TWI400087B - 抗-整合蛋白免疫接合體,方法及用途 - Google Patents
抗-整合蛋白免疫接合體,方法及用途 Download PDFInfo
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- TWI400087B TWI400087B TW094143287A TW94143287A TWI400087B TW I400087 B TWI400087 B TW I400087B TW 094143287 A TW094143287 A TW 094143287A TW 94143287 A TW94143287 A TW 94143287A TW I400087 B TWI400087 B TW I400087B
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Description
本發明係有關腫瘤專一性抗體與胞毒化合物之接合體。較佳之接合體含有利用二硫鍵結連接於抗-整合蛋白抗體之類美登素(maytansinoid)化合物。
迄今業界已進行過藉由接合抗腫瘤藥物與對抗腫瘤相關抗原之單株抗體(Mabs),俾使利用標靶導向遞送至腫瘤,提升藥物之局部濃度而增進該藥物效力之許多嘗試。相反地,可能實際破壞腫瘤細胞之抗體限制於利用封阻配位體與受體之結合或封阻受體(ErbB 1與ErbB2)之傳訊作用之針對封阻增殖刺激之彼等抗體例如生長因子EGF與Her-2,或引起效應子功能(ADCC或CDC)之彼等抗體。因此,業界一直在探索結合單株抗體之專一性與代謝毒物之扼殺潛力之產物。前者之實例為接合單株抗體BR96之小紅莓(doxorubicin)(Braslawsky,et al.Cancer Immunol Immunother 33:367-374,1991)及稠合於抗-生長因子抗體或片段之假單胞桿菌外毒素(Kreitment,et al.,Internat.J.Immunopharm.14(3):465-72,1992)。
彼等嘗試已遭遇未預見之限制,例如相較於每個細胞之外部結合位點數,需要相當高之毒素細胞內濃度。如果癌症細胞表面之腫瘤相關抗原數估計為105
個分子/細胞,則可有效地於彼等接合體中使用之胞毒劑對抗標靶癌細胞之IC5 0
值必須為10- 1 0
至10- 1 1
M(Chari,R.V.J.Adv.Drug Delivery Rev.
1998,31
,89-104)。其次,該藥物必須於與標靶結合後被釋放並滲透入細胞中,或整個構築體必須被轉運至細胞中,在那裏使毒素裂解或者活化。
有些彼等缺陷藉由使用接合於內化抗體之具高度效力之藥物及使用於細胞內條件下增進不穩定性的化學鍵可或多或少獲得解決。Chari等(Cancer Res.52:127-131,1992;Liu et al.,Proc.Natl.Acad.Sci USA 93:8618-8623,1996;美國專利案5,208,020)開發出抗體接合體,其中該抗體經由二硫鍵結連接於類美登素。
類美登素係衍生自植物之抗真菌劑及抗腫瘤劑。S.M.Kupchan等首先記述得自美登木屬之Maytenus ovatus
與Maytenus buchananii
的乙醇萃取物之三種柄大環內酯之單離,此為美國專利案3,896,111之主題,並證明其於鼠類模式中在微克/公斤劑量範圍之抗-白血病效力。然而,類美登素具有不被接受之毒性,導致中樞與周邊神經病變及副作用:特別是噁心、嘔吐、腹瀉、肝功能試驗值上升及,較不常見地,虛弱與昏睡。因此,有一段時間研究的焦點在於尋找正確的標靶基團以及適當的化學程序,以形成具有可接受的降解半衰期之美登素-抗體接合體。
