <213〉現代人 <400〉 935

Gly Gly Asn Ala Thr His Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45 -1410- 200927761

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Met Gly Asn Tyr 50 55 60

Thr Asn Gly Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95

<210〉 936 <211〉 96 <212> PRT <213〉現代人 <400> 936

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Arg Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr -1411 - 200927761 65 70 75 80

Tyr Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210> 937 <211> 96 <212〉PRT <213〉現代人 <400> 937

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Cys Ala Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 -1412- 200927761 <210> 938 <211> 96 <212〉 PRT <213〉現代人 <400〉 938

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30 〇

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80 ❹

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210> 939 <211> 96 <212> PRT <213〉現代人 <400〉 939 -1413 - 200927761 F115突變成Ala或Tyr可影響U2-4 5抗體之結合親和力。然而’ U2-45抗體結合作用不會被1133及H135之突變影響，而這些突變確實會影響第7箱之某些其他抗體製劑。當IHGE人HB-EGF序列改變成LHDGV(其存於老鼠 HB-EGF及人雙調蛋白中）時，所有第7箱抗體製劑均無法結合。因此，IHGE殘基（117-120)似乎形成第7箱抗體製 0 劑之抗原決定部位。

其他涉及HB-EGF突變種與EGFR之結合的定點突變硏究指出包含 Asp-106和Pro-107之殘基對HB-EGF與 EGF受體之理想結合均爲必要。再者，對HB-EGF與EGF 受體之結合而言爲必要之Leu-148並未顯示出涉及任何抗 HB-EGF抗體製劑之結合作用。

HH.實例24 :抗HB-EGF抗體之關鍵成分的序列此實例提供第1 -2 1圖中之抗體製劑的序列。實例25A:刮劃分析-對由HB-EGF誘導之CLS354表皮鱗狀癌細胞（口）移行的抑制作用進行刮劃實驗以檢查本發明之抗體是否阻斷可由HB_ EGF直接誘導之細胞移行。將lxlO6個CLS354細胞接種在12-槽盤中之1毫升介質（帶有10%FCS之RPMI介質）中，令細胞血清飢餓（帶有 0.5%FCS之介質）一整夜。當細胞達到匯合成片之細胞層 -163- 200927761

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Thr Tyr Thr Gly Tyr 85 90 95 <210> 940 <211> 96 <212> PRT <213〉現代人 <400> 940

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Gly Gly Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30 1414- 200927761

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉 941 <211〉 96 <212〉PRT <213〉現代人 <400> 941

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60 -1415- 200927761

Thr Asn Cys Ala Arg Gly Cys Asn Gly Ala Tyr Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210> 942 <211> 96 <212〉 PRT <213〉現代人 <400〉 942

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Gly Gly Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Cys Asn Tyr Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr -1416- 200927761 85 90 95 <210〉 943 <211〉 96 <212> PRT <213〉現代人 <400〉 943

Gly Gly Asn Gly Thr Asn Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Gly Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr 65 70 75 80

Asn Gly Cys Asn Gly Thr Asn Thr Thr Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉 944 <211> 96 <212〉 PRT <213〉現代人 -1417- 200927761 <4〇〇> 944

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Ala Ala Arg Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉 945 <211〉 96 <212〉 PRT <213〉現代人 <400〉 945

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15 -1418- 200927761

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉946 <211〉 96 <212> PRT <213〉現代人 <400〉946

Gly Gly Asn Ala Thr His Cys Cys Asn Gly Cys Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Arg Thr Thr Tyr Cys Ala Asn 35 40 45 -1419- 200927761

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Trp Ser Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉947 <211〉 96 <212〉 PRT <213〉現代人 <400〉 947

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80 -1420 - 200927761

Tyr Gly Cys Asn Gly Cys Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210> 948 <211> 96 <212> PRT <213〉現代人 <400> 948

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Gly 15 10 15

Thr Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Met Gly Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉 949 -1421 - 200927761 <211> 96 <212〉 PRT <213〉現代人 <400〉 949

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉 950 <211> 96 <212〉 PRT <213〉現代人 <400> 950

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr -1422 - 200927761 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60 ❹

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95

<210> 951 <211〉 96 <212> PRT ❹ <213〉現代人 <400〉 951

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30 -1423 - 200927761 時’利用無菌塑膠尖端在槽中央進行刮劃實驗。以PBS清洗細胞並在有或無10微克/毫升U2-39、Erbitux或人IgG 之存在下處理單獨之刮劃過的CLS354細胞或含有20奈克 /毫升HB-EGF之細胞。在37°C培育12小時後終止實驗。抽出介質，以PBS清洗細胞並以-20°C之100%冰冷甲醇固定之，以結晶紫染色、清洗並乾燥一整夜。照相以供文件紀錄。第40A圖顯示出HB-EGF之處理可刺激刮痕閉合，而本發明之抗體U2-39抑制由HB-EGF促成之CLS354表皮鱗狀癌細胞移行入刮劃區。實例25B :轉移分析-對由HB-EGF誘導之底特律562 表皮癌細胞（喉）移行的抑制作用。進行轉移實驗以檢查本發明之抗體是否可阻斷可由 HB-EGF直接誘導之細胞移行。將5 00毫升經血清飢餓之人上皮癌細胞的細胞懸浮液 (50,000個細胞）置於經纖維黏連蛋白塗覆之轉移盤（BD Falcon，8微米孔洞）的頂端小室中。在37°C下預先培育 30分鐘後，將單獨或含有20奈克/毫升HB-EGF(R&D系統）之一份份750毫升介質（在艾爾氏（Earle)BSS中之最低必需培養介質（伊格爾氏），其中帶有非必需胺基酸、丙酮酸鈉（lmM)及水解乳蛋白（0.1%)，90% ;胎牛血清、 Pen-Strept，0.1%BSA)在有或無 10 微克 / 毫升人 IgG、U2_ 39或Erbitux抗體之存在下置於底部小室中。在37 °C培育 -164- 200927761

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉 952 <211> 96 <212〉 PRT <213〉現代人 <400〉 952

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Trp Ser Asn Trp Ser Asn Tyr 50 55 60 -1424 - 200927761

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210〉 953 <211〉 96 <212〉 PRT <213〉現代人

<400〉 953

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45 ❹

Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr 65 70 75 80

Tyr Gly Cys Asn Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 -1425 - 200927761 <210〉 954 <211> 96 <212> PRT <213〉現代人 <400〉 954

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Gly Asn Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Ala Thr 65 70 75 80

His Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 <210> 955 <211〉 96 <212〉 PRT <213>現代人 -1426 - 200927761 <400> 955

Gly Gly Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Thr 15 10 15

Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser 20 25 30

Asn Gly Ala Arg Cys Ala Asn Gly Ala Tyr Thr Thr Tyr Cys Ala Asn 35 40 45

Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Trp Ser Asn Tyr 50 55 60

Thr Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Gly Ala Tyr Ala Thr 65 70 75 80

His Gly Cys Asn Cys Ala Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 85 90 95 ❹ <210〉 956 <211〉 30 <212> PRT <213〉現代人 <400> 956

Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Met 15 10 15

Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg -1427 - 200927761 20 25 30 <210> 957 <211〉 30 <212> PRT <213>現代人 <400〉 957

Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Met 15 10 15

Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Thr His 20 25 30 <210〉 958 <211〉 30 <212〉 PRT <213>現代人 <400> 958

Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 20 25 30 <210〉 959 <211> 30 <212〉 PRT <213〉現代人 -1428 - 200927761 <400> 959

Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 20 25 30

<210> 960 <211〉 30 <212〉 PRT <213〉現代人 <400〉 960

Thr Thr Tyr Gly Gly Asn Cys Ala Tyr Gly Gly Asn Cys Ala Asn Met 15 10 15

Gly Asn Tyr Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 20 25 30 <210〉 961 Q <211> 30 <212〉PRT <213〉現代人 <400> 961

Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala Arg 20 25 30 -1429 - 200927761 <210> 962 <211> 30 <212〉PRT <213>現代人 <400> 962

Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 20 25 30 <210〉 963 <211〉 30 <212> PRT <213〉現代人 <400> 963

Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 20 25 30 <210〉 964 <211> 30 <212〉 PRT <213>現代人 <400〉 964 -1430- 200927761

Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Gly Thr Asn Gly Cys Asn Ala Thr His Ala Ala Arg 20 25 30 <210> 965 <211> 30 <212〉PRT <213>現代人

<400> 965

Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Ala Thr Gly Gly Ala Tyr Ala Thr His Ala Ala Arg 20 25 30 <210〉 966 <211> 30 <212〉 PRT <213〉現代人 <400〉 966

Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Gly Thr Asn Gly Ala Arg Thr Thr Tyr Ala Ala Arg 20 25 30 -1431 - 200927761 <210〉 967 <211〉 30 <212〉 PRT <213〉現代人 <400> 967

Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Met Gly Asn 20 25 30 <210〉 968 <211> 75 <212〉PRT <213〉現代人 <400〉 968

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60 -1432 - 200927761

Gly Tyr Ala Ala Arg Gly Cys Asn Trp Ser Asn 65 70 75 <210〉 969 <211〉 75 <212〉 PRT <213〉現代人 <400> 969

Cys Ala Arg Gly Thr Asn Cys Ala Tyr Tyr Thr Asn Gly Thr Asn Cys

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60 ◎

Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn 65 70 75 <210〉 970 <211〉 75 <212〉 PRT <213〉現代人 <400> 970 -1433 - 200927761 並移行6小時後，固定細胞，以DAPI染色，爲轉移盤照相以供評估。結果證明HB-EGF抗體U2-39可有效抑制由HB-EGF 誘導之底特律562表皮癌細胞移行，其抑制程度與藉由 Erbitux治療來抑制由HB-EGF促成之細胞移行相當。實例2 6 :以球形體爲基礎之細胞血管新生分析-對經

VEGF刺激之內皮細胞萌生的抑制作用進行以球形體爲基礎之細胞血管新生分析，以檢查本發明之抗體是否能抑制膠原蛋白基質中經VEGF誘導之內皮細胞（EC)萌生。將初代人類臍帶內皮細胞（HUVEC)以每一懸垂滴中500個細胞之密度接種在塑膠盤上，以令細胞球形聚集一整夜。將50個EC球形體接種在0.9毫升膠原蛋白溶液（2毫克/毫升）中，移液至24-槽盤中之個別槽中使其聚合。在聚合前將本發明之U2-39抗體直接在膠原蛋白溶液中混合（不同濃度），將1 〇〇微升之1 〇倍濃縮的操作稀釋液移至聚合之凝膠上方30分鐘後加入生長因子 VEGF-A(25奈克/毫升）。將盤在37°C培育24小時，加入 4%多聚甲醛固定之。利用倒立顯微鏡及數位影像軟體分析 3.2，經由影像分析系統測定每一累積之球形物的萌生長度來定量EC球形物之萌生強度。第41A圖記述10個隨機選擇之球形物在每一數據點累積的萌生長度平均値。第41B圖顯示出10個隨機選擇之球形物在每一數據點累積的萌生長度受U2-39抑制之相 -165- 200927761

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Met Gly Asn Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn 65 70 75 <210> 971 <211〉 75 <212> PRT <213〉現代人 <400> 971

Cys Ala Arg Gly Thr Asn Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Thr Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Gly Ala Arg 35 40 45 -1434 - 200927761

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn 65 70 75

<210〉 972 <211> 75 <212〉 PRT <213〉現代人 <400〉 972

Cys Ala Arg Ala Thr His Cys Ala Asn Tyr Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Cys Ala Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Cys Ala Asn Cys Ala Arg Q 35 40 45

Cys Ala Asn Tyr Thr Asn Cys Ala Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Thr Thr Tyr Trp Ser Asn 65 70 75 <210〉 973 -1435 - 200927761 <211> 75 <212〉 PRT <213〉現代人 <400> 973

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn 65 70 75 <210〉 974 <211> 75 <212〉 PRT <213〉現代人 <400〉 974

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Tyr Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr -1436 - 200927761 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn 65 70 75

O <210> 975 <211〉75 <212〉 PRT <213〉現代人 <400> 975

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Tyr Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60 -1437- 200927761

Gly Tyr Cys Ala Asn Gly Cys Asn Trp Ser Asn 65 70 75 <210〉 976 <211> 75 <212〉 PRT <213〉現代人 <400> 976

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn 65 70 75 <210〉 977 <211> 75 <212〉 PRT <213〉現代人 <400> 977 -1438- 200927761

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Tyr Thr Asn Met Gly Asn Tyr Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn 65 70 75 <210> 978 <211〉 75 <212〉 PRT <213>現代人 <400> 978 ❹

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45 -1439- 200927761

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn 65 70 75 <210> 979 <211> 75 <212〉 PRT <213〉現代人 <400〉 979

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 1 5 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Ala Ala Tyr Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn 65 70 75 <210> 980 <211> 75 -1440 - 200927761 <212〉 PRT <213〉現代人 <400> 980

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Cys 15 10 15

Ala Arg Thr Gly Gly Gly Gly Asn Gly Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Tyr Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr 65 70 75 <210〉 981 〇 <211〉 75 <212> PRT <213〉現代人 <400> 981

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30 -1441 - 200927761

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn 65 70 75 <210> 982 <211> 75 <212> PRT <213〉現代人 <400〉 982

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Tyr Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Ala Arg 35 40 45

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Gly Asn Trp Ser Asn -1442 - 200927761 65 70 75 <210〉 983 <211> 75 <212> PRT <213〉現代人 <400> 983

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Ala Arg 35 40 45

Trp Ser Asn Tyr Thr Asn Ala Ala Arg Ala Thr His Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Gly Asn Trp Ser Asn 65 70 75 <210〉 984 <211> 75 <212> PRT <213〉現代人 <400> 984

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Cys -1443 - 200927761 對抑制程度。以GraphPad Prism4.03進行IC50曲線配合並計算IC50値。實例26之結果證明本發明之U2-39抗體在利用膠原蛋白基質之以球形物爲基礎的分析中以劑量倚賴方式抑制經VEGF-A刺激之人臍帶內皮細胞萌生。抑制HUVEC萌生之IC50値爲5.2xl(T8莫耳。實例27 :人類腫瘤異體移植樣本之免疫組織化學 (IHC)分析-對活體內腫瘤CD31染色之抑制作用爲了檢查本發明之U2-39抗體在活體內抑制血管新生之效力，藉由免疫組織化學分析以U2-39或Erbitux治療之人類腫瘤異體移植。將人類卵巢腺癌細胞株EF027進行遺傳工程處理以表現HB-EGF並選擇選殖株EF027-CI58用於SCID小鼠中之異體移植硏究。將3x106個在100微升PBS/基質膠（1: 1) 中之 EF027-CI58細胞經皮下注射入 7週大雌 C.B-17 SCID小鼠的左脅腹。將具有平均腫瘤體積250毫米3之腫瘤攜帶小鼠任意分配至包含1 〇隻動物之組別。以週劑量 25毫克/公斤U2-39或25毫克/公斤Erbitux或對照載劑 (PBS )經腹膜內途徑治療動物3週。28天後殺死動物，收集初代腫瘤組織，將一半腫瘤在液態氮中速凍並貯存在-8 0 °C。將在玻璃腔室玻片上製備之5-8微米之腫瘤切片在 4 °C’ 100 %丙酮中固定10分鐘並使之完全乾燥。爲了封閉 -166- 200927761 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Ala Thr His Trp Ser Asn 65 70 75 <210〉 985 <211> 42 <212〉 PRT <213>現代人 <400> 985

Thr Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Gly Cys Asn Cys 1 5 10 15

Cys Asn Gly Gly Asn Cys Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Ala Thr Gly Gly Gly Asn 35 40 -1444 - 200927761 <210> 986 <211> 42 <212〉PRT <213>現代人 <400〉 986

Thr Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Gly Cys Asn Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30 ❹

Arg Thr Gly Gly Ala Thr Gly Gly Gly Asn 35 40 <210> 987 <211〉 42 <212〉 PRT <213〉現代人 <400> 987

Thr Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Tyr Thr Asn Gly Cys Asn 35 40 -1445 - 200927761 <210〉 988 <211〉 42 <212> PRT <213〉現代人 <400〉 988

Thr Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Tyr Thr Asn Gly Thr Asn 35 40 <210> 989 <211> 42 <212〉 PRT <213>現代人 <400〉 989

Thr Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Gly Cys Asn Cys 1 5 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Gly Thr Asn Trp Ser Asn 35 40 -1446 - 200927761 <210〉 990 <211> 42 <212〉 PRT <213>現代人 <400〉 990

Thr Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Gly Cys Asn Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30 〇

Arg Thr Gly Gly Gly Thr Asn Gly Cys Asn 35 40 <210〉 991 <211> 42 <212〉 PRT <213〉現代人 <400〉 991

Thr Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys 1 5 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Ala Thr His Gly Gly Asn 35 40 -1447 - 200927761 <210> 992 <211> 42 <212〉 PRT <213>現代人 <400〉 992

Thr Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Cys Ala Tyr Cys 1 5 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Ala Thr His Gly Gly Asn 35 40 <210〉 993 <211〉 42 <212〉 PRT <213>現代人 <400〉 993

Thr Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Ala Thr His Gly Gly Asn 35 40 -1448 - 200927761 <210〉 994 <211> 42 <212〉 PRT <213〉現代人 <400> 994

Thr Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Gly 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30 ❹

Arg Thr Gly Gly Ala Thr His Gly Gly Asn 35 40 <210〉 995 <211> 42 <212> PRT <213〉現代人 <400〉 995

Thr Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Ala Thr Gly Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Ala Thr Gly Gly Gly Asn 35 40 -1449 - 200927761 <210〉 996 <211〉 42 <212> PRT <213〉現代人 <400> 996

Thr Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Trp Ser Asn Cys 15 10 15

Cys Asn Trp Ser Asn Met Gly Asn Gly Gly Asn Tyr Thr Asn Gly Ala 20 25 30

Arg Thr Gly Gly Tyr Thr Asn Gly Gly Asn 35 40 <210〉 997 <211> 96 <212〉 PRT <213〉現代人 <400> 997

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Cys Ala Asn Trp Ser 20 25 30

Asn Cys Ala Asn Gly Cys Asn Thr Ala Tyr Ala Thr Gly Gly Ala Arg 35 40 45 -1450 - 200927761

Tyr Thr Asn Met Gly Asn Trp Ser Asn Tyr Thr Asn Met Gly Asn Trp 50 55 60

Ser Asn Gly Ala Tyr Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95

<210> 998 <211> 96 <212〉PRT <213〉現代人 <400> 998

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr Gly Cys Ala Asn Met 15 10 15

Gly Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Thr His Trp Ser 20 25 30 〇

Asn Cys Ala Asn Gly Cys Asn Thr Ala Tyr Ala Thr Gly Gly Ala Arg 35 40 45

Tyr Thr Asn Trp Ser Asn Met Gly Asn Tyr Thr Asn Met Gly Asn Trp 50 55 60

Ser Asn Gly Ala Tyr Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80 -1451 - 200927761

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 999 <211> 96 <212〉 PRT <213〉現代人 <400> 999

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr Gly Tyr Thr Asn Gly 15 10 15

Ala Arg Gly Ala Tyr Cys Ala Asn Trp Ser Asn Cys Ala Asn Gly Ala 20 25 30

Tyr Cys Ala Asn Gly Cys Asn Thr Ala Tyr Ala Thr Gly Gly Ala Arg 35 40 45

Tyr Thr Asn Trp Ser Asn Trp Ser Asn Tyr Thr Asn Met Gly Asn Trp 50 55 60

Ser Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Cys Ala Asn 85 90 95 <210〉 1000 <211> 96 -1452 - 200927761 <212〉 PRT <213〉現代人 <400〉 1000

Met Gly Asn Tyr Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Ala 15 10 15

Ala Arg Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Trp Ser 20 25 30

Asn Cys Ala Arg Gly Thr Asn Gly Thr Asn Tyr Thr Asn Cys Ala Asn 35 40 45

Ala Thr Gly Cys Ala Asn Ala Ala Tyr Ala Thr Gly Gly Ala Tyr Cys 50 55 60

Cys Asn Gly Thr Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Cys Ala 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn ◎ 85 90 95 <210〉 1001 <211〉 96 <212〉 PRT <213〉現代人 <400> 1001

Met Gly Asn Tyr Thr Asn Cys Ala Asn Ala Thr His Cys Ala Asn Ala 15 10 15 -1453 - 200927761

❹ 特殊結合部位’以抗生物素蛋白D封閉試劑（15分鐘）、生物素封閉試劑（15分鐘）及1.25%BSA溶液（1小時）處理具有固定之腫瘤切片的玻片。各處理步驟間以PBS清洗二次。爲了進行腫瘤血管之免疫組織化學檢查，以2微克/毫升抗CD31抗體（在1.25%BSA溶液中稀釋並在室溫下，濕潤之小室中培育2小時）處理玻片來分析典型內皮細胞標記CD3 1(亦稱爲PECAM-1 (血小板內皮細胞黏附分子-1))。施放生物素化之山羊抗大鼠IgG抗體（在室溫中30分鐘）及Alexa 546抗生蛋白鏈菌素（在黑暗中15分鐘）以進行偵測。在各處理步驟間進行PB S清洗步驟。在黑暗中以帶有 DAPI之VECTASHIELD封固劑將切片封固，照相（螢光顯微鏡）以供文件記錄並貯存在4°C。第42圖證明以U2-3 9處理之人類腫瘤異體移植物顯示出與經Erbitux治療或經對照組治療之腫瘤異體移植物相比較，以U2-3 9治療之人類腫瘤異體移植物顯示出內皮細胞標記染色（CD3 1染色）減弱。此結果證明本發明之抗體在活體內之抗血管新生效力。實例28:活體內卵巢腫瘤異體移植模型-U2-39與順鈾及癌思停之組合治療爲了評估本發明之抗體以單一藥物療法之形式投服或與順鉑或癌思停組合之形式投服的效力，進行卵巢癌異體移植硏究。將人類卵巢腺癌細胞株EF027進行遺傳工程處理以過 -167- 200927761

Ala Arg Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Gly Thr Asn Gly Thr Asn Tyr Thr Asn Cys Ala Asn 35 40 45

Ala Thr Gly Cys Ala Asn Ala Ala Tyr Ala Thr Gly Gly Ala Tyr Cys 50 55 60

Cys Asn Gly Thr Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Cys Ala 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Cys Ala Tyr 85 90 95 <210> 1002 <211> 96 <212〉 PRT <213〉現代人 <400> 1002

Met Gly Asn Tyr Thr Asn Cys Ala Asn Ala Thr His Cys Ala Asn Ala 15 10 15

Ala Arg Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Cys Ala 20 25 30

Asn Cys Ala Arg Gly Thr Asn Gly Thr Asn Tyr Thr Asn Cys Ala Asn -1454 - 200927761 35 40 45

Gly Thr Asn Cys Ala Asn Gly Ala Tyr Ala Thr Gly Gly Ala Tyr Cys 50 55 60

Cys Asn Gly Thr Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Cys Ala 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Cys Ala Tyr 85 90 95 〇 <210〉 1003 <211〉 96 <212〉 PRT <213〉現代人 <400〉 1003

Met Gly Asn Tyr Thr Asn Cys Ala Asn Ala Thr His Cys Ala Asn Ala 15 10 15

Ala Arg Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Gly Thr Asn Gly Thr Asn Tyr Thr Asn Cys Ala Asn 35 40 45

Ala Thr Gly Cys Ala Asn Ala Ala Tyr Tyr Thr Asn Gly Ala Tyr Cys 50 55 60 -1455 - 200927761

Cys Asn Gly Thr Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Cys Ala 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Cys Ala Tyr 85 90 95 <210〉 1004 <211〉 96 <212〉 PRT <213〉現代人 <400〉 1004

Met Gly Asn Tyr Thr Asn Cys Ala Asn Ala Thr His Cys Ala Asn Ala 15 10 15

Ala Arg Gly Cys Asn Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Gly Thr Asn Gly Thr Asn Tyr Thr Asn Cys Ala Asn 35 40 45

Ala Thr Gly Cys Ala Asn Ala Ala Tyr Ala Thr Gly Gly Ala Tyr Cys 50 55 60

Cys Asn Gly Thr Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Cys Ala 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Cys Ala Tyr 85 90 95 -1456- 200927761 <210> 1005 <211〉 96 <212〉 PRT <213>現代人 <400> 1005

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Trp Ser Asn Tyr Thr Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210〉 1006 <211> 96 <212〉 PRT <213〉現代人 <400> 1006 -1457 - 200927761

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Ala Ala Arg 85 90 95 <210> 1007 <211〉 96 <212〉 PRT <213〉現代人 <400〉 1007

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30 -1458- 200927761

Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Ala 65 70 75 80

Arg Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Ala Ala Arg 85 90 95 <210〉 1008 <211> 96 <212〉 PRT <213>現代人 <400> 1008

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met ◎15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser Asn Ala Thr Gly Ala Ala 20 25 30

Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly -1459 - 200927761 50 55 60

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 1009 <211> 96 <212〉 PRT <213〉現代人 <400> 1009

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80 -1460 200927761

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 1010 <211> 96 <212〉 PRT <213〉現代人 <400> 1010

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15 〇

Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Asn Tyr Thr Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60 〇

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Thr Asn Tyr Thr Asn 85 90 95

<210〉 1011 <211> 96 <212〉 PRT -1461 - 200927761 <213〉現代人 <400〉 1011

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Asn Tyr Thr Asn Gly Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210〉 1012 <211> 96 <212〉PRT <213〉現代人 <400> 1012

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15 -1462 - 200927761

Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Trp Ser Asn Tyr Thr Asn Thr Thr Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Tyr Thr Asn 85 90 95 <210> 1013 <211> 96 <212〉 PRT <213〉現代人 <400> 1013

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Trp Ser Asn Gly Thr Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45 -1463 - 200927761

度表現HB-EGF。選擇選殖株EF027-CI58用於SCID小鼠中之異體移植硏究。將3x1 06個在1〇〇微升PBS/基質膠（1 :1)中之EF027-CI58細胞經皮下注射入7週大之雌C.B-17 SCID小鼠的左脅腹。將具有平均腫瘤體積介於75和 175毫米3間之腫瘤攜帶小鼠任意分配至包含1〇隻動物之組別。以週劑量25毫克/公斤U2-3 9、25毫克/公斤癌思停或5毫克/公斤順鉑或對照載劑（PBS)經腹膜內途徑治療動物。U2-39與癌思停之組合係各爲12.5毫克/公斤，U2-39 與順鉑之組合爲25毫克/公斤抗體加5毫克/公斤順鉑。一週測定3次初代腫瘤之尺寸。以測徑器測量後，根據公式 W2xL/2(L=長度，W=腫瘤之垂直寬度）計算腫瘤尺寸。使用 Kaplan-Meier對數-秩法（log-rank method)來界定進展至5 00毫米3之時間（定義爲統計理由之“事件”）。

第43A圖證明與單獨以順鈾治療相比較，U2-39與順銷之組合可在投服期間使腫瘤減小較多。另外，與U2-39 單一藥物療法相比較，U2-3 9與順鉑之組合可延遲從中位數腫瘤尺寸進展至500毫米3之時間。第43B圖之結果顯示出雖然僅投服單一作用劑之一半劑量，與癌思停單一藥物療法相比較時，U 2 - 3 9與癌思停之組合明顯延遲進展至500毫米3腫瘤體積之時間。此處所參考或提及之所有專利及刊物爲本發明相關技藝中之技藝熟習人士的技術水準之直陳，且各這類參考之專利或刊物倂爲此文參考資料之程度如同其全部內容被個別倂爲參考資料或其全文列於此處。本申請者保留將來自 -168- 200927761

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210〉 1014 <211> 96 <212〉 PRT <213〉現代人 <400> 1014

Met Gly Asn Thr Thr Tyr Cys Ala Asn Ala Thr His Trp Ser Asn Met 15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Trp Ser Asn Tyr Thr Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr -1464 - 200927761 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 1015 <211> 96 <212〉 PRT <213>現代人 <400> 1015

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Gly 15 10 15

Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Tyr 35 40 45

Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 -1465 - 200927761 <210> 1016 <211> 96 <212> PRT <213〉現代人 <400> 1016

Met Gly Asn Gly Thr Asn Ala Ala Tyr Ala Thr Gly Trp Ser Asn Gly 15 10 15

Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Arg 35 40 45

Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 1017 <211〉 96 <212> PRT <213>現代人 <400> 1017 -1466 - 200927761

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Gly 15 10 15

Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Arg 35 40 45

Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 1018 <211〉 96 <212> PRT <213>現代人 <400〉 1018

Met Gly Asn Ala Thr His Cys Ala Asn Ala Thr His Trp Ser Asn Gly 15 10 15

Cys Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30 -1467 - 200927761

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Arg 35 40 45

Tyr Thr Asn Ala Ala Tyr Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 1019 <211> 96 <212> PRT <213〉現代人 <400> 1019

Met Gly Asn Ala Thr His Cys Ala Asn Ala Ala Arg Trp Ser Asn Gly 15 10 15

Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Arg 35 40 45

Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60 -1468 - 200927761

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95

<210> 1020 <211〉 96 <212〉PRT <213〉現代人 <400〉 1020

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Gly 15 10 15

Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Arg 35 40 45

Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Trp Ser Asn -1469 - 200927761 85 90 95 <210〉 1021 <211> 96 <212〉 PRT <213〉現代人 <400〉 1021

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Gly 15 10 15

Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Arg 35 40 45

Tyr Thr Asn Thr Thr Tyr Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Thr Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 1022 <211> 96 <212〉 PRT <213〉現代人 1470 - 200927761 <400〉 1022

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr Gly Trp Ser Asn Gly 15 10 15

Thr Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Arg 35 40 45 ❹

Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 ❹ <210> 1023 <211> 96 <212> PRT <213>現代人 <400〉 1023

Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Ala 15 10 15 -1471 - 200927761

Thr His Gly Thr Asn Cys Ala Asn Trp Ser Asn Met Gly Asn Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Ala Ala Arg 35 40 45

Tyr Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Cys Ala Asn Gly 50 55 60

Cys Asn Gly Cys Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210〉 1024 <211> 96 <212〉 PRT <213〉現代人 <400> 1024

Cys Ala Arg Gly Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Gly 15 10 15

Cys Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn Ala Thr His Trp Ser 20 25 30

Asn Cys Ala Asn Gly Cys Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45 -1472- 200927761

Thr Gly Gly Trp Ser Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Gly 50 55 60

Cys Asn Trp Ser Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Ala Thr 65 70 75 80

Gly Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95

<210> 1025 <211> 96 <212〉 PRT <213>現代人 <400〉 1025

Cys Ala Arg Gly Thr Asn Cys Ala Asn Ala Thr His Trp Ser Asn Gly 15 10 15

Cys Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn Ala Thr His Ala Ala 20 25 30

Tyr Cys Ala Asn Gly Cys Asn Thr Ala Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Thr Gly Gly Trp Ser Asn Trp Ser Asn Tyr Thr Asn Ala Ala Arg Gly 50 55 60

Cys Asn Trp Ser Asn Gly Ala Tyr Cys Ala Asn Gly Cys Asn Ala Thr 65 70 75 80 -1473 - 200927761 任何這類列舉之專利或刊物的任何及所有素材和資料實際倂入本專利說明書之權利。〇

此處所描述之特殊方法和組成物爲較佳體系之代表且僅用於示範而不欲限制本發明之範圍。本技藝之技術熟習人士在考量本專利說明書時將可察明其他目標、觀點及較佳體系，且其包含在申請專利範圍所定義之本發明的精神內。熟習本技藝之人士可輕易察明可在不悖離本發明之範圍和精神下對此處所揭示之本發明進行不同取代和修改。此處解說之本發明可適合在無任何要素或限制（其在此文中並未被特別揭示爲必要項）之存在下執行。此處解說之方法和過程可適合以不同之步驟順序操作，且其不必受限於此文中或申請專利範圍中指出之步驟順序。除非內容中另外明確指出，此文及所附之申請專利範圍中所使用之單數型“一 ”及“該”包括複數參考項。因此，例如：提及 “ 一種抗體”時包括這類抗體之多數（如：抗體之溶液或一系列抗體製劑），等。本專利在任何情況下均不被解釋爲侷限於此處所特別揭示之特殊實例或較佳體系或方法。本專利在任何情況下均不被解釋爲侷限於任何檢查者或該專利及商標辦公室之任何其他幹事或僱員所做的任何聲明，除非這類聲明爲具體指明且無申請者之回應著作中所明白採用之資格限制或保留意見。此處所使用之名詞和措詞僅作爲描述之名詞而非限制用，且不欲使用這類名詞和措詞來排除任何顯示及描述之同等特性或其部分，但可在所主張之本發明範圍內進行不 -169- 200927761

Gly Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210> 1026 <211> 96 <212〉 PRT <213〉現代人 <400〉 1026

Met Gly Asn Ala Thr His Cys Ala Asn Ala Thr His Ala Ala Tyr Cys 15 10 15

Cys Asn Gly Ala Tyr Cys Ala Asn Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Arg Thr Thr Tyr Trp Ser Asn Tyr Thr Asn Cys Ala Arg 35 40 45

Tyr Thr Asn Ala Ala Tyr Trp Ser Asn Gly Thr Asn Cys Ala Asn Cys 50 55 60

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 <210〉 1027 -1474 - 200927761 <211> 33 <212〉 PRT <213>現代人 <400> 1027

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Tyr 15 10 15

Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn <210〉 1028 <211〉 33 <212> PRT <213〉現代人 <400〉 1028

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Cys ©15 10 15

Ala Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn <210> 1029 -1475 - 200927761 <211> 33 <212〉PRT <213〉現代人 <400> 1029

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Ala 15 10 15

Thr Gly Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn <210> 1030 <211> 33 <212> PRT <213〉現代人 <400> 1030

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Trp Ser Asn Tyr 15 10 15

Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Cys Cys 20 25 30

Asn <210> 1031 -1476 - 200927761 <211> 33 <212〉 PRT <213〉現代人 <400〉1031

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Cys Ala Asn Ala 15 10 15

Ala Arg Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn <210> 1032 <211〉 33 <212〉 PRT <213〉現代人 <400〉 1032

Thr Gly Gly Gly Gly Asn Met Gly Asn Gly Gly Asn Cys Ala Asn Tyr 0 1 5 10 15

Thr Asn Gly Thr Asn Cys Ala Asn Gly Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn <210> 1033 -1477 - 200927761 <211> 16 <212〉 PRT <213〉現代人 <220〉 <221> MISC_#tt <222〉（ 1) ·. (1)

<223> )(1係選自H或LI <400〉 1033

Xaa He Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser 1 5 <210〉 1034 <211〉 16 <212> PRT <213〉現代人 <220〉 <221〉 MISC_特性 <222> (6)..(6) <223〉 XI係選自D 或V <220> <221> MISC_特性 <222〉 (7)..(7) <223〉 X2係選自D 或E <220> <221> MISC_特性 <222〉 (15)..(15) <223> X3係選自K 或R <400> 1034 -1478 - 200927761

Leu lie Tyr Trp Asn Xaa Xaa Lys Arg Tyr Ser Pro Ser Leu Xaa Ser 15 10 15 <210> 1035 <211> 13 <212〉 PRT <213〉現代人 <220〉

<221〉MISC_ 特性 <222〉（1). · (1) <223> XI係選自E或S <220〉 <221〉MISC_ 特性 <222〉（2)..(2) <223> X2係選自D、G或無胺基酸 <220〉 <221〉MISC一特性 <222〉（3)..(3) <223〉X3係選自D、N或無胺基酸 <220〉 <221〉MISC—特性 <222〉（4)..(4) <223〉X4係選自G或無胺基酸 <220〉 <221> MISC_特性 <222〉（5)..(5) <223〉X係選自G或無胺基酸 <220> <221〉MISC一特性 <222> (6)..(6) -1479 - 200927761 <223> X6係選自W、Y或無胺基酸 <220> <221> MISC_特性 <222> (7)..(7) <223> X7係選自I、N或Y <220〉 <221> MISC_特性 <222> ⑻··⑻ <223〉 X8係選自A或Y <220> <221> MISC_#tt <222> (9)..(9) <223> X9係選自G、V或Y <220〉 <221> MISC—特性 <222〉 (10)..(10) <223> X10係選自A、F或G <220> <221> MI SC一特性 <222〉 (11)..(11) <223> Xll係選自F、L或M <220〉 <221> MISC_· <222〉 (13)..(13) <223> X12係選自V或Y <400〉 1035

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Xaa 1 5 10 -1480- 200927761 <210> 1036 <211〉 18 <212〉 PRT <213〉現代人 <220> <221〉MISC_特性 <222〉（2)..(2) <223〉XI係選自G或無胺基酸 <220〉

<221〉MISC_特性 <222〉（3)..(3)

<223> X2係選自K、L或Y <220> <221〉MISCjt性 <222〉（4)..(4)

<223〉Χ3係選自A、G或S <220〉 <221〉MISC_特性 <222〉（5)..(5)

<223> X4係選自S、V或Y <220> <221> MISC—特性 <222〉（6)..(6)

<223> X5係選自A或G <220> <221> MISC_特性 <222〉（7)..(7) <223> X6係選自G或無胺基酸 <220〉 <221〉MISC—特性 200927761 <222〉 ⑻··⑻ <223〉 X7係選自T或無胺基酸 <220> <221〉 <222〉 (9)..(9) <223〉 X8係選自S或無胺基酸 <220〉 <221> MISC_特性 <222〉 (10)..(10) <223> X9係選自Y或無胺基酸 <220〉 <221> MISC_特性 <222〉 (11)..(11) <223> X10係選自W或Y <220> <221> MISC_特性 <222〉 (12)..(12) <223> XII係選自G、S或Y <220〉 <221> MISC_特性 <222〉 (14)..(14) <223> X12係選自F或Y <220〉 <221> MISCJNHi <222〉 (15)..(15) <223> Ή3係選自G或無胺基酸 <220〉 <221> MISC_特性 <222> (16)..(16) <223〉 X14係選自Μ或無胺基酸 200927761 <220〉 <221〉MISC_特性 <222> (18)..(18)

<223> X15係選自V或Y <400〉 1036

Gin Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Xaa Xaa Xaa 1 5 10 15

Asp Xaa

<210> 1037 <211〉 14 <212〉 PRT <213> 現代人

<220〉 <221> MISCJ^4 <222〉 (1)..(1) <223> XI係選自D、 G、 L、 S或無胺基酸 <220〉 <221> MISC—特性 <222> (2)..(2) <223> X2係選自G、 H、 W、 Y或無胺基酸 <220〉 <221> MISC_特性 <222〉 (3)..(3) <223> X3係選自A、 F、 W、 Υ或無胺基酸 <220〉 <221> MISC—特性 1483 - 200927761 同之修改。因此’雖然本發明已藉由較佳體系及選擇性之特性具體揭示’熟習本技藝之人士可修正及改變此處所揭示之觀念’且這類修正及變化被認爲係在如附屬之申請專利範圍所定義之本發明的範圍內。此文已廣泛及普遍描述本發明。落在該一般揭示內容之範圍內的較狹窄之型式及較不普遍之編組亦形成本發明之一部分。此包括本發明之種類描述，其先決條件或消極限制爲去除種類事項’不論該去除之物質是否具體列舉於【圖式簡單說明】第1A-1P圖描述抗原結合蛋白之不同輕鏈可變區。 CDR1、CDR2及CDR3區指示於劃線區中。第2A-20圖描述抗原結合蛋白之不同重鏈可變區。 CDR1、CDR2及CDR3區指示於劃線區中。〇第3 A-3K圖描述抗原結合蛋白之不同輕鏈的胺基酸序列。第4 A-4 0圖描述抗原結合蛋白之不同重鏈的胺基酸序列。第5A圖描述示範之抗原結合蛋白的輕鏈恆定區之胺基酸序列。第5B圖描述示範之抗原結合蛋白的重鏈恆定區之胺基酸序列。第6A-6F圖描述抗原結合蛋白之輕鏈可變區的不同 -170- 200927761 <222〉（4)..(4) <223〉X4係選自D、G、Q、T或無胺基酸 <220〉 <221> MISC_特性 <222〉（5)..(5) <223〉X5係選自G、I、Q、S或無胺基酸 <220〉 <221> MISC_#tt <222〉（6)..(6) <223〉X6係選自A、D、N、Q、S或無胺基酸 <220> <221〉MISC_特性 <222〉（7)..(7) <223〉X7係選自G、Y或無胺基酸 <220> <221〉MISC_特性 <222〉（8)..(8) <223> X8係選自D、Y或無胺基酸 <220> <221〉MISC_· <222〉（9)..(9) <223> X9係選自Y或無胺基酸 <220> <221〉MISC_特性 <222〉（10)..(10)

<223〉X10係選自 A、E、N或Y <220> <221> MISC_#tt <222〉（11)..(11)

<223〉Xll係選自 G、P、T、V或Y -1484 - 200927761 ❹ 〇 <220〉 <221> MISC—特性 <222> (12)..(12) <223〉 X12係選自F或I <220〉 <221> MISC_特性 <222> (13)..(13) <223> X13係選自D或Q <220〉 <221> MISC_特性 <222〉 (14)..(14) <223> X14係選自C、Η、V或Y <400〉 1037 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa : 1 5 <210〉 1038 <211> 19 <212〉 PRT <213〉現代人 <220> <221〉 MISC_特性 <222〉 (1)..(1) <223> XI係選自E、D或無胺基酸 <220> <221> MI SC一特性 <222〉 (2)..(2) <223> <220〉 X2係選自G、R或無胺基酸 10 -1485 - 200927761 <221> MISC_特性 <222〉 (3)..(3) <223〉 X3係選自I、V、Y或無胺基酸 <220〉 <221> MISC_特性 <222〉 (4)..(4) <223> X4係選自A、G、L或N <220〉 <221> MISC_#tt <222〉 (5)..(5) <223> X5係選自A、G、V或W <220〉 <221〉 MISC_特性 <222〉 (6)..(6) <223> X6係選自A、N、R或T <220〉 <221> MISC_#tt <222〉 (7)..(7) <223> X7係選自G、Μ、P或無胺基酸 <220〉 <221〉 MISC—特性 <222〉 (8)..(8) <223> X8係選自G、T或無胺基酸 <220〉 <221> MISC_特性 <222〉 (9)..(9) <223> X9係選自A或無胺基酸 <220> <221〉 MISC_特性 <222〉 (10)..(10) <223> X10係選自D、E或無胺基酸

-1486 - 200927761 <220> <221〉MISC_特性 <222〉（11)..(11) <223> XII係選自S、Y或無胺基酸 <220〉 <221〉MISC—特性 <222〉（12)..(12) <223〉X12係選自G、Y或無胺基酸 <220〉

<221〉MISC_特性 <222> (13)..(13) <223> X13係選自N、Y或無胺基酸 <220> <221> MISCjf性 <222〉（14)..(14) <223〉X14係選自Y或無胺基酸 <220〉 <221〉MISC—特性 <222〉（15)..(15) <223> X15係選自D、Y或無胺基酸〇<220> <221> MISCJf性 <222〉（16)..(16) <223〉X16係選自A、G或無胺基酸 <220> <221> MISC_特性 <222〉（17)..(17) <223〉XI7係選自F或Μ <220〉 <221〉MISC—特性 200927761 <222〉（19)..(19)

<223〉X18係選自I、V或Y <400〉 1038

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 15 10 15

Xaa Asp Xaa

<210> 1039 <211> 23 <212〉 PRT <213〉現代人 <220〉 <221> MISC_特性 <222〉（ 1) _. (1) <223〉XI 係選自 A、D、G、S或T <220〉

<221> MISC_特性 <222〉（2)..(2)

<223〉X2係選自 A、E、G、L、N、R、Y 或無胺基酸 <220〉 <221〉MISC_特性 <222〉（3)..(3) <223〉X3係選自 A、G、L、N、R、T、Y 或無胺基酸 <220> <221> MISC_特性 -1488 - 200927761 <222〉 (4)..(4) <223〉 X4係選自D、 G、 R、S、V、Y或無胺基酸 <220> <221> MISC_#tt <222〉 (5)..(5) <223> X5係選自A、 G、 I、S、V、Y或無胺基酸 <220〉 <221〉 MISC_#tt <222〉 (6)..(6) <223> X6係選自F、 G、 L、R、V或無胺基酸 <220> <221〉 MISC—特性 <222> (7)..(7) <223> X7係選自L、 T、 Y或無胺基酸 <220> <221> MISC_特性 <222〉 (8)..(8) <223> X8係選自Y或無胺基酸

<220〉 <221〉MISC_特性 <222〉（9)..(9) <223> X9係選自Y或無胺基酸 <220〉 <221> MISC_特性 <222〉（10)..(10) <223〉X10係選自D或無胺基酸 <220〉 <221〉MISCJ^I^ <222〉（11)..(11) <223〉XII係選自S或無胺基酸 -1489 - 200927761 <220〉 <221> MISC_#tt <222> (12)..(12) <223> X12係選自S或無胺基酸 <220〉 <221> MISC_特性 <222〉（13)..(13) <223> X13係選自G或無胺基酸 <220〉 <221〉MISC一特性 <222> (14)..(14) <223〉X14係選自D、L、M、S、Y或無胺基酸 <220> <221〉MISC_特性 <222〉（15)..(15) <223〉X15係選自H、I、P、V、W或無胺基酸 <220〉 <221> MISC—特性 <222> (16)..(16) <223〉X16係選自F、G、L、R、S、Y或無胺基酸 <220〉 <221〉MISC_特性 <222〉（17)..(17) <223〉X17係選自D、F、V、W、Y或無胺基酸 <220> <221〉MISC一特性 <222〉（18)..(18) <223〉X18係選自 C、F、L、P、S或Y <220〉 <221〉MISC_特性 <222> (19)..(19) -1490 - 200927761 <223〉X19係選自 D、F、G或Υ <220〉 <221> MISC_#tt <222〉（20)..(20)