與游離類美登素之高胞毒性對照下,抗體接合體對抗原陰性細胞之毒性比抗原陽性細胞低了數十倍。二硫鍵結之優點為彼等鍵於標靶細胞內易於被細胞內麩胱甘肽切割,釋放不含高度毒性之藥物。此方法曾應用於對抗腫瘤相關抗原之抗體,例如,C242-DM1接合體(Liu et al.,Proc.Natl.Acad.Sci USA 93:8618-8623,1996)、與HuN901-DM1(Chari et al.,2000)。然而,彼等接合體之應用由於各個標靶抗原表現有限,因而受到限制。
因此,業界對於藉由使用標靶導向更高度表現之腫瘤相關抗原,及視需要地,於惡性腫瘤增殖及轉移階段高度表現之抗原,因而對最劇毒之細胞提供天然濃度毒素之抗體,以增進此方法仍有所需求。
相當多的證據顯示,進展中之腫瘤生長取決於血管新生、新血管的形成,以提供腫瘤營養素與氧氣,帶走廢物及作為腫瘤細胞轉移遠端部位之導管(Gasti et al.,Oncol.54:177-184)。新近之研究已進一步界定整合蛋白於血管新生過程中之角色。血管新生期間,於活化內皮細胞表面表現的許多整合蛋白調控與各種ECM蛋白之關鍵性黏著作用,以調控不同之生物情況例如細胞遷移、增殖及分化。具體而言,密切相關卻互不相同之整合蛋白,αVβ3與αVβ5,已被證實於血管新生過程中傳介獨立之途徑:對抗αVβ3產生之抗體封阻鹼性纖維母細胞生長因子(bFGF)誘發之血管新生;而對αVβ5具專一性之抗體抑制血管之內皮生長因子(VEGF)誘發之血管新生[Eliceiri,et al.,J.Clin.Invest.103:1227-1230(1999);Friedlander et al.,Science 270:1500-1502(1995)]。因此,整合蛋白及尤其是含整合蛋白之αV次單元為涉及血管新生的疾病例如眼疾與贅瘤疾病、組織再造例如動脈再狹窄、及特定種類細胞增殖特別是上皮與鱗狀細胞癌之合理之治療用標靶劑。
細胞結合劑與高度胞毒性類美登素之接合體已被敘述(美國專利案5,208,020與5,416,064;R.V.J.Chari et al.,1992 Cancer Res.52:127-131)。與蛋白質胺基反應之特定試劑或反應物例如N-羥基琥珀醯亞胺基酯類(NHS)已被開發用以形成藥物-蛋白質接合體。此類試劑已由Carlsson等概括性地敘述(Biochem.J 173:723,1978及美國專利案4,149,003)。供類美登素與單株抗體及其他蛋白質接合用之硝基-吡啶基連接劑試劑揭示於WO2004/016801。
上文提及之程序中,細胞結合劑係以二官能劑例如N-琥珀醯亞胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)修飾以引入活性二硫基團。與含硫醇之胞毒藥物之反應提供細胞結合劑(例如單株抗體)與藥物經由二硫鍵結連接之接合體。頃發現C-3羥基位置可予以修飾而不喪失活性,事實上,發現特定酯類具有增強之細胞扼殺活性(其綜述參閱Cassady,et al.Chem Pharm Bull 52(1):1-26,2004)。美國專利案5,208,020與5,416,064具體地教示N-甲基-N-(3-甲基二硫基丙醯基)-L-丙胺酸之活化美登醇酯(maytansol ester)。得自此反應之類美登素基團(其係還原性切割該二硫鍵結後釋出者)命名為DM1[N2 ’
-脫乙醯基-N2 ’
-(3-巰基-1-酮基丙基)-美登素,CAS Reg.No.139504-50-0]。因此,使用甲基二硫醇化型DM1製備之所有接合體保留接合體藥物側二硫鍵結鄰接未經取代之伸甲基碳(圖1)。
為了提高此二硫環節之活體內穩定性,如同文獻先前已提及(Thorpe,et al.Cancer Research 47:5924-31,1987),提供立體阻礙之二硫鍵結相當重要。使用於鄰接二硫鍵之碳原子上帶有一或兩個甲基取代基之交聯劑或使用於鄰接硫氫基或二硫取代基之α-碳原子上帶有至少一個取代基之活化藥物可達成此目標。
儘管標靶導向遞送問題頃已清楚地被認知,抗體專一性與親和性、接合化學、及毒素之適當組合卻不可預料。本發明之目的在於提供新穎之抗體美登素接合體,其中該抗體係足量導向細胞表面抗原,以遞送殺細胞劑量之類美登素,及該接合體具有適當化學及生物穩定性,以於投與病患時提供治療有效之釋放率。
本發明之目的在於提供新穎之抗體美登素接合體,其中該抗體係足量導向細胞表面抗原,以遞送殺細胞劑量之類美登素,及已知該抗體於結合標靶抗原後,被細胞內化。於特定具體實例中,該等接合體包含二硫鍵結,其已透過鄰接伸甲基碳之取代作用被建造,以於投與病患時提供治療有效之釋放率。於特定具體實例中,本發明係有關一種抗體-藥物接合體,其含有與接合胞毒劑(IC50值為10- 9
M或更小)之人類αV整合蛋白次單元結合之抗體,其中該抗體-藥物接合體對表現αV整合蛋白之癌症細胞株發揮胞毒作用或細胞生長抑制作用。於此具體實例中,本發明抗體對雜二聚體整合蛋白受體之至少一個αV次單元(例如αVβ1、αVβ3、αVβ5、αVβ6、或αVβ8雜二聚體整合蛋白或其片段)具專一性。較佳接合體含有利用二硫鍵結連接於抗體之類美登素化合物及該抗體能結合透明質蛋白與纖維蛋白原(fibrogen)。
於一態樣中,本發明之抗體接合體以下式表示[C-L]m
-A I式中A係人類αV整合蛋白次單元專一性抗體,其中該抗體能被表現該αV次單元之細胞內化;C係IC5 0
值為10- 9
M或更小之細胞毒素;L係結合抗體與細胞毒素之連接基,其進一步含有可被細胞內環境成分切割之鍵結;及m代表連接於抗體的細胞毒素分子之平均數,其為1至10(特別是3至4)之整數。細胞毒素可選自下述組群:類美登素、硝礦黴素(calicheamicins)、依波西隆(epothilones)、狄可德莫(discodermolide)、愛柳洛平(eleuthrobins)、多拉司丁(dolastatins)、隱花植物素(cryptophycins)、喜樹鹼、利索新(rhizoxin)(CAS註冊號90996546)、或紫杉烷衍生物及對腫瘤細胞生長具有10- 9
M或更小之一半最大抑制值(IC50或GI50)之彼等其他化合物。
於本發明第一目的之態樣中,抗-αV整合蛋白抗體-類美登素接合體包含由和單株抗體CNTO 95競爭結合於雜二聚體人類整合蛋白受體的α V次單元之抗體構成的分子之任何蛋白質或胜肽。於一具體實例中,該抗體包含衍生自命名CNTO 95的抗體之重鏈或輕鏈或其配位體結合部分之互補決定區(CDR)之至少一部分,組合重鏈或輕鏈可變區、重鏈或輕鏈恒定區、基本結構區、或其可與CDR一起併入抗體中之任何部分。本文敘述之抗體CNTO 95係由免疫處理含有表現人類免疫球蛋白基因之基因轉殖小鼠衍生之人類抗-αV抗體。因此,於一具體實例中,本發明係有關含有衍生自CNTO 95抗體之至少一個CDR區或可變區之抗體。於較佳具體實例中,該抗體為CNTO 95。
於本發明之另一態樣中,該抗體-類美登素接合體包含美登素醇酯,其於連接細胞毒素,C,與連接劑,L,之鍵結被細胞內環境成分切割後,即釋出。於一具體實例中,以醯基化之胺基酸(該醯基帶有經保護之硫氫基)使類美登素於C-3、C-14、C-15、或C-20處酯化,其中鄰接經保護之硫氫基的醯基之碳原子具有一或兩個取代基,該等取代基為CH3
、C2
H5
、具有1至10個碳原子之直鏈烷基或烯基、具有3至10個碳原子之分支鏈或環狀烷基或烯基、苯基、經取代之苯基、或雜環芳基、雜環烷基基團、或H;及其中醯基於羰基官能基與硫原子之間具有至少兩個碳原子之直鏈鏈長。於較佳具體實例中,該類美登素為3-美登素醇酯,及該醯基化之胺基酸於鄰接經保護之硫氫基之碳原子上具有0、1或2個甲基。於較佳具體實例中,酯化之美登素醇係選自N2 ’
-脫乙醯基-N2 ’
-(3-巰基-1-酮基丙基)-美登素(DM1,CAS Reg.No.139504-50-0)、N2 ’
-脫乙醯基-N2 ’
-(4-巰基-1-酮基戊基)-美登素(DM3)、與N2 ’
-脫乙醯基-N2 ’