<223〉X20係選自 A、C、G、P、R、V或 Y <220〉 <221> MISC_特性 <222〉（21)..(21) <223〉X21係選自F、L、M、S或無胺基酸 <220〉 <221〉MISC_特性 <222〉（22)..(22) <223〉X22係選自A、D或無胺基酸 ❹ <220〉 <221> MISC—特性 <222〉（23)..(23) <223〉X23係選自I、L、V、Y或無胺基酸 <400〉 1039

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 0 1 5 10 15

Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 <210> 1040 <211> 14 <212〉 PRT <213>現代人 -1491 - 200927761 <220〉 <221> MISC_特性 <222> (1)..(1)

<223> XI係選自Μ或V <220> <221> MISC—特性 <222〉（7)..(7) <223〉X2係選自S或無胺基酸 <220> <221〉MISC_特性 <222〉（8)..(8) <223〉X3係選自F或無胺基酸 <220> <221〉MISC一特性 <222〉（11)..(11) <223> X4係選自V或無胺基酸 <220〉 <221> MISC—特性 <222〉（12)..(12) <223> X5係選自F或Μ <220〉 <221〉MISC_特性 <222〉（14)..(14)

<223> X6係選自V或Y <400> 1040

Xaa Tyr Ser Ser Gly Trp Xaa Xaa Tyr Gly Xaa Xaa Asp Xaa 1 5 10 <210> 1041 -1492 - 200927761 <211> 8 <212〉 PRT <213>現代人 <220〉 <221> MISC—特性 <222〉（2)..(2)

<223〉XI係選自 G、H、L、N或R

<220〉 <221> MISC_特性 <222〉 (3)..(3) <223> X2係選自E、 T或W <220〉 <221> MISC—特性 <222〉 ⑷·_(4) <223> X3係選自L、 N、T或 V

<220> <221〉MISC_特性 <222〉（7)..(7) <223> X4係選自D或E <400> 1041 ❹

Arg Xaa Xaa Xaa Pro Phe Xaa Tyr 1 <210〉 1042 <211〉 208 <212〉 PRT <213> 現代人 <400> 1042 200927761 CDR區之胺基酸序列。第 7A-7E圖描述抗原結合蛋白之重鏈可變區的不同 CDR區之胺基酸序列。第 8A-8H圖描述抗原結合蛋白之輕鏈可變區的不同 FR區之胺基酸序列。第 9A-9F圖描述抗原結合蛋白之重鏈可變區的不同 FR區之胺基酸序列。第10A和10B圖描述抗原結合蛋白之輕鏈可變序列之胺基酸序列的排序。CDR1、CDR2及CDR3區指示於框線區中。第11A和11B圖描述抗原結合蛋白之重鏈可變序列之胺基酸序列的排序。CDR1、CDR2及CDR3區指示於框線區中。第12A圖描述顯示出抗原結合蛋白之輕鏈可變區之關係的支序圖。

第12B圖描述顯示出抗原結合蛋白之輕鏈CDRL3區之關係的支序圖。第12C圖描述顯示出抗原結合蛋白之重鏈可變區之關係的支序圖。第13A-13V圖描述抗原結合蛋白之不同輕鏈可變區的核苷酸序列。第14A-14AC圖描述抗原結合蛋白之不同重鏈可變區的核苷酸序列。第15A-15M圖描述抗原結合蛋白的不同輕鏈之核苷 -171 - 200927761

Met Lys Leu Leu Pro Ser Val Val Leu Lys Leu Phe Leu Ala Ala Val 15 10 15

Leu Ser Ala Leu Val Thr Gly Glu Ser Leu Glu Arg Leu Arg Arg Gly 20 25 30

Leu Ala Ala Gly Thr Ser Asn Pro Asp Pro Pro Thr Val Ser Thr Asp 35 40 45

Gin Leu Leu Pro Leu Gly Gly Gly Arg Asp Arg Lys Val Arg Asp Leu 50 55 60

Gin Glu Ala Asp Leu Asp Leu Leu Arg Val Thr Leu Ser Ser Lys Pro 65 70 75 80

Gin Ala Leu Ala Thr Pro Asn Lys Glu Glu His Gly Lys Arg Lys Lys 85 90 95

Lys Gly Lys Gly Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr 100 105 110

Lys Asp Phe Cys He His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg 115 120 125

Ala Pro Ser Cys lie Cys His Pro Gly Tyr His Gly Glu Arg Cys His 130 135 140

Gly Leu Ser Leu Pro Val Glu Asn Arg Leu Tyr Thr Tyr Asp His Thr 145 150 155 160 -1494 - 200927761

Thr He Leu Ala Val Val Ala Val Val Leu Ser Ser Val Cys Leu Leu 165 170 175

Val lie Val Gly Leu Leu Met Phe Arg Tyr His Arg Arg Gly Gly Tyr 180 185 190

Asp Val Glu Asn Glu Glu Lys Val Lys Leu Gly Met Thr Asn Ser His 195 200 205

<210> 1043 <211> 19 <212> PRT <213〉現代人 <400> 1043

Met Lys Leu Leu Pro Ser Val Val Leu Lys Leu Phe Leu Ala Ala Val 15 10 15

Leu Ser Ala ❿ <210〉 1044 <211〉 149 <212〉 PRT <213〉現代人 <400> 1044

Met Lys Leu Leu Pro Ser Val Val Leu Lys Leu Phe Leu Ala Ala Val 15 10 15 -1495 - 200927761

Leu Ser Ala Leu Val Thr Gly Glu Ser Leu Glu Arg Leu Arg Arg Gly 20 25 30

Leu Ala Ala Gly Thr Ser Asn Pro Asp Pro Pro Thr Val Ser Thr Asp 35 40 45

Gin Leu Leu Pro Leu Gly Gly Gly Arg Asp Arg Lys Val Arg Asp Leu 50 55 60

Gin Glu Ala Asp Leu Asp Leu Leu Arg Val Thr Leu Ser Ser Lys Pro 65 70 75 80

Gin Ala Leu Ala Thr Pro Asn Lys Glu Glu His Gly Lys Arg Lys Lys 85 90 95

Lys Gly Lys Gly Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr 100 105 110

Lys Asp Phe Cys He His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg 115 120 125

Ala Pro Ser Cys lie Cys His Pro Gly Tyr His Gly Glu Arg Cys His 130 135 140

Gly Leu Ser Leu Pro 145 -1496 - 200927761 <210〉 1045 <211〉 87 <212> PRT <213〉現代人 <400> 1045

Asp Leu Gin Glu Ala Asp Leu Asp Leu Leu Arg Val Thr Leu Ser Ser 15 10 15

Lys Pro Gin Ala Leu Ala Thr Pro Asn Lys Glu Glu His Gly Lys Arg 20 25 30 〇

Lys Lys Lys Gly Lys Gly Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg 35 40 45

Lys Tyr Lys Asp Phe Cys lie His Gly Glu Cys Lys Tyr Val Lys Glu 50 55 60

Leu Arg Ala Pro Ser Cys lie Cys His Pro Gly Tyr His Gly Glu Arg 65 70 75 80 ❿

Cys His Gly Leu Ser Leu Pro 85 <210> 1046 <211> 43 <212> PRT <213>現代人 <400> 1046 -1497 - 200927761

Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys lie His Gly Glu Cys Lys 15 10 15

Tyr Val Lys Glu Leu Arg Ala Pro Ser Cys lie Cys His Pro Gly Tyr 20 25 30

His Gly Glu Arg Cys His Gly Leu Ser Leu Pro 35 40 <210> 1047 <211> 149 <212〉 PRT <213〉現代人 <400〉 1047

Met Lys Leu Leu Pro Ser Val Val Leu Lys Leu Phe Leu Ala Ala Val 15 10 15

Leu Ser Ala Leu Val Thr Gly Glu Ser Leu Glu Arg Leu Arg Arg Gly 20 25 30

Leu Ala Ala Gly Thr Ser Asn Pro Asp Pro Pro Thr Val Ser Thr Asp 35 40 45

Gin Leu Leu Pro Leu Gly Gly Gly Arg Asp Arg Lys Val Arg Asp Leu 50 55 60

Gin Glu Ala Asp Leu Asp Leu Leu Arg Val Thr Leu Ser Ser Lys Pro 65 70 75 80 -1498 - 200927761

Gin Ala Leu Ala Thr Pro Asn Lys Glu Glu His Gly Lys Arg Lys Lys 85 90 95

Lys Gly Lys Gly Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr 100 105 110

Lys Asp Phe Cys lie His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg 115 120 125 〇〇

Ala Pro Ser Cys lie Cys His Pro Gly Tyr His Gly Glu Arg Cys His 130 135 140

Gly Leu Ser Leu Pro 145 <210〉 1048 <211〉 32 <212〉 DNA <213> Artificial <220> <223> forward primer <400> 1048 gggttaacgc caccatgaag ctgctgccgt eg <210> 1049 <211〉 28 <212〉 DNA <213> Artificial -1499 - 200927761 <220〉 <223> reverse primer <400> 1049 ccgctcgagg tgggaattag tcatgccc 28 <210> 1050 <211〉 31 <212〉 DNA <213> Artificial <220> <223> forward primer <400〉 1050 ggaattcgcc accatgaagc tgctgccgtc g 31 <210〉 1051 <211> 30 <212〉 DNA <213> Artificial <220〉 <223> reverse primer <400〉 1051 ccgctcgagg tgggagctag cagccacgcc 30 <210〉 1052 <211> 44 <212〉 <213> PRT 現代人 <400〉 1052 -1500- 200927761

Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys lie His Gly Glu Cys 1 5 10 15

Lys Tyr Val Lys Glu Leu Arg Ala Pro Ser Cys He Cys His Pro Gly 20 25 30

Tyr His Gly Glu Arg Cys His Gly Leu Ser Leu Pro 35 40

<210〉 1053 <211〉 49 <212> PRT <213〉現代人 <400〉 1053

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Tyr Cys 15 10 15

He His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg Ala Pro Ser Cys 20 25 30 ❹

He Cys His Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser Leu 35 40 45

Pro <210〉 1054 <211〉 49 <212〉 PRT -1501 - 200927761 <213〉現代人 <400> 1054

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys 15 10 15 lie His Gly Glu Cys Lys Tyr Val Lys Glu Phe Arg Ala Pro Ser Cys 20 25 30

He Cys His Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser Leu 35 40 45

Pro <210> 1055 <211> 49 <212〉 PRT <213〉現代人 <400> 1055

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys 15 10 15

He His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg Ala Pro Ser Cys 20 25 30 lie Cys His Pro Gly Tyr His Gly His Arg Cys His Gly Leu Ser Leu 35 40 45 1502- 200927761

Pro <210> 1056 <211> 49 <212〉 PRT <213〉現代人 <400> 1056

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys

lie His Gly Glu Cys Arg Tyr Leu Gin Glu Leu Arg Ala Pro Ser Cys 20 25 30

He Cys His Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser Leu 35 40 45

Pro 〇 <210> 1057 <211〉 49 <212> PRT <213〉現代人 <400〉 1057

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Tyr Cys 15 10 15 -1503 - 200927761 酸序列。第16A-16L圖描述抗原結合蛋白的不同重鏈之核苷酸序列。第17A圖描述抗原結合蛋白之輕鏈恆定區的核苷酸序列。第17B圖描述抗原結合蛋白之重鏈恆定區的核苷酸序列。

第18 A-18F圖描述抗原結合蛋白之輕鏈可變區的不同 CDR區之核苷酸序列。第19A-19G圖描述抗原結合蛋白之重鏈可變區的不同 CDR區之核苷酸序列。第20A-20K圖描述抗原結合蛋白之輕鏈可變區的不同 FR區之核苷酸序列。第21A-21K圖描述抗原結合蛋白之重鏈可變區的不同 FR區之核苷酸序列。

第22A圖示說明此處所提供之不同抗-HB-EGF IgG2 抗體製劑抑制由HB-EGF誘導之表皮生長因子受體（EGFR) 酪胺酸磷酸化的程度。圖中提供抗體U2-1至U2-68製劑之結果。如圖示者，單株抗體製劑U2-18、U2-24、U2-19 及U2-42強烈抑制EGFR酪胺酸磷酸化。第22B圖示說明此處所提供之不同抗-HB-EGF IgG4 抗體製劑抑制由HB-EGF誘導之表皮生長因子受體（EGFR) 酪胺酸磷酸化的程度。圖中提供抗體U2-2至U2-66製劑之結果。如圖示者，單株抗體製劑U2-39、U2-34、U2-45 -172- 200927761 lie His Gly Glu Cys Arg Tyr Leu Gin Glu Leu Arg Ala Pro Ser Cys 20 25 30 lie Cys His Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser Leu 35 40 45

Pro <210> 1058 <211> 49 <212〉 PRT <213〉現代人 <400> 1058

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys 15 10 15 lie His Gly Glu Cys Arg Tyr Leu Gin Glu Leu Arg Ala Pro Ser Cys 20 25 30 lie Cys His Pro Gly Tyr His Gly His Arg Cys His Gly Leu Ser Leu 35 40 45

Pro <210〉 1059 <211〉 49 -1504- 200927761 <212〉 PRT <213>現代人 <400> 1059

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys 15 10 15

He His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg Ala Pro Ser Cys 20 25 30

Lys Cys Leu Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser Leu 35 40 45

Pro <210> 1060 <211> 49 <212> PRT <213〉現代人 <400> 1060

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Tyr Cys 15 10 15

He His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg Ala Pro Ser Cys 20 25 30

Lys Cys Leu Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser Leu 35 40 45 -1505 - 200927761

Pro <210> 1061 <211〉 49 <212〉 PRT <213〉現代人 <400> 1061

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys 15 10 15

He His Gly Glu Cys Lys Tyr Val Lys Glu Phe Arg Ala Pro Ser Cys 20 25 30

Lys Cys Leu Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser Leu 35 40 45

Pro <210> 1062 <211〉 49 <212〉 PRT <213〉現代人 <400> 1062

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys 15 10 15 -1506- 200927761 lie His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg Ala Pro Ser Cys 20 25 30

He Cys His Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser Thr 35 40 45

Pro

<210> 1063 <211> 49 <212〉 PRT <213〉現代人 <400> 1063

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys 15 10 15 lie His Gly Glu Cys Lys Tyr Val Lys Glu Leu Arg Ala Pro Ser Cys 20 25 30

He Cys His Pro Gly Tyr His Gly His Arg Cys His Gly Leu Ser Thr 35 40 45

Pro <210> 1064 -1507- 200927761 <211〉 50 <212〉 PRT <213〉現代人 <400> 1064

Leu Gly Lys Lys Arg Asp Pro Cys Leu Arg Lys Tyr Lys Asp Phe Cys 15 10 15

Leu His Asp Gly Val Cys Lys Tyr Val Lys Glu Leu Arg Ala Pro Ser 20 25 30

Cys lie Cys His Pro Gly Tyr His Gly Glu Arg Cys His Gly Leu Ser 35 40 45

Leu Pro 50 <210> 1065 <211> 214 <212〉PRT <213〉現代人 <400> 1065

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser He Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -1508 - 200927761 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Leu Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gin Gin Ser Phe Tyr Thr Pro He 85 90 95 〇

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 o

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 -1509 - 200927761

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210> 1066 <211> 23 <212〉 PRT <213〉現代人 <400> 1066

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 <210〉 1067 <211> 23 <212> PRT <213〉現代人 <400〉 1067

Asn He Val Met Thr Gin Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys 20 -1510- 200927761 <210> 1068 <211> 23 <212〉 PRT <213〉現代人 <400〉 1068

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Thr Val Ser Leu Gly 1 5 10 15

Glu Arg Ala Thr lie Asn Cys

<210> 1069 <211〉 23 <212> PRT <213〉現代人 <400> 1069

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Gly Val Thr He Thr Cys 20 <210> 1070 <211〉 23 <212〉 PRT <213〉現代人 <400> 1070 -1511 - 200927761

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Ala lie Thr Cys 20 <210> 1071 <211> 23 <212〉PRT <213〉現代人 <400> 1071

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 <210〉 1072 <211〉 23 <212〉 PRT <213>現代人 <400> 1072

Asp He Gin Met Thr Gin Ser Pro Ser Ser Arg Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys 20 -1512- 200927761 <210> 1073 <211> 23 <212〉PRT <213〉現代人 <400> 1073

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 ❹ <210〉 1074 <211> 15 <212〉 PRT <213〉現代人 <400> 1074 ‘

Trp Phe Gin Gin Arg Pro Gly Gin Ser Pro Arg Arg Leu lie Tyr 15 10 15

<210> 1075 <211〉 32 <212〉 PRT <213〉現代人 <400> 1075

Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe Leu Gin 15 10 15

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg -1513- 200927761 及U2-6強烈抑制EGFR酪胺酸磷酸化。第23圖說明抗體抑制COS-7細胞中由溶血磷脂酸 (LPA)誘導之EGFR酪胺酸磷酸化。LPA爲活化TMPS通〇路，使 HB-EGF釋出，接著將 EGFR酪胺酸磷酸化之 GPCR配體。依指示以抗體預先處理COS-7細胞並以LP A 刺激之，然後，製備細胞溶胞產物，藉由聚丙烯醯胺凝膠電泳法將溶胞產物蛋白質分開。製備印跡（blot)後，使用抗磷酸酪胺酸抗體來偵測磷酸化之EGFR。如下端所示，在作爲對照組方面，使用 WB抗-EGFR抗體來偵測總 EGFR。如所示，抗-HB-EGF抗體製劑U2-24、U2-19及 U2-42強烈抑制由LPA誘導之EGFR磷酸化。第24圖示說明此處所提供之不同抗體以劑量倚賴方式抑制由HB-EGF誘導之EGF受體酪胺酸磷酸化作用。在刺激SCC9鱗狀細胞癌之細胞前，將不同濃度之候選抗體製劑U2-39、U2-42及U2-45預先與HB-EGF —起培育並 ^ 偵測EGFR酪胺酸磷酸化之量。如所示，抗體U2-42和 U2-39之抑制效果可達到1 1 1%。所測得之抗體的1C50値分別爲 0.167nM(U2-39)、lnM(U2-42)及 2nM(U2-45)。第25圖示說明抗-HB-EGF抗體製劑在MDA-MB231 細胞中以劑量倚賴方式抑制由凝血酶誘導之經由TMP S的 EGFR磷酸化。在凝血酶之存在下，將ΜΕ>Α·ΜΒ231細胞與候選抗體製劑U2-42、U2-39及U2-45 —起培育並利用實例6中所描述之程序偵測EGFR酪胺酸磷酸化之量。如所示，抗體U2-42和U2-39之抑制效果可達到1〇〇°/° ° -173- 200927761 20 25 30 <210> 1076 <211> 69 <212> PRT <213〉現代人 <400> 1076

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210〉 1077 <211〉 69 <212〉 PRT <213〉現代人 <400> 1077

Gly Ala Arg Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys -1514- 200927761 5 10 15

Ala Arg Cys Ala Asn Cys Cys Asn Tyr Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn Cys Cys Asn Gly Thr Asn Cys Ala Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr 65 <210> 1078 <211〉 69 <212〉 PRT <213〉現代人 <400> 1078

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Tyr Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45 -1515- 200927761

Gly Ala Arg Met Gly Asn Gly Cys Asn Cys Ala Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr 65 <210> 1079 <211> 69 <212> PRT <213>現代人 <400> 1079

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Gly 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210> 1080 <211> 69 <212〉 PRT -1516- 200927761 <213〉現代人 <400> 1080

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Gly Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210> 1081 <211〉 69 <212> PRT <213〉現代人 <400> 1081

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30 -1517- 200927761

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 <210> 1082 <211> 69 <212> PRT <213〉現代人 <400> 1082

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly Cys Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr 65 -1518- 200927761 <210> 1083 <211> 69 <212> PRT <213>現代人 <400> 1083

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Cys Ala Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Tyr Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Tyr Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Cys Ala Asn Ala Thr His Cys 50 55 60

Ala Asn Thr Gly Tyr ❹ 65 <210> 1084 <211> 45 <212〉 PRT <213〉現代人 <400> 1084

Thr Gly Gly Thr Thr Tyr Cys Ala Arg Cys Ala Arg Met Gly Asn Cys 15 10 15 -1519- 200927761

Cys Asn Gly Gly Asn Cys Ala Arg Trp Ser Asn Cys Cys Asn Met Gly 20 25 30

Asn Met Gly Asn Tyr Thr Asn Ala Thr His Thr Ala Tyr 35 40 45 <210> 1085 <211〉75 <212〉 PRT <213〉現代人 <400> 1085

Cys Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Cys Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn 65 70 75 <210> 1086 -1520- 200927761 <211> 75 <212〉 PRT <213>現代人 <400> 1086

Gly Ala Arg Gly Thr Asn Cys Ala Arg Tyr Thr Asn Cys Ala Arg Cys 15 10 15

Ala Arg Thr Gly Gly Gly Gly Asn Gly Cys Asn Gly Gly Asn Tyr Thr 20 25 30

Asn Tyr Thr Asn Ala Ala Arg Cys Cys Asn Trp Ser Asn Gly Ala Arg 35 40 45

Cys Ala Asn Tyr Thr Asn Trp Ser Asn Tyr Thr Asn Cys Ala Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr 65 70 75 <210> 1087 <211> 42 <212〉 PRT <213〉現代人 <400〉 1087

Thr Gly Gly Gly Thr Asn Met Gly Asn Cys Ala Arg Gly Cys Asn Cys 15 10 15

Cys Asn Gly Gly Asn Ala Ala Arg Gly Gly Asn Tyr Thr Asn Gly Ala -1521 - 200927761 20 25 30

Arg Thr Gly Gly Gly Thr Asn Trp Ser Asn 35 40 <210> 1088 <211〉 96 <212> PRT <213>現代人 <400> 1088

Met Gly Asn Thr Thr Tyr Cys Ala Asn Gly Thr Asn Trp Ser Asn Met 15 10 15

Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser Asn Ala Ala Arg Ala Ala 20 25 30

Tyr Cys Ala Asn Tyr Thr Asn Thr Thr Tyr Tyr Thr Asn Cys Ala Arg 35 40 45

Ala Thr Gly Ala Ala Tyr Trp Ser Asn Tyr Thr Asn Met Gly Asn Gly 50 55 60

Cys Asn Gly Ala Arg Gly Ala Tyr Cys Ala Asn Gly Cys Asn Gly Thr 65 70 75 80

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Gly Cys Asn Met Gly Asn 85 90 95 -1522 - 200927761 <210> 1089 <211〉 9 <212> PRT <213〉現代人 <220〉 <221〉MISC_特性 <222〉（ 1) ·· (1)

<223> XI係選自I或M <220〉

<221〉MISC_特性 <222〉（3)..(3)

<223〉X2係選自A、G或S <220〉 <221> MISC_特性 <222〉（4)..(4)

<223> X3係選自I或T <220> <221〉MISC—特性 <222〉（5)..(5)

<223> X4係選自H或Q <220〉 <221〉MISC_特性 <222〉（6)..(6)

<223> X5係選自F、L或W <220> <221〉MISC—特性 <222〉（8)..(8) <223〉X6係選自 C、I、H、L 或 T <220〉 <221〉MISC_特性 -1523 - 200927761 第26圖說明抗-HB-EGF抗體製劑在PPC-1細胞中以劑量倚賴方式抑制由LPA誘導之經由TMPS的EGFR酪胺酸磷酸化。將PPC-1細胞與候選抗體製劑U2-42、U2-39 及U2-45 —起培育並利用實例4中所描述之程序偵測以 LPA刺激後，EGFR酪胺酸磷酸化之量。如所示’抗體 U2-42、U2-3 9及U2-45之抑制效果可達到1 00%。第27圖說明抗-HB-EGF抗體製劑抑制至多1 〇〇%由神經鞘氨醇-1-磷酸酯誘導之MDA-MB231乳癌細胞移行。利用經膠原蛋白I塗覆之轉移盤（transwell)(BD Falcon’ 8微米孔）測試候選抗-HB-EGF抗體製劑U2-42、U2-39及U2-45抑制細胞移行之作用。如所示，抗-HB-EGF抗體製劑 U 2 - 4 2可抑制約 7 0 %之由神經鞘氨醇-1 -磷酸酯誘導之 MDA-MB231 細胞移行，而 U2-39 及 U2-45 抗- HB-EGF 抗體製劑抑制約1〇〇%之MDA-MB231細胞移行。因此’此處所提供之抗-HB-EGF抗體強烈抑制MDA-MB231細胞移行。第28圖示說明三種抗-HB-EGF抗體製劑（U2-42、U2-39及U2-45單株抗體製劑）抑制由HB-EGF誘導之MCF-7 乳癌細胞移行。第29圖說明抗-HB-EGF抗體製劑以劑量倚賴之方式抑制由HB-EGF誘導之HER4酪胺酸磷酸化。在刺激前將 U2-42.1 或 U2-39.1 抗-HB-EGF 抗體製劑與 HB-EGF —起培育並偵測HER4酪胺酸磷酸化。如所示，可觀察到 HER4酪胺酸磷酸化1 〇〇%受抑制。注意，顯示在X-軸上之 -174- 200927761 <222〉（9)..(9)

<223> X7係選自S或T <400> 1089

Xaa Gin Xaa Xaa Xaa Xaa Pro Xaa Xaa 1 5 <210> 1090 <211> 9 <212〉 PRT <213〉現代人 <220> <221> MISC_特性 <222〉（3)..(3)

<223〉XI係選自I或S <220> <221〉MISC—特性 <222> (4)..(4)

<223〉X2係選自F或Y <220> <221〉MISCjt性 <222〉（5)..(5) <223〉X3 係選自 F、I、S 或 Y <220〉 <221> MISC_#tt <222〉（6)..(6)

<223〉X4係選自A、S或T <220〉 <221〉MISCJ^ <222〉（7)..(7) 1524- 200927761 <223〉X5係選自P或S <400> 1090

Gin Gin Xaa Xaa Xaa Xaa Xaa He Thr 1 5 <210> 1091 <211> 9 <212> PRT <213〉現代人

<220〉 <221> MISCJ^Ht <222> (1)..(1)

<223> XI係選自L或Q <220〉 <221〉MI SC一特性 <222〉（2)..(2)

<223〉X2係選自K、N或Q <220〉 <221> MISC_特性 <222〉（3)..(3) <223> X3 係選自 A、H、S 或 Y <220〉 <221〉MISC_ 特性 <222〉（4)..(4)

<223〉X4係選自Η、N或Y <220> <221〉MISC一特性 <222〉（5)..(5)

<223〉X5係選自N、S或T -1525 - 200927761 <220〉 <221> MISC_特性 <222> (6)..(6) <223〉X6係選自 A、F、I、T、V或Y <220> <221〉MISC—特性 <222〉（7)..(7) <223〉X7係選自P或無胺基酸 <220〉 <221> MISC_特性 <222〉（8)..(8)

<223> X8係選自F、L或P <400〉 1091

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Thr 1 5 <210> 1092 <211〉 9 <212> PRT <213>現代人 <220〉 <221〉MISC_特性 <222〉（2)..(2)

<223> XI係選自H或Q <220> <221> MISC—特性 <222〉（3)..(3)

<223> X2係選自C或Y -1526- 200927761 <220> <221〉MISCJ#性 <222〉（5)..(5) <223〉X3 係選自 D、I、N、S 或 Y <220> <221〉MI SC一特性 <222〉（8)..(8) <223〉X4係選自F、I或L <220〉 <221〉MISC—特性 <222〉（9)..(9)

<223〉X5係選自A、S或T <400> 1092

Gin Xaa Xaa Asp Xaa Leu Pro Xaa Xaa 1 5 <210> 1093 <211〉 10 <212〉 PRT <213〉現代人

<220> <221> MISC—特性 <222〉 (3)..(3) <223> XI係選自H 或Y <220〉 <221> MISC_#f4 <222〉 (4)..(4) <223> X2係選自G 或N ❹ <220〉 200927761 <221> MISC_#tt <222〉（5)..(5)

<223〉X3係選自N或S <220〉 <221> MISC_特性 <222〉（6)..(6)

<223> X4係選自S或W <220> <221〉MISC—特性 <222〉（8)..(8) <223〉X5係選自P或無胺基酸 <220〉 <221> MISC_特性 <222〉（9)..(9)

<223> X6係選自R或W <220> <221> MISC_特性 <222〉（10)..(10)

<223〉X7係選自S或T <400> 1093

Gin Gin Xaa Xaa Xaa Xaa Pro Xaa Xaa Xaa 1 5 10 <210> 1094 <211〉 10 <212〉PRT <213〉現代人 <220〉 <221〉MISC_特性 -1528 - 200927761 <222> (1)..(1)

<223> XI係選自Η或Q <220〉 <221〉MISC_特性 <222〉（4)..(4) <223〉X2係選自F或Y <220〉 <221〉MISC_特性 <222〉（5)..(5)

<223〉X3係選自G、I或S

<220> <221〉MISC_特性 <222> (6)..(6) <223〉X4係選自F、I或T <220> <221〉MISC_特性 <222〉（7)..(7) <223〉X5 係選自 Μ、P、S 或 T <220> <221〉MISC_特性 <222〉（8)..(8) <223〉X6 係選自 F、L、R 或 W <220> <221〉MISC—特性 <222〉（9)..(9) <223> X7係選自S或T <400> 1094

Xaa Gin Tyr Xaa Xaa Xaa Xaa Xaa Xaa Phe 1 5 10 -1529- 200927761 <210> 1095 <211> 10 <212〉PRT <213〉現代人 <220〉 <221> MISC_#tt <222〉（4)..(4)

<223> XI係選自F或L <220〉 <221> MISC_#|4 <222> (6)..(6)

<223〉X2係選自E、G或S <220〉 <221〉MISC—特性 <222〉（7)..(7)

<223> X3係選自H、L或Y <220〉 <221〉MISC—特性 <222〉（8)..(8)

<223> X4係選自G、S或Y <220〉 <221> MISC_#tt <222〉（9)..(9)

<223> X5係選自I或M <220〉 <221〉MISC_特性 <222〉（10)..(10) <223> X6係選自H或S <400> 1095 200927761

Gly Tyr Thr Xaa Thr Xaa Xaa Xaa Xaa Xaa 1 5 10 <210〉 1096 <211> 10 <212〉 PRT <213〉現代人 <220〉 <221> MISC—特性 <222〉 (3)..(3) <223> XI係選自R或S <400〉 1096 Gly Tyr Xaa Phe Thr Ser Tyr Trp lie Gly 1 5 10 <210〉 1097 <211〉 10 <212〉 PRT <213> 現代人

<220〉 <221> MISC—特性 <222〉 (5)..(5) <223> XI係選自R 或s <220> <221> MISC_特性 <222> (7)..(7) <223> X2係選自H 或Y

-1531 - 200927761 <220〉 <221> MISC_· <222> ⑻·.⑻ <223> X3係選自D或G <400〉 1097

Gly Phe Thr Phe Xaa Ser Xaa Xaa Met His 1 5 10 <210> 1098 <211> 10 <212〉 PRT <213〉現代人 <220〉 <221> MISC_特性 <222> (3)..(3) <223> XI係選自P或T <220〉 <221> MISCJf性 <222〉（6)..(6) <223> X2係選自A、R或S <220> <221> MISC_特性 <222〉（8)..(8) <223> X3係選自A或S <220> <221> MISC_特性 <222〉（10)..(10) <223> X4係選自N或S <400> 1098 -1532- 200927761

Gly Phe Xaa Phe Ser Xaa Tyr Xaa Met Xaa 1 5 10 <210> 1099 <211> 12 <212> PRT <213>現代人 <220>

<221〉MISC—特性 <222〉（2)..(2) <223> XI係選自D或G <220> <221〉MISC_特性 <222〉（4)..(4)

<223> X2係選自F、I或V <220> <221> <222> (6)..(6) <223〉X3係選自R、S或無胺基酸 ❹ <22〇> <221〉MISC一特性 <222〉（7)..(7) <223〉X4係選自G、Y或無胺基酸 <220> <221> MISC一特性 <222〉（8)..(8) <223〉X5係選自D、G、S或無胺基酸 <220> <221〉MISC一特性 -1533 - 200927761 抗體量以對數形式減少。

第30A圖顯示利用HEK-293細胞（其係經表現彌猴 HB-EGF之DNA載體轉染），藉由流式細胞計數儀（FACS) 評估單株抗體製劑與來自彌猴之HB-EGF交叉反應。如所示，在經對照之空載體轉染的HEK-2 93對照組細胞方面可觀察到非常低之X-平均値（1-2)。相反地，當以編碼彌猴 HB-EGF之表現匣轉染HEK-29 3細胞時可觀察到250或更高之X-平均値。第30B圖顯示利用HEK-293細胞（其係經表現老鼠 HB-EGF之DNA載體轉染），藉由流式細胞計數儀（FACS) 評估單株抗體U2-45製劑與來自老鼠之HB-EGF交叉反應。當以編碼老鼠HB-EGF之表現匣轉染HEK-293細胞時可觀察到33.7之X-平均値。第30C圖顯示HB-EGF抗體與雙調蛋白（amphiregulin )交叉反應的程度。第31圖顯示藉由FACS分析偵測時指出HB-EGF係表現在人類血管內皮細胞（HUVECs)上。第32A-32B圖顯示雖然HB-EGF刺激HUVEC細胞增殖，抗-HB-EGF抗體製劑抑制約8%至14%之基礎增殖。 HB-EGF刺激約38%之HUVEC細胞增殖（第32A圖）。然而，當加入抗-HB-EGF抗體製劑U2-42、U2-39或U2-45時，可抑制約8%至14%之基礎細胞增殖（第32B圖）。第33A-33L圖說明抗-HB-EGF抗體加速HUVEC脈管退化。HUVEC脈管形成爲用於內皮細胞血管新生之模型 -175- 200927761 <222> (9)..(9) <223> X6係選自A、S或Y <220> <221> MISC_特性 <222〉 (10)..(10) <223> X7係選自A或Y <220〉 <221〉 MISC_特性 <222〉 (12)..(12) <223> X8係選自N或S <400> 1099 Gly Xaa Ser Xaa Ser Xaa Xaa Xaa Xaa Xaa Trp Xaa 1 5 10 <210> 1100 <211〉 12 <212〉 PRT <213〉現代人 <220〉 <221〉 MISC_特性 <222〉 (5)..(5) <223> XI係選自S或N <400〉 1100 Gly Phe Ser Leu Xaa Thr Gly Gly Val Gly Val Gly 1 5 10 <210〉 1101 <211〉 16 -1534- 200927761 <212> PRT <213〉現代人 <220> <221〉MISCJ^Hi <222> (1).. (1) <223> XI係選自S或W <220> <221〉MI SC一特性 <222〉（2)..(2)

<223> X2係選自F或I

<220> <221〉MISC一特性 <222> (3)..(3) <223> X3係選自D、N或S <220〉 <221〉MISCjt性 <222〉（4)..(4) <223> X4係選自A或P <220> <221〉MISC一特性 <222〉（5)..(5) <223〉X5係選自E、N或S <220〉 <221〉MISC_特性 <222〉（6)..(6) <223〉X6係選自D、N或S <220> <221> MISC_ 特性 <222〉（8)..(8)

<223〉X7係選自E、G或N 200927761 <220〉 <221> MISC_特性 <222〉（10)..(10)

<223> X8係選自I或N <220> <221> MISC_#tt <222〉（11)..(11)

<223> X9係選自C、Η或Y <220〉 <221> MISC_特性 <222〉（12)..(12)

<223> X10係選自A或T <220> <221〉MISC_ 特性 <222〉（15)..(15)

<223〉XII係選自F或L <220〉 <221> MISC_#tt <222〉（16)..(16)

<223〉XI2係選自D或G <400〉 1101

Xaa Xaa Xaa Xaa Xaa Xaa Gly Xaa Thr Xaa Xaa Xaa Gin Lys Xaa Xaa 15 10 15 <210> 1102 <211> 17 <212〉 PRT <213> 現代人 -1536 200927761 <220〉 <221> MI SC一特性 <222〉 (5)..(5) <223> XI係選自D或G <220〉 <221> MISC_特性 <222〉 (9)..(9) <223〉 X2係選自A、I或T <400> 1102

He lie Tyr Pro Xaa Asp Ser Asp Xaa Arg Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210〉 1103 <211〉 17 <212〉 PRT <213〉現代人 <220〉 <221> MI SC一特性 <222> (1)..(1) <223> XI係選自F或V <220> <221〉 MISC_特性 <222〉 (3)..(3) <223> X2係選自S或W <220〉 <221> MISCJRHi -1537- 200927761 <222〉（4)..(4)

<223> X3係選自D、S或Y <220> <221> MISC_#tt <222〉（8)..(8)

<223〉X4係選自I、N或T <220〉 <221> MISC_#tt <222〉（9)..(9)

<223〉X5係選自K或Q <220〉 ' <221〉MISC_ 特性 <222〉（10)..(10)

<223> X6係選自N、R或Y <220〉 <221> MISC_特性 <222〉（12)..(12)

<223> X7係選自A、T或V <220〉 <221〉MISC_特性 <222〉（16)..(16)

<223> X8係選自K或R <400〉 1103

Xaa He Xaa Xaa Asp Gly Ser Xaa Xaa Xaa Tyr Xaa Asp Ser Val Xaa 15 10 15

Gly -1538 - 200927761 <210〉1104 <211〉 17 <212〉PRT <213〉現代人 <220〉 <221〉MISC一特性 <222〉（1)··(1) <223〉XI係選自A、H或Y <220〉

<221〉MISCjf性 <222〉（4)..(4) <223> X2係選自G、R或S <220> <221〉MISCjf性 <222〉（6)..(6) <223> X3係選自G或S <220〉 <221〉MISC_ 特性 <222〉（7)..(7) <223〉X4係選自G、R或S <220> <221> MISC_ 特性 <222〉（8)..(8) <223〉X5係選自S、T或Y <220> <221> MISC_#tt <222〉（9)..(9) <223> X6係選自I或T <400> 1104 200927761

Xaa He Ser Xaa Ser Xaa Xaa Xaa Xaa Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly <210〉 1105 <211> 18 <212〉PRT <213〉現代人

<220〉 <221> MISC_特性 <222> (1).. (1) <223〉XI係選自E、R或Y <220> <221〉MISC_特性 <222〉（2)..(2) <223> X2係選自I或T <220〉 <221〉MISC一特性 <222〉（3)..(3) <223〉X3係選自Η、N或Y <220〉 <221> MISC_#ft <222〉（4)..(4) <223〉X4係選自 C、H、S、T或Y <220> <221〉MISC—特性 <222〉（5)..(5) <223> X5係選自S或R -1540- 200927761 <220〉 <221> MISC_· <222〉（6)..(6)

<223〉X6係選自G或S <220〉 <221〉MISC_特性 <222〉（7)..(7)

<223〉X7係選自 G、K、S或T <220〉

<221〉MISC一特性 <222〉（8)..(8)

<223> X8係選自T或W <220〉 <221〉MISC_特性 <222> (9)..(9)

<223> X9係選自N或Y <220〉 <221> MISC_#f4 <222> (10)..(10) <223〉X10係選自N或無胺基酸 <220> <221> MISC_#tt <222〉（11)..(11) <223〉XI1係選自D或無胺基酸 <220〉 <221〉MISC—特性 <222〉（13)..(13)

<223〉X12係選自A或N <220> <221〉MISC_特性 200927761 <222〉（14)..(14)

<223〉X13係選自P或V <220〉 <221〉MISC_特性 <222〉（16)..(16)

<223> X14係選自L或V <400> 1105

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Xaa Xaa Ser Xaa 15 10 15

Lys Ser <210〉 1106 <211> 16 <212> PRT <213〉現代人

<220> <221> MISC_特性 <222〉 (1)..(1) <223> XI係選自K或R <220> <221> MISC_特性 <222〉 (7)..(7) <223> X2係選自L或V <220〉 <221> MISC一特性 <222〉 (8)..(8) <223〉 X3係選自H或Y -1542- 200927761 <220〉 <221> MISC_特性 <222〉 (12)..(12) <223> X4係選自K或N <220〉 <221〉 MISC_特性 <222〉 (16)..(16) <223> X5係選自N、S或Y <400> 1106

Xaa Ser Ser Gin Ser Leu Xaa Xaa Ser Asp Gly Xaa Thr Tyr Leu Xaa 15 10 15 <210〉 1107 <211> 11 <212〉 PRT <213〉現代人 <220〉 <221> MISC_#14 <222〉（5)..(5)

<223> XI係選自R、S或T <220> <221>MISC_^14 <222〉（8)..(8)

<223> X2係選自R或S <400> 1107

Arg Ala Ser Gin Xaa lie Ser Xaa Tyr Leu Asn 1 5 10 -1543 - 200927761 系統。第33A-33C圖提供不加入抗-HB-EGF抗體所進行之對照組分析。如所示，HUVEC細胞連結以形成許多圓形構造或“脈管”。第33D-33F圖說明在形成脈管時加入抗-HB-EGF U2-39抗體製劑的效果。第33G-33I圖說明在形成脈管時加入抗-HB-EGF U2-42抗體製劑的效果。第 33J-33L圖說明在形成脈管時加入抗-HB-EGF U2-45抗體製劑的效果。如所示’當存有U2-42、U2-39及U2-45抗-HB-EGF抗體製劑時可見到較少之HUVEC脈管及網路。第33M圖示說明加入此處所提供之抗-HB-EGF抗體製劑後定量評估形成之HUVEC脈管的結果，此結果支持 HB-EGF抗體於抑制血管新生的用途。繪出使用 U2-42、 U2-39或U2-45抗-HB-EGF抗體製劑時，每一顯微鏡視野中之脈管或閉合細胞構造之數目。如所示，當無抗-HB-EGF抗體存在時，每一視野可見到約10個HUVEC脈管，當加入U2-39抗-HB-EGF抗體製劑時每一視野僅可觀察到約4個HUVEC脈管。當存有U2-42抗-HB-EGF抗體製劑時僅可觀察到約1個HUVEC脈管。當存有U2-45抗-HB-EGF抗體製劑時僅可觀察到約6個HUVEC脈管。第34A圖說明抗-HB-EGF抗體抑制經HB-EGF刺激之 OVCAR-8卵巢癌細胞之株落形成。如所示，HB-EGF刺激 OVCAR-8細胞形成較對照組OVCAR-8細胞（培養時不加入 HB-EGF)明顯爲大之平均株落尺寸。然而，當在HB-EGF 之存在下將OVCAR-8細胞與抗-HB-EGF U2-39抗體一起培養時，平均株落尺寸減至基線尺寸（於未經HB-EGF處 -176- 200927761 <210〉 1108 <211> 11 <212〉 PRT <213> 現代人 <220〉 <221〉 MISC_特性 <222〉 (5)..(5) <223> XI係選自D、 <220> <221> MISC_特性 <222〉 (7)..(7) <223> X2係選自A、 <220〉 <221> MISC_特性 <222〉 ⑻··⑻ <223> X3係選自Η、 <220〉 <221> MISC_特性 <222〉 (9)..(9) <223> X4係選自D、 <220〉 <221> MISC_特性 <222〉 (11)..(11) <223> X5係選自A、 <400〉 1108 G、S或Τ

R或S

I、Ν' R、S 或T

W或Y

G或N

Arg Ala Ser Gin Xaa lie Xaa Xaa Xaa Leu Xaa 1 5 10 -1544 200927761 <210〉 1109 <211〉 11 <212〉 PRT <213〉現代人 <220〉 <221> MISC_#tt <222〉（7)..(7) <223> XI係選自S或T <220〉

<221> MISC_#f4 <222〉（8)..(8) <223> X2係選自D或N <220〉 <221〉MI SC一特性 <222〉（9)..(9) <223> X3係選自S或Y <400> 1109

Gin Ala Ser Gin Asp lie Xaa Xaa Xaa Leu Asn 1 5 10 ❹ <210〉 1110 <211> 12 <212〉 PRT <213〉現代人 <220> <221> MISC_特性 <222〉（5)..(5)

<223> XI係選自S或T -1545 - 200927761 <220> <221> MISC_· <222〉（7)..(7)

<223> X2係選自I或S <220> <221〉MISC_特性 <222〉（8)..(8)

<223> X3係選自R或S <220> <221> MISC_特性 <222〉（9)..(9) <223〉X4係選自S、N或無胺基酸 <220〉 <221> MISC_特性 <222〉（10)..(10) <223> X5係選自Y或無胺基酸 <400〉 1110

Arg Ala Ser Gin Xaa Val Xaa Xaa Xaa Xaa Leu Ala 1 5 10 <2io> mi <211> 17 <212> PRT <213〉現代人 <220〉 <221> MISC_特性 <222〉（5)..(5)