-(4-甲基-4-巰基-1-酮基戊基)-美登素(DM4)。
本發明之第二目的在於提供用以治療由不正常增殖引起及特徵為新血管生成之人類增殖性疾病之抗-整合蛋白抗體-類美登素接合體化合物。於特佳具體實例中,本發明化合物於治療癌症(包括乳癌、結腸癌、直腸癌、肺癌、前列腺癌、腎臟癌、肝癌、胰臟癌、食道癌、胃癌、子宮內膜癌、卵巢癌、子宮頸癌、或骨癌)之方法中使用。本發明化合物可單獨使用或與預防或治療原發性癌症或預防或治療轉移性疾病之其他藥劑組合使用。
本發明第二目的之另一方法係有關於癌症治療方法中組合使用抗-整合蛋白抗體類美登素接合體化合物與化療劑。較佳之接合體含有利用二硫鍵結連接於抗體之類美登素化合物,較佳之化療劑為小紅莓、紫杉烷、喜樹鹼、鬼臼素、核苷類似物、或嘧啶類似物。
於本發明之第三目的中,該抗體-類美登素接合體係利用下述方法製備:使抗體與雙專一性化學連接劑試劑例如N-琥珀醯亞胺基-(2-吡啶基硫基)烷羧酸酯反應,接著與預活化之類美登素反應,從而發生二硫鍵交換作用,於抗體和類美登素之間獲得位阻之二硫鍵結。
於本發明之另一態樣中,該抗體-類美登素接合體之製備係使用美登素醇酯,其中醯基基團具有經保護之硫氫基。於一具體實例中,係使用醯基化之胺基酸(該醯基帶有經保護之硫氫基)使類美登素於C-3、C-14、C-15、或C-20處酯化,其中鄰接經保護之硫氫基的醯基之碳原子具有一或兩個取代基,該等取代基係選自:CH3
、C2
H5
、具有1至10個碳原子之直鏈烷基或烯基、具有3至10個碳原子之分支鏈或環狀烷基或烯基、苯基、經取代之苯基、雜環芳基、雜環烷基、或H;及其中醯基於羰基官能基與硫原子之間具有至少兩個碳原子之直鏈鏈長。於較佳具體實例中,該類美登素為3-美登素醇酯,及該醯基化之胺基酸於鄰接經保護之硫氫基之碳原子上具有0、1或2個甲基。於較佳具體實例中,酯化之美登素醇係選自N2 ’
-脫乙醯基-N2 ’
-(3-巰基-1-酮基丙基)-美登素(DM1,CAS註冊號139504-50-0)、N2 ’
-脫乙醯基-N2 ’
-(4-巰基-1-酮基戊基)-美登素(DM3)、與N2 ’
-脫乙醯基-N2 ’
-(4-甲基-4-巰基-1-酮基戊基)-美登素(DM4)。
於本發明另一態樣中,該抗-αV整合蛋白抗體-類美登素接合體主要係利用使具有反應性酯之類美登素與未先行化學活化之抗-整合蛋白抗體反應之單一步驟予以製備。類美登素之反應性酯可為N-琥珀醯亞胺基、N-磺酸琥珀醯亞胺基、N-酞醯亞胺基、N-磺酸酞醯亞胺基、2-二硝苯基、4-二硝苯基、2,4-二硝苯基、3-磺醯基-4-二硝苯基或3-羧基-4-二硝苯基酯。
為了更容易瞭解本發明,乃先行界定特定名詞。附加之界定於整個詳細說明中提出。
本文中交換使用「αV整合蛋白」、「αV次單元整合蛋白」、與「含整合蛋白之αV次單元」等詞意指功能性整合蛋白雜二聚體之αV跨膜醣蛋白次單元,包括αV之所有變異體、同功型與物種同質物。因此,特定情形下,本發明抗體可與得自人類以外的其他物種或結構上與人類αV相關的其他蛋白質(例如,人類αV同質物)之αV交叉反應。其他情形下,抗體可對人類αV具完全專一性及未展現物種或其他種類之交叉反應性。
本文所用之「抗體」包含整個抗體及其任何抗原結合片段或單鍵。因此抗體包含由免疫球蛋白分子之至少一部分組成之任何含蛋白質或胜肽之分子,例如惟不限於,重鏈或輕鏈或其配位體結合部分之至少一個互補決定區(CDR)、重鏈或輕鏈可變區、重鏈或輕鏈恒定區、基本結構區(FR)、或其可併入本發明抗體中之任何部分、或結合蛋白質之至少一部分。抗體可為鼠類、人類、人類化、或嵌合型。