<223> XI係選自N或S -1546 - <220> 200927761 <221〉 MI SC一特性 <222〉 (6)..(6) <223> X2係選自I或V <220> <221> MISC_特性 <222〉 ⑻..(8) <223> X3係選自D或Y <220〉 <221〉 MISC_特性 <222> (9)..(9) <223> X4係選自N、R或S O <220> <221> MISC_特性 <222> (17)..(17) <223> X5係選自A或V <400> 1111

Lys Ser Ser Gin Xaa Xaa Leu Xaa Xaa Ser Asn Asn Lys Asn Tyr Leu 15 10 15

Xaa <210> 1112 <211〉 7 <212> PRT <213>現代人 <220> <221〉MISC_特性 <222〉（1) ·.(1) -1547- 200927761 <223> XI係選自E或K <220> <221> MISC_特性 <222〉 (2)..(2) <223> X2係選自I或V <220〉 <221〉 MISC_特性 <222〉 (5)..(5) <223> X3係選自R或W <220> <221> MISC_特性 <222> (6)..(6) <223> X4係選自D或F <400〉 1112 Xaa Xaa Ser Asn Xaa Xaa Ser 1 5 <210> 1113 <211〉 7 <212> PRT <213〉現代人

<220> <221> MISC_特性 <222> (1)..(1) <223> XI係選自A或T <220> <221> MISC_特性 <222> (2)..(2) <223> X2係選自A、E或V 200927761 <220> <221> MISC_#f4 <222〉（4)..(4)

<223〉X3係選自S或T <400> 1113

Xaa Xaa Ser Xaa Leu Gin Ser 1 5

<210> 1114 <211> 7 <212〉 PRT <213〉現代人 <220〉 <221> MISC_特性 <222> (1).. (1) <223> XI係選自A或V <220〉 <221〉MISC_特性 <222〉（4)..(4)

<223> X2係選自S或T <400> 1114

Xaa Ala Ser Xaa Leu Gin Ser 1 5 <210〉 1115 <211〉 7 <212〉 PRT <213〉現代人 200927761 <220〉 <221〉MISC_特性 <222〉（4)..(4)

<223〉XI係選自I或N <400> 1115

Asp Ala Ser Xaa Leu Glu Thr 1 5 <210〉 1116 <211〉 7 <212〉 PRT <213〉現代人 <220〉 <221> MISC_特性 <222> (4)..(4) <223〉 XI係選自AST <400〉 1116

Trp Ala Ser Xaa Arg Glu Ser 1 5 200927761 理時所觀察到之對照組細胞的尺寸）。

第3 4B圖說明抗-HB-EGF抗體抑制經HB-EGF刺激之 BM1604攝護腺癌細胞在軟瓊脂上形成株落。如所示，HB-EGF刺激BM 1 6 04細胞在每槽中形成較對照組BM 1 604細胞（培養時不加入HB-EGF)爲多之株落。然而，當在HB-EGF之存在下將BM 1 604細胞與抗-HB-EGF U2-39抗體一起培養時，平均株落尺寸減至與從未經HB-EGF處理時所觀察到之對照組細胞類似之大小。在此分析中，抗-HB-EGF U2-45及U2-42抗體部分抑制株落形成，而U2-39 抗-HB-EGF抗體完全抑制株落形成。第3 4C圖說明抗-HB-EGF抗體抑制經HB-EGF刺激之 NCI-H226肺癌細胞之株落形成。如所示，經HB-EGF刺激之NCI-H226細胞形成較對照組NCI-H226細胞（培養時不加入 HB-EGF)明顯爲大之平均株落尺寸。然而，當在 HB-EGF之存在下將NCI-H226細胞與抗-HB-EGF U2-39抗體一起培養時，平均株落尺寸減至基線尺寸（於未經HB-EGF處理時所觀察到之對照組細胞尺寸）。第34D圖說明抗-HB-EGF抗體抑制SkOV-3 HB-EGF 選殖株71細胞（源自經HB-EGF表現載體轉染，以組成性過度表現HB-EGF之SkOV-3卵巢癌細胞）之基礎株落形成。如所示，對照組SkOV-3 HB-EGF選殖株71細胞形成大量株落。然而，當將SkOV-3 HB-EGF選殖株71細胞與抗-HB-EGF U2-42或U2-39抗體一起培養時，該株落數目大量減少。 -177- 200927761 第34E圖說明抗-HB-EGF抗體抑制SkOV-3 HB-EGF 選殖株74細胞（源自經HB-EGF表現載體轉染而以組成性過度表現HB-EGF之SkOV-3卵巢癌細胞）之基礎株落形成。如所示，對照組SkOV-3 HB-EGF選殖株74細胞形成大量株落。然而，當將SkOV-3 HB-EGF選殖株74細胞與抗-HB-EGF U2_39抗體一起培養時，該株落數目大量減少〇第34F圖說明抗-HB-EGF抗體抑制生長在軟瓊脂之 BxPC3胰臟腺癌細胞的基礎株落形成。如所示，對照組 BxPC 3細胞形成大量株落。然而，當在HB-EGF之存在下，將BxPC3細胞與抗-HB-EGF U2-42或U2-39抗體一起培養時，該株落數目大量減少。第35圖說明抗-HB-EGF抗體抑制生長在軟瓊脂之過度表現HB-EGF的EFO-27 HB-EGF選殖株58卵巢癌細胞之基礎株落形成。如所示，對照組細胞形成大量株落。然而，當將EFO-27 HB-EGF選殖株5 8細胞與抗-HB-EGF U2-42、U2-39或U2-45抗體一起培養時，該株落數目大量減少。再者，抗-HB-EGF抗體與抗-EGFR抗體Erbitux 之組合療法可完全抑制株落形成。第36圖顯示抗- HB-EGF抗體抑制活體內由HB-EGF 誘導之血管新生。在老鼠基質膠栓子（m a t r i g e 1 p 1 u g)分析中可藉抗體U2-42、U2-39及U2-45，以劑量倚賴方式阻斷血管新生網之形成。第37圖說明藉抗體U2-42及U2-39抑制老鼠異體移 -178- 200927761 植模型中已設立之BxPC3腫瘤的生長。第38A-38C圖說明藉抗體U2-42、U2-39及U2-45抑制老鼠異體移植模型中已設立之EFO-27 HB-EGF選殖株 58腫瘤的生長（第38A圖）。如第38B圖所示，藉抗體U2-42及U2-39抑制異體移植腫瘤的生長的作用顯示出爲劑量倚賴性。再者，與抗-EGFR抗體Erbitux組合治療時導致腫瘤生長完全退化並顯示出抗HB-EGF抗體作爲組合療 ^ 法之治療劑的強力協同活性（第3 8 C圖）。第39A-39B圖說明使用人類抗- HB-EGF抗體藉免疫組織化學（第39A圖）及ELISA(第39B圖）來偵測人類組織中之 HB-EGF。第 40A圖說明刮劃分析（scratch assay)，其指出由 HB-EGF誘導之CLS354表皮鱗狀癌細胞（口）移行的抑制情形。第40B圖說明轉移分析（transmigration assay)，其指 0 出由HB-EGF誘導之底特律（Detroit)562表皮癌細胞（喉）移行的抑制情形。第41圖說明球形物爲基礎之細胞血管新生分析，其指出經VEGF刺激之內皮細胞萌生的抑制情形。第42圖說明人類腫瘤異體移植樣本之免疫組織化學 (IHC)分析，其指出活體內腫瘤CD31染色之抑制情形。第43圖說明活體內卵巢腫瘤異體移植模型，其指出 U2-39與順鉑（Cisplatin)及癌思停（Avastin)之組合治療。 -179- 200927761 200927761 序列表 <110> U3 Pharma AG/Amgen Inc. <120>與肝素結合之似表皮生長因子的生長因子抗原結合蛋白

<130> 39562PTW <141> 2008-12-11 <160〉 1116

<170〉Patentln 第 3.3 版 <210> 1 <211〉 219 <212> PRT <213>現代人 <400> 1

Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 15 10 15

Q

Gin Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Val Tyr Ser 20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gin Gin Arg Pro Gly Gin Ser 35 40 45

Pro Arg Arg Leu lie Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60 200927761

Asp Arg Phe Asn Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ser 85 90 95

Thr His Trp Pro lie Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 -2- 200927761 <210〉 2 <211> 219 <212〉 PRT <213〉現代人 <400> 2

Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Val Tyr Ser 20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gin Gin Arg Pro Gly Gin Ser 35 40 45

Pro Arg Arg Leu lie Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys He 0 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys lie Gin Gly 85 90 95

Thr His Trp Pro Thr Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 200927761 115 120 125

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210〉 3 <211> 219 <212〉 PRT <213〉現代人 <400〉 3

Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 15 10 15 -4 200927761

Gin Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Val Tyr Ser 20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Leu Gin Gin Arg Pro Gly Gin Ser 35 40 45

Pro Arg Arg Leu lie Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys He

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Gly 85 90 95

Thr His Trp Pro lie Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125 ❹

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175 200927761

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210〉 4 <211> 219 <212> PRT <213〉現代人 <400〉 4

Asp lie Val Met Thr Gin Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15

Gin Pro Ala Ser He Ser Cys Lys Ser Ser Gin Ser Leu Leu His Ser 20 25 30

Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gin Lys Pro Gly Gin Pro 35 40 45

Pro Gin Leu Leu lie Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie -6- 200927761 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Gly 85 90 95 lie Gin Leu Pro Cys Ser Phe Gly Gin Gly Thr Lys Leu Glu He Lys 100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125 o

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175 ❹

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 -7- 200927761 <210> 5 <211> 219 <212〉 PRT <213〉現代人 <400〉 5

Asp lie Val Met Thr Gin Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Lys Ser Ser Gin Ser Leu Leu His Ser 20 25 30

Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gin Lys Pro Gly Gin Pro 35 40 45

Pro Gin Leu Leu lie Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys He 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ser 85 90 95

He Gin Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125 200927761

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 Q <210〉 6 <211> 219 <212〉PRT <213〉現代人 <400〉 6

Asp He Val Met Thr Gin Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Lys Ser Ser Gin Ser Leu Leu His Ser 200927761 20 25 30

Asp Gly Lys Thr Tyr Leu Tyr Trp Phe Leu Gin Lys Pro Gly Gin Pro 35 40 45

Pro Gin Pro Leu lie Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ser 85 90 95 lie Gin Leu Pro lie Thr Phe Gly His Gly Thr Arg Leu Glu He Lys 100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175 -10- 200927761

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215

<210> 7 <211> 214 <212〉 PRT <213〉現代人 <400〉 7

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ala Asn Tyr 20 25 30 〇

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu Leu lie 35 40 45

Tyr Val Ala Ser Thr Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 -11 - 200927761

Glu Asp Val Ala Thr Tyr Tyr Cys Gin Asn Tyr Asn Ser Ala Pro Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 -12- 200927761 v <210> 8 <211〉 214 <212> PRT <213〉現代人 <400> 8

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15

Asp Arg Val Thr lie lie Cys Arg Ala Ser Gin Gly lie Ser Asn Asp 20 25 30 〇

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu Leu lie 35 40 45

Tyr Ala Ala Ser Thr Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80 o

Glu Asp Val Ala Thr Tyr Tyr Cys Gin Lys Tyr Asn Ser Val Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125 -13- 200927761

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 9 <211> 219 <212〉 PRT <213〉現代人 <400> 9

Asn lie Val Met Thr Gin Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Val His Ser 20 25 30 -14- 200927761

Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gin Gin Arg Pro Gly Gin Pro 35 40 45

Pro Arg Leu Leu lie Tyr Lys lie Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95

Thr Gin Phe Pro His Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 115 120 125

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175 -15 200927761

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210〉 10 <211〉 219 <212> PRT <213〉現代人 <400> 10

Glu lie Val Met Thr Gin Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser He Ser Cys Arg Ser Ser Gin Ser Leu Val His Ser 20 25 30

Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gin Gin Arg Pro Gly Gin Pro 35 40 45

Pro Arg Leu Leu lie Tyr Lys He Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Thr Gly Ala Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80 -16- 200927761

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95

Thr Gin Phe Pro His Thr Phe Gly Gly Gly Thr Lys Val Glu He Lys 100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu 115 120 125

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 145 150 155 160

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 0 180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 11 -17- 200927761 <211〉 215 <212〉PRT <213〉現代人 <400> 11

Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Thr Val He Ser Ser 20 25 30

Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 35 40 45 lie Ser Gly Ala Ser Ser Arg Ala Thr Gly lie Pro Asp Arg Phe Ser 50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu 65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Pro 85 90 95

Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110

Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser 115 120 125 -18- 200927761

Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140

Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser 145 150 155 160

Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190

Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 195 200 205

Ser Phe Asn Arg Gly Glu Cys 210 215

<210〉 12 <211> 213 0 <212〉 PRT <213〉現代人 <400〉 12

Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Arg Leu 20 25 30 -19- 200927761

Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie Tyr 35 40 45

Gly Ala Ser Arg Arg Ala Thr Gly He Pro Asp Arg Phe Ser Gly Ser 50 55 60

Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu Pro Glu 65 70 75 80

Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Pro Arg Ser 85 90 95

Phe Gly Gin Gly Thr Lys Leu Glu He Lys Arg Thr Val Ala Ala Pro 100 105 110

Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140

Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155 160

Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala -20- 200927761 180 185 190

Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205

Asn Arg Gly Glu Cys 210

<210> 13 <211> 214 <212> PRT <213〉現代人 <400〉 13

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly lie Arg Asn Asp 20 25 30

Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu He 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80 200927761

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Pro 85 90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 14 <211> 220 22- 200927761 <212〉 PRT <213〉現代人 <400〉 14

Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Val Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Phe lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 〇 85 90 95

Tyr Tyr Ser Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn -23 - 200927761 130 135 . 140

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210〉 15 <211> 220 <212〉 PRT <213〉現代人 <400〉 15

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30 -24- 200927761

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin

Tyr Tyr Ser Thr Thr Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 〇

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 -25- 200927761

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210〉 16 <211> 220 <212〉 PRT <213〉現代人 <400〉 16

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr He Asn Cys Lys Ser Ser Gin Asn Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Phe Cys Gin Gin -26- 200927761 85 90 95

Tyr Tyr Gly Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140

O

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 〇

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220

<210> 17 <211> 220 <212〉 PRT 27- 200927761 <213〉現代人 <400> 17

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr He Asn Cys Lys Ser Ser Gin Asn Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Phe Cys Gin Gin 85 90 95

Tyr Tyr Gly Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 -28 - 200927761

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 18 <211〉 220 <212〉 PRT <213〉現代人〇 <400> 18

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Thr Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin -29- 200927761 35 40 45

Pro Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95

Tyr Tyr Ser lie Ser Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 -30- 200927761

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 19 <211> 220 <212〉 PRT <213〉現代人

<400〉 19

Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Asn 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45 〇

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Asp Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95 -31 - 200927761

Tyr Tyr Ser Thr Thr Trp Thr Phe Gly Pro Gly Thr Lys Val Glu He 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 20 <211> 220 <212〉 PRT <213〉現代人 -32- 200927761 <400> 20

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Asn 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45 ❹

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Asp Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95 〇

Tyr Tyr Ser Thr Thr Trp Thr Phe Gly Pro Gly Thr Lys Val Glu lie 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 -33- 200927761

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210〉 21 <211> 220 <212〉PRT <213〉現代人 <400> 21

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45 -34- 200927761

Pro Pro Lys Val Leu lie Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Gly Leu Gin Ala Glu Asp Val Ala Leu Tyr Tyr Cys Gin Gin 85 90 95 0

Tyr Tyr Ser Thr Met Phe Ser Phe Gly Gin Gly Thr Lys Leu Glu He 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 -35- 200927761

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 22 <211> 220 <212> PRT <213>現代人 <400〉 22

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr He Asn Cys Lys Ser Ser Gin Ser Val Leu Asp Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Phe Tyr Cys His Gin 85 90 95 -36- 200927761

Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Ala lie 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 〇 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210〉 23 <211〉 220 <212> PRT <213〉現代人 -37- 200927761 <400〉 23

Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser lie Leu Tyr Arg 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu He Tyr Trp Ala Ser Ala Arg Glu Ser Gly Val 50 55 60

Tyr Phe lie Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu lie 100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe He Phe Pro Pro Ser Asp 115 120 125

Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 38- 200927761

Phe Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu 145 150 155 160

Gin Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp 165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser 195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210〉 24 <211〉 214 <212> PRT <213〉現代人 <400〉 24 〇

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp lie Ser His Tyr 20 25 30

Leu Ala Trp Phe Gin Gin Lys Pro Gly Lys Ala Pro Lys Ser Leu lie 35 40 45 -39- 200927761

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Asn Tyr Pro Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp He Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser -40- 200927761 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 25 <211> 214 <212> PRT <213〉現代人 <400〉 25

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Ala lie Thr Cys Arg Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30

Leu Ala Trp Leu Gin Gin Lys Pro Gly Lys Ala Pro Lys Ser Leu He 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Thr Tyr Pro Phe 85 90 95 -41 200927761

Thr Phe Gly Pro Gly Thr Lys Met Asp lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 26 <211> 215 <212> PRT <213〉現代人 <400〉 26 42- 200927761

Glu lie Val Met Thr Gin Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Asn 20 25 30

Leu Ala Trp Tyr Gin Gin Asp Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45 o

Tyr Gly Ala Ser Arg Arg Ala Thr Gly lie Pro Ala Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr He Ser Ser Leu Gin Ser 65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin His Asn Asn Trp Pro Pro 85 90 95

Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 〇 100 105 110

Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser 115 120 125

Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140

Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser -43- 200927761 145 150 155 160

Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190

Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 195 200 205

Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 27 <211> 214 <212〉 PRT <213>現代人 <400> 27

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp lie Ser Arg Trp 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 -44- 200927761

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Ser Phe Pro Pro 85 90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Phe Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 -45- 200927761

Phe Asn Arg Gly Glu Cys 210 <210〉 28 <211> 214 <212〉 PRT <213>現代人 <400〉 28

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser lie Ser Thr Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Phe Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Ala Tyr Tyr Cys Gin Gin Ser His Ser Ala Pro Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp He Lys Arg Thr Val Ala Ala -46- 200927761 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160 〇

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 ❹

Phe Asn Arg Gly Glu Cys 210 <210〉 29 <211> 213 <212〉 PRT <213>現代人 <400> 29 47- 200927761

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Thr lie Ser lie Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Ser Thr Leu Thr 85 90 95

Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala Pro 100 105 110

Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly Thr 115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140

Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin Glu 145 150 155 160 -48 - 200927761

Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190

Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205

Asn Arg Gly Glu Cys 210 <210> 30 <211> 214 <212> PRT <213〉現代人 <400> 30

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 〇 1 5 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Arg Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Arg Pro Gly Asn Ala Pro Lys Leu Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Val Ser Gly -49- 200927761 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Arg Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Ser He Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 -50- 200927761

Phe Asn Arg Gly Glu Cys 210 <210> 31 <211> 214 <212> PRT <213〉現代人 <400〉 31

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Arg Ser Ala Ser Val Gly

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Thr lie Ser Arg Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45

Tyr Ala Ala Ser Thr Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 ❹

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Leu Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin lie Tyr Ser Thr Ser He 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110 -51 - 200927761

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 32 <211> 214 <212> PRT <213〉現代人 <400〉 32

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly -52- 200927761 5 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Arg lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu lie 35 40 45

Tyr Ala Glu Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 〇

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr lie Thr Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie He Arg Thr Val Ala Ala 100 105 110 〇

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160 -53 - 200927761

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210> 33 <211〉 214 <212> PRT <213〉現代人 <400〉 33

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser lie Ser Arg Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 -54- 200927761

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asn Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Phe Thr Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu He Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 -55- 200927761

Phe Asn Arg Gly Glu Cys 210 <210> 34 <211> 214 <212〉PRT <213〉現代人 <400〉 34

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Phe Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Phe Ser Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110 -56- 200927761

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 〇 210 <210> 35 <211> 433 <212> PRT <213〉現代人 <400〉 35

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 -57- 200927761

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Leu Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gin Gin Ser Phe Tyr Thr Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu He Lys Ala Ser Thr Lys Gly 100 105 110

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 115 120 125

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 130 135 140

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 145 150 155 160 58- 200927761

Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 165 170 175

Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val 180 185 190

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys 195 200 205

Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 210 215 220

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser 225 230 235 240

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 245 250 255

Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 260 265 270 〇

Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val 275 280 285

Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu 290 295 300

Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys 305 310 315 320 -59- 200927761

Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 325 330 335

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 340 345 350

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 355 360 365

Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu 370 375 380

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 385 390 395 400

Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 405 410 415

Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 420 425 430

Lys <210〉 36 <211> 214 <212> PRT <213〉現代人 -60- 200927761 <400〉 36

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser He Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

O

Tyr Thr Val Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Phe Thr Pro He 85 90 95 〇

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 -61 - 200927761

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 37 <211〉 214 <212〉 PRT <213〉現代人 <400〉 37

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 -62- 200927761

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gin'Gin Ser Phe Tyr Ala Pro He 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 -63- 200927761

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210> 38 <211> 214 <212〉 PRT <213〉現代人 <400> 38

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val PraSer Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Phe Thr Pro lie 85 90 95 -64- 200927761

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 〇 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 39 <211〉 214 <212> PRT <213〉現代人 65- 200927761 <400〉 39

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Tyr Leu Pro Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 66- 200927761

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉40 <211> 214 <212> PRT <213〉現代人 <400〉 40 〇

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp He Ser Asn Ser 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Glu Leu Leu lie 35 40 45 -67- 200927761

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Cys Asp Asp Leu Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser -68 - 200927761 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉41 <211〉 214 <212〉 PRT <213>現代人 <400> 41

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asp Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin His Tyr Asp Asn Leu Pro Leu 85 90 95 -69 200927761

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210> 42 <211〉 214 <212〉 PRT <213〉現代人 <400> 42 70- 200927761

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Ala lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp He Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Asn Leu Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala Ala © 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin -71 - 200927761 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 43 <211> 214 <212〉 PRT <213>現代人 <400〉 43

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Ser 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 -72- 200927761

Tyr Asp Ala Ser lie Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Glu Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Cys Asp He Leu Pro Leu 85 90 95 o

Ser Phe Gly Gly Gly Thr Lys Val Glu He Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 -73- 200927761

Phe Asn Arg Gly Glu Cys 210 <210〉 44 <211〉 214 <212〉 PRT <213>現代人 <400> 44

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp He Ser Asn Ser 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Asn Leu Pro Leu 85 90 95

Ala Phe Gly Gly Gly Thr Lys Val Glu lie Arg Arg Thr Val Ala Ala -74- 200927761 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 〇

Phe Asn Arg Gly Glu Cys 210 <210〉45 <211> 214 <212> PRT <213>現代人 <400> 45 200927761

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Gly Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Ser Leu Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160 -76- 200927761

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210> 46 <211〉 214 <212> PRT <213〉現代人 <400> 46

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 〇 1 5 10 15

Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Leu Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

His Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly -77- 200927761 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Asn Leu Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 -78 - 200927761

Phe Asn Arg Gly Glu Cys 210 <210〉47 <211> 214 <212〉PRT <213〉現代人 <400〉47

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asp Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 o

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp He Ala Thr Tyr Tyr Cys Gin His Tyr Asp Asn Leu Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110 -79- 200927761

Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210> 48 <211〉 214 <212〉 PRT <213〉現代人 <400〉 48

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly -80- 200927761 15 10

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Ser 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 ❹

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin His Tyr Asp Asn Leu Pro He 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys Arg Thr Val Ala Ala 100 105 110 〇

Pro Ser Val Phe He Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140

Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160 -81 - 200927761

Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190

Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys 210 <210〉 49 <211> 446 <212> PRT <213〉現代人 <400> 49

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30

Gly lie Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Trp He Ser Ala Ser Asn Gly Asn Thr Asn Tyr Ala Gin Lys Leu 50 55 60 -82- 200927761

Gin Asp Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Glu Asp Asn Trp Asn Tyr Gly Phe Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 -83- 200927761

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val 210 215 220

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro 245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270

Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285

Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val 290 295 300

Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser 325 330 335

Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 340 345 350

Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 355 360 365 -84- 200927761

Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly 370 375 380

Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415

Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430

Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 50 <211> 443 <212> PRT <213>現代人 ❿ <400〉 50

Gin Val His Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Gly His 20 25 30

Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met -85- 200927761 35 40 45

Gly Trp lie Asn Pro Asn Ser Gly Gly Thr Asn Cys Ala Gin Lys Phe 50 55 60

Gin Gly Arg Val Thr Met Thr Arg Asp Thr Ser lie Ser Thr Ala Tyr 65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser lie Ala Val Ala Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser 165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn 180 185 190 -86- 200927761

Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205

Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro 210 215 220

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr 245 250 255

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Asn 260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285

Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val © 290 295 300

Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320

Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr He Ser Lys Thr Lys 325 330 335

Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu -87- 200927761 340 345 350

Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365

Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe 385 390 395 400

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly 405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430

Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210> 51 <211〉 443 <212> PRT <213〉現代人 <400〉 51

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15 -88 200927761

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30

Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Trp He Asn Pro Asn Ser Gly Gly Thr Asn His Thr Gin Lys Phe 50 55 60

Gin Gly Arg Val Thr Met Thr Arg Asp Thr Ser lie Ser Thr Ala Tyr 65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser lie Ala Val Ala Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 〇

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser 165 170 175 -89- 200927761

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn 180 185 190

Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205

Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro 210 215 220

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr 245 250 255

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Asn 260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285

Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val 290 295 300

Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 90- 200927761

Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr He Ser Lys Thr Lys 325 330 335

Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu 340 345 350

Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365

Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe 385 390 395 400

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly 405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 〇

Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210> 52 <211〉 448 <212〉 PRT <213〉現代人 <400〉 52 -91 - 200927761

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Arg Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu 20 25 30

Ser Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly Ser Phe Asp Pro Glu Asp Gly Glu Thr lie Tyr Ala Gin Lys Phe 50 55 60

Gin Gly Arg Val Thr Met Leu Glu Asp Thr Ser Thr Asp Thr Ala Tyr 65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Thr Glu Gly Asp Gly Gly Tyr Tyr Tyr Tyr Gly Met Asp Val Trp 100 105 110 〇

Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125

Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr -92- 200927761 145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175

Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190

Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp 195 200 205 〇

His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys 210 215 220

Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser 225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg 245 250 255 〇

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270

Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285

Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val 290 295 300 -93 - 200927761

Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr 325 330 335 lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser 370 375 380

Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp 385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415

Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430

Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 53 -94- 200927761 <211〉 448 <212〉 PRT <213〉現代人 <400〉 53

Gin Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Ala 20 25 30

O

Arg Met Gly Val Ser Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala His He Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Ser Lys Asp Thr Ser Lys Ser Gin Val 65 70 75 SO

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala Arg Met Tyr Ser Ser Gly Trp Tyr Gly Val Phe Asp Tyr Trp 100 105 110

Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 -95- 200927761

Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175

Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190

Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp 195 200 205

His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys 210 215 220

Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser 225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg 245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270

Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 -96- 200927761

Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val 290 295 300

Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr 325 330 335 o

He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser 370 375 380

Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp 385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415

Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 -97- 200927761

Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 54 <211> 449 <212> PRT <213〉現代人 <400> 54

Gin Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 15 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Ala 20 25 30

Arg Met Gly Val Ser Trp He Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Val Leu lie Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Ser Lys Asp Thr Ser Lys Ser Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala Arg Val Tyr Ser Ser Gly Trp Ser Phe Tyr Gly Met Asp Val 100 105 110 -98- 200927761

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175

Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190

Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val 195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys 〇 210 215 220

Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp -99- 200927761 260 265 270

Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val 290 295 300

Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys 325 330 335

Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380

Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu 385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 -100 200927761

Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430

Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445

Lys

<210〉 55 <211> 444 <212〉 PRT <213〉現代人 <400> 55

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30 〇

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu He Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Asn Gin Val 65 70 75 80 -101 - 200927761

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Arg Glu Leu Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220 102- 200927761

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320

Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr He Ser Lys Thr 325 330 335 〇

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380 -103- 200927761

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210〉 56 <211> 444 <212〉 PRT <213〉現代人 <400> 56

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu He Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser -104- 200927761 50 55 60

Leu Lys Ser Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Thr Gin Val 65 70 75 80

Val Leu Thr Val Thr Asp Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Asn Trp Thr Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

O

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 〇

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 -105- 200927761

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320

Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser Lys Thr 325 330 335

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly -106- 200927761 355 360 365

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415 〇

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440

<210〉 57 <211> 444 <212〉 PRT 〇 <213〉現代人 <400〉 57

Gin He Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Asn Thr Gly 20 25 30 -107- 200927761

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu He Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr He Thr Lys Asp Thr Ser Lys Asn Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Leu Glu Leu Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 -108- 200927761

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320

Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr He Ser Lys Thr 325 330 335 -109- 200927761

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210> 58 <211〉 444 <212> PRT <213〉現代人 <400〉 58

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15 -110- 200927761

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30

Gly Val Gly Val Gly Trp He Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu lie Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr He Thr Lys Asp Thr Ser Lys Asn Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Leu Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Arg Glu Val Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro © 115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin -111 - 200927761 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 -112- 200927761

Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Thr 325 330 335

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Q 420 425 430

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210> 59 <211〉 444 <212〉 PRT <213〉現代人 -113 - 200927761 <400> 59

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu lie Tyr Trp Asn Val Glu Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Arg Ser Arg Leu Thr He Thr Lys Ala Thr Ser Lys Asn Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 o

Cys Ala His Arg His Thr Asn Pro Phe Glu Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140 114- 200927761

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255 〇

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300 -115- 200927761

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320

Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser Lys Thr 325 330 335

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 116- 200927761 <210> 60 <211〉 444 <212〉 PRT <213〉現代人 <400〉60

Gin He Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu lie Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr He Thr Lys Asp Thr Ser Lys Asn Gin Val 65 70 75 80 〇

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Gly Glu Leu Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 -117- 200927761

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr Pro Glu Val 245 250 255

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro -118- 200927761 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320

Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Thr 325 330 335

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380 o

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 -119- 200927761

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210〉 61 <211〉 447 <212> PRT <213〉現代人 <400〉61

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Ser Arg Tyr 20 25 30

Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ala lie Ser Ser Ser Ser Ser Tyr lie Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Val Gly Ala Thr Pro Asp Ala Phe Asp lie Trp Gly 100 105 110 -120- 200927761

Gin Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175

Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190

Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His 195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255 121- 200927761

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr He 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 -122- 200927761

Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

<210〉 62 <211> 454 <212〉PRT <213〉現代人 <400> 62

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 〇 35 40 45

Ser Ala lie Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys -123 - 200927761 85 90 95

Ala Lys Glu Gly lie Ala Val Ala Gly Thr Ala Glu Tyr Tyr Tyr Tyr 100 105 110

Tyr Ala Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 130 135 140

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 145 150 155 160

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 165 170 175

Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 180 185 190

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr 195 200 205

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 210 215 220

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 225 230 235 240 -124- 200927761

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255

Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270

Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 275 280 285

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 290 295 300

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp 305 310 315 320

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 325 330 335

Ala Pro lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu © 340 345 350

Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365

Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He 370 375 380

Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr -125- 200927761 385 390 395 400

Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415

Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys 420 425 430

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 435 440 445 〇

Ser Leu Ser Pro Gly Lys 450 <210> 63 <211〉451 <212〉 PRT <213>現代人 <400〉 63

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 -126- 200927761

Ser Ala lie Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Glu Gly lie Ala Ala Arg Asp Ser Tyr Tyr Tyr Tyr Ala Met 100 105 110

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175

Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190

Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys 195 200 205 -127- 200927761

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220

Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270

Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe 290 295 300

Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly 305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie 325 330 335

Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 128- 200927761

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu 370 375 380

Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415

Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445

Pro Gly Lys 450 〇 <210〉 64 <211> 451 <212〉 PRT <213〉現代人 <400〉 64

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 -129- 200927761

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ala lie Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Glu Tyr Tyr Cys 85 90 95

Ala Lys Glu Gly lie Ala Gly Arg Asp Ser Tyr Tyr Tyr Tyr Gly Met 100 105 110

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His -130- 200927761 ί ( 165 170 175

Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190

Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys 195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220 c

Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255

He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 〇

Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe 290 295 300

Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly 305 310 315 320 -131 - 200927761

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro He 325 330 335

Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu 370 375 380

Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415

Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445

Pro Gly Lys 450 <210〉 65 -132- 200927761 <211> 449 <212> PRT <213>現代人 <400〉 65

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Phe lie Ser Asp Asp Gly Ser Thr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Met Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Gly Phe Asp Tyr 100 105 110

Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 -133- 200927761

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175

Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190

Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val 195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys 210 215 220

Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270

Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 -134- 200927761

Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val 290 295 300

Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys 325 330 335

Thr He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu 370 375 380

Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu 385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415

Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 -135 - 200927761

Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445

Lys <210> 66 <211〉 440 <212〉PRT <213>現代人 <400〉 66

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -136- 200927761

Ala Arg Asn Val lie Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 100 105 110

Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys 115 120 125

Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140

Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160

Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu 165 170 175

Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr 180 185 190

Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Q 195 200 205

Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro 210 215 220

Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 225 230 235 240

Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val -137- 200927761 245 250 255

Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val 260 265 270

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin 275 280 285

Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin 290 295 300

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly 305 310 315 320

Leu Pro Ala Pro He Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro 325 330 335

Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 340 345 350

Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365

Asp He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr 370 375 380

Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 385 390 395 400 -138 200927761

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe 405 410 415

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys 420 425 430

Ser Leu Ser Leu Ser Pro Gly Lys 435 440

<210〉 67 <211〉 446 <212〉 PRT <213>現代人 <400〉 67

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 〇

Asp Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val He Trp Tyr Asp Gly Ser He Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 -139- 200927761

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Gly Gly Ala Thr Gly Ala Glu Tyr Phe Gin His Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val 210 215 220 140- 200927761

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro 245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270

Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285

Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val 290 295 300

Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser 325 330 335 ❹

Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 340 345 350

Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 355 360 365

Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 -141 - 200927761

Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415

Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430

Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 68 <211〉 444 <212> PRT <213〉現代人 <400〉 68

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15 〇

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val He Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val -142- 200927761 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Val Leu Leu Trp Phe Gly Glu Thr Phe Asp Tyr Trp Gly Gin Gly Ser 100 105 110 〇

Leu Val Thr Val Ser Pro Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 -143 - 200927761

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320

Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr He Ser Lys Thr 325 330 335

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly -144- 200927761 355 360 365

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415 〇

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440

<210> 69 <211〉 441 <212> PRT Q <213>現代人 <400> 69

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 -145 - 200927761

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Ser Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asn Leu Pro Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 100 105 110

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125

Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val 130 135 140

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly 165 170 175

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly 180 185 190 -146- 200927761

Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys 195 200 205

Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 210 215 220

Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 225 230 235 240

Pro Lys Asp Thr Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255

Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr 260 265 270

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285

Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His 290 295 300

Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 305 310 315 320

Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser Lys Thr Lys Gly Gin 325 330 335 -147- 200927761

Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350

Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365

Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn 370 375 380

Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 385 390 395 400

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val 405 410 415

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin 420 425 430

Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210〉 70 <211> 449 <212> PRT <213〉現代人 <400> 70

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15 -148 - 200927761

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Asp Asp Gly Ser Asn Gin Tyr Tyr Thr Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser His Tyr Gly Gly Asp Tyr Asp Tyr Tyr Gly Met Asp Val 100 105 110

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Q 115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe -149- 200927761 165 170 175

Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190

Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val 195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys 210 215 220

Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser 245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270

Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val 290 295 300

Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 -150- 200927761

Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys 325 330 335

Thr He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu 370 375 380

Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu 385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415

Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Q 420 425 430

Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445

Lys <210〉 71 -151 - 200927761 <211〉446 <212〉PRT <213>現代人 <400〉 71

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Tyr Asp Gly Ser Asn Lys Arg Tyr Val Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Gly Trp Gin Gin Gin Ala Pro Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 152- 200927761

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val 210 215 220

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro 245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270

Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 -153- 200927761

Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val 290 295 300

Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser 325 330 335

Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 340 345 350

Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 355 360 365

Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser Asn Gly 370 375 380

Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415

Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 -154- 200927761

Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 72 <211> 444 <212> PRT <213〉現代人 <400〉 72

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15 ❹

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Ala Asp Ser Val 50 55 60 ❹

Arg Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Asp 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Trp Gly lie Ser Ala Pro Phe Asp Cys Trp Gly Gin Gly Thr 100 105 110 -155 - 200927761

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe -156- 200927761 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320

O

Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Thr 325 330 335

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 ❹

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415 -157- 200927761

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210> 73 <211> 441 <212〉 PRT <213〉現代人 <400〉 73

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr 20 25 30

Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Tyr lie Ser Ser Ser Gly Arg Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 -158- 200927761

Ala Leu Trp Ala Pro Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 100 105 110

Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125

Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val 130 135 140

Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala 145 150 155 160

Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly 165 170 175

Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly 180 185 190

Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys 195 200 205

Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys 210 215 220

Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 225 230 235 240 -159- 200927761

Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255

Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr 260 265 270

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285

Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His 290 295 300

Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 305 310 315 320

Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser Lys Thr Lys Gly Gin 325 330 335

Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350

Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365

Ser Asp He Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn 370 375 380

Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu 385 390 395 400 -160- 200927761

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val 405 410 415

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin 420 425 430

Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440

<210〉74 <211〉 451 <212〉 PRT <213〉現代人 <400> 74

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 〇 20 25 30

Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser His lie Ser Ser Ser Ser Arg Thr He Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Val Tyr -161 - 200927761 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Gly Tyr Asn Trp Asn Gly Gly Gly Asn Tyr Tyr Gly Met 100 105 110

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175

Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190

Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys 195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220 162- 200927761

Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 o

Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe 290 295 300

Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly 305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro He 〇 325 330 335

Glu Lys Thr He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu -163- 200927761 370 375 380

Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415

Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445

Pro Gly Lys 450 <210> 75 <211> 451 <212〉 PRT <213>現代人 <400〉 75

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 -164- 200927761

Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser His He Ser Arg Ser Ser Arg Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys

Ala Arg Asp Gly Tyr Asn Trp Asn Asn Gly Gly Tyr Tyr Tyr Gly Met 100 105 110

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 〇

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175

Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 -165- 200927761

Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys 195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220

Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255

He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270

Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe 290 295 300

Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly 305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie 325 330 335 -166 t 200927761

Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg'Glu Pro Gin Val 340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu 370 375 380

Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415

Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445 〇

Pro Gly Lys 450 <210> 76 <211〉444 <212> PRT <213〉現代人 <400> 76 -167- 200927761

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr lie His Ser Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr He Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Gly Pro Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr 100 105 110

Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn -168- 200927761 145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin 165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190

Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 ❹

Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 210 215 220

Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255 o

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe 260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285

Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 290 295 300 -169- 200927761

Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320

Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser Lys Thr 325 330 335

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350

Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365

Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro 370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 385 390 395 400

Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430

Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210〉 77 -170- 200927761 <211〉 453 <212> PRT <213〉現代人 <400〉 77

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Arg Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr He Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Asn Met Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Ala Leu Arg Gly lie Val Leu Met Val Tyr Val Leu Gly 100 105 110

Ala Leu Asp lie Trp Gly Gin Gly Thr Lys Val Thr Val Ser Ser Ala 115 120 125 -171 - 200927761

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 130 135 140

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 145 150 155 160

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175

Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu 180 185 190

Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr 195 200 205

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr 210 215 220

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro 225 230 235 240

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255

Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270

Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val 275 280 285 -172- 200927761

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser 290 295 300

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu 305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala 325 330 335

Pro He Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro 340 345 350

Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin 355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala 370 375 380

Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415

Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser 420 425 430 -173 - 200927761

Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser 435 440 445

Leu Ser Pro Gly Lys 450 <210〉 78 <211> 453 <212〉 PRT <213〉現代人 <400> 78

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp lie Gly Tyr He Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 174- 200927761

Cys Ala Arg Asp Glu Thr Val Val Arg Gly Leu lie Arg Tyr Cys Tyr 100 105 110

Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 130 135 140

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 145 150 155 160

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175

Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu 180 185 190

Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr 〇 195 200 205

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr 210 215 220

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro 225 230 235 240

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr -175 - 200927761 245 250 255

Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270

Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val 275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser 290 295 300

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu 305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala 325 330 335

Pro He Glu Lys Thr He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro 340 345 350

Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin 355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala 370 375 380

Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400 -176- ( 200927761

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415

Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser 420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser 435 440 445

Leu Ser Pro Gly Lys 450 <210〉 79 <211〉448 <212> PRT <213〉現代人 <400> 79

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Asn Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp lie Gly Tyr lie His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 -177- 200927761

Leu Lys Ser Arg He Thr lie Ser Ala Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Asp Arg Gly Gly Gly Asp Tyr Gly Arg Met Asp Val Trp 100 105 110

Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125

Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175

Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190

Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp 195 200 205 -178- 200927761

His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys 210 215 220

Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser 225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270

Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285

Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val 290 295 300

Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr 325 330 335

He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 355 360 365 -179- 200927761

Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser 370 375 380

Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp 385 390 395 400

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415

Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430

Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 80 <211> 448 <212〉 PRT <213〉現代人 <400〉80

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Asn Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu -180- 200927761 35 40 45

Trp lie Gly Tyr lie His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg lie Thr lie Ser Ala Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

O

Cys Ala Arg Asp Arg Gly Gly Gly Asp Tyr Gly Arg Met Asp Val Trp 100 105 110

Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125

Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 〇

Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160

Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175

Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 -181 - 200927761

Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp 195 200 205

His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys 210 215 220

Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser 225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270

Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285

Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val 290 295 300

Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320

Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr 325 330 335

He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu -182- 200927761 340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys 355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser 370 375 380

Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp 385 390 395 400

O

Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415

Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430

Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 〇 <210> 81 <211〉445 <212> PRT <213〉現代人 <400〉 81

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15 -183 200927761

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser He Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr lie His Ser Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg lie Thr Lys Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Ser Asn Asn Tyr Gly Cys Phe Ala Leu Trp Gly Arg Gly 100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125

Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 -184- 200927761

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205

Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu 210 215 220 〇

Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu 245 250 255

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin 260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285

Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300

Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 -185- 200927761

Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr He Ser Lys 325 330 335

Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350

Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 355 360 365

Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin 370 375 380

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 405 410 415

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 82 <211> 445 <212> PRT <213〉現代人 <400〉 82 -186- 200927761

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser He Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp lie Gly Tyr lie His Ser Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg lie Thr Lys Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Ser Asn Asn Tyr Gly Cys Phe Ala Leu Trp Gly Arg Gly 〇 100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125

Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp -187- 200927761 145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175

Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190

Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205

Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu 210 215 220

Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu 245 250 255

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin 260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285

Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 188- 200927761

Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320

Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr He Ser Lys 325 330 335 .

Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350

Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 355 360 365

Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser Asn Gly Gin 370 375 380

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Q 405 410 415

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 83 -189- 200927761 <211> 459 <212〉PRT <213〉現代人 <400〉83

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr He His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr He Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Ser Gly Tyr Asn Tyr Gly Leu Tyr Tyr Tyr Asp Ser Ser Gly 100 105 110

Tyr Pro Ser Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr 115 120 125 -190- 200927761

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 130 135 140

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 145 150 155 160

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 165 170 175

o

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gin Ser 180 185 190

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn 195 200 205

Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 210 215 220

Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro 225 230 235 240

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro 245 250 255

Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr 260 265 270

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gin Phe Asn 275 280 285 -191 - 200927761

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 290 295 300

Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val 305 310 315 320

Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 325 330 335

Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser Lys Thr Lys 340 345 350

Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu 355 360 365

Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe 370 375 380

Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu 385 390 395 400

Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe 405 410 415

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly 420 425 430 -192- 200927761

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 435 440 445

Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 84 <211〉 451 <212〉 PRT <213〉現代人

<400〉 84

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Asp Tyr Tyr Trp Asn Trp Val Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45 〇

Trp lie Gly Tyr He Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Phe Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe 85 90 95 -193 - 200927761

Cys Ala Arg Thr Tyr Tyr Asp He Leu Thr Gly Tyr Pro Phe Tyr Phe 100 105 110

Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175

Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190

Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys 195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220

Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met -194- 200927761 245 250 255

He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270

Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe 290 295 300 ❾

Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly 305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie 325 330 335

Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 〇

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu 370 375 380

Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 -195 - 200927761

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415

Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445

Pro Gly Lys 450 <210〉 85 <211> 451 <212> PRT <213〉現代人 <400〉 85

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Asp Tyr Tyr Trp Asn Trp Val Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp lie Gly Tyr lie Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser 50 55 60 -196- 200927761

Leu Lys Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Phe Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe 85 90 95

Cys Ala Arg Thr Tyr Tyr Asp lie Leu Thr Gly Tyr Pro Phe Tyr Phe 100 105 110

Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175

Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190

Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys 195 200 205 -197- 200927761

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220

Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255

He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270

Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe 290 295 300

Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly 305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie 325 330 335

Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365 -198- 200927761

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu 370 375 380

Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415

O

Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445

Pro Gly Lys 450 <210> 86 <211> 446 <212> PRT <213〉現代人 <400> 86

Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr -199- 200927761 20 25 30

Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 35 40 45

Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60

Ser Arg Val Thr He Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95

Arg Gly Gly Tyr Ser Ser Ser Trp Tyr Trp Phe Asp Pro Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 200 200927761

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val 210 215 220

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro 245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270

Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285

Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val 290 295 300

Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser · -201 - 200927761 325 330 335

Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 340 345 350

Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 355 360 365

Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly 370 375 380

Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415

Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430

Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 87 <211> 446 <212〉 PRT <213〉現代人 <400〉 87 -202- 200927761

Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30

Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp He 35 40 45

Gly Glu He Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60

Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95

Arg Gly Gly Tyr Ser Ser Ser Trp Phe Trp Phe Asp Pro Trp Gly Gin 100 105 110 〇

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 -203 - 200927761

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val 210 215 220

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro 245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270

Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285

Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val 290 295 300 -204- 200927761

Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser 325 330 335

Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 340 345 350

Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 355 360 365

Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn Gly 370 375 380

Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 ❹

Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430

Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 88 <211〉 449 -205 - 200927761 <212〉 PRT <213〉現代人 <400〉 88

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser He Ser Ser Tyr 20 25 30

Tyr Trp Ser Trp lie Arg Gin Pro Ala Gly Lys Gly Leu Glu Trp lie 35 40 45

Gly Arg He Tyr Thr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60

Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95

Arg Asp Gly Tyr Ser Tyr Gly His Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser -206- 200927761 130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175

Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 〇

Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val 195 200 205

Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys 210 215 220

Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 225 230 235 240

Q

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser 245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270

Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 -207- 200927761

Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val 290 295 300

Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu 305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys 325 330 335

Thr He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr 340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr 355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu 370 375 380

Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu 385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415

Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430

Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly -208- 200927761 435 440 445

Lys <210〉 89 <211> 452 <212> PRT <213>現代人 <400〉 89

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30

Gly Ser Tyr Trp Ser Trp He Arg Gin Pro Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr He Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr He Ser He Val Thr Ser Arg Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 -209- 200927761

Cys Ala Arg Ser Ala Leu Arg Tyr Phe Asp Trp Leu Phe Ser Asp Val 100 105 110

Ser Asp lie Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser Ala Ser 115 120 125

Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr 130 135 140

Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 145 150 155 160

Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 165 170 175

His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser 180 185 190

Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr 195 200 205

Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val 210 215 220

Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val 225 230 235 240

Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 -210- 200927761

Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270

His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr 290 295 300

Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn 305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro 325 330 335 lie Glu Lys Thr He Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin 340 345 350

Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val 355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val 370 375 380

Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 -211 - 200927761

Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415

Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val 420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu 435 440 445

Ser Pro Gly Lys 450 <210〉 90 <211〉 446 <212〉 PRT <213>現代人 <400〉 90

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Leu Lys Lys Pro Gly Glu 15 10 15

Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr 20 25 30

Trp He Gly Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly lie lie Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 -212- 200927761

Gin Gly Gin Val Thr He Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80

Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95

Ala Arg Gin Lys Ser Tyr Gly Tyr Ser Tyr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175

Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190

Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val -213- 200927761 210 215 220

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro 245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270

Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285

Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser Val 290 295 300

Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie Ser 325 330 335

Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro 340 345 350

Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val 355 360 365 -214- 200927761

Lys Gly Phe Tyr Pro Ser Asp He Ala Val Glu Trp Glu Ser Asn Gly 370 375 380

Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415

Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430

Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 91 <211〉 447 <212> PRT <213〉現代人 ❹ <400〉 91

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15

Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30

Trp lie Gly Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 -215- 200927761

Gly lie lie Tyr Pro Asp Asp Ser Asp Ala Arg Tyr Ser Pro Ser Phe 50 55 60

Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Asn Thr Ala Tyr 65 70 75 80

Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95

Ala Arg Gin Gly Tyr Gly Ser Gly Trp Gly Tyr Phe Asp Tyr Trp Gly 100 105 110

Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125

Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175

Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 -216- 200927761

Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn Val Asp His 195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220

Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270

Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285

Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 295 300 ❹

Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350 -217- 200927761

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp Glu Ser Asn 370 375 380

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415

Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210〉 92 <211> 453 <212〉 PRT <213〉現代人 <400〉 92

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15

Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr -218- 200927761 20 25 30

Trp He Gly Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly lie lie Tyr Pro Gly Asp Ser Asp lie Arg Tyr Ser Pro Ser Phe 50 55 60

Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80 ❹

Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95

Ala Arg Gin Gly Leu Ala Val Ala Gly Thr Ser Tyr Tyr Tyr Tyr Tyr 100 105 110

Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala 115 120 125 ❹

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser 130 135 140

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 145 150 155 160

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175 -219- 200927761

Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu 180 185 190

Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr 195 200 205

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr 210 215 220

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro 225 230 235 240

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255

Leu Met He Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 260 265 270

Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val 275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser 290 295 300

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu 305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala -220- 200927761 325 330 335

Pro lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro 340 345 350

Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin 355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala 370 375 380 〇

Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415

Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser 420 425 430 0

Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser 435 440 445

Leu Ser Pro Gly Lys 450

<210> 93 <211〉 451 <212〉 PRT -221 - 200927761 <213〉現代人 <400> 93

Gin Val Gin Leu Gin Gin Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Ala He Ser Gly Asp Ser Val Ser Ser Tyr 20 25 30

Ser Ala Ala Trp Asn Trp lie Arg Gin Ser Pro Ser Arg Gly Leu Glu 35 40 45

Trp Leu Gly Arg Thr Tyr Cys Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60

Val Ser Val Lys Ser Arg He Thr lie Asn Pro Asp Thr Ser Lys Asn 65 70 75 80

Gin Phe Ser Leu Gin Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95

Tyr Tyr Cys Ala Arg Asp Arg Ala Val Ala Gly Tyr Tyr Tyr Gly Met 100 105 · 110

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 -222- 200927761

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175

Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190

Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys 195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 210 215 220

Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 225 230 235 240

Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 -223 - 200927761

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe 290 295 300

Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp Leu Asn Gly 305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro lie 325 330 335

Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu 370 375 380

Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400

Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415

Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445 -224- 200927761

Pro Gly Lys 450 <210> 94 <211> 112 <212〉 PRT <213〉現代人 <400〉 94

Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Val Tyr Ser 20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gin Gin Arg Pro Gly Gin Ser 35 40 45

Pro Arg Arg Leu He Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60

Asp Arg Phe Asn Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ser 85 90 95

Thr His Trp Pro lie Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys -225- 200927761 100 105 110 <210〉 95 <211〉 112 <212> PRT <213〉現代人 <400> 95

Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Val Tyr Ser 20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gin Gin Arg Pro Gly Gin Ser 35 40 45

Pro Arg Arg Leu lie Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys He 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys lie Gin Gly 85 90 95

Thr His Trp Pro Thr Thr Phe Gly Gin Gly Thr Arg Leu Glu He Lys 100 105 110 -226- 200927761 <210〉 96 <211> 112 <212〉 PRT <213〉現代人 <400> 96

Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Val Tyr Ser 20 25 30 〇

Asp Gly Asn Thr Tyr Leu Asn Trp Leu Gin Gin Arg Pro Gly Gin Ser 35 40 45

Pro Arg Arg Leu lie Tyr Lys Val Ser Asn Trp Asp Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80 V Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Gly 85 90 95

Thr His Trp Pro He Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 110

<210〉 97 <211> 112 <212〉 PRT -227- 200927761 <213〉現代人 <400> 97

Asp lie Val Met Thr Gin Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Lys Ser Ser Gin Ser Leu Leu His Ser 20 25 30

Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gin Lys Pro Gly Gin Pro 35 40 45

Pro Gin Leu Leu lie Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys He 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Gly 85 90 95 lie Gin Leu Pro Cys Ser Phe Gly Gin Gly Thr Lys Leu Glu He Lys 100 105 110 <210〉 98 <211> 112 <212> PRT <213〉現代人 <400〉 98 -228 - 200927761

Asp He Val Met Thr Gin Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Lys Ser Ser Gin Ser Leu Leu His Ser 20 25 30

Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gin Lys Pro Gly Gin Pro 35 40 45

Pro Gin Leu Leu He Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ser 85 90 95 lie Gin Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 110 <210〉 99 <211> 112 <212〉 PRT <213〉現代人 <400> 99

Asp He Val Met Thr Gin Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15 -229- 200927761

Gin Pro Ala Ser He Ser Cys Lys Ser Ser Gin Ser Leu Leu His Ser 20 25 30

Asp Gly Lys Thr Tyr Leu Tyr Trp Phe Leu Gin Lys Pro Gly Gin Pro 35 40 45

Pro Gin Pro Leu lie Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys He 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ser 85 90 95

He Gin Leu Pro lie Thr Phe Gly His Gly Thr Arg Leu Glu He Lys 100 105 110 <210> 100 <211> 107 <212〉 PRT <213〉現代人 <400〉 100

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ala Asn Tyr -230- 200927761 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu Leu lie 35 40 45

Tyr Val Ala Ser Thr Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 ❹

Glu Asp Val Ala Thr Tyr Tyr Cys Gin Asn Tyr Asn Ser Ala Pro Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105

<210> 101 <211> 107 <212> PRT <213>現代人 <400> 101

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie He Cys Arg Ala Ser Gin Gly He Ser Asn Asp 20 25 30 -231 - 200927761

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu Leu lie 35 40 45

Tyr Ala Ala Ser Thr Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gin Lys Tyr Asn Ser Val Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210〉 102 <211〉 112 <212〉 PRT <213>現代人 <400> 102

Asn He Val Met Thr Gin Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser He Ser Cys Arg Ser Ser Gin Ser Leu Val His Ser 20 25 30

Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gin Gin Arg Pro Gly Gin Pro 35 40 45 -232- 200927761

Pro Arg Leu Leu lie Tyr Lys lie Ser Asn Arg Phe Ser Gly Val Pro 50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys lie 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95

Thr Gin Phe Pro His Thr Phe Gly Pro Gly Thr Lys Val Asp He Lys 100 105 110 <210〉 103 <211〉 112 <212〉 PRT <213〉現代人 <400> 103

Glu lie Val Met Thr Gin Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Val His Ser 20 25 30

Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gin Gin Arg Pro Gly Gin Pro 35 40 45

Pro Arg Leu Leu He Tyr Lys He Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 -233 - 200927761

Asp Arg Phe Ser Gly Thr Gly Ala Gly Thr Asp Phe Thr Leu Lys He 65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gin Ala 85 90 95

Thr Gin Phe Pro His Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 110 <210> 104 <211〉 108 <212〉 PRT <213〉現代人 <400〉 104

Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Thr Val He Ser Ser 20 25 30

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Arg Leu Glu -234- 200927761 65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Pro 85 90 95

Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 100 105

<210〉 105 <211〉 106 <212> PRT <213〉現代人 <400〉 105

Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Arg Leu 20 25 30

Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie Tyr 35 40 45

Gly Ala Ser Arg Arg Ala Thr Gly lie Pro Asp Arg Phe Ser Gly Ser 50 55 60

Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Arg Leu Glu Pro Glu 65 70 75 80 -235 - 200927761

Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Gly Ser Ser Pro Arg Ser 85 90 95

Phe Gly Gin Gly Thr Lys Leu Glu lie Lys 100 105 <210> 106 <211> 107 <212> PRT <213>現代人 <400〉 106

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Gly lie Arg Asn Asp 20 25 30

Leu Gly Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu He 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gin His Asn Ser Tyr Pro Pro 85 90 95 -236 200927761

Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 100 105 <210〉 107 <211> 113 <212〉 PRT <213〉現代人 <400〉 107

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr He Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Val Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Phe lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 〇

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80

He Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95

Tyr Tyr Ser Phe Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110 -237 - 200927761

Lys <210〉 108 <211> 113 <212〉 PRT <213〉現代人 <400〉 108

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr He Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80

He Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95

Tyr Tyr Ser Thr Thr Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie -238 - 200927761 100 105 110

Lys <210> 109 <211〉 113 <212> PRT <213〉現代人 <400〉 109

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Asn Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu He Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Phe Cys Gin Gin 85 90 95 -239- 200927761

Tyr Tyr Gly Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110

Lys <210〉 110 <211> 113 <212> PRT <213〉現代人 <400〉 110

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Asn Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Phe Cys Gin Gin 85 90 95 -240- 200927761

Tyr Tyr Gly Thr Pro Arg Thr Phe Gly Gin Gly Thr Lys Val Glu lie 100 105 110

Lys <210〉 111 <211〉 113 <212> PRT <213〉現代人 €) <400> 111

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Thr Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr He Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45 〇

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80

He Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95 -241 - 200927761

Tyr Tyr Ser lie Ser Arg Thr Phe Gly Gin Gly Thr Lys Val Glu He 100 105 110

Lys <210〉 112 <211〉 113 <212〉PRT <213>現代人 <400〉 112

Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Asn 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 lie Ser Ser Leu Gin Ala Asp Asp Val Ala Val Tyr Tyr Cys Gin Gin -242- 200927761 85 90 95

Tyr Tyr Ser Thr Thr Trp Thr Phe Gly Pro Gly Thr Lys Val Glu lie 100 105 110

Lys

<210> 113 <211> 113 <212> PRT <213〉現代人 <400〉 113

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Asn 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 -243 - 200927761 lie Ser Ser Leu Gin Ala Asp Asp Val Ala Val Tyr Tyr Cys Gin Gin 85 90 95

Tyr Tyr Ser Thr Thr Trp Thr Phe Gly Pro Gly Thr Lys Val Glu lie 100 105 110

Lys <210〉 114 <211> 113 <212〉 PRT <213〉現代人 <400〉 114

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser Val Leu Tyr Ser 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Val Leu lie Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 -244- 200927761 lie Ser Gly Leu Gin Ala Glu Asp Val Ala Leu Tyr Tyr Cys Gin Gin 85 90 95

Tyr Tyr Ser Thr Met Phe Ser Phe Gly Gin Gly Thr Lys Leu Glu lie 100 105 110

Lys

<210> 115 <211〉 113 <212> PRT <213〉現代人 <400〉 115

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr He Asn Cys Lys Ser Ser Gin Ser Val Leu Asp Ser 20 25 30 〇

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 -245- 200927761 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Phe Tyr Cys His Gin 85 90 95

Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Ala He 100 105 110

Lys <210〉 116 <211> 113 <212〉 PRT <213>現代人 <400〉 116

Asp He Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys Lys Ser Ser Gin Ser lie Leu Tyr Arg 20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin 35 40 45

Pro Pro Lys Leu Leu lie Tyr Trp Ala Ser Ala Arg Glu Ser Gly Val 50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr -246- 200927761 65 70 75 80 lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Phe Cys Gin Gin 85 90 95

Tyr Phe lie Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu lie 100 105 110

Lys ❹ <210> 117 <211> 107 <212> PRT <213〉現代人 <400> 117

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Asp He Ser His Tyr 20 25 30

Leu Ala Trp Phe Gin Gin Lys Pro Gly Lys Ala Pro Lys Ser Leu He 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Lys Phe Ser Gly 50 55 60 247- 200927761

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Asn Tyr Pro Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105 <210〉 118 <211> 107 <212> PRT <213〉現代人 <400> 118

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Ala lie Thr Cys Arg Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30

Leu Ala Trp Leu Gin Gin Lys Pro Gly Lys Ala Pro Lys Ser Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 -248- 200927761

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Thr Tyr Pro Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Met Asp lie Lys 100 105 <210> 119 <211〉108 <212> PRT <213〉現代人

<400> 119

Glu He Val Met Thr Gin Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Asn 20 25 30

Leu Ala Trp Tyr Gin Gin Asp Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45 ❹

Tyr Gly Ala Ser Arg Arg Ala Thr Gly lie Pro Ala Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Ser 65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin His Asn Asn Trp Pro Pro 85 90 95 -249- 200927761

Trp Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 100 105 <210〉 120 <211> 107 <212> PRT <213>現代人 <400〉 120

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Val Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Asp lie Ser Arg Trp 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ala Asn Ser Phe Pro Pro 85 90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Phe Lys -250- 200927761 100 105 <210> 121 <211> 107 <212〉 PRT <213〉現代人 <400〉 121

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Ser Thr Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Phe Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Ala Tyr Tyr Cys Gin Gin Ser His Ser Ala Pro Phe 85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105 -251 - 200927761 <210〉 122 <211〉 106 <212> PRT <213>現代人 <400〉 122

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Thr lie Ser lie Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Ser Thr Leu Thr 85 90 95

Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105

<210> 123 <211> 107 <212〉 PRT -252- 200927761 <213〉現代人 <400> 123

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Arg Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Arg Pro Gly Asn Ala Pro Lys Leu Leu He 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Val Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Arg Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Ser He Pro Leu 85 90 95 〇

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210〉 124 <211> 107 <212> PRT <213〉現代人 <400〉 124 -253 - 200927761

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Arg Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Thr lie Ser Arg Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Ala Ala Ser Thr Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Leu Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin He Tyr Ser Thr Ser lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210> 125 <211> 107 <212〉 PRT <213>現代人 <400> 125

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 -254- 200927761

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Arg lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He 35 40 45

Tyr Ala Glu Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr lie Thr Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie He 100 105 <210〉 126 <211〉 107 <212〉 PRT <213〉現代人 <400〉 126

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser lie Ser Arg Tyr -255 - 200927761 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asn Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Phe Thr Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu He Lys 100 105 <210〉 127 <211> 107 <212〉PRT <213〉現代人 <400〉 127

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30 -256 200927761

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Phe Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Phe Ser Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210〉 128 <211> 107 <212〉PRT <213〉現代人 <400〉 128

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser He Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45 -257- 200927761

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Leu Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gin Gin Ser Phe Tyr Thr Pro He 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210> 129 <211〉 107 <212> PRT <213〉現代人 <400> 129

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Thr Val Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 -258- 200927761

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Phe Thr Pro He 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 U <210〉 130 <211> 107 <212> PRT <213〉現代人 <400〉 130

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Ser He Ser Ser Tyr

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro -259- 200927761 65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gin Gin Ser Phe Tyr Ala Pro lie • 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105

<210〉 131 <211〉 107 <212〉PRT <213〉現代人 <400> 131

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Arg Ala Ser Gin Ser lie Ser Ser Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Thr Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 -260 200927761

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Ser Tyr Phe Thr Pro He 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210〉 132 <211〉 107 <212〉PRT <213〉現代人

<400〉 132

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Tyr Leu Pro Phe 85 90 95 -261 - 200927761

Thr Phe Gly Pro Gly Thr Lys Val Asp lie Lys 100 105 <210〉 133 <211〉 107 <212〉 PRT <213〉現代人 <400〉 133

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Ser 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Glu Leu Leu He 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Cys Asp Asp Leu Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu He Lys 100 105 -262 200927761 <210> 134 <211〉 107 <212〉 PRT <213〉現代人 <400〉 134

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asp Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin His Tyr Asp Asn Leu Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210〉 135 -263 200927761 <211> 107 <212〉 PRT <213〉現代人 <400〉 135

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Ala lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Asn Leu Pro Leu 85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210> 136 <211〉 107 <212> PRT <213〉現代人 -264- 200927761 <400> 136

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Ser 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 ❹

Tyr Asp Ala Ser He Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Glu Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp He Ala Thr Tyr Tyr Cys Gin Gin Cys Asp He Leu Pro Leu 85 90 95

Ser Phe Gly Gly Gly Thr Lys Val Glu lie Lys 100 105 <210> 137 <211> 107 <212> PRT <213〉現代人 <400〉 137 -265 - 200927761

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp He Ser Asn Ser 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Asn Leu Pro Leu 85 90 95

Ala Phe Gly Gly Gly Thr Lys Val Glu lie Arg 100 105 <210> 138 <211〉 107 <212〉 PRT <213〉現代人 <400〉 138

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 -266- 200927761

Asp Gly Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Thr Asn Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp He Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Ser Leu Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210〉 139 <211〉 107 <212〉 PRT <213〉現代人 <400〉 139

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp He Ser Asn Tyr 20 25 30 -267- 200927761

Leu Asn Trp Tyr Gin Gin Lys Leu Gly Lys Ala Pro Lys Leu Leu lie 35 40 45

His Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr lie Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp He Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Asn Leu Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210〉 140 <211〉 107 <212〉 PRT <213〉現代人 <400> 140

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Gin Ala Ser Gin Asp lie Ser Asp Tyr 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie -268- 200927761 35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp lie Ala Thr Tyr Tyr Cys Gin His Tyr Asp Asn Leu Pro He 85 90 95 ❹

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210〉 141 <211> 107 <212> PRT <213>現代人 <400> 141

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asp lie Ser Asn Ser 20 25 30

Leu Asn Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu He 35 40 45 -269 - 200927761

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp He Ala Thr Tyr Tyr Cys Gin His Tyr Asp Asn Leu Pro lie 85 90 95

Thr Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 100 105 <210> 142 <211〉 120 <212〉PRT <213>現代人 <400〉 142

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30

Gly He Ser Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Trp lie Ser Ala Ser Asn Gly Asn Thr Asn Tyr Ala Gin Lys Leu 50 55 60 -270- 200927761

Gin Asp Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Glu Asp Asn Trp Asn Tyr Gly Phe Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 143 <211> 117 <212〉 PRT <213〉現代人 <400〉 143

Gin Val His Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Gly His 20 25 30

Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Trp He Asn Pro Asn Ser Gly Gly Thr Asn Cys Ala Gin Lys Phe 、50 55 60 -271 - 200927761

Gin Gly Arg Val Thr Met Thr Arg Asp Thr Ser He Ser Thr Ala Tyr 65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser He Ala Val Ala Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110

Val Thr Val Ser Ser 115 <210〉 144 <211> 117 <212〉 PRT <213〉現代人 <4〇〇> 144

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30

Tyr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met 35 40 45

Gly Trp He Asn Pro Asn Ser Gly Gly Thr Asn His Thr Gin Lys Phe -272- 200927761 50 55 60

Gin Gly Arg Val Thr Met Thr Arg Asp Thr Ser lie Ser Thr Ala Tyr 65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser lie Ala Val Ala Leu Asp Tyr Trp Gly Gin Gly Thr Leu 100 105 110 ❹

Val Thr Val Ser Ser 115 <210〉 145 <211> 122 <212> PRT <213>現代人 <400> 145

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Arg Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu 20 25 30

Ser Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 -273 - 200927761

Gly Ser Phe Asp Pro Glu Asp Gly Glu Thr lie Tyr Ala Gin Lys Phe 50 55 60

Gin Gly Arg Val Thr Met Leu Glu Asp Thr Ser Thr Asp Thr Ala Tyr 65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Thr Glu Gly Asp Gly Gly Tyr Tyr Tyr Tyr Gly Met Asp Val Trp 100 105 110

Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 <210〉 146 <211〉 122 <212〉 PRT <213〉現代人 <400> 146

Gin Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 15 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Ala 20 25 30

Arg Met Gly Val Ser Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45 274 200927761

Trp Leu Ala His lie Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Ser Lys Asp Thr Ser Lys Ser Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala Arg Met Tyr Ser Ser Gly Trp Tyr Gly Val Phe Asp Tyr Trp 100 105 110

Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210〉 147 <211> 123 <212> PRT <213〉現代人 <400〉 147

Gin Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 15 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Ala 20 25 30

Arg Met Gly Val Ser Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45 -275 - 200927761

Trp Leu Val Leu lie Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Ser Lys Asp Thr Ser Lys Ser Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala Arg Val Tyr Ser Ser Gly Trp Ser Phe Tyr Gly Met Asp Val 100 105 110

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 <210〉 148 <211> 118 <212> PRT <213〉現代人 <400〉 148

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30

Gly Val Gly Val Gly Trp He Arg Gin Pro Pro Gly Lys Ala Leu Glu -276- 200927761 35 40 45

Trp Leu Ala Leu lie Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Asn Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

O

Cys Ala His Arg Arg Glu Leu Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser 115

<210〉 149 <211> 118 <212〉 PRT <213〉現代人 <400> 149

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30 -277- 200927761

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu He Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Thr Gin Val 65 70 75 80

Val Leu Thr Val Thr Asp Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Asn Trp Thr Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser 115 <210〉 150 <211〉 118 <212> PRT <213〉現代人 <400> 150

Gin He Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Asn Thr Gly 20 25 30 -278 - 200927761

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu lie Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Asn Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Leu Glu Leu Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser 115 <210> 151 <211> 118 <212> PRT <213〉現代人 <400〉 151

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30 -279- 200927761

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu He Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Asn Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Leu Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Arg Glu Val Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser 115 <210> 152 <211> 118 <212> PRT <213〉現代人 <400〉 152

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly -280- 200927761 20 25 30

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu lie Tyr Trp Asn Val Glu Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Arg Ser Arg Leu Thr lie Thr Lys Ala Thr Ser Lys Asn Gin Val 65 70 75 80 ❹

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg His Thr Asn Pro Phe Glu Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser 115

<210> 153 <211〉 118 <212> PRT <213〉現代人 <400〉 153

Gin lie Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15 -281 200927761

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly 20 25 30

Gly Val Gly Val Gly Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu 35 40 45

Trp Leu Ala Leu lie Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60

Leu Lys Ser Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Asn Gin Val 65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95

Cys Ala His Arg Gly Glu Leu Pro Phe Asp Tyr Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser 115 <210> 154 <211〉 121 <212〉 PRT <213〉現代人 <400〉 154

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15 -282- 200927761

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Ser Arg Tyr 20 25 30

Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ala lie Ser Ser Ser Ser Ser Tyr lie Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Arg Val Gly Ala Thr Pro Asp Ala Phe Asp lie Trp Gly 100 105 110

Gin Gly Thr Met Val Thr Val Ser Ser

<210〉 155 <211> 128 <212> PRT <213〉現代人 <400> 155

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 -283 - 200927761

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ala He Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Glu Gly He Ala Val Ala Gly Thr Ala Glu Tyr Tyr Tyr Tyr 100 105 110

Tyr Ala Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210〉 156 <211> 125 <212〉 PRT <213〉現代人 <400〉 156

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly -284- 200927761 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ala lie Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60

O

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Lys Glu Gly He Ala Ala Arg Asp Ser Tyr Tyr Tyr Tyr Ala Met 100 105 110 〇

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210〉 157 <211〉 125 <212〉 PRT <213〉現代人 <400〉 157 -285 - 200927761

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ala Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Ala He Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Glu Tyr Tyr Cys 85 90 95

Ala Lys Glu Gly He Ala Gly Arg Asp Ser Tyr Tyr Tyr Tyr Gly Met 100 105 110

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210〉 158 <211> 123 <212〉PRT <213〉現代人 <400> 158 -286- 200927761

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Phe He Ser Asp Asp Gly Ser Thr Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Met Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Gly Phe Asp Tyr 100 105 110

Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 159 <211〉 114 <212〉 PRT <213>現代人 -287- 200927761 <400〉 159

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asn Val He Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val 100 105 110

Ser Ser <210〉 160 <211〉 120 <212> PRT <213〉現代人 -288 - 200927761 <400〉 160

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Asp Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 ❹

Ala Val lie Trp Tyr Asp Gly Ser He Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Q

Ala Arg Gly Gly Ala Thr Gly Ala Glu Tyr Phe Gin His Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120

<210〉 161 <211〉 118 <212〉 PRT -289- 200927761 <213〉現代人 <400〉 161

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val He Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Val Leu Leu Trp Phe Gly Glu Thr Phe Asp Tyr Trp Gly Gin Gly Ser 100 105 110

Leu Val Thr Val Ser Pro 115 <210> 162 <211〉 115 -290- 200927761 <212〉 PRT <213>現代人 <400> 162

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Ser Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asn Leu Pro Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 100 105 110

Val Ser Ser 115 <210〉 163 -291 - 200927761 <211> 123 <212〉 PRT <213〉現代人 <400> 163

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Asp Asp Gly Ser Asn Gin Tyr Tyr Thr Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Ser His Tyr Gly Gly Asp Tyr Asp Tyr Tyr Gly Met Asp Val 100 105 110

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 -292- 200927761 <210> 164 <211> 120 <212〉 PRT <213〉現代人 <400> 164

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

O

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Tyr Asp Gly Ser Asn Lys Arg Tyr Val Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 〇

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Gly Trp Gin Gin Gin Ala Pro Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120 -293 - 200927761 <210〉 165 <211> 118 <212〉 PRT <213〉現代人 <400> 165

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His 20 25 30

Gly Met His Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ala Val lie Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Ala Asp Ser Val 50 55 60

Arg Gly Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Asp 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Trp Gly He Ser Ala Pro Phe Asp Cys Trp Gly Gin Gly Thr 100 105 110

Leu Val Thr Val Ser Ser 115 -294- 200927761 <210> 166 <211> 115 <212〉PRT <213〉現代人 <400〉 166

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ala Tyr 20 25 30

Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser Tyr He Ser Ser Ser Gly Arg Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Leu Trp Ala Pro Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 100 105 110

Val Ser Ser -295- 115 200927761 <210> 167 <211〉 125 <212> PRT <213〉現代人 <400> 167

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser His He Ser Ser Ser Ser Arg Thr He Tyr Tyr Ala Asp Ser Val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Val Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Gly Tyr Asn Trp Asn Gly Gly Gly Asn Tyr Tyr Gly Met 100 105 110 -296- 200927761

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 168 <211> 125 <212> PRT <213〉現代人 <400〉 168

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 ❸

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30

Ser Met Asn Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45

Ser His He Ser Arg Ser Ser Arg Thr lie Tyr Tyr Ala Asp Ser Val 50 55 60 〇

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95

Ala Arg Asp Gly Tyr Asn Trp Asn Asn Gly Gly Tyr Tyr Tyr Gly Met 100 105 110 -297- 200927761

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210〉 169 <211> 118 <212> PRT <213〉現代人 <400〉 169

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr He His Ser Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr He Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Gly Pro Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr 100 105 110 -298- 200927761

Thr Val Thr Val Ser Ser 115 <210〉 170 <211> 127 <212> PRT <213〉現代人 <400> 170

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser He Ser Arg Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp lie Gly Tyr lie Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser ❹ 50 55 60

Leu Lys Ser Arg Val Asn Met Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Ala Leu Arg Gly He Val Leu Met Val Tyr Val Leu Gly -299- 200927761 100 105 110

Ala Leu Asp He Trp Gly Gin Gly Thr Lys Val Thr Val Ser Ser 115 120 125 <210〉 171 <211> 127 <212〉 PRT <213〉現代人 <400〉 171

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr lie Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 -300 200927761

Cys Ala Arg Asp Glu Thr Val Val Arg Gly Leu He Arg Tyr Cys Tyr 100 105 110

Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210〉 172 <211〉 122 <212〉 PRT <213〉現代人

<400〉 172

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Asn Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp He Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45 ❹

Trp lie Gly Tyr lie His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg lie Thr lie Ser Ala Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 -301 - 200927761

Cys Ala Arg Asp Arg Gly Gly Gly Asp Tyr Gly Arg Met Asp Val Trp 100 105 110

Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 173 <211〉 122 <212〉 PRT <213〉現代人 <400〉 173

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Asn Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr lie His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg He Thr lie Ser Ala Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 -302- 200927761

Cys Ala Arg Asp Arg Gly Gly Gly Asp Tyr Gly Arg Met Asp Val Trp 100 105 110

Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120

<210> 174 <211〉 119 <212> PRT <213〉現代人 <400> 174

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp lie Gly Tyr lie His Ser Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg He Thr Lys Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr -303 - 200927761 85 90 95

Cys Ala Arg Ser Asn Asn Tyr Gly Cys Phe Ala Leu Trp Gly Arg Gly 100 105 110

Thr Leu Val Thr Val Ser Ser 115

<210> 175 <211> 119 <212〉 PRT <213>現代人 — <400〉 175

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr lie His Ser Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg lie Thr Lys Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80 -304 200927761

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Ser Asn Asn Tyr Gly Cys Phe Ala Leu Trp Gly Arg Gly 100 105 110

Thr Leu Val Thr Val Ser Ser 115

<210> 176 <211> 133 <212〉 PRT <213〉現代人 <400> 176

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30 ❹

Gly Tyr Tyr Trp Ser Trp lie Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr lie His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80 -305 - 200927761

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Ser Gly Tyr Asn Tyr Gly Leu Tyr Tyr Tyr Asp Ser Ser Gly 100 105 110

Tyr Pro Ser Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gin Gly Thr Thr 115 120 125

Val Thr Val Ser Ser 130 <210> 177 <211> 125 <212〉 PRT <213>現代人 <400〉 177

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Gly 20 25 30

Asp Tyr Tyr Trp Asn Trp Val Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp lie Gly Tyr lie Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser 50 55 60 -306- 200927761

Leu Lys Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Phe Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe 85 90 95

Cys Ala Arg Thr Tyr Tyr Asp He Leu Thr Gly Tyr Pro Phe Tyr Phe 100 105 110

Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210〉 178 <211〉 125 <212> PRT <213〉現代人 <400〉 178

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin ❹ 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser He Ser Ser Gly 20 25 30

Asp Tyr Tyr Trp Asn Trp Val Arg Gin His Pro Gly Lys Gly Leu Glu 35 40 45

Trp He Gly Tyr He Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser -307 - 200927761 50 55 60

Leu Lys Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Phe Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe 85 90 95

Cys Ala Arg Thr Tyr Tyr Asp lie Leu Thr Gly Tyr Pro Phe Tyr Phe 100 105 110

Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210〉 179 <211〉 120 <212〉 PRT <213〉現代人 <400〉 179

Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30

Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45 -308 - 200927761

Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60

Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95

Arg Gly Gly Tyr Ser Ser Ser Trp Tyr Trp Phe Asp Pro Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120 <210〉 180 <211〉120 <212〉PRT <213〉現代人 <400> 180

Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30

Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie 35 40 45 -309 - 200927761

Gly Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60

Ser Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95

Arg Gly Gly Tyr Ser Ser Ser Trp Phe Trp Phe Asp Pro Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120 <210〉 181 <211> 123 <212> PRT <213>現代人 <400〉 181

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser lie Ser Ser Tyr 20 25 30

Tyr Trp Ser Trp He Arg Gin Pro Ala Gly Lys Gly Leu Glu Trp lie 35 40 45 -310- 200927761

Gly Arg lie Tyr Thr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60

Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu 65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95

Arg Asp Gly Tyr Ser Tyr Gly His Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 <210〉 182 <211> 126 <212> PRT <213〉現代人 <400〉 182

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30

Gly Ser Tyr Trp Ser Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu -311 - 200927761 35 40 45

Trp He Gly Tyr He Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60

Leu Lys Ser Arg Val Thr lie Ser lie Val Thr Ser Arg Asn Gin Phe 65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95

Cys Ala Arg Ser Ala Leu Arg Tyr Phe Asp Trp Leu Phe Ser Asp Val 100 105 110

Ser Asp He Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 115 120 125 <210> 183 <211〉 120 <212> PRT <213〉現代人 <400〉 183

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Leu Lys Lys Pro Gly Glu 15 10 15

Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr 20 25 30 -312- 200927761

Trp He Gly Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly lie lie Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60

Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser He Ser Thr Ala Tyr 65 70 75 80

Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95

Ala Arg Gin Lys Ser Tyr Gly Tyr Ser Tyr Phe Asp Tyr Trp Gly Gin 100 105 110

Gly Thr Leu Val Thr Val Ser Ser 115 120 <210〉 184 <211> 121 <212〉PRT <213>現代人 <400〉 184

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15

Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 -313 - 200927761

Trp lie Gly Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly lie lie Tyr Pro Asp Asp Ser Asp Ala Arg Tyr Ser Pro Ser Phe 50 55 60

Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Asn Thr Ala Tyr 65 70 75 80

Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95

Ala Arg Gin Gly Tyr Gly Ser Gly Trp Gly Tyr Phe Asp Tyr Trp Gly 100 105 110

Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210〉 185 <211> 127 <212〉 PRT <213〉現代人 <400〉 185

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15

Ser Leu Lys He Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 -314- 200927761

Trp lie Gly Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly lie He Tyr Pro Gly Asp Ser Asp lie Arg Tyr Ser Pro Ser Phe 50 55 60

Gin Gly Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr 65 70 75 80

Leu Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95

Ala Arg Gin Gly Leu Ala Val Ala Gly Thr Ser Tyr Tyr Tyr Tyr Tyr 100 105 110

Gly Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210〉 186 <211> 125 <212> PRT <213〉現代人 <400〉 186

Gin Val Gin Leu Gin Gin Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Ala He Ser Gly Asp Ser Val Ser Ser Tyr -315 - 200927761 20 25 30

Ser Ala Ala Trp Asn Trp lie Arg Gin Ser Pro Ser Arg Gly Leu Glu 35 40 45

Trp Leu Gly Arg Thr Tyr Cys Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60

Val Ser Val Lys Ser Arg He Thr lie Asn Pro Asp Thr Ser Lys Asn 65 70 75 80

Gin Phe Ser Leu Gin Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95

Tyr Tyr Cys Ala Arg Asp Arg Ala Val Ala Gly Tyr Tyr Tyr Gly Met 100 105 110

Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210〉 187 <211> 107 <212> PRT <213〉現代人 <400〉 187

Arg Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu 1 5 10 15 -316 200927761

Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30

Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Ala Leu Gin 35 40 45

Ser Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser 50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser 85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 188 <211> 326 <212〉PRT <213>現代人 <400> 188

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 15 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 -317 200927761

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gin Thr 65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125

Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 130 135 140

Val Ser His Glu Asp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn 165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gin Asp Trp -318- 200927761 180 185 190

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro 195 200 205

Ala Pro lie Glu Lys Thr lie Ser Lys Thr Lys Gly Gin Pro Arg Glu 210 215 220

Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240

O

Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie 245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 260 265 270

Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 〇

Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys 290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu 305 310 315 320

Ser Leu Ser Pro Gly Lys 325 -319- 200927761 <210> 189 <211> 16 <212〉 PRT <213〉現代人 <400〉 189

Arg Ser Ser Gin Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn 15 10 15 <210> 190 <211> 16 <212〉 PRT <213>現代人 <400〉 190

Lys Ser Ser Gin Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Tyr 15 10 15 <210〉 191 <211> 11 <212〉 PRT <213>現代人 <400> 191

Arg Ala Ser Gin Gly lie Ala Asn Tyr Leu Ala 1 5 10 <210> 192 <211〉 11 <212> PRT <213>現代人 -320- 200927761 <400> 192

Arg Ala Ser Gin Gly lie Ser Asn Asp Leu Ala 1 5 10 <210> 193 <211> 16 <212> PRT <213〉現代人 <400〉 193

Arg Ser Ser Gin Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser 15 10 15 <210〉 194 <211> 12 <212〉 PRT <213〉現代人 <400〉 194

Arg Ala Ser Gin Thr Val lie Ser Ser Tyr Leu Ala 〇 1 5 10 <210〉 195 <211> 10 <212> PRT <213〉現代人 <400> 195

Arg Ala Ser Gin Ser Val Ser Arg Leu Ala 1 5 10 -321 - 200927761 <210〉 196 <211〉 11 <212〉 PRT <213〉現代人 <400〉 196

Arg Ala Ser Gin Gly He Arg Asn Asp Leu Gly 1 5 10

<210〉 197 <211> 17 <212〉 PRT <213〉現代人 <400> 197

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu 15 10 15

Val 〇 <210> 198 <211〉 17 <212〉 PRT <213〉現代人 <400〉 198

Lys Ser Ser Gin Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu 15 10 15 -322- 200927761 <210> 199 <211> 17 <212〉 PRT <213〉現代人 <400> 199

Lys Ser Ser Gin Asn Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu 15 10 15

Ala <210〉 200 <211〉 17 <212> PRT <213>現代人 <400> 200 〇

Lys Ser Ser Gin Ser Val Leu Tyr Asn Ser Asn Asn Lys Asn Tyr Leu 15 10 15

Ala

<210> 201 <211> 17 <212> PRT -323 - 200927761 <213〉現代人 <400> 201

Lys Ser Ser Gin Ser Val Leu Asp Ser Ser Asn Asn Lys Asn Tyr Leu 15 10 15

Ala <210> 202 <211〉 17 <212〉 PRT <213〉現代人 <400> 202

Lys Ser Ser Gin Ser lie Leu Tyr Arg Ser Asn Asn Lys Asn Tyr Leu 15 10 15

Ala <210〉 203 <211〉 11 <212〉 PRT <213〉現代人 <400〉 203

Arg Ala Ser Gin Asp lie Ser His Tyr Leu Ala 1 5 10 -324- 200927761 <210> 204 <211> 11 <212> PRT <213〉現代人 <400> 204

Arg Ala Ser Gin Asp lie Ser Asn Tyr Leu Ala 1 5 10

<210> 205 <211〉 11 <212> PRT <213〉現代人 <400〉 205

Arg Ala Ser Gin Ser Val Ser Ser Asn Leu Ala 1 5 10 <210〉 206 <211〉 11 <212〉 PRT <213>現代人 <400> 206

Arg Ala Ser Gin Asp lie Ser Arg Trp Leu Ala 1 5 10 <210> 207 <211〉 11 <212〉 PRT <213〉現代人 -325 - 200927761 <400〉 207

Arg Ala Ser Gin Ser lie Ser Thr Tyr Leu Asn 1 5 10 <210〉 208 <211〉 11 <212〉 PRT <213〉現代人 <400〉 208

Arg Ala Ser Gin Thr He Ser He Tyr Leu Asn 1 5 10 <210〉209 <211〉 11 <212〉 PRT <213>現代人 <400> 209

Arg Ala Ser Gin Ser He Arg Ser Tyr Leu Asn 1 5 10

<210〉 210 <211〉 11 <212> PRT <213〉現代人 <400〉 210

Arg Ala Ser Gin Thr lie Ser Arg Tyr Leu Asn 1 5 10 -326- 200927761 <210〉 211 <211〉 11 <212> PRT <213> 現代人 <400〉 211 Arg Ala Ser Gin Arg He Ser Ser Tyr Leu Asn 1 5 10 <210〉 212 <211〉 11 <212〉 PRT <213〉現代人 <400〉 212 Arg Ala Ser Gin Ser He Ser Arg Tyr Leu Asn 1 5 10 <210〉 213 <211> 11 <212〉 PRT <213> 現代人 <400〉 213

Arg Ala Ser Gin Ser He Ser Ser Tyr Leu Asn 1 5 10 <210〉 214 <211〉 11 <212〉 PRT <213〉現代人 -327- 200927761 <400> 214

Gin Ala Ser Gin Asp He Ser Asn Tyr Leu Asn 1 5 10 <210〉 215 <211> 11 <212> PRT <213〉現代人 <400〉 215

Gin Ala Ser Gin Asp He Ser Asn Ser Leu Asn 1 5 10 <210〉 216 <211> 11 <212〉 PRT <213〉現代人 <400〉 216

Gin Ala Ser Gin Asp lie Ser Asp Tyr Leu Asn 1 5 10 <210> 217 <211> 11 <212> PRT <213〉現代人 <400> 217

Gin Ala Ser Gin Asp He Thr Asn Tyr Leu Asn 1 5 10 -328 200927761 <210> 218 <211> 7 <212> PRT <213>現代人 <400〉 218

Lys Val Ser Asn Trp Asp Ser 1 5

<210> 219 <211〉 7 <212〉 PRT <213〉現代人 <400> 219

Glu Val Ser Asn Arg Phe Ser 1 5 <210〉 220 <211〉 7 <212> PRT <213> 現代人 <400> 220 Val Ala Ser Thr Leu Gin Ser 1 5

<210〉 221 <211〉 7 <212〉 PRT 200927761 <213〉現代人 <400〉 221

Ala Ala Ser Thr Leu Gin Ser 1 5 <210〉 222 <211> <212> <213〉 7 PRT 現代人 <400> 222

Lys lie Ser Asn Arg Phe Ser 1 5 <210〉 <211〉 223 7 <212> <213> PRT 現代人 <400〉 223

Gly Ala Ser Ser Arg Ala Thr 1 5 <210〉 224 <211> <212〉 <213〉 7 PRT 現代人 <400> 224

Gly Ala Ser Arg Arg Ala Thr -330- 200927761 1 5 <210〉 225 <211〉 7 <212> PRT <213> 現代人 <400〉 225 Ala Ala Ser Ser Leu Gin Ser 1 5 <210> 226 <211〉 7 <212> PRT <213> 現代人 <400〉 226 Trp Ala Ser Thr Arg Glu Ser 1 5 <210〉 227 <211〉 7 <212> PRT <213〉現代人 <400〉 227 Trp Ala Ser Thr Arg Lys Ser 1 5

<210〉 228 <211〉 7 200927761 <212> PRT <213〉現代人 <400〉 228

Trp Ala Ser Ala Arg Glu Ser 1 5 <210〉 229 <211〉 7 <212〉 PRT <213〉現代人

<400> 229

Ala Glu Ser Ser Leu Gin Ser

1 5 <210〉 230 <211> 7 <212〉 PRT <213〉現代人 <400〉 230 Thr Ala Ser Ser Leu Gin Ser 1 5 <210〉 231 <211> 7 <212〉 PRT <213> 現代人 <400〉 231 332- 200927761

Thr Val Ser Ser Leu Gin Ser 1 5 <210〉 232 <211> 7 <212> PRT <213>現代人 <400> 232

Asp Ala Ser Asn Leu Glu Thr 1 5 〇 <210> 233 <211> 7 <212> PRT <213〉現代人 <400〉 233

Asp Ala Ser He Leu Glu Thr 1 5 〇 <210> <211> <212〉 <213〉 234 9 PRT 現代人 <400〉 234

Met Gin Ser Thr His Trp Pro lie Thr 1 5 <210〉 235 -333 - 200927761 <211〉 <212> <213> 9 PRT 現代人 <400〉 235 lie Gin Gly Thr His Trp Pro Thr Thr 1 5 <210〉 236 <211> <212〉 <213〉 9 PRT 現代人 <400〉 236

Met Gin Gly Thr His Trp Pro He Thr 1 5 <210〉 <211> 237 9 <212〉 <213> PRT 現代人 <400〉 237

Met Gin Gly lie Gin Leu Pro Cys Ser 1 5 <210〉 238 <211〉 9 <212〉 PRT <213〉現代人 <400> 238 200927761

Met Gin Ser lie Gin Leu Pro Leu Thr 1 5 <210> 239 <211> 9 <212〉 PRT <213〉現代人 <400> 239

Met Gin Ser He Gin Leu Pro lie Thr 1 5 <210> 240 <211〉 9 <212> PRT <213〉現代人 <400〉 240

Gin Asn Tyr Asn Ser Ala Pro Phe Thr 1 5 <210> 241 <211〉 9 <212〉 PRT <213〉現代人 <400> 241

Gin Lys Tyr Asn Ser Val Pro Leu Thr 1 5 - 335 - 200927761 <210〉 242 <211> <212> <213> 9 PRT 現代人 <400〉 242

Met Gin Ala Thr Gin Phe Pro His Thr 1 5 <210> 243 <211> <212〉 <213〉 9 PRT 現代人 <400> 243

Gin Gin Tyr Gly Ser Ser Pro Arg Thr 1 5 <210〉 244 <211> <212〉 <213> 9 PRT 現代人 <400> 244

Gin Gin Tyr Gly Ser Ser Pro Arg Ser 1 5 <210〉 245 <211〉 9 <212〉 <213> PRT 現代人 336- 200927761 <400> 245

Leu Gin His Asn Ser Tyr Pro Pro Thr 1 5 <210〉246 <211> 9 <212> PRT <213〉現代人 <400> 246 _ Gin Gin Tyr Tyr Ser Phe Pro Trp Thr O 1 5 <210〉 247 <211> 9 <212〉 PRT <213〉現代人 <400> 247

Gin Gin Tyr Tyr Ser Thr Thr Trp Thr 1 5 <210> 248 <211〉 9 <212> PRT <213〉現代人 <400〉 248

Gin Gin Tyr Tyr Gly Thr Pro Arg Thr 1 5 -337 - 200927761 <210〉 249 <211> 9 <212〉PRT <213>現代人 <400> 249

Gin Gin Tyr Tyr Ser lie Ser Arg Thr 1 5 <210> 250 <211> 9 <212> PRT <213〉現代人 <400〉 250

Gin Gin Tyr Tyr Ser Thr Met Phe Ser 1 5 <210〉 251 <211> 9 <212〉 PRT <213〉現代人 <400> 251

His Gin Tyr Tyr Ser Thr Pro Leu Thr 1 <210〉 252 <211〉 9 <212> PRT <213> 現代人 -338- 200927761 <400> 252

Gin Gin Tyr Phe lie Thr Pro Leu Thr 1 5 <210〉 253 <211〉 9 <212> PRT <213〉現代人 <400〉 253

Gin Gin Tyr Asn Asn Tyr Pro Phe Thr 1 5 <210> 254 <211〉 9 <212〉 PRT <213〉現代人 <400〉 254

Gin Gin Tyr Asn Thr Tyr Pro Phe Thr 〇 1 5 <210〉 255 <211〉 10 <212〉 PRT <213〉現代人 <400〉 255

Gin Gin His Asn Asn Trp Pro Pro Trp Thr 1 5 10 -339- 200927761 <210> 256 <211> 9 <212> PRT <213>現代人 <400〉 256

Gin Gin Ala Asn Ser Phe Pro Pro Thr 1 5

<210> 257 <211〉 9 <212〉 PRT <213>現代人 <400> 257

Gin Gin Ser His Ser Ala Pro Phe Thr 1 5 <210〉 258 <211> 8 <212〉 PRT <213〉現代人〇 <400〉 258

Gin Gin Ser Tyr Ser Thr Leu Thr 1 5 <210〉 259 <211> 9 <212〉 PRT -340- 200927761 <213〉現代人 <400〉 259

Gin Gin Ser Tyr Ser lie Pro Leu Thr 1 5 <210> 260 <211〉 9 <212〉 PRT <213〉現代人

<400〉 260

Gin Gin lie Tyr Ser Thr Ser He Thr 1 5 <210〉 261 <211〉 9 <212> PRT <213〉現代人 <400〉 261

Gin Gin Ser Tyr lie Thr Pro He Thr 1 5 <210〉 262 <211> 9 <212〉PRT <213〉現代人 <400〉 262

Gin Gin Ser Tyr Phe Thr Pro lie Thr 200927761 1 5 <210〉 263 <211〉 9 <212〉PRT <213〉現代人 <400〉 263

Gin Gin Ser Tyr Phe Ser Pro He Thr 1 5 <210> 264 <211〉 9 <212〉 PRT <213〉現代人 <400〉 264 Gin Gin Ser Phe Tyr Thr Pro He Thr 1 5 <210〉 265 <211> 9 <212〉 PRT <213> 現代人 <400〉 265

Gin Gin Ser Phe Tyr Ala Pro lie Thr 1 5 <210〉 266 <211> 9 -342- 200927761 <212〉PRT <213〉現代人 <400〉 266

Gin Gin Tyr Asp Tyr Leu Pro Phe Thr 1 5 <210> 267 <211〉 9 <212〉 PRT <213〉現代人

<400〉 267

Gin Gin Cys Asp Asp Leu Pro Leu Thr 1 5 <210〉 268 <211> 9 <212〉 PRT <213>現代人 <400> 268

Gin His Tyr Asp Asn Leu Pro Leu Thr 1 5 <210〉 269 <211〉 9 <212〉 PRT <213〉現代人 <400〉 269 -343 - 200927761

Gin Gin Tyr Asp Asn Leu Pro Leu Thr 1 5 <210〉 270 <211> 9 <212〉 PRT <213〉現代人 <400〉 270

Gin Gin Cys Asp He Leu Pro Leu Ser 1 5 <210> 271 <211> 9 <212〉PRT <213>現代人 <400〉 271

Gin Gin Tyr Asp Asn Leu Pro Leu Ala 1 5 <210> 272 <211> 9 <212〉 PRT <213〉現代人 <400〉 272

Gin Gin Tyr Asp Ser Leu Pro lie Thr 1 5 <210> 273 -344- 200927761

<211> 9 <212〉 PRT <213> 現代人 <400〉 273 Gin Gin Tyr Asp Asn Leu Pro lie Thr 1 5 <210> 274 <211〉 9 <212〉 PRT <213〉現代人 <400〉 274 Gin His Tyr Asp Asn Leu Pro He Thr 1 5 <210〉 275 <211〉 10 <212> PRT <213> 現代人 <400> 275

Gly Tyr Thr Phe Thr Ser Tyr Gly lie Ser 1 <210> 276 <211〉 10 <212〉 PRT <213〉現代人 <400〉 276 -345 200927761

Gly Tyr Thr Phe Thr Gly His Tyr Met His 1 5 10 <210> 277 <211> 10 <212> PRT <213〉現代人 <400> 277

Gly Tyr Thr Phe Thr Gly Tyr Tyr Met His 1 5 10 <210〉 278 <211> 10 <212〉 PRT <213〉現代人 <400〉 278

Gly Tyr Thr Leu Thr Glu Leu Ser Met His 1 5 10 <210> 279 <211> 12 <212> PRT <213〉現代人 <400> 279

Gly Phe Ser Leu Ser Asn Ala Arg Met Gly Val Ser 1 5 10 -346- 200927761 <210> 280 <211〉 12 <212〉 PRT <213> 現代人 <400〉 280 Gly Phe Ser Leu Ser Thr Gly Gly Val Gly Val Gly 1 5 10 <210〉 281 <211> 12 <212〉 PRT <213> 現代人 <400〉 281 Gly Phe Ser Leu Asn Thr Gly Gly Val Gly Val Gly 1 5 10 <210〉 282 <211〉 10 <212〉 PRT <213〉現代人 <400〉 282

Gly Phe Pro Phe Ser Arg Tyr Ser Met Asn 1 5 10 <210> 283 <211〉 10 <212〉 PRT <213> 現代人 -347 - 200927761 <400〉 283

Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn 1 5 10 <210〉 284 <211> 10 <212〉 PRT <213>現代人 <400> 284

Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser 1 5 10 <210> 285 <211> 10 <212> PRT <213〉現代人 <400〉 285

Gly Phe Thr Phe Ser Ser Tyr Gly Met His 1 5 10 <210> 286 <211〉 10 <212〉 PRT <213〉現代人 <400> 286

Gly Phe Thr Phe Ser Ser Tyr Asp Met His 1 5 10 -348 200927761 <210〉 287 <211〉 10 <212〉 PRT <213> 現代人 <400〉 287 Gly Phe Thr Phe Arg Ser His Gly Met His 1 5 10 <210〉 288 <211> 10 <212〉 PRT <213> 現代人 <400> 288 Gly Phe Thr Phe Ser Ala Tyr Ser Met Asn 1 5 10 <210〉 289 <211〉 10 <212〉 PRT <213> 現代人 <400〉 289

Gly Phe Thr Phe Ser Ser Tyr Ser Met Asn 1 5 10 <210〉 290 <211〉 12 <212〉 PRT <213> 現代人 -349 200927761 <400> 290

Gly Gly Ser Val Ser Ser Gly Gly Tyr Tyr Trp Ser 1 5 10 <210> 291 <211> 12 <212〉 PRT <213〉現代人 <400> 291

Gly Gly Ser He Ser Arg Gly Gly Tyr Tyr Trp Ser 1 5 10 <210> 292 <211〉 12 <212〉 PRT <213〉現代人 <400〉 292

Gly Gly Ser He Ser Ser Gly Gly Tyr Tyr Trp Ser 1 5 10 <210> 293 <211〉 12 <212〉 PRT <213>現代人 <400〉 293

Gly Gly Ser lie Ser Ser Gly Asp Tyr Tyr Trp Asn 1 5 10 -350- 200927761 <210〉 294 <211> 10 <212> PRT <213〉現代人 <400> 294

Gly Gly Ser Phe 1 <210〉 295 <211〉 10 <212〉 PRT <213> 現代人 <400〉 295

Ser Gly Tyr Tyr Trp Ser 5 10

Gly Gly Ser lie Ser Ser Tyr Tyr Trp Ser 1 5 10

<210〉 296 <211〉 12 <212〉 PRT <213〉現代人 <400> 296

Gly Gly Ser Val Ser Ser Gly Gly Ser Tyr Trp Ser 1 5 10

<210> 297 <211〉 10 <212> PRT -351 - 200927761 <213〉現代人 <400> 297

Gly Tyr Arg Phe Thr Ser Tyr Trp lie Gly 1 5 10 <210〉 298 <211> 10 <212> PRT <213〉現代人 <400> 298

Gly Tyr Ser Phe Thr Ser Tyr Trp lie Gly 1 5 10 <210> 299 <211> 12 <212〉 PRT <213〉現代人 <400> 299

Gly Asp Ser Val Ser Ser Tyr Ser Ala Ala Trp Asn 1 5 10 <210〉 300 <211> 17 <212〉PRT <213>現代人 <400> 300

Trp lie Ser Ala Ser Asn Gly Asn Thr Asn Tyr Ala Gin Lys Leu Gin -352- 200927761 15 10 15

Asp <210〉 301 <211〉 17 <212〉 PRT <213〉現代人 <400〉 301

Trp He Asn Pro Asn Ser Gly Gly Thr Asn Cys Ala Gin Lys Phe Gin 15 10 15

Gly <210> 302 <211> 17 <212> PRT <213〉現代人〇 <400〉 302

Trp lie Asn Pro Asn Ser Gly Gly Thr Asn His Thr Gin Lys Phe Gin 15 10 15

Gly <210〉 303 -353 - 200927761 <211> 17 <212〉PRT <213〉現代人 <400〉 303

Ser Phe Asp Pro Glu Asp Gly Glu Thr lie Tyr Ala Gin Lys Phe Gin 15 10 15

Gly <210> 304 <211〉 16 <212> PRT <213〉現代人 <400> 304

His lie Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser 15 10 15 <210〉 305 <211〉 16 <212> PRT <213〉現代人 <400〉 305

Leu lie Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Ser 15 10 15 <210〉 306 <211> 16 -354 200927761 <212〉 PRT <213〉現代人 <400> 306

Leu lie Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser Leu Lys Ser 15 10 15 <210> 307 <211> 16 <212> PRT <213〉現代人

<400〉 307

Leu lie Tyr Trp Asn Val Glu Lys Arg Tyr Ser Pro Ser Leu Arg Ser 15 10 15 <210> 308 <211> 17 <212〉PRT <213〉現代人 <400> 308 〇

Ala lie Ser Ser Ser Ser Ser Tyr lie Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly

<210〉 309 <211> 17 <212〉PRT -355 - 200927761 <213>現代人 <400> 309

Ala lie Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly <210> 310 <211〉 17 <212〉 PRT <213〉現代人 <400〉 310

Phe lie Ser Asp Asp Gly Ser Thr Lys Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly <210> 311 <211> 17 <212> PRT <213〉現代人 <400> 311

Val lie Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 15 10 15 -356- 200927761

Gly <210> 312 <211> 17 <212> PRT <213〉現代人 <400〉 312

Val lie Trp Tyr Asp Gly Ser lie Lys Tyr Tyr Ala Asp Ser Val Lys 15 10 15

O

Gly <210〉 313 <211〉 17 <212〉 PRT <213〉現代人 <400〉 313

Val He Trp Ser Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly <210〉 314 <211> 17 <212〉 PRT <213〉現代人 -357 - 200927761 <400〉 314

Val He Trp Asp Asp Gly Ser Asn Gin Tyr Tyr Thr Asp Ser Val Lys 15 10 15

Gly <210> 315 <211> 17 <212〉 PRT <213>現代人 <400〉 315

Val lie Trp Tyr Asp Gly Ser Asn Lys Arg Tyr Val Asp Ser Val Lys 15 10 15

Gly <210〉 316 <211〉 17 <212> PRT <213〉現代人 <400> 316

Val He Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Ala Asp Ser Val Arg 15 10 15

Gly 358- 200927761 <210〉 317 <211> 17 <212〉 PRT <213〉現代人 <400〉 317

Tyr lie Ser Ser Ser Gly Arg Thr lie Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly <210〉 318 <211> 17 <212〉 PRT <213〉現代人 <400〉 318

His He Ser Ser Ser Ser Arg Thr He Tyr Tyr Ala Asp Ser Val Lys Q 1 5 10 15

Gly <210> 319 <211> 17 <212> PRT <213〉現代人 -359- 200927761 <400〉 319

His lie Ser Arg Ser Ser Arg Thr lie Tyr Tyr Ala Asp Ser Val Lys 15 10 15

Gly <210〉 320 <211〉 16 <212〉 PRT <213>現代人 <400> 320

Tyr lie His Ser Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 15 10 15 <210〉 321 <211〉 16 <212> PRT <213〉現代人 <400〉 321

Tyr lie Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 15 10 15 <210> 322 <211> 16 <212〉 PRT <213〉現代人 <400> 322 -360 200927761

Tyr lie Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 15 10 15 <210〉323 <211> 16 <212〉PRT <213〉現代人 <400> 323

Tyr He His Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 15 10 15 <210〉 324 <211> 16 <212> PRT <213〉現代人 <400〉 324

Tyr lie Tyr Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 15 10 15 〇 <210〉 325 <211> 16 <212〉PRT <213〉現代人 <400〉 325

Glu lie Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser 15 10 15 -361 - 200927761 <210> 326 <211> 16 <212〉PRT <213〉現代人 <400〉 326

Arg lie Tyr Thr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser 15 10 15 <210> 327 <211> 16 <212> PRT <213〉現代人 <400〉 327

Tyr lie Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser 15 10 15 <210〉 328 <211> 17 <212〉 PRT <213>現代人 <400〉 328

He lie Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210〉 329 -362- 200927761 <211> 17 <212〉 PRT <213〉現代人 <400> 329 lie lie Tyr Pro Asp Asp Ser Asp Ala Arg Tyr Ser Pro Ser Phe Gin 15 10 15

Gly

<210〉 330 <211> 17 <212> PRT <213〉現代人 <400> 330 lie He Tyr Pro Gly Asp Ser Asp lie Arg Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210〉 331 <211> 18 <212> PRT <213〉現代人 <400〉 331

Arg Thr Tyr Cys Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Val Ser Val 15 10 15 -363 - 200927761

Lys Ser <210> 332 <211> 11 <212〉 PRT <213〉現代人 <400> 332

Glu Asp Asn Trp Asn Tyr Gly Phe Phe Asp Tyr 1 5 10 <210〉 333 <211〉 8 <212> PRT <213〉現代人 <400〉 333

Ser lie Ala Val Ala Leu Asp Tyr 1 5 <210〉 334 <211〉 13 <212〉 PRT <213〉現代人 <400> 334

Glu Gly Asp Gly Gly Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 -364- 200927761 <210〉 335 <211> 12 <212> PRT <213〉現代人 <400〉 335

Met Tyr Ser Ser Gly Trp Tyr Gly Val Phe Asp Tyr 1 5 10

<210> 336 <211> 13 <212> PRT <213〉現代人 <400〉 336

Val Tyr Ser Ser Gly Trp Ser Phe Tyr Gly Met Asp Val 1 5 10 <210〉 337 <211> 8 <212> PRT <213〉現代人 <400> 337

Arg Arg Glu Leu Pro Phe Asp Tyr 1 5 <210> 338 <211> 8 <212〉 PRT <213〉現代人 365 - 200927761 <400〉 338

Arg Asn Trp Thr Pro Phe Asp Tyr 1 5 <210〉 339 <211〉 8 <212〉 PRT <213〉現代人 <400> 339

Arg Leu Glu Leu Pro Phe Asp Tyr 1 5 <210〉 340 <211> 8 <212> PRT <213>現代人 <400〉 340

Arg Arg Glu Val Pro Phe Asp Tyr 1 5 <210〉 341 <211〉 8 <212〉 PRT <213〉現代人 <400> 341

Arg His Thr Asn Pro Phe Glu Tyr 1 5 -366 200927761 <210> 342 <211〉 8 <212〉 PRT <213〉現代人 <400〉 342

Arg Gly Glu Leu Pro Phe Asp Tyr 1 5

<210〉 343 <211> 12 <212〉 PRT <213>現代人 <400〉 343

Asp Arg Val Gly Ala Thr Pro Asp Ala Phe Asp lie 1 5 10 <210〉 344 <211> 19 <212> PRT <213〉現代人 <4〇〇> 344

Glu Gly He Ala Val Ala Gly Thr Ala Glu Tyr Tyr Tyr Tyr Tyr Ala 15 10 15

Met Asp Val -367 - 200927761 <210> 345 <211> 16 <212〉PRT <213〉現代人 <400〉 345

Glu Gly lie Ala Ala Arg Asp Ser Tyr Tyr Tyr Tyr Ala Met Asp Val 15 10 15 <210> 346 <211〉 16 <212〉 PRT <213〉現代人 <400> 346

Glu Gly He Ala Gly Arg Asp Ser Tyr Tyr Tyr Tyr Gly Met Asp Val 15 10 15 <210〉347 <211> 14 <212> PRT <213>現代人 <400〉 347

Ser Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Gly Phe Asp Tyr 1 5 10 <210〉 348 <211〉 5 <212〉 PRT <213>現代人 -368 - 200927761 <400〉 348

Asn Val lie Asp Tyr 1 5

Gly Gly Ala Thr 1 <210> 350 <211> 9 <212〉 PRT <213> 現代人 <400〉 350

Gly Ala Glu Tyr Phe Gin His 5 10 <210> 349 <211〉 11 <212〉 PRT <213> 現代人 <400> 349

Leu Trp Phe Gly Glu Thr Phe Asp Tyr 〇 1 5 <210〉 351 <211> 6 <212> PRT <213〉現代人 <400> 351 Asn Leu Pro Phe Asp Tyr 1 5 -369 - 200927761 <210> 352 <211> 14 <212〉 PRT <213〉現代人 <400> 352

Ser His Tyr Gly Gly Asp Tyr Asp Tyr Tyr Gly Met Asp Val 1 5 10 <210〉 353 <211> 11 <212> PRT <213〉現代人 <400〉 353

Asp Gly Trp Gin Gin Gin Ala Pro Phe Asp Tyr 1 5 10 <210〉 354 <211〉 9 <212> PRT <213〉現代人 <400〉 354

Trp Gly He Ser Ala Pro Phe Asp Cys 1 5 <210〉 355 <211> 6 <212〉 PRT -370- 200927761 <213>現代人 <400〉 355

Trp Ala Pro Phe Asp Tyr 1 5 <210〉 356 <211〉 16 <212〉PRT <213〉現代人

<400〉 356

Asp Gly Tyr Asn Trp Asn Gly Gly Gly Asn Tyr Tyr Gly Met Asp Val 15 10 15 <210〉 357 <211> 16 <212〉 PRT <213〉現代人 <400〉 357

Asp Gly Tyr Asn Trp Asn Asn Gly Gly Tyr Tyr Tyr Gly Met Asp Val 15 10 15 <210> 358 <211> 8 <212〉 PRT <213>現代人 <400〉 358

Gly Pro Tyr Tyr Gly Met Asp Val 371 - 200927761 <210〉 359 <211> 17 <212> PRT <213〉現代人 <400> 359

Ala Leu Arg Gly lie Val Leu Met Val Tyr Val Leu Gly Ala Leu Asp 15 10 15 lie <210〉 360 <211〉 17 <212> PRT <213>現代人 <400〉 360

Asp Glu Thr Val Val Arg Gly Leu lie Arg Tyr Cys Tyr Gly Met Asp 15 10 15

Val <210> 361 <211> 12 <212〉 PRT <213〉現代人 -372 200927761 <400> 361

Asp Arg Gly Gly Gly Asp Tyr Gly Arg Met Asp Val 1 5 10 <210〉 362 <211〉 9 <212〉PRT <213〉現代人 <400> 362

Ser Asn Asn Tyr Gly Cys Phe Ala Leu 1 5 <210〉 363 <211> 23 <212〉 PRT <213〉現代人 <400〉 363

Gly Tyr Asn Tyr Gly Leu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Pro Ser 15 10 15

Tyr Tyr Tyr Gly Met Asp Val 20 <210〉 364 <211> 15 <212〉 PRT <213〉現代人 <400〉 364 -373 - 200927761

Thr Tyr Tyr Asp lie Leu Thr Gly Tyr Pro Phe Tyr Phe Asp Tyr 15 10 15 <210> 365 <211> 12 <212> PRT <213〉現代人 <400〉 365

Gly Gly Tyr Ser Ser Ser Trp Tyr Trp Phe Asp Pro 1 5 10 <210〉 366 <211> 12 <212> PRT <213〉現代人 <400〉 366

Gly Gly Tyr Ser Ser Ser Trp Phe Trp Phe Asp Pro 1 5 10 <210〉 367 <211> 15 <212〉 PRT <213〉現代人 <400〉 367

Asp Gly Tyr Ser Tyr Gly His Tyr Tyr Tyr Tyr Gly Met Asp Val 15 10 15 -374 200927761 <210〉 368 <211> 16 <212〉 PRT <213〉現代人 <400〉 368 Ser Ala Leu Arg Tyr Phe Asp Trp Leu Phe Ser Asp Val Ser Asp lie 1 5 10 15 <210〉 369 <211〉 11 <212〉 PRT <213> 現代人 <400〉 369 Gin Lys ;Ser Tyr Gly Tyr Ser Tyr Phe Asp Tyr 1 5 10 <210> 370 <211〉 12 <212> PRT <213> 現代人 <400> 370

Gin Gly Tyr Gly Ser Gly Trp Gly Tyr Phe Asp Tyr 1 5 10 <210> 371 <211> 18 <212> PRT <213〉現代人 -375 - 200927761 <400> 371

Gin Gly Leu Ala Val Ala Gly Thr Ser Tyr Tyr Tyr Tyr Tyr Gly Met 15 10 15

Asp Val <210〉 372 <211> 13 <212〉 PRT <213>現代人 <400〉 372

Asp Arg Ala Val Ala Gly Tyr Tyr Tyr Gly Met Asp Val 1 5 10 <210> 373 <211> 23 <212〉 PRT <213〉現代人 <400> 373

Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys 20 <210〉 374 <211> 23 -376- 200927761 <212> PRT <213〉現代人 <400> 374

Asp Val Val Met Thr Gin Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser lie Ser Cys 20 o <210> 375 <211> 23 <212〉 PRT <213>現代人 <400〉 375

Asp lie Val Met Thr Gin Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15

Gin Pro Ala Ser He Ser Cys 20 o <210〉 376 <211> 23 <212> PRT <213〉現代人 <400> 376

Asp lie Val Met Thr Gin Thr Pro Leu Ser Leu Ser Val Thr Pro Gly 15 10 15 -377- 200927761

Gin Pro Ala Ser lie Ser Cys 20 <210〉 377 <211> 23 <212〉 PRT <213〉現代人 <400〉 377

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie He Cys 20 <210〉 378 <211> 23 <212〉 PRT <213>現代人 <400> 378

Glu lie Val Met Thr Gin Thr Pro Leu Ser Ser Pro Val Thr Leu Gly 15 10 15

Gin Pro Ala Ser He Ser Cys 20

<210〉 379 <211> 23 <212> PRT -378- 200927761 <213〉現代人 <400> 379

Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys 20

<210〉 380 <211> 23 <212〉 PRT <213>現代人 <400> 380

Glu lie Val Leu Thr Gin Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys 20 <210〉 381 <211> 23 <212> PRT <213〉現代人 <400〉 381

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15 -379 - 200927761

Asp Arg Val Thr lie Thr Cys 20 <210〉 382 <211> 23 <212〉 PRT <213〉現代人 <400〉 382

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys 20 <210> 383 <211> 23 <212〉 PRT <213〉現代人 <400〉 383

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys 20 <210〉 384 <211〉 23 <212〉 PRT <213〉現代人 -380 200927761 <400> 384

Asp lie Val Met Thr Gin Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 15 10 15

Glu Arg Ala Thr lie Asn Cys 20

<210〉 385 <211〉 23 <212> PRT <213>現代人 <400> 385

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 <210> 386 <211〉 23 <212> PRT <213〉現代人 <400〉 386

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Ala He Thr Cys -381 - 20 20200927761 <210〉 387 <211> 23 <212〉PRT <213>現代人 <400> 387

Glu lie Val Met Thr Gin Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys 20 <210> 388 <211> 23 <212> PRT <213〉現代人 <400〉 388

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 <210> 389 <211〉 23 <212〉 PRT <213>現代人 382- 200927761 <400> 389

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20

<210〉 390 <211〉 23 <212〉 PRT <213〉現代人 <400> 390

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 <210〉 391 <211> 23 <212〉 PRT <213〉現代人 <400〉 391

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 -383 - 200927761 <210> 392 <211> 23 <212> PRT <213〉現代人 <400> 392

Asp He Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 <210> 393 <211> 23 <212〉 PRT <213〉現代人 <400> 393

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 15 10 15

Asp Arg Val Thr lie Thr Cys 20 <210〉 394 <211〉 15 <212〉 PRT <213〉現代人 <400> 394 -384- 200927761

Trp Leu Gin Gin Arg Pro Gly Gin Ser Pro Arg Arg Leu lie Tyr 15 10 15 <210> 395 <211> 15 <212> PRT <213〉現代人 <400> 395

Trp Tyr Leu Gin Lys Pro Gly Gin Pro Pro Gin Leu Leu lie Tyr 15 10 15 <210〉 396 <211> 15 <212〉PRT <213〉現代人 <400〉 396

Trp Phe Leu Gin Lys Pro Gly Gin Pro Pro Gin Pro Leu lie Tyr 15 10 15 <210〉 397 <211> 15 <212〉PRT <213〉現代人 <400> 397

Trp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu Leu lie Tyr 15 10 15 - 385 - 200927761 <210> 398 <211〉 15 <212〉 PRT <213〉現代人 <400> 398

Trp Leu Gin Gin Arg Pro Gly Gin Pro Pro Arg Leu Leu lie Tyr 1 5 10 15 <210〉 399 <211> 15 <212〉 PRT <213〉現代人 <400〉 399 Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie Ser 1 5 10 15 <210> 400 <211> 15 <212〉 PRT <213〉現代人 <400〉 400 Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie Tyr 1 5 10 15 <210〉 401 <211〉 15 <212〉 PRT <213> 現代人 -386 200927761 <400> 401

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu lie Tyr 15 10 15 <210〉 402 <211> 15 <212> PRT <213〉現代人 <400> 402

Trp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Phe He Tyr 15 10 15 <210〉403 <211〉 15 <212〉 PRT <213〉現代人 <400〉 403

Trp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu He Tyr 15 10 15 <210> 404 <211〉 15 <212〉 PRT <213〉現代人 <400〉 404

Trp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Val Leu lie Tyr 15 10 15 -387- 200927761 <210〉 405 <211> 15 <212〉 PRT <213〉現代人 <400〉 405

Trp Phe Gin Gin Lys Pro Gly Lys Ala Pro Lys Ser Leu lie Tyr 15 10 15 <210> 406 <211> 15 <212〉PRT <213>現代人 <400〉 406

Trp Leu Gin Gin Lys Pro Gly Lys Ala Pro Lys Ser Leu lie Tyr 15 10 15 <210> 407 <211> 15 <212〉 PRT <213>現代人 <400〉 407

Trp Tyr Gin Gin Asp Pro Gly Gin Ala Pro Arg Leu Leu He Tyr 15 10 15 <210〉 408 <211〉 15 <212> PRT <213〉現代人 -388 200927761 <400〉 408

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie Tyr 15 10 15 <210> 409 <211> 15 <212〉 PRT <213〉現代人 <400〉 409

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Phe Leu lie Tyr 15 10 15 <210〉 410 <211〉 15 <212> PRT <213〉現代人 <400〉 410

Trp Tyr Gin Gin Arg Pro Gly Asn Ala Pro Lys Leu Leu lie Tyr ❹ 1 5 10 15 <210〉 411 <211〉 15 <212〉 PRT <213〉現代人 <400> 411

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Val Leu He Tyr 15 10 15 - 389 - 200927761 <210> 412 <211> 15 <212> PRT <213〉現代人 <400> 412

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Glu Leu Leu lie Tyr 15 10 15 <210> 413 <211> 15 <212〉 PRT <213〉現代人 <400〉 413

Trp Tyr Gin Gin Lys Leu Gly Lys Ala Pro Lys Leu Leu He His 15 10 15 <210> 414 <211〉 32 <212〉 PRT <213〉現代人 <400〉 414

Gly Val Pro Asp Arg Phe Asn Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Lys He Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys 20 25 30 -390- 200927761 <210> 415 <211> 32 <212〉PRT <213〉現代人 <400〉 415

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Lys lie Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys 20 25 30 <210> 416 <211〉 32 <212〉 PRT <213〉現代人 <400〉 416

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15 〇

Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 30 <210> 417 <211〉 32 <212> PRT <213〉現代人 <400> 417 -391 - 200927761

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr 15 10 15

Leu Lys lie Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys 20 25 30 <210〉 418 <211> 32 <212〉 PRT <213>現代人 <400> 418

Gly Val Pro Asp Arg Phe Ser Gly Thr Gly Ala Gly Thr Asp Phe Thr 15 10 15

Leu Lys He Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys 20 25 30 <210> 419 <211〉 32 <212〉 PRT <213〉現代人 <400〉 419

Gly lie Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr lie Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 -392- 200927761 <210> 420 <211> 32 <212〉 PRT <213〉現代人 <400> 420

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 15 10 15

Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 ❹ <210> 421 <211> 32 <212> PRT <213〉現代人 <400〉 421

Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr He Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys 20 25 30 <210> 422 <211> 32 <212〉PRT <213>現代人 <400〉 422

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr -393 - 200927761 15 10 15

Leu Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys 20 25 30 <210> 423 <211〉 32 <212〉 PRT <213〉現代人 <400〉 423

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Phe Cys 20 25 30 <210> 424 <211〉 32 <212> PRT <213〉現代人 <400> 424

Gly Val Pro Asp Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Tyr Tyr Cys 20 25 30 <210〉 425 •394- 200927761 <211> 32 <212〉 PRT <213〉現代人 <400〉 425

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr lie Ser Ser Leu Gin Ala Asp Asp Val Ala Val Tyr Tyr Cys 20 25 30

<210〉 426 <211> 32 <212〉 PRT <213〉現代人 <400> 426

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr lie Ser Gly Leu Gin Ala Glu Asp Val Ala Leu Tyr Tyr Cys 20 25 30 <210> 427 <211> 32 <212〉PRT <213〉現代人 <400〉 427

Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15 -395 - 200927761

Leu Thr lie Ser Ser Leu Gin Ala Glu Asp Val Ala Val Phe Tyr Cys 20 25 30 <210〉 428 <211> 32 <212〉 PRT <213〉現代人 <400> 428

Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr He Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210〉 429 <211> 32 <212〉 PRT <213〉現代人 <400> 429

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210> 430 <211〉 32 -396- 200927761 <212〉 PRT <213>現代人 <400> 430

Gly lie Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 15 10 15

Leu Thr lie Ser Ser Leu Gin Ser Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30

<210> 431 <211> 32 <212> PRT <213〉現代人 <400> 431

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15

Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Ala Tyr Tyr Cys 20 25 30 o <210> 432 <211> 32 <212〉 PRT <213〉現代人 <400〉 432

Gly Val Pro Ser Arg Val Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15 -397 - 200927761

Leu Thr lie Arg Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210〉 433 <211> 32 <212> PRT <213〉現代人 <400〉 433

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr Leu Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210〉 434 <211> 32 <212〉 PRT <213>現代人 <4〇〇> 434

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr lie Ser Ser Leu Gin Pro Glu Asn Phe Ala Thr Tyr Tyr Cys 20 25 30

<210〉 435 <211> 32 <212> PRT -398- 200927761 <213〉現代人 <400〉 435

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr Phe Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30

<210〉 436 <211〉 32 <212〉 PRT <213〉現代人 <400〉 436

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Leu Thr Leu Ser Ser Leu Gin Pro Glu Asp Phe Ala Ser Tyr Tyr Cys 20 25 30 <210> 437 <211> 32 <212> PRT <213>現代人 <400〉 437

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15 -399 - 200927761

Leu Thr lie Ser Ser Leu Gin Pro Glu Asp Phe Ala Ser Tyr Tyr Cys 20 25 30 <210〉 438 <211> 32 <212〉 PRT <213〉現代人 <400〉 438

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15

Phe Thr He Ser Ser Leu Gin Pro Glu Asp He Ala Thr Tyr Tyr Cys 20 25 30 <210〉 439 <211> 32 <212〉 PRT <213〉現代人 <400> 439

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr 15 10 15

Phe Thr He Ser Ser Leu Gin Pro Glu Asp lie Ala Thr Tyr Tyr Cys 20 25 30 <210〉 440 <211> 10 <212> PRT <213〉現代人 •400 200927761 <4〇〇> 440

Phe Gly Gin Gly Thr Arg Leu Glu lie Lys 1 5 10 <210〉 441 <211> 10 <212> PRT <213>現代人 <400〉 441

Phe Gly Gin Gly Thr Arg Leu Glu lie lie 1 5 10 <210> 442 <211〉 10 <212> PRT <213〉現代人 <400> 442

Phe Gly Gin Gly Thr Lys Leu Glu lie Lys

Ol 5 10 <210〉 443 <211> 10 <212〉 PRT <213〉現代人 <4〇〇> 443

Phe Gly Gly Gly Thr Lys Val Glu He Lys 1 5 10 -401 200927761 <210〉 444 <211> 10 <212〉 PRT <213>現代人 <4〇〇> 444

Phe Gly His Gly Thr Arg Leu Glu He Lys 1 <210〉 445 <211> 10 <212〉 PRT <213〉現代人 <400〉 445 10

Phe Gly Pro Gly Thr Lys Val Asp lie Lys 1 <210〉 446 <211> 10 <212〉 PRT <213〉現代人 <400> 446 10

Phe Gly Gin Gly Thr Lys Val Glu lie Lys

1 5 10 <210〉 447 <211> 10 <212〉 PRT -402 200927761 <213〉現代人 <400〉 447 Phe Gly Pro Gly Thr Lys Val Glu He Lys 1 5 10 <210〉 448 <211> 10 <212> PRT <213> 現代人 <400〉 448 Phe Gly Gly Gly Thr Lys Val Ala He Lys 1 5 10 <210〉 449 <211〉 10 <212〉 PRT <213> 現代人 <400〉 449

Phe Gly Pro Gly Thr Lys Met Asp lie Lys V 1 5 10 <210〉 450 <211〉 10 <212〉 PRT <213> 現代人 <400〉 450

Phe Gly Gin Gly Thr Lys Val Glu Phe Lys -403 200927761 <210> 451 <211> 10 <212〉 PRT <213〉現代人 <400〉 451

Phe Gly Gly Gly Thr Lys Val Glu He Arg 1 5 10 <210> 452 <211> 25 <212〉 PRT <213〉現代人 <400〉 452

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser 20 25 <210〉 453 <211> 25 <212> PRT <213〉現代人 <400> 453

Gin Val His Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15 404- 200927761

Ser Val Lys Val Ser Cys Lys Val Ser 20 25 <210〉 454 <211> 25 <212> PRT <213〉現代人 <4〇〇> 454

Gin Val Gin Leu Val Gin Ser Gly Ala Glu Val Arg Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Val Ser 20 25 <210> 455 <211> 25 <212〉 PRT <213〉現代人 <400〉 455

Gin Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 15 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser 20 25 <210〉 456 <211> 25 -405 - 200927761 <212〉 PRT <213〉現代人 <400〉 456

Gin He Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gin 15 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser 20 25 <210〉 457 <211〉 25 <212〉 PRT <213>現代人 <400〉 457

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 458 <211> 25 <212〉 PRT <213〉現代人 <400〉 458

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15 -406 200927761

Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 459 <211> 25 <212〉 PRT <213〉現代人 <400> 459

Glu Val Gin Leu Leu Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser 20 25 <210> 460 <211> 25 <212> PRT <213〉現代人 <400〉 460

Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25

<210〉 461 <211> 25 <212〉 PRT -407- 200927761 <213〉現代人 <400〉 461

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 462 <211> 25 <212> PRT <213〉現代人 <400〉 462

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser 20 25 <210> 463 <211> 25 <212> PRT <213>現代人 <400〉 463

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15 -408- 200927761

Thr Leu Ser Leu Asn Cys Thr Val Ser 20 25 <210> 464 <211> 25 <212〉 PRT <213〉現代人 <4〇〇> 464

Gin Val Gin Leu Gin Gin Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 15 10 15

O

Thr Leu Ser Leu Thr Cys Ala Val Tyr 20 25 <210〉 465 <211> 25 <212〉 PRT <213〉現代人 <400> 465

Gin Val Gin Leu Gin Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 15 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser 20 25 <210〉 466 <211〉 25 <212> PRT <213〉現代人 -409- 200927761 <400〉 466

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Leu Lys Lys Pro Gly Glu 15 10 15

Ser Leu Lys lie Ser Cys Lys Gly Ser 20 25 <210> 467 <211> 25 <212> PRT <213>現代人 <400〉 467

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys lie Ser Cys Lys Gly Ser 20 25 <210〉 468 <211〉 25 <212〉 PRT <213〉現代人 <400〉 468

Gin Val Gin Leu Gin Gin Ser Gly Pro Gly Leu Val Lys Pro Ser Gin 15 10 15

Thr Leu Ser Leu Thr Cys Ala He Ser -410 200927761 20 25 <210> 469 <211〉 14 <212〉 PRT <213〉現代人 <400〉 469

Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly 1 5 10 O <210> 470 <211〉 14 <212> PRT <213>現代人 <400〉 470

Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Met Gly 1 5 10

<210> 471 <211〉 14 <212〉 PRT <213〉現代人 <400〉 471

Trp lie Arg Gin Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala 1 5 10 <210〉 472 <211> 14 -411 - 200927761 <212〉 PRT <213〉現代人 <400> 472

Trp He Arg Gin Pro Pro Gly Lys Ala Leu Glu Trp Leu Val 1 5 10 <210> 473 <211> 14 <212〉 PRT <213〉現代人 <400〉 473

Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 1 5 10 <210> 474 <211> 14 <212〉PRT <213>現代人 <4〇〇> 474

Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 1 5 10 <210> 475 <211> 14 <212〉 PRT <213〉現代人 <400〉 475 -412- 200927761

Trp He Arg Gin His Pro Gly Lys Gly Leu Glu Trp lie Gly 1 5 10 <210> 476 <211〉 14 <212〉 PRT <213〉現代人 <400〉 476

Trp Val Arg Gin His Pro Gly Lys Gly Leu Glu Trp lie Gly 1 5 10

O <210〉 477 <211〉 14 <212〉 PRT <213〉現代人 <400> 477

Trp lie Arg Gin Pro Pro Gly Lys Gly Leu Glu Trp lie Gly 1 5 10

<210〉 478 <211> 14 <212〉 PRT <213〉現代人 <400〉 478

Trp lie Arg Gin Pro Ala Gly Lys Gly Leu Glu Trp lie Gly 1 5 10 <210〉 479 -413 - 200927761 <211> 14 <212〉 PRT <213>現代人 <400〉 479

Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 1 5 10 <210〉 480 <211> 14 <212〉 PRT <213〉現代人 <400〉 480

Trp lie Arg Gin Ser Pro Ser Arg Gly Leu Glu Trp Leu Gly 1 5 10 <210〉 481 <211> 32 <212> PRT <213〉現代人 <400> 481

Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu 15 10 15

Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 482 <211> 32 -414- 200927761 <212> PRT <213〉現代人 <400〉 482

Arg Val Thr Met Thr Arg Asp Thr Ser lie Ser Thr Ala Tyr Met Glu 15 10 15

Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30

<210〉 483 <211〉 32 <212〉 PRT <213〉現代人 <400〉 483

Arg Val Thr Met Leu Glu Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu 15 10 15

Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr 20 25 30 〇 <210> 484 <211〉 32 <212〉 PRT <213〉現代人 <4〇〇> 484

Arg Leu Thr lie Ser Lys Asp Thr Ser Lys Ser Gin Val Val Leu Thr 15 10 15 -415- 200927761

Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala Arg 20 25 30 <210> 485 <211〉 32 <212〉PRT <213〉現代人 <400> 485

Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Asn Gin Val Val Leu Thr 15 10 15

Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala His 20 25 30 <210〉 486 <211> 32 <212〉 PRT <213〉現代人 <400> 486

Arg Leu Thr lie Thr Lys Asp Thr Ser Lys Thr Gin Val Val Leu Thr 15 10 15

Val Thr Asp Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala His 20 25 30

<210> 487 <211> 32 <212〉 PRT -416- 200927761 <213〉現代人 <400> 487

Arg Leu Thr He Thr Lys Asp Thr Ser Lys Asn Gin Val Val Leu Thr 15 10 15

Met Thr Asn Leu Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala His 20 25 30

<210> 488 <211> 32 <212〉 PRT <213〉現代人 <400> 488

Arg Leu Thr lie Thr Lys Ala Thr Ser Lys Asn Gin Val Val Leu Thr 15 10 15

Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala His 20 25 30 o <210> 489 <211> 32 <212> PRT <213〉現代人 <400> 489

Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin 1 5 10 15 -417- 200927761

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 490 <211〉 32 <212〉 PRT <213〉現代人 <400〉 490

Arg Phe Thr He Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 15 10 15

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 20 25 30 <210〉 491 <211> 32 <212〉 PRT <213〉現代人 <400> 491

Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 1 5 10 15

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Glu Tyr Tyr Cys Ala Lys 20 25 30 <210> 492 <211> 32 <212〉 PRT <213〉現代人 -418- 200927761 <400〉 492

Arg Phe Thr lie Ser Arg Asp Asn Ser Met Asn Thr Leu Tyr Leu Gin 15 10 15

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30

<210〉 493 <211〉 32 <212> PRT <213>現代人 <400〉 493

Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 15 10 15

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 494 <211> 32 <212〉 PRT <213>現代人 <4〇〇> 494

Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 15 10 15

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Val Leu -419- 200927761 20 25 30 <210> 495 <211〉 32 <212〉 PRT <213〉現代人 <400> 495

Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Asp Leu Gin 15 10 15

Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210〉 496 <211〉 32 <212〉 PRT <213〉現代人 <400〉 496

Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe Leu Gin 15 10 15

Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Leu 20 25 30 <210> 497 <211> 32 <212〉 PRT <213〉現代人 -420- 200927761 <400> 497

Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Val Tyr Leu Gin 15 10 15

Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30

<210〉 498 <211> 32 <212〉 PRT <213〉現代人 <400〉 498

Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gin 15 10 15

Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 499 <211> 32 <212〉 PRT <213〉現代人 <400> 499

Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Asn 15 10 15

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 -421 - 200927761 <210〉 500 <211> 32 <212〉 PRT <213>現代人 <400> 500

Arg Val Asn Met Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Lys 15 10 15

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 501 <211〉 32 <212> PRT <213〉現代人 <400> 501

Arg Val Thr He Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Lys 15 10 15

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 502 <211〉 32 <212> PRT <213>現代人 <400〉 502 -422- 200927761

Arg lie Thr lie Ser Ala Asp Thr Ser Lys Asn Gin Phe Ser Leu Lys 15 10 15

Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210〉 503 <211> 32 <212> PRT <213〉現代人 O <400〉 503

Arg lie Thr Lys Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Lys 15 10 15

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30

<210> 504 <211〉 32 <212〉 PRT <213〉現代人 <400〉 504

Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Lys 15 10 15

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Ser 20 25 30 -423 - 200927761 <210> 505 <211> 32 <212> PRT <213〉現代人 <400〉 505

Arg Val Thr lie Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Lys 15 10 15

Leu Phe Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala Arg 20 25 30 <210> 506 <211> 32 <212〉 PRT <213〉現代人 <400> 506

Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gin Phe Ser Leu Lys 15 10 15

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 507 <211〉 32 <212〉 PRT <213〉現代人 <400> 507 -424- 200927761