「抗原結合片段」或其部分,包含單鏈抗體及其片段。功能性片段包含與哺乳動物α-V次單元結合之抗原結合片段。涵蓋於抗體之「抗原結合部分」一詞內之結合片段之實例包含(i)Fab片段,由VL、VH、CL與CH功能部位組成之單價片段;(ii)F(ab’)2片段,包含於鉸合區利用二硫鍵結連接的兩個Fab片段之二價片段;(iii)由VH與CH功能部位組成之Fd片段;(iv)由抗體單臂之VL與VH功能部位組成之Fv片段;(v)dAb片段,其中VH與VL功能部位於單一多肽鏈上表現,惟使用太短而不容許相同鏈上的兩個功能部位配對,因而迫使該功能部位與另一鏈之功能部位配對以產生兩個抗原結合位點之連接劑;及(vi)單離之互補決定區(CDR)。再者,雖然Fv片段之二功能部位,VL與VH,係由不同基因編碼,惟彼等可使用基因重組方法,利用賦能彼等製成單一蛋白鏈之合成連接劑予以連結,其中VL與VH區域配對形成單價分子[所謂單鏈Fv(scFv)]。此等單鏈抗體亦意欲涵蓋於抗體之「抗原結合部分」一詞內。彼等抗體片段係使用熟習此項技藝者已知之習用技術製得,及以與完整抗體相同之方式篩檢其效用。此等片段可利用如此項技藝中已知及/或知本文所述之酵素切割、合成或基因重組技術予以製造。
「抗原決定部位」一詞意指能專一性地與抗體結合之蛋白質決定子。抗原決定部位通常由分子例如胺基酸或糖側鏈之化學活性表面群組形成,及通常具有專一性立體結構特性、以及專一性電荷特性。構像與非構像抗原決定部位之區別在於,與前者之結合於變性溶劑存在下喪失,與後者之結合則不然。於本文中交換使用「原態構像抗原決定部位」或「原態蛋白質抗原決定部位」等詞,及包括由於整合蛋白分子構像摺疊所產生之蛋白質抗原決定部位,其形成發生於整合蛋白分子直鏈序列不同部分之胺基酸於3度空間內密切靠在一起時。此等構像抗原決定部位分佈於原生質膜之胞外側。
本文所用之「人類抗體」一詞意欲包含具有衍生自人類胚細胞免疫球蛋白序列或與其密切相配之可變區與恒定區之抗體。本發明之人類抗體包含不為人類胚細胞免疫球蛋白序列編碼之胺基酸殘基(例如,隨機引入之突變或試管內位點-專一性突變形成或活體內體細胞突變)。因此本文所用之「人類抗體」係指其中實質上蛋白質之每一部分(例如,CDR、基本結構、CL
、CH
功能部位[例如,CH
1、CH
2、CH
3)、鉸合區、(VL
、VH
)]實質上類似於人類胚細胞抗體之抗體。人類抗體已根據其胺基酸序列相似性分成數個類別,參閱例如http://people.cryst.bbk.ac.uk/~ubcgO7s/。因此,使用序列相似性搜尋,可挑選具有相似直鏈序列之抗體作為模板以產生「人類化抗體」。
「人類化」(亦稱為再塑造或CDR-嫁接)目前係用以減少得自異種來源(通常為齧齒類)單株抗體(mAbs)的免疫原性及增進效應子功能(ADCC、補體活化、Clq結合)之已健全確立之技術。經建造之單株抗體係使用分子生物技術建造,然而齧齒類互補決定區(CDRs)之簡單CDR-嫁接入人類基本結構中,常導致原始單株抗體結合親和性及/或專一性之喪失。為了將抗體人類化,該人類化抗體之設計包括例如CDRs殘基中之保守性胺基酸取代、使得自齧齒類單株抗體之殘基逆取代入人類基本結構區中(逆突變)等變異。彼等位置可利用供結構分析之序列比較法或利用分析可變區3D結構之同質性模式予以識別或鑑定。親和性成熟法新近係使用噬菌體庫以更改所選擇位置之胺基酸。同樣地,許多方法被用來挑選於其中嫁接齧齒類CDRs之最適當人類基本結構。由於抗體結構已知參數之資料庫增加,因此彼等技術之複雜性與精細性亦增加。可使用得自數個不同人類單株抗體之各單或重鏈可變區內的基本結構序列之單一抗體或片段之一致序列或胚細胞序列。人類化之另一方法為以人類單株抗體之最常見殘基只修飾齧齒類序列之表面殘基,稱為「表面鋪設」或「虛飾」。已知之人類Ig序列揭示於,例如,www.ncbi.nlm.nih.gov/entrez/query.fcgi;www.ncbi.nih.gov/igblast;www.atcc.org/phage/hdb.html;www.kabatdatabase.com/top.html;www.abtibodyresource.com/onlinecomp.html;www.appliedbiosystems.com;www.biodesign.com;abtibody.bath.ac.uk;http://www.unizh.ch/~antibody/;www.cryst.bbk.ac.uk/~ubcg07s;Kabat et al.,Sequences of Proteins of Immunological Interest,U.S.Dept.Health(1983);各者全部內容均併入本文以資參考。