Arg Val Thr lie Ser He Val Thr Ser Arg Asn Gin Phe Ser Leu Lys 15 10 15

Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 508 <211> 32 <212〉 PRT <213〉現代人

<400〉 508

Gin Val Thr lie Ser Ala Asp Lys Ser lie Ser Thr Ala Tyr Leu Gin 15 10 15

Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg 20 25 30 <210> 509 <211〉 32 <212〉 PRT <213〉現代人 <400> 509

Gin Val Thr lie Ser Ala Asp Lys Ser lie Asn Thr Ala Tyr Leu Gin 15 10 15

Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg 20 25 30 -425 - 200927761 <210〉 510 <211> 32 <212〉 <213> PRT 現代人 <400〉 510

Arg lie Thr lie Asn Pro Asp Thr Ser Lys Asn Gin Phe Ser Leu Gin 15 10 15

Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 511 <211〉 11 <212> <213> PRT 現代人 <400> 511

Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210〉 512 <211〉 11 <212〉 <213> PRT 現代人 <400> 512

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> 513 -426 200927761

<211> 11 <212> PRT <213> 現代人 <400> 513 Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 1 5 10 <210〉 514 <211〉 11 <212〉 PRT <213> 現代人 <400〉 514 Trp Gly Gin Gly Ser Leu Val Thr Val Ser Pro 1 5 10 <210〉 515 <211> 11 <212〉 PRT <213> 現代人 <400〉 515

Trp Gly Gin Gly Thr Lys Val Thr Val Ser Ser 1 <210〉 516 <211〉 11 <212〉 PRT <213> 現代人 <400> 516 -427- 200927761

Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 517 <211> 657 <212〉PRT <213〉現代人 <400〉 517

Gly Ala Tyr Gly Thr Asn Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Met Thr Asn Trp Ser Asn Met Thr 20 25 30

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Met Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Met Thr Asn Gly Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Ala Cys Asn Thr Ala Tyr Met 100 105 110 -428- 200927761

Thr Asn Ala Ala Tyr Thr Gly Gly Thr Thr Tyr Cys Ala Arg Cys Ala 115 120 125

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Trp Ser Asn 130 135 140

Cys Cys Asn Met Gly Asn Met Gly Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Thr Gly 165 170 175

Gly Gly Ala Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Ala Ala Tyr Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255 -429- 200927761

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Trp Ser Asn 275 280 285

Ala Cys Asn Cys Ala Tyr Thr Gly Gly Cys Cys Asn Ala Thr His Ala 290 295 300

Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys 305 310 315 320

Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335

Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys 340 345 350

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr 355 360 365

Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg 370 375 380

Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala 385 390 395 400

Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly 405 410 415 -430- 200927761

Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr 420 425 430

Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala 435 440 445

Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr 450 455 460

Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg 465 470 475 480

Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly 485 490 495

Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala 500 505 510

Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn 515 520 525

Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540

Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser 545 550 555 560 -431 - 200927761

Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg 565 570 575

Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly 580 585 590

Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala 595 600 605

Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 610 615 620

Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr 625 630 635 640

Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly 645 650 655

Tyr <210> 518 <211〉 657 <212〉 PRT <213〉現代人 <400〉 518

Gly Ala Tyr Gly Thr Asn Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15 -432- 200927761

Ala Arg Trp Ser Asn Cys Cys Asn Met Thr Asn Trp Ser Asn Met Thr 20 25 30

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Met Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Met Thr Asn Gly Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Ala Cys Asn Thr Ala Tyr Met 100 105 110

Thr Asn Ala Ala Tyr Thr Gly Gly Thr Thr Tyr Cys Ala Arg Cys Ala 115 120 125

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Trp Ser Asn 130 135 140

Cys Cys Asn Met Gly Asn Met Gly Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Thr Gly -433 - 200927761 165 170 175

Gly Gly Ala Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr His Cys Ala Arg Gly Gly Asn 275 280 285

Ala Cys Asn Cys Ala Tyr Thr Gly Gly Cys Cys Asn Ala Cys Asn Ala 290 295 300

Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys 305 310 315 320 -434- 200927761

Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335

Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys 340 345 350

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr 355 360 365

Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg 370 375 380

Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala 385 390 395 400

Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly 405 410 415

Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr 420 425 430

Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala 435 440 445

Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr 450 455 460

Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg -435 - 200927761 465 470 475 480

Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly 485 490 495

Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala 500 505 510

Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn 515 520 525

Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540

Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser 545 550 555 560

Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg 565 570 575

Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly 580 585 590

Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala 595 600 605

Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 610 615 620 -436- 200927761

Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr 625 630 635 640

Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly 645 650 655

Tyr

<210> 519 <211〉 657 <212> PRT <213〉現代人 <400> 519

Gly Ala Tyr Gly Thr Asn Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Met Thr Asn Trp Ser Asn Met Thr 20 25 30 〇

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Met Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80 -437- 200927761

Arg Trp Ser Asn Met Thr Asn Gly Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Ala Cys Asn Thr Ala Tyr Met 100 105 110

Thr Asn Ala Ala Tyr Thr Gly Gly Met Thr Asn Cys Ala Arg Cys Ala 115 120 125

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Trp Ser Asn 130 135 140

Cys Cys Asn Met Gly Asn Met Gly Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Thr Gly 165 170 175

Gly Gly Ala Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly Ala 210 215 220 -438 200927761

Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Gly Gly Asn 275 280 285

Ala Cys Asn Cys Ala Tyr Thr Gly Gly Cys Cys Asn Ala Thr His Ala 290 295 300

Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys 305 310 315 320

Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335 〇

Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys 340 345 350

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr 355 360 365

Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg 370 375 380 -439- 200927761

Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala 385 390 395 400

Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly 405 410 415

Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr 420 425 430

Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala 435 440 445

Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr 450 455 460

Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg 465 470 475 480

Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly 485 490 495

Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala 500 505 510

Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn 515 520 525 -440- 200927761

Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540

Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser 545 550 555 560

Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg 565 570 575

Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly 580 585 590

Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala 595 600 605

Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 610 615 620

Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr 625 630 635 640

Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly 645 650 655

Tyr <210〉 520 <211> 657 -441 - 200927761 <212〉 PRT <213〉現代人 <400> 520

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Ala Cys Asn Cys Cys Asn Met Thr Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Ala Cys Asn Cys Cys Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Met Thr Asn Met Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Arg Ala Cys Asn Thr Ala Tyr Met 100 105 110

Thr Asn Thr Ala Tyr Thr Gly Gly Thr Ala Tyr Met Thr Asn Cys Ala 115 120 125

Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn -442- 200927761 130 135 140

Cys Cys Asn Cys Ala Arg Met Thr Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Gly Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190 〇

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Gly Gly Asn 275 280 285 -443 - 200927761

Ala Thr His Cys Ala Arg Met Thr Asn Cys Cys Asn Thr Gly Tyr Trp 290 295 300

Ser Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys 305 310 315 320

Asn Ala Ala Arg Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335

Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys 340 345 350

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr 355 360 365

Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg 370 375 380

Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala 385 390 395 400

Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly 405 410 415

Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr 420 425 430

Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala -444- 200927761 435 440 445

Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr 450 455 460

Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg 465 470 475 480

Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly 485 490 495 ❹

Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala 500 505 510

Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn 515 520 525

Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540 0

Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser 545 550 555 560

Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg 565 570 575

Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly 580 585 590 -445 - 200927761

Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala 595 600 605

Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 610 615 620

Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr 625 630 635 640

Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly 645 650 655

Tyr <210〉 521 <211> 657 <212> PRT <213〉現代人 <400> 521

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Ala Cys Asn Cys Cys Asn Met Thr Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Ala Cys Asn Cys Cys Asn Gly Gly Asn 35 40 45 -446- 200927761

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Met Thr Asn Met Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Arg Ala Cys Asn Thr Ala Tyr Met 100 105 110

Thr Asn Thr Ala Tyr Thr Gly Gly Thr Ala Tyr Met Thr Asn Cys Ala 115 120 125

Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Cys Ala Arg Met Thr Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Gly Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190 -447- 200927761

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Trp Ser Asn 275 280 285

Ala Thr His Cys Ala Arg Met Thr Asn Cys Cys Asn Met Thr Asn Ala 290 295 300

Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala Cys 305 310 315 320

Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335

Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys 340 345 350 -448- 200927761

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr 355 360 365

Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg 370 375 380

Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala 385 390 395 400

Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly 405 410 415

Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr 420 425 430

Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala 435 440 445

Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr 450 455 460

Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg 465 470 475 480

Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly 485 490 495 -449- 200927761

Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala 500 505 510

Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn 515 520 525

Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540

Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser 545 550 555 560

Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg 565 570 575

Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly 580 585 590

Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala 595 600 605

Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 610 615 620

Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr 625 630 635 640

Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly 645 650 655 -450- 200927761

Tyr <210〉 522 <211〉 657 <212> PRT <213〉現代人 <400〉 522

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Ala Cys Asn Cys Cys Asn Met Thr Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Ala Cys Asn Cys Cys Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Met Thr Asn Met Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Arg Ala Cys Asn Thr Ala Tyr Met -451 - 200927761 100 105 110

Thr Asn Thr Ala Tyr Thr Gly Gly Thr Thr Tyr Met Thr Asn Cys Ala 115 120 125

Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Cys Ala Arg Cys Cys Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Gly Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255 -452- 200927761

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Trp Ser Asn 275 280 285

Ala Thr His Cys Ala Arg Met Thr Asn Cys Cys Asn Ala Thr His Ala 290 295 300

Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Tyr Gly Gly Asn Ala Cys 305 310 315 320

Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335

Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys 340 345 350

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr 355 360 365

Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg 370 375 380

Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala 385 390 395 400

Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly -453 - 200927761 405 410 415

Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr 420 425 430

Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala 435 440 445

Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr 450 455 460

Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg 465 470 475 480

Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly 485 490 495

Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala 500 505 510

Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn 515 520 525

Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540

Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser 545 550 555 560 -454- 200927761

Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg 565 570 575

Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly 580 585 590

Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala 595 600 605

Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 610 615 620

Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr 625 630 635 640

Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly 645 650 655

Tyr ❹ <210〉 523 <211〉 642 <212> PRT <213〉現代人 <400> 523

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15 -455 - 200927761

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Gly Asn Ala Thr His Gly Cys Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Thr 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Thr Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Met 145 150 155 160 456 200927761

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Ala Ala Tyr Thr Ala 260 265 270 〇

Tyr Ala Ala Tyr Trp Ser Asn Gly Cys Asn Cys Cys Asn Thr Thr Tyr 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320 -457- 200927761

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -458 - 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575 〇

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620 -459- 200927761

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210> 524 <211〉 642 <212〉 PRT <213〉現代人 <400〉 524

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Thr His Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Gly Asn Ala Thr His Trp Ser Asn Ala Ala Tyr Gly Ala Tyr -460- 200927761 85 90 95

Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Thr 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140 ❹

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190 ❹

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240 -461 - 200927761

Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Ala Ala Arg Thr Ala 260 265 270

Tyr Ala Ala Tyr Trp Ser Asn Gly Thr Asn Cys Cys Asn Met Thr Asn 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr -462- 200927761 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

O

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495 〇

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540 -463 - 200927761

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210〉 525 <211> 657 <212〉 PRT <213>現代人 <400〉 525

Ala Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15 -464- 200927761

Ala Arg Ala Cys Asn Cys Cys Asn Met Thr Asn Trp Ser Asn Trp Ser 20 25 30

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Met Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Met Thr Asn Gly Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Ala Cys Asn Thr Ala Tyr Met 100 105 110

Thr Asn Trp Ser Asn Thr Gly Gly Met Thr Asn Cys Ala Arg Cys Ala 115 120 125

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Met Gly Asn Met Thr Asn Met Thr Asn Ala Thr His Thr 145 150 155 160 -465 - 200927761

Ala Tyr Ala Ala Arg Ala Thr His Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp 195 200 205

Ser Asn Gly Gly Asn Gly Cys Asn Gly Gly Asn Ala Cys Asn Gly Ala 210 215 220

Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Gly Cys Asn 275 280 285

Ala Cys Asn Cys Ala Arg Thr Thr Tyr Cys Cys Asn Cys Ala Tyr Ala 290 295 300

Cys Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Ala Cys 305 310 315 320 -466- 200927761

Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala Arg 325 330 335

Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys 340 345 350

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr 355 360 365

Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg 370 375 380

Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala 385 390 395 400

Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly 405 410 415

Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr 420 425 430

Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala 435 440 445

Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr 450 455 460 -467- 200927761

Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg 465 470 475 480

Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly 485 490 495

Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala 500 505 510

Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn 515 520 525

Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540

Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser 545 550 555 560

Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg 565 570 575

Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly 580 585 590

Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala 595 600 605

Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 610 615 620 -468 - 200927761

Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr 625 630 635 640

Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly 645 650 655

Tyr

<210〉 526 <211〉 657 <212〉 PRT <213〉現代人 <400> 526

Gly Ala Arg Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Ala Cys Asn Cys Cys Asn Met Thr Asn Trp Ser Asn Trp Ser Q 20 25 30

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Met Thr Asn Gly Gly Asn 35 40 45

Cys Ala Arg Cys Cys Asn Gly Cys Asn Trp Ser Asn Ala Thr His Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Trp Ser Asn Trp Ser Asn Cys Ala -469- 200927761 65 70 75 80

Arg Trp Ser Asn Met Thr Asn Gly Thr Asn Cys Ala Tyr Trp Ser Asn 85 90 95

Gly Ala Tyr Gly Gly Asn Ala Ala Tyr Ala Cys Asn Thr Ala Tyr Met 100 105 110

Thr Asn Trp Ser Asn Thr Gly Gly Met Thr Asn Cys Ala Arg Cys Ala 115 120 125

Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Cys Ala Arg Cys Cys Asn 130 135 140

Cys Cys Asn Met Gly Asn Met Thr Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Ala Ala Arg Ala Thr His Trp Ser Asn Ala Ala Tyr Met Gly 165 170 175

Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys Asn 180 185 190

Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Ala 195 200 205

Cys Asn Gly Gly Asn Gly Cys Asn Gly Gly Asn Ala Cys Asn Gly Ala 210 215 220 470- 200927761

Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Ala Arg Ala Thr His 225 230 235 240

Trp Ser Asn Met Gly Asn Gly Thr Asn Gly Ala Arg Gly Cys Asn Gly 245 250 255

Ala Arg Gly Ala Tyr Gly Thr Asn Gly Gly Asn Gly Thr Asn Thr Ala 260 265 270

Tyr Thr Ala Tyr Thr Gly Tyr Ala Thr Gly Cys Ala Arg Gly Cys Asn 275 280 285

Ala Cys Asn Cys Ala Arg Thr Thr Tyr Cys Cys Asn Cys Ala Tyr Ala 290 295 300

Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala Cys 305 310 315 320

Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg 325 330 335

Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys 340 345 350

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr 355 360 365

Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg -471 - 200927761 370 375 380

Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala 385 390 395 400

Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly 405 410 415

Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr 420 425 430

Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala 435 440 445

Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr 450 455 460

Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg 465 470 475 480

Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly 485 490 495

Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala 500 505 510

Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn 515 520 525 -472- 200927761

Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp 530 535 540

Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser 545 550 555 560

Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg 565 570 575

Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly 580 585 590

Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala 595 600 605

Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 610 615 620

Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr 625 630 635 640

Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly 645 650 655

Tyr <210〉 527 -473 - 200927761 <211> 645 <212〉 PRT <213〉現代人 <400> 527

Gly Ala Arg Ala Thr His Gly Thr Asn Met Thr Asn Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Cys Asn Met Thr 20 25 30

Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Met Thr Asn Trp 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Ala Cys Asn Gly Thr Asn Ala Thr His Trp Ser Asn Trp Ser Asn 85 90 95

Thr Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys 100 105 110

Ala Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala 115 120 125 -474- 200927761

Arg Gly Cys Asn Cys Cys Asn Met Gly Asn Met Thr Asn Met Thr Asn 130 135 140

Ala Thr His Trp Ser Asn Gly Gly Asn Gly Cys Asn Trp Ser Asn Trp 145 150 155 160

Ser Asn Met Gly Asn Gly Cys Asn Ala Cys Asn Gly Gly Asn Ala Thr 165 170 175

His Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn 180 185 190

Gly Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala 195 200 205

Cys Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys 210 215 220

Asn Ala Thr His Trp Ser Asn Met Gly Asn Met Thr Asn Gly Ala Arg 225 230 235 240

Cys Cys Asn Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Gly 245 250 255

Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala 260 265 270

Arg Thr Ala Tyr Gly Gly Asn Trp Ser Asn Trp Ser Asn Cys Cys Asn 275 280 285 -475 - 200927761

Met Gly Asn Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly 290 295 300

Gly Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr 305 310 315 320

His Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn 325 330 335

Gly Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala 340 345 350

Thr His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala 355 360 365

Tyr Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn 370 375 380

Gly Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly 385 390 395 400

Thr Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala 405 410 415

Tyr Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg 420 425 430 -476- 200927761

Gly Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala 435 440 445

Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr 450 455 460

Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn 465 470 475 480

Cys Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly 485 490 495

Ala Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala 500 505 510

Tyr Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn 515 520 525

Trp Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met 530 535 540 c

Thr Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala 545 550 555 560

Tyr Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn 565 570 575

Thr Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala 580 585 590 -477- 200927761

Cys Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser 595 600 605

Asn Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg 610 615 620

Trp Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly 625 630 635 640

Ala Arg Thr Gly Tyr 645 <210〉 528 <211> 639 <212〉 PRT <213〉現代人 <400〉 528

Gly Ala Arg Ala Thr His Gly Thr Asn Met Thr Asn Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Cys Asn Met Thr 20 25 30

Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Met Thr Asn Trp -478- 200927761 50 55 60

Ser Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Trp Ser Asn Met Gly Asn Met Thr Asn 85 90 95

Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys Ala Arg Ala 100 105 110

O

Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys 115 120 125

Asn Met Gly Asn Met Thr Asn Met Thr Asn Ala Thr His Thr Ala Tyr 130 135 140

Gly Gly Asn Gly Cys Asn Trp Ser Asn Met Gly Asn Met Gly Asn Gly 145 150 155 160 ❹

Cys Asn Ala Cys Asn Gly Gly Asn Ala Thr His Cys Cys Asn Gly Ala 165 170 175

Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Trp Ser Asn 180 185 190

Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly Ala Tyr Thr 195 200 205 -479- 200927761

Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr His Trp Ser 210 215 220

Asn Met Gly Asn Met Thr Asn Gly Ala Arg Cys Cys Asn Gly Ala Arg 225 230 235 240

Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr 245 250 255

Ala Tyr Thr Gly Tyr Cys.Ala Arg Cys Ala Arg Thr Ala Tyr Gly Gly 260 265 270

Asn Trp Ser Asn Trp Ser Asn Cys Cys Asn Met Gly Asn Trp Ser Asn 275 280 285

Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala 290 295 300

Ala Arg Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg Met Gly 305 310 315 320

Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys Cys Asn 325 330 335

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr Tyr Cys 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg Cys Ala -480- 200927761 355 360 365

Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala Cys Asn 370 375 380

Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly Tyr Met 385 390 395 400

Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr Thr Ala 405 410 415 ❹

Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala Ala Arg 420 425 430

Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr Asn Gly 435 440 445

Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg Trp Ser 450 455 460 〇

Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly Ala Arg 465 470 475 480

Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala Arg Gly 485 490 495

Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn Ala Cys 500 505 510 -481 - 200927761

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 515 520 525

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser Asn Ala 530 535 540

Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg Ala Ala 545 550 555 560

Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly Cys Asn 565 570 575

Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala Tyr Cys 580 585 590

Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Cys Cys 595 600 605

Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr Thr Tyr 610 615 620

Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly Tyr 625 630 635 <210> 529 <211> 642 <212〉 PRT <213〉現代人 -482- 200927761 <400> 529

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Gly Asn Ala Thr His Met Gly Asn Ala Ala Tyr Gly Ala Tyr 85 90 95

Met Thr Asn Gly Gly Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Gly Asn Met Thr Asn Ala Thr His 130 135 140 -483 - 200927761

Thr.Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Arg Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Met Thr Asn Cys Ala Arg Cys Ala 260 265 270

Tyr Ala Ala Tyr Trp Ser Asn Thr Ala Tyr Cys Cys Asn Cys Cys Asn 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300 -484- 200927761

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445 -485 - 200927761

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 -486- 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

<210> 530 <211〉 660 <212〉 PRT <213〉現代人 <400〉 530

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala -487- 200927761 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Thr Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Thr Thr Tyr Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Ala Cys Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220 -488 - 200927761

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Thr Thr Tyr Cys Cys Asn Thr 290 295 300

Gly Gly Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr -489 - 200927761 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525 •490- 200927761

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660 <210〉 531 -491 - 200927761 <211〉 660 <212> PRT <213〉現代人 <400> 531

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125 -492- 200927761

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285 -493 - 200927761

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Ala Cys Asn Ala Cys Asn Thr 290 295 300

Gly Gly Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430 -494- 200927761

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540 〇

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590 -495 - 200927761

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660 <210> 532 <211> 660 <212〉 PRT <213〉現代人 <400〉 532

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn -496 - 200927761 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Ala Ala Tyr Gly Thr Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

O

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140 〇

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190 -497- 200927761

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Cys Asn Cys Cys Asn Met 290 295 300

Gly Asn Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly -498- 200927761 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400 ❹

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445 c

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495 -499- 200927761

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala -500- 200927761 645 650 655

Arg Thr Gly Tyr 660 <210〉 533 <211〉 660 <212〉 PRT <213〉現代人 <400> 533

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Ala Ala Tyr Gly Thr Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95 -501 - 200927761

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly 245 250 255 -502- 200927761

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Cys Asn Cys Cys Asn Met 290 295 300

Gly Asn Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400 -503 - 200927761

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560 -504- 200927761

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660 <210> 534 <211〉 660 <212> PRT <213>現代人 <400〉 534

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys -505 - 200927761 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala 145 150 155 160 -506- 200927761

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Gly Gly Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Ala Thr His Trp Ser Asn Met 290 295 300

Gly Asn Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly -507- 200927761 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 41.0 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460 -508- 200927761

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn -509- 200927761 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660

O <210> 535 <211〉 660 <212> PRT <213>現代人 <400〉 535

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 1 5 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60 -510- 200927761

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Met Thr Asn Thr Ala Tyr Ala Ala Tyr 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175 〇

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220 -511 - 200927761

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Tyr Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Ala Cys Asn Ala Cys Asn Thr 290 295 300

Gly Gly Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365 512 200927761

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525 -513 - 200927761

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660 -514- 200927761 <210〉 536 <211〉 660 <212〉 PRT <213〉現代人 <400〉 536

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

O

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80 〇

Arg Trp Ser Asn Gly Thr Asn Met Thr Asn Thr Ala Tyr Ala Ala Tyr 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125 -515- 200927761

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Tyr Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg -516- 200927761 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Ala Cys Asn Ala Cys Asn Thr 290 295 300

Gly Gly Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335 c

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380 〇

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430 -517- 200927761

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr -518- 200927761 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640 ❹

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660

<210〉 537 <211〉 660 <212〉 PRT <213〉現代人 <400> 537

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30 -519- 200927761

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Gly Thr Asn Met Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175

Asn Met Gly Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190 -520- 200927761

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Gly Gly Asn Met Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Met Thr 260 265 270

Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Ala Cys Asn Ala Thr Gly Thr 290 295 300

Thr Tyr Trp Ser Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Met Thr Asn Gly Ala Arg Ala Thr His 325 330 335 -521 - 200927761

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495 -522- 200927761

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640 -523 - 200927761

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660 <210〉 538 <211> 660 <212> PRT <213〉現代人 <400〉 538

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Met Thr Asn Gly Ala Tyr Trp Ser Asn 85 90 95 -524- 200927761

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala 145 150 155 160

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Ala Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly - 525 - 200927761 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Thr Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Tyr Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Ala Tyr Trp Ser Asn Ala Cys Asn Cys Cys Asn Met 290 295 300

Thr Asn Ala Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Cys Asn Ala Thr His 325 330 335

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400 -526- 200927761

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr -527- 200927761 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660 <210〉 539 <211> 660 <212〉PRT <213〉現代人 <400〉 539 -528- 200927761

Gly Ala Tyr Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Ala Tyr Trp Ser Asn Met Thr 20 25 30

Asn Gly Cys Asn Gly Thr Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Ala Tyr Thr Gly Tyr Ala Ala Arg Trp Ser Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Met Thr Asn Thr Ala Tyr Met Gly Asn 85 90 95

Trp Ser Asn Ala Ala Tyr Ala Ala Tyr Ala Ala Arg Ala Ala Tyr Thr 100 105 110 〇

Ala Tyr Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala 115 120 125

Arg Cys Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Cys Ala Arg 130 135 140

Cys Cys Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala 145 150 155 160 -529 - 200927761

Thr His Thr Ala Tyr Thr Gly Gly Gly Cys Asn Trp Ser Asn Gly Cys 165 170 175

Asn Met Gly Asn Gly Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn 180 185 190

Cys Cys Asn Gly Ala Tyr Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly 195 200 205

Gly Asn Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys 210 215 220

Asn Gly Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn 225 230 235 240

Ala Thr His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Gly 245 250 255

Cys Asn Gly Ala Arg Gly Ala Tyr Gly Thr Asn Gly Cys Asn Gly Thr 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg 275 280 285

Thr Ala Tyr Thr Thr Tyr Ala Thr His Ala Cys Asn Cys Cys Asn Met 290 295 300 -530- 200927761

Thr Asn Ala Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly 305 310 315 320

Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His 325 330 335

Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr 355 360 365

His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr 370 375 380

Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly 385 390 395 400

Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr 405 410 415 ❹

Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr 420 425 430

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 435 440 445

Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala 450 455 460 -531 - 200927761

Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn 465 470 475 480

Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys 485 490 495

Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala 500 505 510

Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr 515 520 525

Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp 530 535 540

Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr 565 570 575

Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr 580 585 590

Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys 595 600 605 -532- 200927761

Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn 610 615 620

Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp 625 630 635 640

Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala 645 650 655

Arg Thr Gly Tyr 660 <210> 540 <211〉642 <212> PRT <213〉現代人 <400〉 540

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60 - 533 - 200927761

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Cys Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Thr Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Trp Ser Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Ala Ala Arg Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr -534- 200927761 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

O

Tyr Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Cys Cys Asn Thr Thr Tyr 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320 〇

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365 -535 - 200927761

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 200927761 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575 ❹

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620 ❹

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

<210〉 541 <211> 642 <212> PRT -537- 200927761 <213〉現代人 <400〉 541

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 1 5 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Gly Cys Asn Thr Gly Gly Met Thr Asn Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Trp Ser Asn Met Thr Asn Ala Thr His 130 135 140 -538 - 200927761

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Ala Ala Tyr Ala Cys Asn Thr Ala Tyr Cys Cys Asn Thr Thr Tyr 275 280 285 -539- 200927761

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Ala Thr Gly Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445 -540- 200927761

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590 -541 - 200927761

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210> 542 <211> 645 <212〉 PRT <213〉現代人 <400〉 542

Gly Ala Arg Ala Thr His Gly Thr Asn Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Gly Cys Asn Ala Cys Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 35 40 45

Gly Ala Arg Met Gly Asn Gly Cys Asn Ala Cys Asn Met Thr Asn Trp 50 55 60 -542- 200927761

Ser Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr 85 90 95

Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Gly Ala Tyr Cys Cys Asn Gly Gly Asn Cys Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Met Gly Asn Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Gly Asn Gly Cys Asn Trp Ser Asn Met Gly Asn Met 145 150 155 160

Gly Asn Gly Cys Asn Ala Cys Asn Gly Gly Asn Ala Thr His Cys Cys 165 170 175

Asn Gly Cys Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Arg Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr -543 - 200927761 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Trp Ser Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Gly Thr Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Cys Ala 260 265 270

Tyr Ala Ala Tyr Ala Ala Tyr Thr Gly Gly Cys Cys Asn Cys Cys Asn 275 280 285

Thr Gly Gly Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly 290 295 300

Gly Asn Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr 305 310 315 320

His Ala Ala Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn 325 330 335

Gly Cys Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala 340 345 350

Thr His Thr Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala 355 360 365 -544- 200927761

Tyr Gly Ala Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn 370 375 380

Gly Gly Asn Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly 385 390 395 400

Thr Asn Thr Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala 405 410 415

Tyr Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg 420 425 430

Gly Cys Asn Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala 435 440 445

Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr 450 455 460

Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn 465 470 475 480

Cys Ala Arg Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly 485 490 495

Ala Arg Cys Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala 500 505 510

Tyr Trp Ser Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn -545- 200927761 515 520 525

Trp Ser Asn Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met 530 535 540

Thr Asn Trp Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala 545 550 555 560

Tyr Gly Ala Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn 565 570 575

Thr Ala Tyr Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala 580 585 590

Cys Asn Cys Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser 595 600 605

Asn Trp Ser Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg 610 615 620

Trp Ser Asn Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly 625 630 635 640

Ala Arg Thr Gly Tyr 645

<210> 543 <211> 642 <212> PRT 546- 200927761 <213〉現代人 <400> 543

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Gly Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Met Gly Asn Thr Gly Gly 85 90 95

Met Thr Asn Gly Cys Asn Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140 -547- 200927761

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Gly Cys 260 265 270

Asn Ala Ala Tyr Trp Ser Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn 275 280 285 -548 - 200927761

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Thr Thr Tyr Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445 -549- 200927761

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590 -550 200927761

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

O <210〉544 <211> 642 <212〉 PRT <213〉現代人 <400〉544

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15 〇

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60 -551 - 200927761

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Ala Cys Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Thr Thr Tyr Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr -552- 200927761 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Gly Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270 〇

Asn Cys Ala Tyr Trp Ser Asn Gly Cys Asn Cys Cys Asn Thr Thr Tyr 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Ala 290 295 300

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365 -553 - 200927761

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn -554- 200927761 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575 ❹

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620 ❹

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

<210> 545 <211〉 639 <212> PRT -555 - 200927761 <213>現代人 <400〉 545

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Met Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Thr His Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140 -556- 200927761

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn 275 280 285 -557- 200927761

Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala Cys Asn Ala 290 295 300

Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala Arg Met Gly 305 310 315 320

Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn Cys Cys Asn 325 330 335

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr Thr Tyr Cys 340 345 350

Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala Arg Cys Ala 355 360 365

Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn Ala Cys Asn 370 375 380

Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr Gly Tyr Met 385 390 395 400

Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr Tyr Thr Ala 405 410 415

Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn Ala Ala Arg 420 425 430

Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly Thr Asn Gly 435 440 445 -558 - 200927761

Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala Arg Trp Ser 450 455 460

Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg Gly Ala Arg 465 470 475 480

Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys Ala Arg Gly 485 490 495

Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser Asn Ala Cys 500 505 510

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 515 520 525

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp Ser Asn Ala 530 535 540

Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala Arg Ala Ala 545 550 555 560

Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr Gly Cys Asn 565 570 575

Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys Ala Tyr Cys 580 585 590 -559- 200927761

Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Cys Cys 595 600 605

Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn Thr Thr Tyr 610 615 620

Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr Gly Tyr 625 630 635 <210〉 546 <211> 642 <212〉 PRT <213〉現代人 <400〉546

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -560- 200927761

Arg Trp Ser Asn Ala Thr His Met Gly Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Met Gly Asn Cys Cys Asn Gly Gly Asn Ala Ala Tyr Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Met Gly Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -561 - 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Trp Ser Asn Ala Thr His Cys Cys Asn Met Thr Asn 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -562- 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp - 563 - 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210〉 547 <211> 642 <212〉 PRT <213〉現代人 <400> 547 -564- 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Gly 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Met Gly Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110 〇

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Met 145 150 155 160 -565 - 200927761

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 210 215 220

Asn Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Ala Thr 260 265 270

His Thr Ala Tyr Trp Ser Asn Ala Cys Asn Trp Ser Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300 566- 200927761

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415 〇

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -567- 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 568- 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

<210〉 548 <211> 642 <212〉 PRT <213〉現代人 <400〉 548

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Q

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -569 - 200927761

Arg Met Gly Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Gly Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Cys Asn Gly Ala Arg Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -570- 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Ala Thr His Ala Cys Asn Cys Cys Asn Ala Thr His 275 280 285 ❹

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Thr 305 310 315 320

His Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335 〇

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -571 - 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -572- 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

O

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210> 549 <211> 642 <212〉PRT <213〉現代人 <400> 549 -573 - 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Met Gly Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Ala Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160 -574- 200927761

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Ala Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Ala Cys Asn Cys Cys Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300 -575 - 200927761

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -576- 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 -577- 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210〉 550 <211> 642 <212> PRT <213〉現代人 <400〉 550

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -578- 200927761

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Ala Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Thr Thr 210 215 220

Tyr Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -579- 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Trp Ser Asn Cys Cys Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -580- 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -581 - 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210〉 551 <211> 642 <212〉 PRT <213〉現代人 <400〉 551 -582 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110 〇

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Ala Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160 -583 - 200927761

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr 210 215 220

Asn Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Trp Ser Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Thr Tyr Thr Ala Tyr Ala Cys Asn Cys Cys Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300 584- 200927761

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala ^ 355 360 365

O

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415 ❹

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -585 - 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 -586- 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

<210> 552 <211> 642 <212> PRT <213〉現代人 <400〉 552

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 1 5 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30 〇

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -587- 200927761

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -588- 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Ala Cys Asn Cys Cys Asn Ala Thr His 275 280 285

O

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335 ❹

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -589- 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -590- 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590 ❹

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210> 553 <211> 642 <212〉 PRT <213〉現代人 <400> 553 -591 - 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Ala Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160 -592- 200927761

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Trp Ser Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Thr Tyr Thr Ala Tyr Gly Cys Asn Cys Cys Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300 -593 - 200927761

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -594- 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 - 595 - 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210〉 554 <211> 642 <212〉 PRT <213〉現代人 <400〉 554

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Met Gly Asn Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -596- 200927761

Arg Trp Ser Asn Ala Thr His Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Ala Cys Asn Gly Cys Asn Trp Ser Asn Trp Ser Asn Met 145 150 155 160

Thr Asn Cys Ala Arg Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -597- 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Thr Thr Tyr Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Trp Ser 260 265 270

Asn Thr Ala Tyr Thr Thr Tyr Ala Cys Asn Cys Cys Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -598 - 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -599- 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210〉 555 <211> 642 <212> PRT <213〉現代人 <400〉 555 -600- 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160 -601 - 200927761

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Gly Ala Tyr Thr Ala Tyr Met Thr Asn Cys Cys Asn Thr Thr Tyr 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Cys Asn Gly Gly Asn Ala 290 295 300 -602- 200927761

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -603 - 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 -604- 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

<210> 556 <211> 642 <212> PRT <213〉現代人 <400〉 556

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30 〇

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -605 - 200927761

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Gly Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -606- 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Gly 260 265 270

Tyr Gly Ala Tyr Gly Ala Tyr Met Thr Asn Cys Cys Asn Met Thr Asn 275 280 285

O

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335 〇

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -607 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -608 - 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

O

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640 ❹

Gly Tyr <210〉 557 <211> 642 <212〉 PRT <213>現代人 <400〉 557 -609- 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Gly Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160 -610- 200927761

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205 ❹

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Tyr Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Met Thr Asn Cys Cys Asn Met Thr Asn 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala 290 295 300 -611 - 200927761

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -612- 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510 〇

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 -613 - 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210〉 558 <211〉 642 <212〉 PRT <213〉現代人 <400〉 558

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 1 ' 5 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -614- 200927761

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Q 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -615- 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Met Thr Asn Cys Cys Asn Met Thr Asn 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 616- 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -617- 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210> 559 <211> 642 <212〉 PRT <213〉現代人 <400〉 559 -618- 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Thr His Met 145 150 155 160 -619- 200927761

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Ala Arg Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Gly 260 265 270

Tyr Gly Ala Tyr Ala Thr His Met Thr Asn Cys Cys Asn Met Thr Asn 275 280 285

Trp Ser Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala 290 295 300 620- 200927761

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -621 - 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 -622 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

<210〉 560 <211〉 642 <212> PRT <213>現代人 <400〉 560

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30 ❹

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -623 - 200927761

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -624- 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Met Thr Asn Cys Cys Asn Met Thr Asn 275 280 285 〇

Gly Cys Asn Thr Thr Tyr Gly Gly Asn Gly Gly Asn Gly Gly Asn Ala 290 295 300

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Arg Ala Thr His Met Gly 305 310 315 320

Asn Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335 〇

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -625 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -626- 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

O

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Gly Tyr <210〉 561 <211> 642 <212〉 PRT <213>現代人 <400〉 561 -627- 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Gly Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Ala Cys Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160 -628- 200927761

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205 0

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Gly Ala Tyr Trp Ser Asn Met Thr Asn Cys Cys Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300 -629- 200927761

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -630 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510 0

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 -631 - 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210> 562 <211〉 642 <212〉PRT <213〉現代人 <400> 562

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -632- 200927761

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Met Thr Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Cys Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 〇 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -633 - 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Arg Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Met Thr Asn Cys Cys Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -634- 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -635 - 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr <210> 563 <211〉 642 <212〉 PRT <213>現代人 <400> 563 -636- 200927761

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 0 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Gly Ala Tyr Thr Ala Tyr 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160 -637- 200927761

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Tyr Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Met Thr Asn Cys Cys Asn Ala Thr His 275 280 285

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300 -638- 200927761

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415 〇

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460 -639- 200927761

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605 -640- 200927761

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Thr Thr Tyr Ala Ala Tyr Met Gly Asn Gly Gly Asn Gly Ala Arg Thr 625 630 635 640

Gly Tyr

<210> 564 <211〉 642 <212> PRT <213〉現代人 <400> 564

Gly Ala Tyr Ala Thr His Cys Ala Arg Ala Thr Gly Ala Cys Asn Cys 15 10 15

Ala Arg Trp Ser Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Met Thr 20 25 30 ❹

Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Gly Asn 35 40 45

Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala Thr His Ala 50 55 60

Cys Asn Thr Gly Tyr Cys Ala Arg Gly Cys Asn Trp Ser Asn Cys Ala 65 70 75 80 -641 - 200927761

Arg Gly Ala Tyr Ala Thr His Trp Ser Asn Ala Ala Tyr Trp Ser Asn 85 90 95

Met Thr Asn Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Cys Ala Arg Cys 100 105 110

Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Ala Ala Arg Gly Cys 115 120 125

Asn Cys Cys Asn Ala Ala Arg Met Thr Asn Met Thr Asn Ala Thr His 130 135 140

Thr Ala Tyr Gly Ala Tyr Gly Cys Asn Trp Ser Asn Ala Ala Tyr Met 145 150 155 160

Thr Asn Gly Ala Arg Ala Cys Asn Gly Gly Asn Gly Thr Asn Cys Cys 165 170 175

Asn Trp Ser Asn Met Gly Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn 180 185 190

Trp Ser Asn Gly Gly Asn Trp Ser Asn Gly Gly Asn Ala Cys Asn Gly 195 200 205

Ala Tyr Thr Thr Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Ala Thr 210 215 220

His Trp Ser Asn Trp Ser Asn Met Thr Asn Cys Ala Arg Cys Cys Asn -642- 200927761 225 230 235 240

Gly Ala Arg Gly Ala Tyr Ala Thr His Gly Cys Asn Ala Cys Asn Thr 245 250 255

Ala Tyr Thr Ala Tyr Thr Gly Tyr Cys Ala Arg Cys Ala Tyr Thr Ala 260 265 270

Tyr Gly Ala Tyr Ala Ala Tyr Met Thr Asn Cys Cys Asn Ala Thr His 275 280 285 ❹

Ala Cys Asn Thr Thr Tyr Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala 290 295 300

Cys Asn Met Gly Asn Met Thr Asn Gly Ala Arg Ala Thr His Ala Ala 305 310 315 320

Arg Met Gly Asn Ala Cys Asn Gly Thr Asn Gly Cys Asn Gly Cys Asn 325 330 335 ❹

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Ala Thr His Thr 340 345 350

Thr Tyr Cys Cys Asn Cys Cys Asn Trp Ser Asn Gly Ala Tyr Gly Ala 355 360 365

Arg Cys Ala Arg Met Thr Asn Ala Ala Arg Trp Ser Asn Gly Gly Asn 370 375 380 -643 - 200927761

Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Thr 385 390 395 400

Gly Tyr Met Thr Asn Met Thr Asn Ala Ala Tyr Ala Ala Tyr Thr Thr 405 410 415

Tyr Thr Ala Tyr Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Cys Asn 420 425 430

Ala Ala Arg Gly Thr Asn Cys Ala Arg Thr Gly Gly Ala Ala Arg Gly 435 440 445

Thr Asn Gly Ala Tyr Ala Ala Tyr Gly Cys Asn Met Thr Asn Cys Ala 450 455 460

Arg Trp Ser Asn Gly Gly Asn Ala Ala Tyr Trp Ser Asn Cys Ala Arg 465 470 475 480

Gly Ala Arg Trp Ser Asn Gly Thr Asn Ala Cys Asn Gly Ala Arg Cys 485 490 495

Ala Arg Gly Ala Tyr Trp Ser Asn Ala Ala Arg Gly Ala Tyr Trp Ser 500 505 510

Asn Ala Cys Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn 515 520 525

Trp Ser Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Trp -644- 200927761 530 535 540

Ser Asn Ala Ala Arg Gly Cys Asn Gly Ala Tyr Thr Ala Tyr Gly Ala 545 550 555 560

Arg Ala Ala Arg Cys Ala Tyr Ala Ala Arg Gly Thr Asn Thr Ala Tyr 565 570 575

Gly Cys Asn Thr Gly Tyr Gly Ala Arg Gly Thr Asn Ala Cys Asn Cys 580 585 590 ❹

Ala Tyr Cys Ala Arg Gly Gly Asn Met Thr Asn Trp Ser Asn Trp Ser 595 600 605

Asn Cys Cys Asn Gly Thr Asn Ala Cys Asn Ala Ala Arg Trp Ser Asn 610 615 620

Gly Tyr <210〉 565 <211> 1338 <212〉 PRT <213〉現代人 <400> 565 645 - 200927761

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr His Trp Ser Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Cys Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Thr Gly Gly Ala Thr His Trp Ser Asn Gly Cys Asn Trp 145 150 155 160 -646- 200927761

Ser Asn Ala Ala Tyr Gly Gly Asn Ala Ala Tyr Ala Cys Asn Ala Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Met Thr Asn 180 185 190

Cys Ala Arg Gly Ala Tyr Met Gly Asn Gly Thr Asn Ala Cys Asn Ala 195 200 205 ❹

Thr Gly Ala Cys Asn Ala Cys Asn Gly Ala Tyr Ala Cys Asn Trp Ser 210 215 220

Asn Ala Cys Asn Trp Ser Asn Ala Cys Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Ala Thr Gly Gly Ala Arg Met Thr Asn Met Gly Asn Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Trp Ser Asn Gly Ala Tyr Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Tyr Ala Ala Tyr Thr 290 295 300 -647- 200927761

Gly Gly Ala Ala Tyr Thr Ala Tyr Gly Gly Asn Thr Thr Tyr Thr Thr 305 310 315 320

Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg 325 330 335

Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys 355 360 365

Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn 370 375 380

Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr 385 390 395 400

Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser 405 410 415

Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn 420 425 430

Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala 435 440 445

Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala 450 455 460 -648- 200927761

Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn 465 470 475 480

Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met 485 490 495

Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala 500 505 510

O

Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn 515 520 525

Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met 530 535 540

Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser 545 550 555 560

Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn 565 570 575

Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala 580 585 590

Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly 595 600 605 -649- 200927761

Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg 610 615 620

Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly 625 630 635 640

Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala 645 650 655

Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn 660 665 670

Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys 675 680 685

Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys 690 695 700

Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr 705 710 715 720

Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys 725 730 735

Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr 740 745 750

Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn 755 760 765 -650- 200927761

Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly 770 775 780

Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala 785 790 795 800

Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn 805 810 815

O

Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly 820 825 830

Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr 835 840 845

Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn 850 855 860

Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys 865 870 875 880

Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr 885 890 895

Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn 900 905 910 -651 - 200927761

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys 915 920 925

Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly 930 935 940

Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr 945 950 955 960

Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly 965 970 975

Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr 980 985 990

His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 995 1000 1005

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1010 1015 1020

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1025 1030 1035

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1040 1045 1050

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1055 1060 1065 -652- 200927761

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr 1070 1075 1080

Cys Ala Arg

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn 1085 1090 1095

Thr Gly Tyr

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn 1100 1105 1110

Thr Thr Tyr 〇 Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr 1115 1120 1125

Ala Thr His

Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly 1130 1135 1140

Gly Ala Arg

Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg 1145 1150 1155

Cys Cys Asn

Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr 1160 1165 1170

Ala Ala Arg

Ala Thr Gly

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn 1175 1180 1185

Gly Gly Asn

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr 1190 1195 1200 -653 - 200927761

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1205 1210 1215

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1220 1225 1230

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1235 1240 1245

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1250 1255 1260

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1265 1270 1275

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1280 1285 1290

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1295 1300 1305

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 1335 <210〉 566 <211> 1329 -654- 200927761 <212〉 PRT <213〉現代人 <400> 566

Cys Ala Arg Gly Thr Asn Cys Ala Tyr Met Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Gly Gly Asn Cys Ala Tyr 85 90 95

Thr Ala Tyr Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Cys Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly -655 - 200927761 130 135 140