「嵌合型抗體」係保留一物種之不同功能部位(通常為可變功能部位),其餘得自另一物種,之彼等抗體;例如小鼠人類嵌合體。
本文所用之「單株抗體」或「單株抗體組成物」係指單一分子組成物抗體分子之製劑。於一具體實例中,人類單株抗體係利用融合瘤製造,該融合瘤包含得自基因轉殖非人類動物(例如,基因轉殖小鼠)之B細胞,其具有由稠合於胚質永存細胞之人類重鏈轉殖基因與輕鏈轉殖基因構成之基因體。然而,通常係轉殖抗體編碼序列,將其嵌入宿主細胞或生產細胞株中。
本文所用之「重組宿主細胞」(或簡稱「宿主細胞」)擬意指已引入重組表現載體之細胞。應瞭解的是,此等名詞不僅擬意指特定對象細胞,亦包括此等細胞之後代。因為後繼世代由於突變或環境影響,可能發生某些改變,事實上,此等後代可能與親代細胞不相同,惟仍涵蓋於本文所用的「宿主細胞」一詞之範圍內。基因重組宿主細胞包含,例如,CHO細胞株或小鼠骨髓癌SP/0衍生之細胞株。
本文所用之「重組人類抗體」一詞包含利用基因重組方式製備、表現、產生或單離之所有人類或人類化抗體,例如(a)自基因轉殖或染色體轉殖入人類免疫球蛋白基因之動物(例如,小鼠)或製造該抗體之融合瘤單離之抗體;(b)自轉形以表現該抗體之宿主細胞(例如,自轉染瘤)單離之抗體;(c)自基因重組、組合人類抗體庫單離之抗體及(d)利用涉及使人類免疫球蛋白基因序列與其他DNA序列接合之任何其他方式製備、表現、產生或單離之抗體。
本文所用之「單離抗體」擬意指實質上不含具有不同抗原專一性之其他抗體之抗體(例如,專一性地與αV結合之單離抗體實質上不含專一性地結合αV以外的抗原之抗體)。然而,與人類αV之抗原決定部位、同功型或變異體專一性結合之單離抗體可與得自其他物種之其他相關抗原(例如,αV物種同質物)具有交叉反應性,此外,單離抗體可實質上不含其他細胞物質及/或化學劑。
本文所用之「專一性結合」係指抗體結合於業已決定之抗原。典型地,抗體係以10- 7
M或更小之游離常數(KD
)結合,而以較其與業已決定抗原或密切相關抗原以外之非專一性抗原(例如,BSA、酪蛋白)結合之KD
至少小兩倍之KD
結合於該業已決定之抗原。
本文所用之「同功型」係指由重鏈恒定區基因編碼之抗體類別(例如,IgM或IgG1)。
Abs 抗體,多株或單株aV 整合蛋白次單元αV b3 整合蛋白次單元β3 bFGF 鹼性纖維母細胞生長因子HUVEC 人類臍靜脈內皮IFN 干擾素Ig 免疫球蛋白IgG 免疫球蛋白G Mab 單株抗體NPB=N-琥珀醯亞胺基-5-硝基-(2-吡啶基二硫基)丁酸酯SMCC=琥珀醯亞胺基4-(N-馬來醯亞胺基甲基)環己烷-1-甲酸酯SMNP=N-琥珀醯亞胺基4-甲基-4-(5-硝基-2-吡啶基二硫基)戊酸酯SMPT=4-琥珀醯亞胺基氧羰基-(2-吡啶基二硫基)甲苯SPDB=N-琥珀醯亞胺基-4-(2-吡啶基二硫基)丁酸酯SPDP=N-琥珀醯亞胺基-3-(2-吡啶基二硫基)丙酸酯SPP=N-琥珀醯亞胺基-4-(2-吡啶基硫基)戊酸酯SP=N-琥珀醯亞胺基4-(2-吡啶基)SS=磺酸琥珀醯亞胺基SSNPP=磺酸琥珀醯亞胺基-N-琥珀醯亞胺基-4-(5-硝基-2-吡啶基二硫基)戊酸酯VEGF 血管內皮生長因子
本發明之抗體接合體以下式表示[C-L]m
-A I
式中A係人類αV整合蛋白次單元專一性抗體,其中該抗體能被表現該αV次單元之細胞內化;C係IC5 0
值為10- 9
M或更小之細胞毒素;L係結合抗體與細胞毒素之連接基,其進一步含有可被細胞內環境成分切割之鍵結;及m代表連接於抗體的細胞毒素分子之平均數,其為1至5(較佳為3至4)之整數。細胞毒素可選自下述組群:類美登素、硝礦黴素、依波西隆、狄可德莫、愛柳洛平、多拉司丁、隱花植物素、喜樹鹼、利索新(CAS註冊號90996546)、或紫杉烷衍生物及對腫瘤細胞生長具有10- 9
M或更小之一半最大抑制值(IC50或GI50)之彼等其他化合物。
連接劑含有可切割之細胞內鍵結,包括酸不穩定鍵結例如順式烏頭醯基鍵結、酯類、酸敏感腙鍵結、溶酶體可降解之胜肽連接劑、水解酶可降解之連接劑、肽酶或蛋白酶專一性連接劑、與二硫化物(硫氫基)連接劑(其綜述參見Dyba,M.,et al.2004 Cuff Pharm Design 10:2311-2334)。相對於在例如,循環中,佔優勢之條件,於細胞內條件下由於能更迅速或選擇性切割,因此連接劑賦與接合體整個藥物動力學進一步之專一性及安全性。二硫鍵結由於在細胞區域內有利之還原潛力以及可誘導之氧化還原酵素活化作用(Saito,G.et al.Adv.Drug Delivery Rev 2003 55:199-215),因此特佳。於本發明之一具體實例中,該鍵結係位於存在抗體分子中之硫原子(例如於半胱胺酸殘基之側鏈)與存在毒性化合物中之另一硫原子之間。於另一具體實例中,連接基團由一或多個原子或化學基團組成。
化學性連接生物分子(例如重組蛋白質)與化學化合物之另一主要考量為,於多數情形下,衍生化學將獲得可能具有迄今未知的生物性質之新分子實體。因此,應瞭解的是,必須設計生理切割產物以獲得具有生物活性之意指衍生物。本發明之類美登素(包括DM1、DM3、DM4及其他如圖1所示者)保留生物活性。
本發明之抗-αV整合蛋白抗體-類美登素接合體之製備係藉由化學連接抗-αV抗體至類美登素分子而不顯著減少該抗體之生物活性並提供類美登素,其於生理條件下釋放時,仍保留胞毒潛力。適當類美登素之實例為美登素醇之酯類及美登素醇類似物,包括惟不限於彼等具有經修飾之芳族環者及於C-19、C-20、或C-14、或C-15、或C-4,5脫氧基處經修飾者。較佳者為美登素醇C-3酯類,特佳之類美登素為美登素醇(N2 ’
-脫乙醯基-美登素)之N-甲基-丙胺酸酯之衍生物。特佳之接合體含有二硫鍵結,其於利用還原切割後,釋放帶有游離硫醇之類美登素。較佳種類之含硫醇之類美登素示於圖1:N2 ’
-脫乙醯基-N2 ’
-(3-巰基-1-酮基丙基)-美登素(DM1,CAS Reg.No.139504-50-0)、N2 ’
-脫乙醯基-N2 ’
-(4-巰基-1-酮基戊基)-美登素(DM3)、與N2 ’
-脫乙醯基-N2 ’
-(4-甲基-4-巰基-1-酮基戊基)-美登素(DM4)。
本發明抗體分子與毒性化合物之接合體可使用目前已知或以後開發之任何技術形成。例如,胞毒化合物可經修飾以獲得游離胺基,然後經由酸-不穩定連接劑或光-不穩定連接劑,連接於抗體分子。毒性化合物可與胜肽縮合,接著連接於抗體分子,以產生肽酶-不穩定連接劑。毒性化合物可經處理以獲得一級羥基,其可被琥珀醯基化,連接於抗體分子,以產生可被細胞內酯酶切割而釋放游離藥物之接合體。
為了在抗體A與細胞毒素C間產生二硫鍵結,較佳為,毒性化合物經處理以產生游離或經保護之硫醇基,然後使一或多個含二硫鍵或硫醇之毒性化合物經由二硫鍵結共價連接於抗體分子。二硫鍵結不需要直接以抗體之游離硫醇基形成,而可利用抗體內之任何反應性基團衍生形成,以引入供二硫鍵交換之位點,例如,利用偶聯二官能連接劑至抗體中之游離胺基。舉例而言,可利用已知方法,使用交聯試劑例如N-琥珀醯亞胺基3-(2-吡啶基二硫基)丙酸酯(SPDP)、4-琥珀醯亞胺基-氧羰基-a-甲基 a-(2-吡啶基二硫基)-甲苯(SMPT)、N-琥珀醯亞胺基-3-(2-吡啶基二硫基)-丁酸酯(SDPB)、N-琥珀醯亞胺基-4-(2-吡啶基二硫基)戊酸酯(SPP)、N-琥珀醯亞胺基-5-(2-吡啶基二硫基)戊酸酯、2-亞胺四氫噻吩(IT)、或乙醯基琥珀酸酐修飾抗體分子。