Gly Gly Asn Thr Gly Gly Ala Thr His Ala Ala Tyr Cys Cys Asn Ala 145 150 155 160

Ala Tyr Trp Ser Asn Gly Gly Asn Gly Gly Asn Ala Cys Asn Ala Ala 165 170 175

Tyr Thr Gly Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr 180 185 190

Cys Ala Arg Gly Gly Asn Met Gly Asn Gly Thr Asn Ala Cys Asn Ala 195 200 205

Thr Gly Ala Cys Asn Met Gly Asn Gly Ala Tyr Ala Cys Asn Trp Ser 210 215 220

Asn Ala Thr His Trp Ser Asn Ala Cys Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Ala Thr Gly Gly Ala Arg Met Thr Asn Trp Ser Asn Met Gly Asn Met 245 250 255

Thr Asn Met Gly Asn Trp Ser Asn Gly Ala Tyr Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285 -656 200927761

Gly Cys Asn Met Gly Asn Trp Ser Asn Ala Thr His Gly Cys Asn Gly 290 295 300

Thr Asn Gly Cys Asn Met Thr Asn Gly Ala Tyr Thr Ala Tyr Thr Gly 305 310 315 320

Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Met Thr Asn 325 330 335

Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly 340 345 350

Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys 355 360 365

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn 370 375 380

Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp 385 390 395 400

Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys 405 410 415

Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr 420 425 430

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr -657- 200927761 435 440 445

Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys 450 455 460

Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn 465 470 475 480

Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly 485 490 495

Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys 500 505 510

Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn 515 520 525

Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met 530 535 540

Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys 545 550 555 560

Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr 565 570 575

Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr 580 585 590 658- 200927761

Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala 595 600 605

Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr 610 615 620

Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala 625 630 635 640

Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly 645 650 655

Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn 660 665 670

Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys 675 680 685

Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser 690 695 700

Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn 705 710 715 720

Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala 725 730 735

Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly -659- 200927761 740 745 750

Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn 755 760 765

Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly 770 775 780

Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys 785 790 795 800

Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr 805 810 815

Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly 820 825 830

Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys 835 840 845

Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn 850 855 860

Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp 865 870 875 880

Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr 885 890 895 -660- 200927761

Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn 900 905 910

Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met 915 920 925

Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala 930 935 940

Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn 945 950 955 960

Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly 965 970 975

Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys 980 985 990

Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 995 1000 1005

Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1010 1015 1020

Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1025 1030 1035

Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn -661 - 200927761 1040 1045 1050

Gly Ala 1055

Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1060 1065

Ala Ala 1070

Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn 1075 1080

Ala Cys 1085

Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1090 1095

Gly Gly 1100

Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1105 1110

Gly Ala 1115

Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1120 1125

Thr Gly 1130

Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn 1135 1140

Cys Ala 1145

Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr 1150 1155

Thr Ala 1160

Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1165 1170

Cys Cys 1175

Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn 1180 1185 -662- 200927761

Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr 1190 1195 1200

Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1205 1210 1215

Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1220 1225 1230

Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn 1235 1240 1245

Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr 1250 1255 1260

Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg 1265 1270 1275

Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr 1280 1285 1290

Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn 1295 1300 1305

Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn 1310 1315 1320

Gly Gly Asn Ala Ala Arg -663 - 200927761 1325 <210> 567 <211> 1329 <212> PRT <213〉現代人 <400〉 567

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Ala Ala Arg Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Ala Cys Asn Gly Gly Asn Thr Ala Tyr 85 90 95

Thr Ala Tyr Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110 -664 - 200927761

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Cys Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Thr Gly Gly Ala Thr His Ala Ala Tyr Cys Cys Asn Ala 145 150 155 160

Ala Tyr Trp Ser Asn Gly Gly Asn Gly Gly Asn Ala Cys Asn Ala Ala 0 165 170 175

Tyr Cys Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr 180 185 190

Cys Ala Arg Gly Gly Asn Met Gly Asn Gly Thr Asn Ala Cys Asn Ala 195 200 205

Thr Gly Ala Cys Asn Met Gly Asn Gly Ala Tyr Ala Cys Asn Trp Ser 210 215 220

Asn Ala Thr His Trp Ser Asn Ala Cys Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Ala Thr Gly Gly Ala Arg Met Thr Asn Trp Ser Asn Met Gly Asn Met 245 250 255

Thr Asn Met Gly Asn Trp Ser Asn Gly Ala Tyr Gly Ala Tyr Ala Cys 260 265 270 -665 - 200927761

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Trp Ser Asn Ala Thr His Gly Cys Asn Gly 290 295 300

Thr Asn Gly Cys Asn Met Thr Asn Gly Ala Tyr Thr Ala Tyr Thr Gly 305 310 315 320

Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Met Thr Asn 325 330 335

Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly 340 345 350

Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys 355 360 365

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn 370 375 380

Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp 385 390 395 400

Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys 405 410 415 -666 - 200927761

Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr 420 425 430

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr 435 440 445

Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys 450 455 460

Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn 465 470 475 480

Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly 485 490 495

Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys 500 505 510

Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn 515 520 525

Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met 530 535 540

Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys 545 550 555 560

Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr 565 570 575 -667- 200927761

Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr 580 585 590

Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala 595 600 605

Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr 610 615 620

Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala 625 630 635 640

Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly 645 650 655

Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn 660 665 670

Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys 675 680 685

Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser 690 695 700

Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn 705 710 715 720 -668 200927761

Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala 725 730 735

Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly 740 745 750

Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn 755 760 765

Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly 770 775 780

Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys 785 790 795 800

Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr 805 810 815

Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly 820 825 830

Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys 835 840 845

Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn 850 855 860

Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp 865 870 875 880 -669- 200927761

Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr 885 890 895

Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn 900 905 910

Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met 915 920 925

Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala 930 935 940

Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn 945 950 955 960

Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly 965 970 975

Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys 980 985 990

Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 995 1000 1005

Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1010 1015 1020 -670- 200927761

Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1025 1030 1035

Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn 1040 1045 1050

Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1055 1060 1065

Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn ❹ 1070 1075 1080

Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1085 1090 1095

Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1100 1105 1110

Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1115 1120 1125

Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn 1130 1135 1140

Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr 1145 1150 1155

Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1160 1165 1170 -671 - 200927761

Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn 1175 1180 1185

Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr 1190 1195 1200

Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1205 1210 1215

Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1220 1225 1230

Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn 1235 1240 1245

Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr 1250 1255 1260

Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg 1265 1270 1275

Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr 1280 1285 1290

Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn 1295 1300 1305 -672- 200927761

Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn 1310 1315 1320

Gly Gly Asn Ala Ala Arg 1325 <210> 568 <211〉 1344 <212> PRT <213〉現代人 0 <400〉 568

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Cys 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Gly Thr 20 25 30

Asn Met Gly Asn Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Cys Asn 35 40 45

G

Trp Ser Asn Gly Thr Asn Ala Ala Arg Gly Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Gly Gly Asn Thr Ala 65 70 75 80

Tyr Ala Cys Asn Met Thr Asn Ala Cys Asn Gly Ala Arg Met Thr Asn 85 90 95 -673 - 200927761

Trp Ser Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Ala Thr Gly 130 135 140

Gly Gly Asn Trp Ser Asn Thr Thr Tyr Gly Ala Tyr Cys Cys Asn Gly 145 150 155 160

Ala Arg Gly Ala Tyr Gly Gly Asn Gly Ala Arg Ala Cys Asn Ala Thr 165 170 175

His Thr Ala Tyr Gly Cys Asn Cys Ala Arg Ala Ala Arg Thr Thr Tyr 180 185 190

Cys Ala Arg Gly Gly Asn Met Gly Asn Gly Thr Asn Ala Cys Asn Ala 195 200 205

Thr Gly Met Thr Asn Gly Ala Arg Gly Ala Tyr Ala Cys Asn Trp Ser 210 215 220

Asn Ala Cys Asn Gly Ala Tyr Ala Cys Asn Gly Cys Asn Thr Ala Tyr 225 230 235 240

Ala Thr Gly Gly Ala Arg Met Thr Asn Trp Ser Asn Trp Ser Asn Met -674- 200927761 245 250 255

Thr Asn Met Gly Asn Trp Ser Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Ala Cys Asn Gly Ala Arg Gly Gly Asn Gly Ala Tyr Gly 290 295 300 o

Gly Asn Gly Gly Asn Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala 305 310 315 320

Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr Gly Gly 325 330 335

Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Cys Asn Gly 340 345 350 〇

Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys 355 360 365

Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn 370 375 380

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly 385 390 395 400 -675 - 200927761

Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser 405 410 415

Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn 420 425 430

Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met 435 440 445

Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr 450 455 460

Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn 465 470 475 480

Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly 485 490 495

Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly 500 505 510

Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn 515 520 525

Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp 530 535 540

Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr -676- 200927761 545 550 555 560

Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn 565 570 575

Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr 580 585 590

Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala 595 600 605

O

Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr 610 615 620

Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala 625 630 635 640

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys 645 650 655 〇

Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr 660 665 670

Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys 675 680 685

Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys 690 695 700 -677 - 200927761

Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn 705 710 715 720

Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys 725 730 735

Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 740 745 750

Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn 755 760 765

Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr 770 775 780

Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr 785 790 795 800

Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn 805 810 815

Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr 820 825 830

Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr 835 840 845

Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn -678 - 200927761 850 855 860

Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly 865 870 875 880

Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser 885 890 895

Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn 900 905 910

O

Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly 915 920 925

Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr 930 935 940

Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr 945 950 955 960 〇

Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala 965 970 975

Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys 980 985 990

Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn 995 1000 1005 -679- 200927761

Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 1010 1015 1020

Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1025 1030 1035

Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1040 1045 1050

Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn 1055 1060 1065

Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1070 1075 1080

Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn 1085 1090 1095

Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1100 1105 1110

Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1115 1120 1125

Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1130 1135 1140

Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn -680- 200927761 1150 1155 1145

Cys Ala 1160

Thr Ala 1175

Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr 1165 1170

Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1180 1185

Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn 1195 1200

Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr 1210 1215

Cys Cys 1190 o Gly Ala 1205

Met Thr 1220

Ala Cys 1235 ❹ Met Gly 1250

Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1225 1230

Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1240 1245

Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn 1255 1260

Ala Ala 1265

Trp Ser 1280

Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr 1270 1275

Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg 1285 1290 -681 - 200927761

Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr 1295 1300 1305

Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn 1310 1315 1320

Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn 1325 1330 1335

Gly Gly Asn Ala Ala Arg 1340 <210〉 569 <211> 1344 <212〉 PRT <213〉現代人 <400〉 569

Cys Ala Arg Gly Thr Asn Ala Cys Asn Met Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Thr Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Ala Cys Asn Gly Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Thr 50 55 60 -682- 200927761

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Ala Ala Tyr Gly Cys Asn 85 90 95

Met Gly Asn Ala Thr Gly Gly Gly Asn Gly Thr Asn Trp Ser Asn Thr 100 105 110

O

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Met Thr Asn Gly Cys Asn Cys Ala Tyr Ala Thr His Thr 145 150 155 160

Thr Tyr Trp Ser Asn Ala Ala Tyr Gly Ala Tyr Gly Ala Arg Ala Ala 165 170 175

Arg Trp Ser Asn Thr Ala Tyr Trp Ser Asn Ala Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Met Thr Asn Ala 195 200 205 -683 - 200927761

Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Trp Ser Asn Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Met Thr Asn Ala Cys Asn Ala Thr Gly Ala Cys Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Ala Cys Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Ala Thr Gly Thr Ala Tyr Trp 290 295 300

Ser Asn Trp Ser Asn Gly Gly Asn Thr Gly Gly Thr Ala Tyr Gly Gly 305 310 315 320

Asn Gly Thr Asn Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr Thr Gly Gly 325 330 335

Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Met Thr Asn Gly 340 345 350

Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys 355 360 365 -684- 200927761

Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn 370 375 380

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly 385 390 395 400

Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser 405 410 415 ❹

Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn 420 425 430

Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met 435 440 445

Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr 450 455 460

Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn 465 470 475 480

Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly 485 490 495

Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly 500 505 510 -685 - 200927761

Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn 515 520 525

Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp 530 535 540

Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr 545 550 555 560

Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn 565 570 575

Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr 580 585 590

Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala 595 600 605

Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr 610 615 620

Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala 625 630 635 640

Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys 645 650 655

Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr 660 665 670 -686- 200927761

Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys 675 680 685

Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys 690 695 700

Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn 705 710 715 720 ❹

Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys 725 730 735

Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 740 745 750

Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn 755 760 765

Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr 770 775 780

Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr 785 790 795 800

Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn 805 810 815 -687- 200927761

Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr 820 825 830

Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr 835 840 845

Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn 850 855 860

Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly 865 870 875 880

Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser 885 890 895

Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn 900 905 910

Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly 915 920 925

Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr 930 935 940

Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr 945 950 955 960

Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala 965 970 975 -688 - 200927761

Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys 980 985 990

Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg 1010 1015 1020

O

Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg 1025 1030 1035

Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn 1040 1045 1050

Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn 1055 1060 1065

Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg 1070 1075 1080

Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn 1085 1090 1095

Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 1100 1105 1110 -689- 200927761

Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn 1115 1120 1125

Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg 1130 1135 1140

Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn 1145 1150 1155

Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr 1160 1165 1170

Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn 1175 1180 1185

Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn 1190 1195 1200

Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr 1205 1210 1215

Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn 1220 1225 1230

Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn 1235 1240 1245

Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn 1250 1255 1260 -690- 200927761

Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr 1265 1270 1275

Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg 1280 1285 1290

Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr 1295 1300 1305 ❹

Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn 1310 1315 1320

Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn 1325 1330 1335

Gly Gly Asn Ala Ala Arg 1340

<210〉570 <211> 1347 <212> PRT <213〉現代人 <400> 570

Cys Ala Arg Gly Thr Asn Ala Cys Asn Met Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Gly Thr Asn Met Thr -691 - 200927761 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Ala Cys Asn Gly Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Thr Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Ala Ala Tyr Gly Cys Asn 85 90 95

Met Gly Asn Ala Thr Gly Gly Gly Asn Gly Thr Asn Trp Ser Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Met Thr Asn Gly Thr Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Thr Tyr Trp Ser Asn Ala Ala Tyr Gly Ala Tyr Gly Ala Arg Ala Ala 165 170 175 -692- 200927761

Arg Trp Ser Asn Thr Ala Tyr Trp Ser Asn Ala Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Met Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Trp Ser Asn Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Met Thr Asn Ala Cys Asn Ala Thr Gly Ala Cys Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Ala Cys Asn Thr Ala Tyr Thr Ala Tyr O 275 280 285

Thr Gly Tyr Gly Cys Asn Met Gly Asn Gly Thr Asn Thr Ala Tyr Trp 290 295 300

Ser Asn Trp Ser Asn Gly Gly Asn Thr Gly Gly Trp Ser Asn Thr Thr 305 310 315 320

Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn -693 - 200927761 325 330 335

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala 340 345 350

Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser 355 360 365

Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn 370 375 380

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met 385 390 395 400

Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly 405 410 415

Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn 420 425 430

Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr 435 440 445

Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala 450 455 460

Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn 465 470 475 480 -694- 200927761

Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp 485 490 495

Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser 500 505 510

Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr 515 520 525

Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp 530 535 540

Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser 545 550 555 560

Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn 565 570 575

Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala 580 585 590

Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys 595 600 605

Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn 610 615 620

Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala -695 - 200927761 625 630 635 640

Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala 645 650 655

Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg 660 665 670

Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys 675 680 685

Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys 690 695 700

Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn 705 710 715 720

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys 725 730 735

Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala 740 745 750

Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn 755 760 765

Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala 770 775 780 -696- 200927761

Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala 785 790 795 800

Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr 805 810 815

Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala 820 825 830 ^ Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly 835 840 845

Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr 850 855 860

Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met 865 870 875 880

Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala 885 890 895

Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn 900 905 910

Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly 915 920 925

Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly -697- 200927761 930 935 940

Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg 945 950 955 960

Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp 965 970 975

Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys 980 985 990

Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg 995 1000 1005

Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 1010 1015 1020

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1025 1030 1035

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1040 1045 1050

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1055 1060 1065

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1070 1075 1080 -698- 200927761

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1085 1090 1095

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1100 1105 1110

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1115 1120 1125

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1130 1135 1140

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1145 1150 1155

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1160 1165 1170

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1175 1180 1185

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1190 1195 1200

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1205 1210 1215

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg -699- 200927761 1220 1225 1230

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1235 1240 1245

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1250 1255 1260

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1265 1270 1275

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1280 1285 1290

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1295 1300 1305

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1310 1315 1320

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345

<210〉 571 <211> 1332 <212〉 PRT 700- 200927761 <213〉現代人 <400> 571

Cys Ala Arg Ala Thr His Ala Cys Asn Met Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Ala Cys Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Ala Cys Asn Cys Ala Arg 0 35 40 45

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Ala Cys Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Met Thr Asn Gly Ala Arg 130 135 140 -701 - 200927761

Thr Gly Gly Met Thr Asn Gly Cys Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Met Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Ala Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Met Thr Asn Ala Cys Asn Ala Thr Gly Ala Cys Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Ala Cys Asn Thr Ala Tyr Thr Ala Tyr 275 280 285 -702- 200927761

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Met Gly Asn Gly 290 295 300

Ala Arg Met Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn 325 330 335

Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn 420 425 430

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445 -703 - 200927761

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560

Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn 565 570 575

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590 -704- 200927761

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala 625 630 635 640

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly 725 730 735

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750 -705 - 200927761

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala 865 870 875 880

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895 -706- 200927761

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala 930 935 940

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn 0 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala 980 985 990

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1010 1015 1020

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1025 1030 1035

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1040 1045 1050 -707- 200927761

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1055 1060 1065

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1070 1075 1080

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1085 1090 1095 〇

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1100 1105 1110

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1115 1120 1125

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1130 1135 1140

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1145 1150 1155

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1160 1165 1170

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1175 1180 1185 -708 - 200927761

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1190 1195 1200

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1205 1210 1215

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1220 1225 1230

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1235 1240 1245

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1250 1255 1260

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1265 1270 1275

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1280 1285 1290

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 -709- 200927761 <210> 572 <211> 1332 <212〉 PRT <213〉現代人 <400> 572

Cys Ala Arg Ala Thr His Ala Cys Asn Met Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Ala Cys Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Ala Cys Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Ala Cys Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys -710- 200927761 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Met Thr Asn Gly Cys Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175 o

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Met Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Ala Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 210 215 220 ❹

Asn Trp Ser Asn Ala Ala Arg Ala Cys Asn Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Ala Cys Asn Gly 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270 -711 - 200927761

Tyr Ala Cys Asn Gly Cys Asn Ala Cys Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Ala Ala Tyr Thr 290 295 300

Gly Gly Ala Cys Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn 325 330 335

Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn -712- 200927761 420 425 430

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480 ❹

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525 〇

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560

Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn 565 570 575 -713 - 200927761

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala 625 630 635 640

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly -714- 200927761 725 730 735

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780 ❹

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830 ❹

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala 865 870 875 880 -715- 200927761

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala 930 935 940

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala 980 985 990

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1010 1015 1020

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr -716- 200927761 1025 1030 1035

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1040 1045 1050

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1055 1060 1065

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1070 1075 1080

O

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1085 1090 1095

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1100 1105 1110

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1115 1120 1125 ❹

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1130 1135 1140

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1145 1150 1155

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1160 1165 1170 -717- 200927761

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1175 1180 1185

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1190 1195 1200

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1205 1210 1215

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1220 1225 1230

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1235 1240 1245

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1250 1255 1260

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1265 1270 1275

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1280 1285 1290

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn -718- 200927761 1310 1315 1320

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 <210〉 573 <211> 1332 <212〉 PRT <213〉現代人 <400〉 573

O

Cys Ala Arg Ala Thr His Ala Cys Asn Met Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Ala Cys Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Ala Cys Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Met Thr Asn Ala Ala Tyr Ala Cys Asn Gly Gly Asn 85 90 95 -719- 200927761

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Met Thr Asn Gly Cys Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Met Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Ala Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Met Thr Asn Ala Cys Asn Ala Thr Gly Ala Cys Asn Ala 245 250 255 -720- 200927761

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Ala Cys Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Met Thr Asn Gly 290 295 300

Ala Arg Met Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn 325 330 335

Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400 -721 - 200927761

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn 420 425 430

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560 -722- 200927761

Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn 565 570 575

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605 ❹

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala 625 630 635 640

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700 -723 - 200927761

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly 725 730 735

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860 -724- 200927761

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala 865 870 875 880

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910 ❹

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala 930 935 940

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala 980 985 990

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005 -725 - 200927761 Ala Ala 1010

Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1015 1020

Gly Ala 1025

Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1030 1035

Ala Cys 1040

Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1045 1050

Met Gly 1055

Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1060 1065

Ala Ala 1070

Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1075 1080

Met Thr 1085

Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1090 1095

Ala Ala 1100

Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1105 1110

Trp Ser 1115

Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1120 1125

Gly Ala 1130

Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1135 1140

Gly Gly 1145

Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1150 1155 -726- 200927761

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1160 1165 1170

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1175 1180 1185

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1190 1195 1200 〇

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1205 1210 1215

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1220 1225 1230

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1235 1240 1245

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1250 1255 1260

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1265 1270 1275

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1280 1285 1290 -727- 200927761

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 <210> 574 <211> 1332 <212〉 PRT <213〉現代人 <400> 574

Cys Ala Arg Ala Thr His Ala Cys Asn Met Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Ala Cys Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Ala Cys Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80 -728 - 200927761

Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Ala Cys Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Met Thr Asn Gly Cys Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Met Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Ala Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn -729- 200927761 225 230 235 240

Gly Thr Asn Met Thr Asn Ala Cys Asn Ala Thr Gly Ala Cys Asn Ala 245 250 255

Ala Tyr Met Thr Asn Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Ala Cys Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Met Gly Asn Gly 290 295 300

Ala Arg Gly Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn 325 330 335

Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380 730 200927761

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn 420 425 430

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp -731 - 200927761 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560

Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn 565 570 575

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala 625 630 635 640

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685 -732- 200927761

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly 725 730 735

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala -733 - 200927761 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala 865 870 875 880

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895 〇

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala 930 935 940 ❹

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg‘Ala Ala 980 985 990 -734- 200927761

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1010 1015 1020

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1025 1030 1035

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1040 1045 1050

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1055 1060 1065

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1070 1075 1080

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1085 1090 1095

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1100 1105 1110

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1115 1120 1125

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr -735 - 200927761 1130 1135 1140

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1145 1150 1155

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1160 1165 1170

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1175 1180 1185

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1190 1195 1200

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1205 1210 1215

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1220 1225 1230

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1235 1240 1245

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1250 1255 1260

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1265 1270 1275 -736- 200927761

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1280 1285 1290

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 <210> 575 <211> 1332 <212> PRT <213〉現代人 <400> 575

Cys Ala Arg Ala Thr His Ala Cys Asn Met Thr Asn Ala Ala Arg Gly

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Ala Cys Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Ala Cys Asn Cys Ala Arg 35 40 45

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Thr 50 55 60 - 737- 200927761

Gly Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Ala Cys Asn Gly Gly Asn 85 90 95

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Met Thr Asn Gly Ala Arg 130 135 140

Thr Gly Gly Met Thr Asn Gly Cys Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Thr Asn Gly Ala Arg Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190

Met Thr Asn Met Gly Asn Trp Ser Asn Met Gly Asn Met Thr Asn Ala 195 200 205 -738- 200927761

Cys Asn Ala Thr His Ala Cys Asn Ala Ala Arg Gly Cys Asn Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Met Thr Asn Ala Cys Asn Ala Thr Gly Ala Cys Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Ala Cys Asn Thr Ala Tyr Thr Ala Tyr 275 ' 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Cys Ala Tyr Ala 290 295 300

Cys Asn Ala Ala Tyr Cys Cys Asn Thr Thr Tyr Gly Ala Arg Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn 325 330 335

Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp 340 345 350

Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365 -739- 200927761

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn 420 425 430

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510 -740- 200927761

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala 625 630 635 640

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670 -741 - 200927761

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly 725 730 735

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815 -742- 200927761

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala ¢) 865 870 875 880

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala 930 935 940

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975 -743 - 200927761

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala 980 985 990

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1010 1015 1020

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1025 1030 1035

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1040 1045 1050

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1055 1060 1065

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1070 1075 1080

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1085 1090 1095

Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1100 1105 1110 744 200927761

Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1115 1120 1125

Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1130 1135 1140

Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1145 1150 1155

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1160 1165 1170

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1175 1180 1185

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1190 1195 1200

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1205 1210 1215

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1220 1225 1230

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1235 1240 1245

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1250 1255 1260 -745 - 200927761

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1265 1270 1275

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1280 1285 1290

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 <210〉 576 <211> 1332 <212> PRT <213〉現代人 <400> 576

Cys Ala Arg Ala Thr His Ala Cys Asn Met Thr Asn Ala Ala Arg Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Cys Cys Asn Ala Cys Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Ala Cys Asn Cys Ala Arg -746- 200927761 35 40 45

Ala Cys Asn Met Thr Asn Ala Cys Asn Met Thr Asn Ala Cys Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Ala Cys Asn Gly Gly Asn 85 90 95

O

Gly Gly Asn Gly Thr Asn Gly Gly Asn Gly Thr Asn Gly Gly Asn Thr 100 105 110

Gly Gly Ala Thr His Met Gly Asn Cys Ala Arg Cys Cys Asn Cys Cys 115 120 125

Asn Gly Gly Asn Ala Ala Arg Gly Cys Asn Met Thr Asn Gly Ala Arg 130 135 140 〇

Thr Gly Gly Met Thr Asn Gly Cys Asn Met Thr Asn Ala Thr His Thr 145 150 155 160

Ala Tyr Thr Gly Gly Ala Ala Tyr Gly Ala Tyr Gly Ala Tyr Ala Ala 165 170 175

Arg Met Gly Asn Thr Ala Tyr Trp Ser Asn Cys Cys Asn Trp Ser Asn 180 185 190 -747- 200927761

Met Thr Asn Ala Ala Arg Trp Ser Asn Met Gly Asn Met Thr Asn Ala 195 200 205

Cys Asn Ala Thr His Ala Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys 210 215 220

Asn Trp Ser Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 225 230 235 240

Gly Thr Asn Met Thr Asn Ala Cys Asn Ala Thr Gly Ala Cys Asn Ala 245 250 255

Ala Tyr Ala Thr Gly Gly Ala Tyr Cys Cys Asn Gly Thr Asn Gly Ala 260 265 270

Tyr Ala Cys Asn Gly Cys Asn Ala Cys Asn Thr Ala Tyr Thr Ala Tyr 275 280 285

Thr Gly Tyr Gly Cys Asn Cys Ala Tyr Met Gly Asn Gly Gly Asn Gly 290 295 300

Ala Arg Met Thr Asn Cys Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn 325 330 335

Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp -748- 200927761 340 345 350

Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400

O

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn 420 425 430

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445 〇

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495 -749- 200927761

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560

Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn 565 570 575

Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala 580 585 590

Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr 595 600 605

Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn 610 615 620

Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala 625 630 635 640

Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala -750- 200927761 645 650 655

Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr 660 665 670

Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys 675 680 685

Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys 690 695 700 〇

Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr 705 710 715 720

Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly 725 730 735

Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser 740 745 750 〇

Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn 755 760 765

Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly 770 775 780

Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala 785 790 795 800 -751 - 200927761

Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr 805 810 815

Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly 820 825 830

Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala 835 840 845

Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn 850 855 860

Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala 865 870 875 880

Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr 885 890 895

Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn 900 905 910

Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr 915 920 925

Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala 930 935 940

Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn -752- 200927761 945 950 955 960

Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys 965 970 975

Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala 980 985 990

Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 995 1000 1005 ❹

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1010 1015 1020

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1025 1030 1035

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1040 1045 1050 〇

Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1055 1060 1065

Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1070 1075 1080

Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1085 1090 1095 753 - 200927761

Ala Ala 1100

Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1105 1110

Trp Ser 1115

Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1120 1125

Gly Ala 1130

Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1135 1140

Gly Gly 1145

Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1150 1155

Ala Ala 1160

Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1165 1170

Cys Cys 1175

Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1180 1185

Trp Ser 1190

Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1195 1200

Thr Thr 1205

Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1210 1215

Met Thr 1220

Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1225 1230

Trp Ser

Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg -754- 200927761 1235 1240 1245

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1250 1255 1260

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1265 1270 1275

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1280 1285 1290 ❹

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1295 1300 1305

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 ❹ <210> 577 <211〉 1341 <212〉 PRT <213〉現代人 <400〉 577

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15 -755 200927761

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Ala Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Cys Cys Asn Thr Thr Tyr Trp Ser Asn Met Gly Asn Thr Ala Tyr 85 90 95

Trp Ser Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Gly Cys Asn Ala Thr His Trp Ser Asn Trp Ser Asn Trp 145 150 155 160

Ser Asn Trp Ser Asn Trp Ser Asn Thr Ala Tyr Ala Thr His Thr Ala 165 170 175 -756- 200927761

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Gly Cys 210 215 220 ❹

Asn Ala Ala Arg Ala Ala Tyr Trp Ser Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Ala Tyr Met Gly Asn Gly Thr Asn Gly 290 295 300

Gly Asn Gly Cys Asn Ala Cys Asn Cys Cys Asn Gly Ala Tyr Gly Cys 305 310 315 320 -757- 200927761

Asn Thr Thr Tyr Gly Ala Tyr Ala Thr His Thr Gly Gly Gly Gly Asn 325 330 335

Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Thr Gly Gly Thr Asn Ala 340 345 350

Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser 355 360 365

Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn 370 375 380

Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys 385 390 395 400

Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys 405 410 415

Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn 420 425 430

Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly 435 440 445

Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys 450 455 460

Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn 465 470 475 480 -758- 200927761

Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly 485 490 495

Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr 500 505 510

Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn 515 520 525

O

Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly 530 535 540

Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser 545 550 555 560

Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn 565 570 575

Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly 580 585 590

Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys 595 600 605

Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr 610 615 620 -759- 200927761

Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala 625 630 635 640

Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr 645 650 655

Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr 660 665 670

Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr 675 680 685

Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr 690 695 700

Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn 705 710 715 720

Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala 725 730 735

Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr 740 745 750

Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn 755 760 765

Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly 770 775 780 -760- 200927761

Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser 785 790 795 800

Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg 805 810 815

Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr 820 825 830

Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala 835 840 845

Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg 850 855 860

Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly 865 870 875 880

Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys 885 890 895

Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn 900 905 910

Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys 915 920 925 -761 - 200927761

Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala 930 935 940

Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg 945 950 955 960

Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala 965 970 975

Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys 980 985 990

Asn Ala Thr His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His 995 1000 1005

Trp Ser Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn 1010 1015 1020

Cys Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn 1025 1030 1035

Cys Ala Arg Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn 1040 1045 1050

Cys Cys Asn Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg 1055 1060 1065

Gly Ala Arg Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr 1070 1075 1080 -762- 200927761

Cys Ala Arg Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn 1085 1090 1095

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn 1100 1105 1110

Thr Thr Tyr Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr 1115 1120 1125 ❹

Ala Thr His Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly 1130 1135 1140

Gly Ala Arg Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg 1145 1150 1155

Cys Cys Asn Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr 1160 1165 1170

Ala Ala Arg Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn 1175 1180 1185

Ala Thr Gly Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr 1190 1195 1200

Gly Gly Asn Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn 1205 1210 1215 -763 - 200927761

Thr Ala Tyr Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn 1220 1225 1230

Gly Thr Asn Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn 1235 1240 1245

Thr Gly Gly Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr 1250 1255 1260

Gly Thr Asn Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn 1265 1270 1275

Gly Thr Asn Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn 1280 1285 1290

Met Thr Asn Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr 1295 1300 1305

Ala Cys Asn Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn 1310 1315 1320

Trp Ser Asn Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn 1325 1330 1335

Ala Ala Arg 1340 <210> 578 <211> 1362 -764- 200927761 <212> PRT <213〉現代人 <400> 578

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Met Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Cys Asn Ala Thr Gly Ala Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn -765 - 200927761 130 135 140

Trp Ser Asn Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Trp 145 150 155 160

Ser Asn Gly Gly Asn Gly Gly Asn Trp Ser Asn Ala Cys Asn Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285 766- 200927761

Gly Cys Asn Ala Ala Arg Gly Ala Arg Gly Gly Asn Ala Thr His Gly 290 295 300

Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Ala Cys Asn Gly Cys 305 310 315 320

Asn Gly Ala Arg Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr 325 330 335

Thr Ala Tyr Gly Cys Asn Ala Thr Gly Gly Ala Tyr Gly Thr Asn Thr 340 345 350

Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Ala Cys 355 360 365

Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser Asn 370 375 380

Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys 385 390 395 400

Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met Thr 405 410 415

Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly Asn 420 425 430

Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn Ala -767- 200927761 435 440 445

Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr Gly 450 455 460

Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala Tyr 465 470 475 480

Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn Ala 485 490 495

Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp Ser 500 505 510

Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser Asn 515 520 525

Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr Cys 530 535 540

Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp Ser 545 550 555 560

Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser Asn 565 570 575

Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn Ala 580 585 590 - 768 - 200927761

Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala Ala 595 600 605

Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys Asn 610 615 620

Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn Gly 625 630 635 640

Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala Ala 645 650 655

Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala Arg 660 665 670

Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg Thr 675 680 685

Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys Cys 690 695 700

Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys Asn 705 710 715 720

Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn Trp 725 730 735

Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys Cys -769- 200927761 740 745 750

Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala Tyr 755 760 765

Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn Met 770 775 780

Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala Cys 785 790 795 800

Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala Tyr 805 810 815

Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr Cys 820 825 830

Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala Ala 835 840 845

Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly Asn 850 855 860

Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr Gly 865 870 875 880

Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met Gly 885 890 895 -770- 200927761

Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala Tyr 900 905 910

Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn Gly 915 920 925

Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly Thr 930 935 940

Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly Gly 945 950 955 960

Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg Thr 965 970 975

Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp Ser 980 985 990

Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys Asn 995 1000 1005

Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg 1010 1015 1020

Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 1025 1030 1035

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn -771 - 200927761 1040 1045 1050

Gly Ala 1055

Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1060 1065

Ala Cys 1070

Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1075 1080

Met Gly 1085

Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1090 1095

Ala Ala 1100

Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1105 1110

Met Thr 1115

Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1120 1125

Ala Ala 1130

Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1135 1140

Trp Ser 1145

Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1150 1155

Gly Ala 1160

Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1165 1170

Gly Gly 1175

Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1180 1185 772- 200927761

Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1190 1195 1200

Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1205 1210 1215

Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1220 1225 1230

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1235 1240 1245

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1250 1255 1260

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1265 1270 1275

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1280 1285 1290

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1295 1300 1305

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1310 1315 1320

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg -773 - 200927761 1325 1330 1335

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1340 1345 1350

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1355 1360 <210> 579 <211> 1353 <212> PRT <213>現代人 <400> 579

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Met Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80 774 200927761

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Cys Asn Ala Thr Gly Trp Ser Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Trp 145 150 155 160

Ser Asn Gly Gly Asn Gly Gly Asn Trp Ser Asn Ala Cys Asn Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240 -775 - 200927761

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Ala Ala Arg Gly Ala Arg Gly Gly Asn Ala Thr His Gly 290 295 300

Cys Asn Gly Cys Asn Met Gly Asn Gly Ala Tyr Trp Ser Asn Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Cys Asn Ala Thr Gly 325 330 335

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350

Gly Asn Ala Cys Asn Ala Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn 370 375 380 776 200927761

Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr 385 390 395 400

Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly 405 410 415

Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn 420 425 430

Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met 435 440 445

Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala 450 455 460

Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg 465 470 475 480

Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr 485 490 495

Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr 500 505 510

Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr 515 520 525

Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met 530 535 540 -777- 200927761

Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr 545 550 555 560

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 565 570 575

Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp 580 585 590

Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys 595 600 605

Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr 610 615 620

Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys 625 630 635 640

Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr 645 650 655

Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg 660 665 670

Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly 675 680 685 -778 - 200927761

Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys 690 695 700

Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn 705 710 715 720

Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met 725 730 735

Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys U 740 745 750

Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly 755 760 765

Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly 770 775 780

Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr 785 790 795 800

Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr 805 810 815

Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys 820 825 830

Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr 835 840 845 -779- 200927761

Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn 850 855 860

Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala 865 870 875 880

Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala 885 890 895

Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr 900 905 910

Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met 915 920 925

Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala 930 935 940

Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn 945 950 955 960

Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala 965 970 975

Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly 980 985 990 780- 200927761

Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His 995 1000 1005

Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 1010 1015 1020

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1025 1030 1035

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1040 1045 1050

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1055 1060 1065

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1070 1075 1080

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1085 1090 1095

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1100 1105 1110

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1115 1120 1125

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1130 1135 1140 -781 - 200927761

Gly Cys 1145

Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1150 1155

Trp Ser 1160

Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1165 1170

Gly Ala 1175

Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1180 1185

Ala Cys 1190

Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1195 1200

Met Thr 1205

Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1210 1215

Trp Ser 1220

Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1225 1230

Trp Ser 1235

Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 1240 1245

Gly Ala 1250

Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1255 1260

Cys Ala 1265

Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1270 1275 -782- 200927761

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1280 1285 1290

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1295 1300 1305

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1310 1315 1320

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345 1350 <210〉 580 <211> 1353 <212> PRT <213〉現代人 <400〉 580

Gly Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Met Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Met Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Gly Gly Asn 35 40 45 -783 - 200927761

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Ala Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Cys Asn Ala Thr Gly Trp Ser Asn Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Trp Ser Asn Gly Cys Asn Ala Thr His Trp Ser Asn Gly Gly Asn Trp 145 150 155 160

Ser Asn Gly Gly Asn Gly Gly Asn Trp Ser Asn Ala Cys Asn Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala -784- 200927761 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255 ❹

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Ala Arg Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Ala Ala Arg Gly Ala Arg Gly Gly Asn Ala Thr His Gly 290 295 300 〇

Cys Asn Gly Gly Asn Met Gly Asn Gly Ala Tyr Trp Ser Asn Thr Ala 305 310 315 320

Tyr Thr Ala Tyr Thr Ala Tyr Thr Ala Tyr Gly Gly Asn Ala Thr Gly 325 330 335

Gly Ala Tyr Gly Thr Asn Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly 340 345 350 -785 - 200927761

Gly Asn Ala Cys Asn Ala Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr 355 360 365

Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn 370 375 380

Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr 385 390 395 400

Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly 405 410 415

Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn 420 425 430

Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met 435 440 445

Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala 450 455 460

Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg 465 470 475 480

Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr 485 490 495

Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr -786- 200927761 500 505 510

Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr 515 520 525

Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met 530 535 540

Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr 545 550 555 560 ❹

Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn 565 570 575

Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp 580 585 590

Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys 595 600 605 〇

Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr 610 615 620

Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys 625 630 635 640

Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr 645 650 655 -787- 200927761

Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg 660 665 670

Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly 675 680 685

Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys 690 695 700

Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn 705 710 715 720

Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met 725 730 735

Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys 740 745 750

Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly 755 760 765

Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly 770 775 780

Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr 785 790 795 800

Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr -788 - 200927761 805 810 815

Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys 820 825 830

Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr 835 840 845

Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn 850 855 860 〇

Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala 865 870 875 880

Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala 885 890 895

Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr 900 905 910 ❿

Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met 915 920 925

Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala 930 935 940

Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn 945 950 955 960 -789- 200927761

Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala 965 970 975

Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly 980 985 990

Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His 995 1000 1005

Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 1010 1015 1020

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1025 1030 1035

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1040 1045 1050

Gly Thr Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1055 1060 1065

Cys Cys Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1070 1075 1080

Ala Thr Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1085 1090 1095

Gly Thr Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr -790- 200927761 1100 1105 1110

Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn 1115 1120 1125

Thr Thr Tyr

Thr Ala Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr 1130 1135 1140

Ala Thr His

Gly Cys Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly 1145 1150 1155 ❹ Trp Ser Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg 1160 1165 1170

Gly Ala Arg

Cys Cys Asn

Gly Ala Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr 1175 1180 1185

Ala Ala Arg

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn 1190 1195 1200 〇

Ala Thr Gly

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr 1205 1210 1215

Gly Gly Asn

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn 1220 1225 1230

Thr Ala Tyr

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn 1235 1240 1245

Gly Thr Asn -791 - 200927761

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1250 1255 1260

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1265 1270 1275

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1280 1285 1290

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1295 1300 1305

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1310 1315 1320

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345 1350 <210> 581 <211> 1347 <212> PRT <213>現代人 <400〉 581

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15 -792- 200927761

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60 〇

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Thr Thr Tyr Ala Thr His Trp Ser Asn Gly Ala Tyr Gly 145 150 155 160 -793 - 200927761

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Thr Gly Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Trp Ser Asn Thr Ala Tyr Thr Ala Tyr Gly 290 295 300

Ala Tyr Trp Ser Asn Trp Ser Asn Gly Gly Asn Thr Ala Tyr Thr Ala 305 310 315 320 -794- 200927761

Tyr Thr Ala Tyr Gly Gly Asn Thr Thr Tyr Gly Ala Tyr Thr Ala Tyr 325 330 335

Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Ala Cys Asn Met 340 345 350

Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Trp Ser 355 360 365

O

Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly Asn 370 375 380

Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn Met 385 390 395 400

Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met Gly 405 410 415

Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser Asn 420 425 430

Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn Thr 435 440 445

Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr Ala 450 455 460 -795 - 200927761

Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr Asn 465 470 475 480

Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr Trp 485 490 495

Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp Ser 500 505 510

Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr Tyr 515 520 525

Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg Trp 530 535 540

Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp Ser 545 550 555 560

Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr Asn 565 570 575

Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser Asn Trp Ser Asn Ala 580 585 590

Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn Cys Ala Arg Ala Cys 595 600 605

Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala Ala Tyr Gly Thr Asn 610 615 620 -796- 200927761

Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys Asn Trp Ser Asn Ala 625 630 635 640

Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn Gly Ala Tyr Ala Ala 645 650 655

Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met Gly Asn Ala Ala Arg 660 665 670 ❹

Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala Arg Thr Gly Tyr Cys 675 680 685

Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn Gly Cys Asn Cys Cys 690 695 700

Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly Gly Asn Cys Cys Asn 705 710 715 720

Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr Asn Thr Thr Tyr Cys 725 730 735

Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn Ala Ala Arg Gly Ala 740 745 750

Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala Thr His Trp Ser Asn 755 760 765 -797- 200927761

Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala Arg Gly Thr Asn Ala 770 775 780

Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn Gly Thr Asn Gly Ala 785 790 795 800

Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly Ala Arg Gly Ala Tyr 805 810 815

Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala Arg Thr Thr Tyr Ala 820 825 830

Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn Gly Ala Tyr Gly Gly 835 840 845

Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys Ala Tyr Ala Ala Tyr 850 855 860

Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala Arg Cys Cys Asn Met 865 870 875 880

Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg Thr Thr Tyr Ala Ala 885 890 895

Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met Gly Asn Gly Thr Asn 900 905 910

Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr Asn Ala Cys Asn Gly 915 920 925 -798- 200927761

Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg Gly Ala Tyr Thr Gly 930 935 940

Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala Ala Arg Gly Ala Arg 945 950 955 960

Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala Arg Gly Thr Asn Trp 965 970 975 ❹

Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn Met Thr Asn Cys Cys 980 985 990

Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly Ala Arg Ala Ala Arg 995 1000 1005

Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala Arg Ala Cys Asn 1010 1015 1020

Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn Met Gly Asn 1025 1030 1035

Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn Thr Ala Tyr 1040 1045 1050

Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn Trp Ser Asn 1055 1060 1065 -799- 200927761

Met Gly 1070

Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly Ala Cys Asn 1075 1080

Ala Ala 1085

Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn Trp Ser Asn 1090 1095

Met Thr 1100

Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn 1105 1110

Ala Ala 1115

Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr Cys Cys Asn 1120 1125

Trp Ser 1130

Asn Gly Ala Tyr Ala Thr His Gly Cys Asn Gly Thr Asn 1135 1140

Gly Ala 1145

Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn Ala Ala Tyr 1150 1155

Gly Gly 1160

Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg Ala Ala Tyr 1165 1170

Ala Ala 1175

Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn Ala Cys Asn 1180 1185

Cys Cys 1190

Asn Cys Cys Asn Ala Thr Gly Met Thr Asn Gly Ala Tyr 1195 1200

Trp Ser 1205

Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn Thr Thr Tyr 1210 1215 -800- 200927761

Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn Ala Ala Arg 1220 1225 1230

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr Ala Ala Arg 1235 1240 1245

Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg Cys Ala Arg 1250 1255 1260 ❹

Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr Trp Ser Asn 1265 1270 1275

Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly Cys Ala Tyr 1280 1285 1290

Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr Ala Ala Tyr 1295 1300 1305

Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg Ala Ala Arg 1310 1315 1320

Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn Trp Ser Asn 1325 1330 1335

Cys Cys Asn Gly Gly Asn Ala Ala Arg 1340 1345 -801 - 200927761 <210> 582 <211> 1320 <212> PRT <213〉現代人 <400> 582

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125 -802- 200927761

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr -803 - 200927761 275 280 285

Gly Cys Asn Met Gly Asn Ala Ala Tyr Gly Thr Asn Ala Thr His Gly 290 295 300

Ala Tyr Thr Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly 305 310 315 320

Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn 325 330 335

Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala 340 345 350

Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr 355 360 365

Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr 370 375 380

Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly 385 390 395 400

Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr 405 410 415

Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg 420 425 430 -804- 200927761

Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys 435 440 445

Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly 450 455 460

Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn 465 470 475 480

Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala 485 490 495

Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr 500 505 510

Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn 515 520 525

Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly 530 535 540

Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn Trp Ser 545 550 555 560

Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala Cys Asn 565 570 575

Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly Tyr Ala - 805 - 200927761 580 585 590

Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg Cys Cys 595 600 605

Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly Thr Asn 610 615 620

Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala Arg Met 625 630 635 640

Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn Gly Ala 645 650 655

Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys Cys Asn 660 665 670

Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys Asn Gly 675 680 685

Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Met Thr 690 695 700

Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys Cys Asn 705 710 715 720

Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr Gly Ala 725 730 735 -806- 200927761

Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn Gly Ala 740 745 750

Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly Thr Asn 755 760 765

Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala Tyr Gly 770 775 780

Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn Cys Ala 785 790 795 800

Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly Thr Asn 805 810 815

Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr Asn Cys 820 825 830

Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn Ala Ala 835 840 845

Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys Ala Arg 850 855 860

Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr Tyr Met 865 870 875 880

Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn Met Thr -807- 200927761 885 890 895

Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys Ala Arg 900 905 910

Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly Asn Ala 915 920 925

Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr Ala Ala 930 935 940

Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly Gly Asn 945 950 955 960

Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr His Gly 965 970 975

Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn Ala Ala 980 985 990

Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg Cys Cys Asn 995 1000 1005

Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg Gly Thr Asn 1010 1015 1020

Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn Cys Cys Asn 1025 1030 1035 -808 - 200927761

Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Ala Thr Gly 1040 1045 1050

Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg Gly Thr Asn 1055 1060 1065

Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr Met Thr Asn 1070 1075 1080

Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr Thr Ala Tyr 1085 1090 1095

Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His Gly Cys Asn 1100 1105 1110

Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg Trp Ser Asn 1115 1120 1125

Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn Gly Ala Arg 1130 1135 1140

Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg Ala Cys Asn 1145 1150 1155

Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly Met Thr Asn 1160 1165 1170

Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn Trp Ser Asn -809- 200927761 1175 1180 1185

Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr Trp Ser Asn 1190 1195 1200

Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Ala Tyr 1205 1210 1215

Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly Cys Ala Arg 1220 1225 1230

Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn Thr Thr Tyr 1235 1240 1245

Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn Ala Thr Gly 1250 1255 1260

Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn Cys Ala Tyr 1265 1270 1275

Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn Cys Ala Arg 1280 1285 1290

Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn Met Thr Asn 1295 1300 1305

Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1310 1315 1320 -810- 200927761 <210> 583 <211〉 1338 <212> PRT <213>現代人 <400> 583

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 0 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Ala Tyr Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125 -811 - 200927761

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Thr His Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270 -812- 200927761

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Cys Asn Met Gly Asn Gly Gly Asn Gly Gly Asn Gly Cys Asn Ala 290 295 300

Cys Asn Gly Gly Asn Gly Cys Asn Gly Ala Arg Thr Ala Tyr Thr Thr 305 310 315 320

Tyr Cys Ala Arg Cys Ala Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg 〇 325 330 335

Gly Gly Asn Ala Cys Asn Met Thr Asn Gly Thr Asn Ala Cys Asn Gly 340 345 350

Thr Asn Trp Ser Asn Trp Ser Asn Gly Cys Asn Trp Ser Asn Ala Cys 355 360 365

Asn Ala Ala Arg Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn 370 375 380

Thr Thr Tyr Cys Cys Asn Met Thr Asn Gly Cys Asn Cys Cys Asn Thr 385 390 395 400

Gly Tyr Trp Ser Asn Met Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser 405 410 415

Asn Gly Ala Arg Trp Ser Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn 420 425 430 -813 - 200927761

Met Thr Asn Gly Gly Asn Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala 435 440 445

Ala Arg Gly Ala Tyr Thr Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala 450 455 460

Arg Cys Cys Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn 465 470 475 480

Thr Gly Gly Ala Ala Tyr Trp Ser Asn Gly Gly Asn Gly Cys Asn Met 485 490 495

Thr Asn Ala Cys Asn Trp Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala 500 505 510

Tyr Ala Cys Asn Thr Thr Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn 515 520 525

Met Thr Asn Cys Ala Arg Trp Ser Asn Trp Ser Asn Gly Gly Asn Met 530 535 540

Thr Asn Thr Ala Tyr Trp Ser Asn Met Thr Asn Trp Ser Asn Trp Ser 545 550 555 560

Asn Gly Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Cys Cys Asn 565 570 575 -814- 200927761

Trp Ser Asn Trp Ser Asn Ala Ala Tyr Thr Thr Tyr Gly Gly Asn Ala 580 585 590

Cys Asn Cys Ala Arg Ala Cys Asn Thr Ala Tyr Ala Cys Asn Thr Gly 595 600 605

Tyr Ala Ala Tyr Gly Thr Asn Gly Ala Tyr Cys Ala Tyr Ala Ala Arg 610 615 620

Cys Cys Asn Trp Ser Asn Ala Ala Tyr Ala Cys Asn Ala Ala Arg Gly 0 625 630 635 640

Thr Asn Gly Ala Tyr Ala Ala Arg Ala Cys Asn Gly Thr Asn Gly Ala 645 650 655

Arg Met Gly Asn Ala Ala Arg Thr Gly Tyr Thr Gly Tyr Gly Thr Asn 660 665 670

Gly Ala Arg Thr Gly Tyr Cys Cys Asn Cys Cys Asn Thr Gly Tyr Cys 675 680 685

Cys Asn Gly Cys Asn Cys Cys Asn Cys Cys Asn Gly Thr Asn Gly Cys 690 695 700

Asn Gly Gly Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr 705 710 715 720

Met Thr Asn Thr Thr Tyr Cys Cys Asn Cys Cys Asn Ala Ala Arg Cys 725 730 735 -815- 200927761

Cys Asn Ala Ala Arg Gly Ala Tyr Ala Cys Asn Met Thr Asn Ala Thr 740 745 750

Gly Ala Thr His Trp Ser Asn Met Gly Asn Ala Cys Asn Cys Cys Asn 755 760 765

Gly Ala Arg Gly Thr Asn Ala Cys Asn Thr Gly Tyr Gly Thr Asn Gly 770 775 780

Thr Asn Gly Thr Asn Gly Ala Tyr Gly Thr Asn Trp Ser Asn Cys Ala 785 790 795 800

Tyr Gly Ala Arg Gly Ala Tyr Cys Cys Asn Gly Ala Arg Gly Thr Asn 805 810 815

Cys Ala Arg Thr Thr Tyr Ala Ala Tyr Thr Gly Gly Thr Ala Tyr Gly 820 825 830

Thr Asn Gly Ala Tyr Gly Gly Asn Gly Thr Asn Gly Ala Arg Gly Thr 835 840 845

Asn Cys Ala Tyr Ala Ala Tyr Gly Cys Asn Ala Ala Arg Ala Cys Asn 850 855 860

Ala Ala Arg Cys Cys Asn Met Gly Asn Gly Ala Arg Gly Ala Arg Cys 865 870 875 880 -816 200927761

Ala Arg Thr Thr Tyr Ala Ala Tyr Trp Ser Asn Ala Cys Asn Thr Thr 885 890 895

Tyr Met Gly Asn Gly Thr Asn Gly Thr Asn Trp Ser Asn Gly Thr Asn 900 905 910

Met Thr Asn Ala Cys Asn Gly Thr Asn Gly Thr Asn Cys Ala Tyr Cys 915 920 925

Ala Arg Gly Ala Tyr Thr Gly Gly Met Thr Asn Ala Ala Tyr Gly Gly 930 935 940

Asn Ala Ala Arg Gly Ala Arg Thr Ala Tyr Ala Ala Arg Thr Gly Tyr 945 950 955 960

Ala Ala Arg Gly Thr Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Gly 965 970 975

Gly Asn Met Thr Asn Cys Cys Asn Gly Cys Asn Cys Cys Asn Ala Thr 980 985 990

His Gly Ala Arg Ala Ala Arg Ala Cys Asn Ala Thr His Trp Ser Asn 995 1000 1005

Ala Ala Arg Ala Cys Asn Ala Ala Arg Gly Gly Asn Cys Ala Arg 1010 1015 1020

Cys Cys Asn Met Gly Asn Gly Ala Arg Cys Cys Asn Cys Ala Arg 1025 1030 1035 -817- 200927761

Gly Thr 1040

Asn Thr Ala Tyr Ala Cys Asn Met Thr Asn Cys Cys Asn 1045 1050

Cys Cys 1055

Asn Trp Ser Asn Met Gly Asn Gly Ala Arg Gly Ala Arg 1060 1065

Ala Thr 1070

Gly Ala Cys Asn Ala Ala Arg Ala Ala Tyr Cys Ala Arg 1075 1080

Gly Thr 1085

Asn Trp Ser Asn Met Thr Asn Ala Cys Asn Thr Gly Tyr 1090 1095

Met Thr 1100

Asn Gly Thr Asn Ala Ala Arg Gly Gly Asn Thr Thr Tyr 1105 1110

Thr Ala 1115

Tyr Cys Cys Asn Trp Ser Asn Gly Ala Tyr Ala Thr His 1120 1125

Gly Cys 1130

Asn Gly Thr Asn Gly Ala Arg Thr Gly Gly Gly Ala Arg 1135 1140

Trp Ser 1145

Asn Ala Ala Tyr Gly Gly Asn Cys Ala Arg Cys Cys Asn 1150 1155

Gly Ala 1160

Arg Ala Ala Tyr Ala Ala Tyr Thr Ala Tyr Ala Ala Arg 1165 1170 -818- 200927761

Ala Cys Asn Ala Cys Asn Cys Cys Asn Cys Cys Asn Ala Thr Gly 1175 1180 1185

Met Thr Asn Gly Ala Tyr Trp Ser Asn Gly Ala Tyr Gly Gly Asn 1190 1195 1200

Trp Ser Asn Thr Thr Tyr Thr Thr Tyr Met Thr Asn Thr Ala Tyr 1205 1210 1215

Trp Ser Asn Ala Ala Arg Met Thr Asn Ala Cys Asn Gly Thr Asn 01220 1225 1230

Gly Ala Tyr Ala Ala Arg Trp Ser Asn Met Gly Asn Thr Gly Gly 1235 1240 1245

Cys Ala Arg Cys Ala Arg Gly Gly Asn Ala Ala Tyr Gly Thr Asn 1250 1255 1260

Thr Thr Tyr Trp Ser Asn Thr Gly Tyr Trp Ser Asn Gly Thr Asn 1265 1270 1275

Ala Thr Gly Cys Ala Tyr Gly Ala Arg Gly Cys Asn Met Thr Asn 1280 1285 1290

Cys Ala Tyr Ala Ala Tyr Cys Ala Tyr Thr Ala Tyr Ala Cys Asn 1295 1300 1305

Cys Ala Arg Ala Ala Arg Trp Ser Asn Met Thr Asn Trp Ser Asn 1310 1315 1320 -819- 200927761

Met Thr Asn Trp Ser Asn Cys Cys Asn Gly Gly Asn Ala Ala Arg 1325 1330 1335 <210〉 584 <211〉 1332 <212> PRT <213〉現代人 <400> 584

Cys Ala Arg Gly Thr Asn Cys Ala Arg Met Thr Asn Gly Thr Asn Gly 15 10 15

Ala Arg Trp Ser Asn Gly Gly Asn Gly Gly Asn Gly Gly Asn Gly Thr 20 25 30

Asn Gly Thr Asn Cys Ala Arg Cys Cys Asn Gly Gly Asn Met Gly Asn 35 40 45

Trp Ser Asn Met Thr Asn Met Gly Asn Met Thr Asn Trp Ser Asn Thr 50 55 60

Gly Tyr Gly Cys Asn Gly Cys Asn Trp Ser Asn Gly Gly Asn Thr Thr 65 70 75 80

Tyr Ala Cys Asn Thr Thr Tyr Trp Ser Asn Trp Ser Asn Thr Ala Tyr 85 90 95

Gly Gly Asn Ala Thr Gly Cys Ala Tyr Thr Gly Gly Gly Thr Asn Met - 820- 200927761 100 105 110

Gly Asn Cys Ala Arg Gly Cys Asn Cys Cys Asn Gly Gly Asn Ala Ala 115 120 125

Arg Gly Gly Asn Met Thr Asn Gly Ala Arg Thr Gly Gly Gly Thr Asn 130 135 140

Gly Cys Asn Gly Thr Asn Ala Thr His Thr Gly Gly Thr Ala Tyr Gly 145 150 155 160 〇

Ala Tyr Gly Gly Asn Trp Ser Asn Ala Ala Tyr Ala Ala Arg Thr Ala 165 170 175

Tyr Thr Ala Tyr Gly Cys Asn Gly Ala Tyr Trp Ser Asn Gly Thr Asn 180 185 190

Ala Ala Arg Gly Gly Asn Met Gly Asn Thr Thr Tyr Ala Cys Asn Ala 195 200 205 ❹

Thr His Trp Ser Asn Met Gly Asn Gly Ala Tyr Ala Ala Tyr Trp Ser 210 215 220

Asn Ala Ala Arg Ala Ala Tyr Ala Cys Asn Met Thr Asn Thr Ala Tyr 225 230 235 240

Met Thr Asn Cys Ala Arg Ala Thr Gly Ala Ala Tyr Trp Ser Asn Met 245 250 255 -821 - 200927761

Thr Asn Met Gly Asn Gly Cys Asn Gly Ala Arg Gly Ala Tyr Ala Cys 260 265 270

Asn Gly Cys Asn Gly Thr Asn Thr Ala Tyr Thr Ala Tyr Thr Gly Tyr 275 280 285

Gly Thr Asn Met Thr Asn Met Thr Asn Thr Gly Gly Thr Thr Tyr Gly 290 295 300

Gly Asn Gly Ala Arg Ala Cys Asn Thr Thr Tyr Gly Ala Tyr Thr Ala 305 310 315 320

Tyr Thr Gly Gly Gly Gly Asn Cys Ala Arg Gly Gly Asn Trp Ser Asn 325 330 335

Met Thr Asn Gly Thr Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Cys 340 345 350

Cys Asn Gly Cys Asn Trp Ser Asn Ala Cys Asn Ala Ala Arg Gly Gly 355 360 365

Asn Cys Cys Asn Trp Ser Asn Gly Thr Asn Thr Thr Tyr Cys Cys Asn 370 375 380

Met Thr Asn Gly Cys Asn Cys Cys Asn Thr Gly Tyr Trp Ser Asn Met 385 390 395 400

Gly Asn Trp Ser Asn Ala Cys Asn Trp Ser Asn Gly Ala Arg Trp Ser -822- 200927761 405 410 415

Asn Ala Cys Asn Gly Cys Asn Gly Cys Asn Met Thr Asn Gly Gly Asn 420 425 430

Thr Gly Tyr Met Thr Asn Gly Thr Asn Ala Ala Arg Gly Ala Tyr Thr 435 440 445

Ala Tyr Thr Thr Tyr Cys Cys Asn Gly Ala Arg Cys Cys Asn Gly Thr 450 455 460 ❹

Asn Ala Cys Asn Gly Thr Asn Trp Ser Asn Thr Gly Gly Ala Ala Tyr 465 470 475 480

Trp Ser Asn Gly Gly Asn Gly Cys Asn Met Thr Asn Ala Cys Asn Trp 485 490 495

Ser Asn Gly Gly Asn Gly Thr Asn Cys Ala Tyr Ala Cys Asn Thr Thr 500 505 510 ❹

Tyr Cys Cys Asn Gly Cys Asn Gly Thr Asn Met Thr Asn Cys Ala Arg 515 520 525

Trp Ser Asn Trp Ser Asn Gly Gly Asn Met Thr Asn Thr Ala Tyr Trp 530 535 540

Ser Asn Met Thr Asn Trp Ser Asn Trp Ser Asn Gly Thr Asn Gly Thr 545 550 555 560 -823 -

Claims

200927761 十、申請專利範圍 1·—種與HB-EGF(與肝素結合之似表皮生長因子的生長因子）結合之經分離的抗原結合蛋白，其包含： A)—或多個選自下列之輕鏈互補決定區（Cdrl): (i) 選自 SEQ ID NO : 189-217 之 CDRL1 ; (ii) 選自 SEQ ID NO : 2 1 8-233 之 CDRL2 ; (iii) 選自 SEQ ID NO : 234-274 之 CDRL3 ;及

(iv) 含有一或多個不超過4個胺基酸的胺基酸取代、缺失或插入之（i)、（Π)或（iii)的CDRL ;或 B)—或多個選自下列之重鏈互補決定區（CDRH): (i) 選自 SEQ ID NO : 275-299 之 CDRH1 ; (ii) 選自 SEQ ID NO : 300-3 3 1 之 CDRH2 ; (iii) 選自 SEQ ID NO : 3 3 2-3 72 之 CDRH3 ;及 (iv) 含有一或多個不超過4個胺基酸的胺基酸取代、缺失或插入之（i)、（ii)或（iii)的CDRH。 2.如申請專利範圍第1項之經分離的抗原結合蛋白，其包含一或多個 A)之輕鏈CDRL及一或多個B)之重鏈 CDRH。 3. 如申請專利範圍第1項之經分離的抗原結合蛋白’ 其包含至少二個A)之CDRL及至少二個B)之CDRH。 4. 如申請專利範圍第1項之經分離的抗原結合蛋白’ 其包含該 CDRH1、 CDRH2、 CDRH3、 CDRL1、 CDRL2 及 CDRL3。 5 /如申請專利範圍第1項之經分離的抗原結合蛋白’ 200927761 其中該A)之CDRL係選自： (i) 選自 SEQ ID NO : 189-217 之 CDRL1 ; (ii) 選自 SEQ ID NO : 2 1 8-23 3 之 CDRL2 ; (iii) 選自 SEQ ID NO : 234-274 之 CDRL3 ;及 (iv) 含有一或多個不超過2個胺基酸之胺基酸取代、缺失或插入的（i)、（ii)或（iii)之CDRL;

該B)之CDRH係選自： ⑴選自 SEQ ID NO : 275-299 之 CDRH1 ； (ii) 選自 SEQ ID NO : 3 00-3 3 1 之 CDRH2 ; (iii) 選自 SEQ ID NO : 3 3 2-3 72 之 CDRH3 ;及 (iv) 含有一或多個不超過2個胺基酸之胺基酸取代、缺失或插入的（i)、（Π)或（iii)之CDRH;或 C)—或多個 A)之輕鏈CDRL及一或多個B)之重鏈 CDRH。

6.如申請專利範圍第1項之經分離的抗原結合蛋白，其中該抗原結合蛋白包含： A) 選自下列之CDRL : (i) 選自 SEQ ID NO : 189-217 之 CDRL1 ; (ii) 選自 SEQ ID NO : 2 1 8-23 3 之 CDRL2 ;及 (iii) 選自 SEQ ID NO : 234-274 之 CDRL3 ; B) 選自下列之CDRH : (i) 選自 SEQ ID NO : 275-299 之 CDRH1 ; (ii) 選自 SEQ ID NO : 3 00-33 1 之 CDRH2 ;及 -2- 200927761 (iii)選自 SEQ ID NO : 332-372 之 CDRH3 ; 或 C)—或多個A)之輕鏈CDRL及一或多個B)之重鏈 CDRH。 7.如申請專利範圍第6項之經分離的抗原結合蛋白，其中該抗原結合蛋白包含： A) SEQ ID NO : 189-217 之 CDRL 1、SEQ ID NO : 0 218-233 之 CDRL2 及 SEQ ID NO : 234-274 之 CDRL3，及 /或 B) SEQ ID NO : 275-299 之 CDRH1、SEQ ID NO : 3 00-3 3 1 之 CDRH2 及 SEQ ID NO : 3 32-3 72 之 CDRH3。 8 .如申請專利範圍第1項之經分離的抗原結合蛋白，其中該抗原結合蛋白包含一輕鏈可變區（VL)(該VL與選自 SE0 ID NO : 94-141之胺基酸序列具有至少80%序列同— 性）及/或一重鏈可變區（VH)(該VH與選自SEQ ID NO : Q 1 42-1 86之胺基酸序列具有至少80%序列同一性）。 9.如申請專利範圍第8項之經分離的抗原結合蛋白，其中該VL與選自SEQ ID NO: 94-141之胺基酸序列具有至少90%序列同一性，及/或該VH與選自SEQ ID NO : 1 4 2 - 1 8 6之胺基酸序列具有至少9 0 %序列同一性。 1 〇 ·如申請專利範圍第8項之經分離的抗原結合蛋白 ’其中該VL係選自SEQ ID NO: 94-141，及/或該係選自 SEQ ID NO : 142-1 86。 11.一種經分離之抗原結合蛋白，其特異辨識至少一 -3- 200927761 個含有IHGE之抗原決定部位及/或HB-EGF之似EGF結構區。 12. —種經分離之抗原結合蛋白，其係與申請專利範圍第1項之抗原結合蛋白競爭結合。 13. —種與ΗΒ-EGF結合之經分離的抗原結合蛋白，其中該抗原結合蛋白包含： A) —或多個選自下列之輕鏈CDR(CDRL):

(i) 與SEQ ID NO: 189-217之序列具有至少80% 序列同一性之CDRL1 ; (ii) 與SEQ ID NO: 218-233之序列具有至少80% 序列同一性之CDRL2 ;及 (iii) 與 SEQ ID NO : 234-274之序列具有至少 8 0%序列同一性之CDRL3 ; B) —或多個選自下列之重鏈CDR(CDRH):

(i) 與SEQ ID NO : 2 75-299之序列具有至少80% 序列同一性之CDRH1 ; (ii) 與SEQ ID NO: 300-331之序列具有至少80% 序列同一性之CDRH2 ;及 (iii)與 SEQ ID NO : 3 3 2-3 72之序列具有至少 8 0%序列同一性之CDRH3 ;或 C) —或多個 A)之輕鏈CDRL及一或多個B)之重鏈 CDRH。 14.如申請專利範圍第13項之經分離的抗原結合蛋白，其中該抗原結合蛋白包含： -4- 200927761 A)~或多個選自下列之CDRL : (i) 與SEQ ID NO: 189-217之序列具有至少90% 序列同一性之CDRL1 ; (ii) 與SEQ ID NO: 218-233之序列具有至少90% 序列同一性之CDRL2 ;及 (iii)與 SEQ ID NO ： 234-274之序列具有至少 90%序列同一性之CDRL3 ;

B)—或多個選自下列之CDRH : (i)與SEQ ID NO: 275-299之序列具有至少90% 序列同一性之CDRH1 ; (ii)與SEQ ID NO : 3 00-3 3 1之序列具有至少90°/。序列同一性之CDRH2 ;及 (iii)與 SEQ ID NO ： 3 3 2-3 72之序列具有至少 9 0%序列同一性之〇〇11113;或 C)—或多個 A)之輕鏈 CDRL及一或多個 B)之重鏈 © CDRH。 15.—種與HB-EGF結合之經分離的抗原結合蛋白，該抗原結合蛋白包含： A)選自下列之輕鏈互補決定區（CDRL): (i) 選自 SEQ ID NO : 234-274 之 CDRL3 ; (ii) 與（i)之CDRL3之胺基酸序列的差異爲不超過 2個胺基酸之胺基酸加入、缺失或取代的CDRL 3;及 (iii)選自下列之CDRL3胺基酸序列： X1QX2X3X4X5PX6X7(SEQ ID NO : 1 089)，其中 200927761 X!係選自I或Μ， x2係選自A、G或S， X3係選自I或T， X4係選自H或Q， X5係選自F、L或W， 7X6係選自C、I、H、L或T， X7係選自S或T ;

QQXiX2X3X4X5IT(SEQ id NO ： 1 090)，其中 Xj係選自i或s， x2係選自F或Y， X3係選自F、I、S或Y， X4係選自A、S或T， X5係選自P或S ; XiX2X3X4X5X6X7X8T(SEQ ID NO ： 1091)，其中 x i係選自L或Q，

X2係選自K、N或Q， X3係選自A、H、S或Y， X4係選自Η、N或Y， X5係選自N、S或T， X6 係選自 A、F、I、T、V*Y， X7係選自P或無胺基酸， X8係選自F、L或P ; QX1X2DX3LPX4X5(SEQ ID NO : 1 092) > 其中 x i係選自H或Q， -6- 200927761 x2係選自c或Υ， χ3係選自D、I、N、S或Υ， Χ4係選自F、I或L， X5係選自A、S或T ; QQXiX2X3X4PX5X6X7(SEQ ID NO : 1 093 )，其中 X i係選自H或Y， X2係選自G或N，

X3係選自N或S， X4係選自S或W， X5係選自P或無胺基酸， X6係選自R或W， X7係選自S或T ;及 XiQYX2X3X4X5X6X7F(SEQ ID NO : 1094)，其中 X i係選自H或Q， X2係選自F或Y， X3係選自G、I或S， X4係選自F、I或T， X5係選自M、P、S或T， X6係選自F'L、R或W， X7係選自S或T ;及/或 B)選自下列之重鏈互補決定區（CDRH): ⑴選自 SEQ ID NO : 332-372 之 CDRH3 ； (ii)與（i)之CDRH3之胺基酸序列的差異爲不超過 2個胺基酸之胺基酸加入' 缺失或取代的CDRH3 ;及 200927761 (iii)選自下列之CDRH3胺基酸序歹！J : X1X2X3X4X5X6X7X8X9Xi〇Xi iDXi2(SEQ ID NO ： 1 03 5) ，其中 X!係選自E或S， x2係選自D、G或無胺基酸， X3係選自D、N或無胺基酸， X4係選自G或無胺基酸，

X5係選自G或無胺基酸， X6係選自W、Y或無胺基酸， Χ7係選自I、Ν或Υ， Χ8係選自Α或Υ， Χ9係選自G、V或Υ， Χ1〇係選自A、F或G， Xu係選自F、L或Μ， X】2係選自V或Υ ;

QX1X2X3X4X5X6X7X8X9Xl〇XllYXl2Xl3Xl4DXi5(SEQ ID NO : 1 03 6)，其中 X!係選自G或無胺基酸， X2係選自K、L或Υ， Χ3係選自A、G或S， X4係選自S、V或Y， X5係選自A或G， X6係選自G或無胺基酸， X7係選自T或無胺基酸， -8- 200927761 x8係選自s或無胺基酸， χ9係選自γ或無胺基酸， X 1 〇係選自w或Υ， Χιι係選自G、S或Υ， X i 2係選自F或Y， X13係選自G或無胺基酸， Xm係選自Μ或無胺基酸，

Χ15係選自V或Υ ; NO ： XJX2X3X4X5X6X7X8X9X10X] 1X12X13 Xl4(SEQ ID 1037)，其中 Xi係選自D、G、L、S或無胺基酸， X2係選自G、H、W、Y或無胺基酸， X3係選自A、F、W、Y或無胺基酸， X4係選自D、G、Q、T或無胺基酸， X5係選自G、I、Q、S或無胺基酸， X6係選自A、D、N、Q、S或無胺基酸， X7係選自G、Y或無胺基酸， X8係選自D、Y或無胺基酸， X9係選自Y或無胺基酸， X1〇係選自A、E、N或Y， Xh係選自G、P、T、V或Y， X! 2係選自F或I， X! 3係選自D或Q， Xi4係選自C、Η、V或Y; -9- 200927761 XlX2X3X4X5X6X7X8X9Xl〇XllXl2Xl3Xl4Xl5Xl6Xl7DX18(SEQ ID NO: 1038)，其中 X!係選自E、D或無胺基酸， X2係選自G、R或無胺基酸， X3係選自I、V、Y或無胺基酸， Χ4係選自A、G、L或Ν， Χ5係選自A、G、V或W，

X6係選自A、N、R或T， X7係選自G、N、P或無胺基酸， X8係選自G、T或無胺基酸， Χ9係選自Α或無胺基酸， X1()係選自D、E或無胺基酸， Xu係選自S、Y或無胺基酸， X12係選自G、Y或無胺基酸， X13係選自N、Y或無胺基酸，

X14係選自Y或無胺基酸， X15係選自D、Y或無胺基酸， X16係選自A、G或無胺基酸， X!7係選自F或Μ， Χ18係選自I、V或Υ; Χ1Χ2Χ3Χ4Χ5Χ6Χ7Χ8Χ9Χ10Χ11Χ12Χ13Χ14Χ15Χ16Χ17Χ18 Xi9X2〇X2iX2 2 X2 3 (SEQ ID NO ： 1 03 9)，其中 Χι係選自A、D、G、S或T， X2係選自八、£、0、1^、；^、11、丫或無胺基酸， -10- 200927761

χ3 係選自 A、 G、 L ‘ Ν、 R、Τ、Υ或無胺基 χ4 係選自 D、 G、 R 、S、 V、Υ或無胺基酸， X5 係選自 A、 G、 I ' S、 V、Υ或無胺基酸， X6 係選自 F、 G、 L、 R、 V或無胺基酸， X7 係選自 L、 T、 Y或無胺基酸， X8 係選自 Y或無胺基酸， X9 係選自 Υ或無胺基酸， Xi 0係選自 D或無胺基酸 ϊ Xi i係選自 S或無胺; 基酸 » Xi 2係選自 S或無胺基酸 5 Xi 3係選自 G或無胺基酸 J Xi 4係選自 D、 L、 Μ 、S - • Υ或無胺基酸， Xi 5係選自 Η、 I > Ρ、 .V、 W或無胺基酸， Xi 6係選自 F、 G、 L 、R、 s、Υ或無胺基酸， Xi 7係選自 D、 F、 V 、W 、Υ或無胺基酸， Xi 8係選自 C、 F、 L 、P、 S或Υ， Xi 9係選自 D、 F、 G 或Y > x2 0係選自 A、 C、 G 、P、 R、V 或 Υ， X2 i係選自 F、 L、 Μ 、S或無胺基酸， x2 2係選自 A、 D或無胺基酸， X2 3係選自 I ' L、 V ' _ Y或無胺基酸； Xi YSSGWX2X3 YGX4X5DX6(SEQ ID NO ： 1 040)，其中 x i係選自M或V， x2係選自s或無胺基酸， -11 - 200927761 Χ3係選自F或無胺基酸， X4係選自V或無胺基酸， x5係選自F或Μ， Χ6係選自V或Υ ;及 RXiX2X3PFX4Y(SEQ ID NO : 1041)，其中 Χι係選自G、H、L、N或R， Χ2係選自Ε、Τ或W， Χ3係選自L、N、T或V，

X4係選自D或E。 16.如申請專利範圍第15項之經分離的抗原結合蛋白，該抗原結合蛋白進一步包含： A)選自下列之CDRL.: (i)選自 SEQ ID NO : 189-217 之 CDRL1 ; (Π)與（i)之CDRL1之胺基酸序列的差異爲不超過 2個胺基酸之胺基酸加入、缺失或取代的CDRL1 ;

(iii)選自下列之CDRL1胺基酸序歹IJ : XiSSQSLX2X3SDGX4TYLX5(SEQ ID NO : 1106)，其中 Χι係選自K或R， X2係選自L或V， X3係選自Η或Y， Χ4係選自Κ或Ν， Χ5係選自Ν、S或Υ ; RASQXiISX2YLN(SEQ ID NO ： 1107)，其中 X!係選自R、S或T， -12- 200927761 Χ2係選自R或S ; RASQX1IX2X3X4LX5(SEQ ID NO : 1108)，其中 Xi係選自D、G、S或T， X2係選自A、R或S， X3 係選自 H、I、N、R、S 或 T， X4係選自D、W或Y， X 5係選自A、G或N ;

QASQDIXiX2X3LN(SEQ id NO ： 1109)，其中 X!係選自s或T， x2係選自D或N， X3係選自S或Y ; RASQXiVX2X3X4X5LA(SEQ ID NO : 1110)，其中 X!係選自s或T， X2係選自I或s， x3係選自R或s， X4係選自s、N或無胺基酸， X5係選自Y或無胺基酸；及 KSSQX1X2LX3X4SNNKNYLX5(SEQ ID NO : 1111)，其中 X!係選自N或S， x2係選自I或V， x3係選自D或Y， X4係選自N、R或S， X5係選自A或V ; -13- 200927761 (iv) 選自 SEQ ID NO : 2 1 8-233 之 CDRL2 ; (v) 與（iv)之CDRL2之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的CDRL2 ;及 (vi) 選自下列之CDRL2胺基酸序列： X1X2SNX3X4S(SEQ ID NO : 1112)，其中

X!係選自E或K， χ2係選自I或v， x3係選自R或w， X4係選自D或F ; XjXzSXsLQS^EQ ID NO : 1113)，其中 X】係選自A或T， X2係選自A、E或V， X3係選自S或T ; Xi ASX2LQS(SEQ ID NO ： 1114)，其中 X J係選自A或V，

X2係選自s或τ ; DASX,LET(SEQ ID NO ： 1115)，其中 x i係選自I或N ; GASSRAT(SEQ ID NO : 223);及 WASX,RES(SEQ ID NO ： 1116)，其中 X!係選自A或T;或 B)選自下列之CDRH : (i) 選自 SEQ ID NO : 275-299 之 CDRH1 ; (ii) 與（i)之CDRH1之胺基酸序列的差異爲不超過 -14- 200927761 2個胺基酸之胺基酸加入、缺失或取代的CDRH1 ; (iii)選自下列之CDRH1胺基酸序列： GYTXiTX2X3X4XsX6(SEQ ID NO : 1 095)，其中 X!係選自F或L ’ X2係選自E、G或S ’ X3係選自Η、L或Y ’ Χ4係選自G、S或Υ， Ο

Χ5係選自I或Μ， Χ6係選自Η或S ; GYXjFTS YWIG(SEQ ID NO ： 1 096)，其中 X i係選自R或s ; GFTFX,SX2X3MH(SEQ ID NO ： 1 097)，其中 X i係選自R或S， x2係選自H或Y， x3係選自D或G ; GFXiFSX2YX3MX4(SEQ ID NO ： 1 098)，其中 x i係選自p或T， x2係選自A、R或S， X3係選自A或S， X4係選自N或S ; GXi SX2SX3X4X5X6X7WXg(SEQ ID NO ： 1 099)，其中 x J係選自D或G， X2係選自F、I或V，係選自R、S或無胺基酸， -15- 200927761 χ4係選自G、Y或無胺基酸， Xs係選自D、G、S或無胺基酸， χ6係選自A、S或Y， X?係選自A或Y， Xs係選自N或S ; -

GFSLSNARMGVS(SEQ ID NO ： 2 79)；及 GFSLX,TGGVGVG(SEQ ID NO ： 1100)，其中 Xi係選自s或N ; (iv) 選自 SEQ ID NO : 300-3 3 1 之 CDRH2 ; (v) 與（iv)之CDRH2之胺基酸序列的差異爲不超過2個胺基酸之胺基酸加入、缺失或取代的CDRH2 ;及 (vi) 選自下列之CDRH2胺基酸序列： XJX2X3X4X5X6GX7TX8X9X10QKX1 !X12(SEQ ID NO： 1101) ，其中 Χί係選自S或W，

X2係選自F或I， X3係選自D、N或S， X4係選自A或P， X5係選自E、N或S， X6係選自D、N或S， X7係選自E、G或N， X 8係選自I或N， X9係選自C、H或Y， X i o係選自A或T， -16- 200927761 x 1 !係選自F或L， x i 2係選自D或G ; IIYPXiDSDX2RYSPSFQG(SEQ id NO ： 1102)，其中 X!係選自D或G， X2係選自A、I或T; Xi IX2X3DGSX4X5X6YX7DS VX8G(SEQ id NO ： 1103)，其中

X!係選自F或V， X2係選自S或W， X3係選自D、S或Y， X4係選自I、N或T， X5係選自K或Q， X6係選自N、R或Y， X7係選自A、T或V， X8係選自K或R ; XiISX2SX3X4X5X6YYADSVKG(SEQ ID NO ： 1104)，其中 Xi係選自A、H或Y， X2係選自G、R或S， X3係選自G或S， X4係選自G、R或S， X5係選自S、T或Y， X6係選自I或T ; XlX2X3X4X5X6X7X8X9Xl〇XllYXl2Xl3SXI4KS(SEQ ID -17- 200927761 NO : 1 1 05)，其中 X!係選自E、R或Y， Χ2係選自I或Τ， Χ3係選自Η、Ν或Υ， Χ4 係選自 C、H、S、T*Y， X 5係選自S或R， X6係選自G或S， X7係選自G、K、S或T，

X8係選自T或w， x9係選自N或Y， Xio係選自N或無胺基酸， Xu係選自D或無胺基酸， X i 2係選自A或Ν， Χΐ3係選自Ρ或V， X ! 4係選自L或V ;

XiIFSNDEKSYSTSLKS(SEQ ID NO ： 1 03 3 )，其中 Xj係選自H或LI ;及 LIYWNXiX2KRYSPSLX3S(SEQ ID NO ： 1 034)，其中 x!係選自D或V， X2係選自D或E， X3係選自K或R。 1 7 ·如申請專利範圍第1 6項之經分離的抗原結合蛋白，其中該抗原結合蛋白包含該第一胺基酸序列和該第一月安基酸序列。 -18- 200927761 1 8 .如申請專利範圍第1 7項之經分離的抗原結合蛋白，其中該第一胺基酸序列與該第二胺基酸序列共價結合。 19.如申請專利範圍第17項之經分離的抗原結合蛋白，其中該第一胺基酸序列包含該SEQ ID NO : 234-274之 CDRL3、SEQ ID NO : 2 1 8-23 3 之 CDRL2 及 SEQ ID NO : 189-217之CDRL1，且該第二胺基酸序列包含該SEQ ID NO : 332-3 72 之 CDRH3、SEQ ID NO : 3 00-3 3 1 之 CDRH2 ❹ 及 SEQ ID NO : 275-299 之 CDRH1。 2 0.如申請專利範圍第1-19項中任一項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲單株抗體、多株抗體、重組抗體、人抗體、人化抗體、嵌合型抗體、多特異性抗體或彼等之抗體片段。 21.如申請專利範圍第20項之經分離的抗原結合蛋白，其中該抗體片段爲Fab片段、Fab’片段、F(ab')2片段、 Fv片段、雙特異性單鏈抗體（diabody)或單鏈抗體分子。 φ 22.如申請專利範圍第20項之經分離的抗原結合蛋白 ’其中該抗原結合蛋白爲人抗體。 23. 如申請專利範圍第20項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲單株抗體。 24. 如申請專利範圍第1-19項中任一項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲IgGl-、IgG2-、 IgG3-或 IgG4-型。 25 ·如申請專利範圍第24項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲IgG2-或IgG4-型。 200927761 26. 如申請專利範圍第1-19項中任一項之經分離的抗原結合蛋白，其中該抗原結合蛋白係與標記基團偶合。 27. 如申請專利範圍第26項之經分離的抗原結合蛋白，其中該標記基團爲放射性同位素、放射性核素、螢光基團、酶催化性基團、化學發光基團、生物素化基團或預定之多狀基團。

2 8 .如申請專利範圍第1 -1 9項中任一項之經分離的抗原結合蛋白，其中該抗原結合蛋白係與效應子基團偶合。 29. 如申請專利範圍第28項之經分離的抗原結合蛋白，其中該效應子基團爲放射性同位素、放射性核素、毒素、治療性基團或化療性基團。 30. 如申請專利範圍第29項之經分離的抗原結合蛋白，其中該治療性基團或化療性基團爲加利車黴素

(calicheamicin)、歐利史汀-PE(auristatin-PE)、苯醌安絲黴素（geldanamycin)、美他納辛（maytanasine)或彼等之衍生物。 3 1 . —種經分離的抗原結合蛋白，其係與申請專利範圍第1-19項中任一項的抗原結合蛋白競爭結合人HB-EGF 32. 如申請專利範圍第31項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲單株抗體、多株抗體、重組抗體、人抗體、人化抗體、嵌合型抗體、多特異性抗體或彼等之抗體片段。 33. 如申請專利範圍第32項之經分離的抗原結合蛋白 -20- 200927761 ，其中該抗體片段爲Fab片段、Fab’片段、F(ab')2片段、 Fv片段、雙特異性單鏈抗體或單鏈抗體分子。 34. 如申請專利範圍第32項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲人抗體。 35. 如申請專利範圍第32項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲單株抗體。

3 6 .如申請專利範圍第31項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲IgGl-、IgG2-、IgG3-或IgG4-型 3 7 .如申請專利範圍第3 6項之經分離的抗原結合蛋白，其中該抗原結合蛋白爲IgG2-或IgG4-型。 3 8 .如申請專利範圍第31項之經分離的抗原結合蛋白，其中該抗原結合蛋白係與標記基團偶合。 39. 如申請專利範圍第38項之經分離的抗原結合蛋白，其中該標記基團爲放射性同位素、放射性核素、螢光基 Q 團、酶催化性基團、化學發光基團、生物素化基團或預定之多肽基團。 40. 如申請專利範圍第3 1項之經分離的抗原結合蛋白，其中該抗原結合蛋白係與效應子基團偶合。 41 .如申請專利範圍第40項之經分離的抗原結合蛋白，其中該效應子基團爲放射性同位素、放射性核素、毒素、治療性基團或化療性基團。 42.如申請專利範圍第41項之經分離的抗原結合蛋白，其中該治療性基團或化療性基團爲加利車黴素、歐利史 -21 - 200927761 汀-PE、苯醌安絲黴素、美他納辛或彼等之衍生物。 43. 如申請專利範圍第1-19項中任一項之經分離的抗原結合蛋白，其中該抗原結合蛋白減少至少部分經ΗΒ· EGF傳介之信號轉導。 44. 一種核酸分子，其編碼申請專利範圍第1-19項中任一項之抗原結合蛋白。

45. 如申請專利範圍第44項之核酸分子，其中該核酸分子係與控制序列操作性連接。 46. —種載體，其包含申請專利範圍第44項之核酸分子。 47. —種載體，其包含申請專利範圍第45項之核酸分子。 48.—種宿主細胞，其包含申請專利範圍第45項之核酸分子。

49. 一種宿主細胞，其包含申請專利範圍第46或47 項之載體。 50. —種製造申請專利範圍第1-19項中任一項之抗原結合蛋白的方法，其包含自分泌該抗原結合蛋白之宿主細胞製備該抗原結合蛋白的步驟。 5 1 . —種醫藥組成物，其包含至少一種申請專利範圍第1-19項中任一項之抗原結合蛋白和藥學上可接受之載體、稀釋劑及/或佐劑。 52.如申請專利範圍第51項之醫藥組成物，其進一步包含額外之活性劑。 -22- 200927761 5 3 .如申請專利範圍第5 2項之醫藥組成物’其中該至少一種其他活性劑爲抗腫瘤劑。 5 4 .如申請專利範圍第5 3項之醫藥組成物，其中該抗腫瘤劑爲抗腫瘤抗體。 55.如申請專利範圍第54項之醫藥組成物，其中該抗腫瘤抗體爲針對受體酪胺酸激酶之抗體。 5 6 .如申請專利範圍第5 3項之醫藥組成物，其中該抗 0 腫瘤抗體係針對EGFR。 5 7 .如申請專利範圍第5 1項之醫藥組成物，其係用於診斷、預防或治療過度增生疾病。 58.如申請專利範圍第57項之醫藥組成物，其中該過度增生疾病係與HB-EGF表現有關。 5 9 ·如申請專利範圍第5 7項之醫藥組成物，其中該過度增生疾病係與經擾亂（例如病態增強）的生長因子受體活化作用有關或伴隨發生此經擾亂（例如病態增強）的生長因 Q 子受體活化作用。 60.如申請專利範圍第59項之醫藥組成物，其中該病態增強的生長因子受體活化作用係與G蛋白及/或與G蛋白偶合之受體的活性病態增加有關或係由彼等引起。 6 1 .如申請專利範圍第5 1項之醫藥組成物，其係用於診斷、預防或治療癌症。 62 _如申請專利範圍第6 1項之醫藥組成物，其中該癌症係選自乳癌、胃腸癌、胰臟癌、攝護腺癌、卵巢癌、胃癌、內膜癌、唾腺癌、肺癌、腎臟癌、結腸癌、結腸直腸 -23- 200927761 癌、甲狀腺癌、膀胱癌、神經膠質瘤、黑色素瘤、癌症’ 尤其是表皮或鱗狀細胞癌、其他HB-EGF表現或過度表現之癌、或腫瘤轉移形成。 63. —種申請專利範圍第1-19項中任一項之至少一種抗原結合蛋白於製造用於診斷、預防或治療過度增生疾病之醫藥組成物上之用途。

64. 如申請專利範圍第63項之用途，其中該過度增生疾病爲申請專利範圍第58項中所定義之過度增生疾病。 65. —種用於診斷與HB-EGF之表現有關的病況之方法，其包含將樣本與申請專利範圍第1-19項之抗原結合蛋白接觸及測定該樣本中是否存有HB-EGF。 66. 如申請專利範圍第65項之方法，其中該病況爲申請專利範圍第58項中所定義之過度增生疾病。

67. —種用於預防或治療與患者體內HB-EGF之表現有關的病況之方法，其包含給予有此需要之患者有效量之至少一種申請專利範圍第1-19項的抗原結合蛋白。 68. 如申請專利範圍第62之方法，其中該病況爲申請專利範圍第57-60項中任一項所定義之過度增生疾病。 69. 如申請專利範圍第57項之方法，其中該患者爲哺乳動物患者。 70. —種套組，其包含申請專利範圍第1-19項之抗原結合蛋白、申請專利範圍第44或45項之核酸分子或申請專利範圍第46或47項之載體。 71. 如申請專利範圍第70項之套組，其包含至少一種 -24- 200927761 其他活性劑。 72. 如申請專利範圍第71項之套組，其中該其他活性劑爲抗腫瘤劑。 73. 如申請專利範圍第53項之醫藥組成物，其中該抗腫瘤劑爲順鉑（Cisplatin)或癌思停（Avastin)。

74. 如申請專利範圍第51至62項中任一項之醫藥組成物，其係欲以單一藥物治療之形式投服或與其他醫藥組成物（宜包含抗腫瘤劑’諸如順鉑或癌思停）一起投服。

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