本發明之抗-αV整合蛋白抗體-胞毒接合體因而可以式II表示,其中美登素醇於C-3被酯化,及該抗體為抗-αV整合蛋白次單元抗體;R1
、R2
、X1
與X2
獨立地為H、Me、C2
H5
、具有1至10個碳原子之直鏈烷基或烯基、具有3至10個碳原子之分支鏈或環狀烷基或烯基、苯基、經取代之苯基、或雜環芳基、或雜環烷基;n為1至5;p為1至5;m為1至10。
於較佳具體實例中,連接劑基團為衍生自SPP之4-硫基戊酸酯、或4-硫基戊酸酯。接著使從而衍生之含游離或經保護之硫醇基之抗體分子與含二硫鍵或硫醇之毒性化合物反應,以製造接合體。此接合體可利用HPLC或利用凝膠層析予以純化。
除了結合αV外,可選擇如上文敘述之人類抗體或抗原結合片段或其部分,以保留本發明抗體之其他功能性,例如:1)結合於表現人類αV之活細胞;2)防止活細胞結合於基質蛋白;3)以10- 8
M或更小(例如,10- 9
M或10- 1 0
M或更小)之KD結合於人類αV;4)展現鈣依存性地結合於αV;5)結合於αV上獨特之抗原決定部位或屬於獨特之與αV結合之抗體互補組群;6)試管內或活體內抑制血管新生;或7)減少腫瘤質量或防止活體內腫瘤生長。
於本發明之另一態樣中,係使用本發明人類抗-αV抗體,CNTO 95,之結構特徵,以產生保留本發明抗體至少一種功能性(例如結合於αV)之結構相關之人類抗-αV抗體。詳言之,可使CNTO 95一或多個CDR區基因重組地與已知人類基本結構區及CDRs組合,以產生附加、重組建造之本發明人類抗-αV抗體。
於較佳具體實例中,用於本文敘述之抗-αV抗體接合體之抗體係免疫處理含有表現人類免疫球蛋白基因之基因轉殖小鼠獲得之人類抗-αV抗體。抗體之製備詳述於PCT公告案WO 02/12501及U.S.公告案2003/040044,均併入本文以資參考。該抗體包含任何含蛋白質或胜狀之分子,其包含衍生自命名「CNTO 95」(參閱PCT公告案WO 02/12501及U.S.公告案2003/040044)的抗體之重鏈或輕鏈或其配位體結合部分之互補決定區(CDR)之至少一部分,組合重鏈或輕鏈可變區、重鏈或輕鏈恒定區、基本結構區、或其可併入抗體中之任何部分。
較佳為,上文敘述之CDR1、2、及/或3建造抗體包含如本文所揭示藉由免疫處理基因轉殖小鼠所產生之名稱為CNTO 95、Gen0101、CNTO 95、C371A之完整人類單株抗體之確切胺基酸序列。然而,一般熟習此項技藝者將認知,稍偏離CNTO 95之確切CDR序列而仍有效保留抗體與αV結合之能力(例如,保守性取代)是可能的。於特定具體實例中,抗體或抗原-結合片段可具有抗原-結合區域,其包含具有對應CDRs 1、2及/或3胺基酸序列(例如,SEQ ID NOS:1、2、及/或3)之至少一重鏈CDR(亦即,CDR1、CDR2及/或CDR3)之至少一部分。於另一特定具體實例中,抗體或抗原-結合部分或變異體可具有抗原-結合區域,其包含具有CNTO95輕鏈之對應CDRs 1、2及/或3胺基酸序列(例如,SEQ ID NOS:4、5、及/或6)之至少一輕鏈CDR(亦即,CDR1、CDR2及/或CDR3)之至少一部分。於較佳具體實例中,抗體或抗原-結合片段之三重鏈CDRs與三輕鏈CDRs具有單株抗體CNTO 95對應CDR之胺基酸序列。因此,於另一具體實例中,建造抗體可由與CNTO 95之一或多個CDRs具有例如,90%、95%、98%或99.5%同一性之一或多個CDRs組成。本發明之抗-α-V次單元抗體可包含,惟不限於,選自SEQ ID NOS:1、2、3、4、5、6之至少一者之5個至全部鄰接胺基酸之至少一部分、序列或組合。抗-α-V次單元抗體可進一步視需要包含SEQ ID NOS:7、8之至少一者之70-100%鄰接胺基酸之至少一者之多肽。例如,輕鏈可變區之胺基酸序列可相較於SEQ ID NO:8序列,或重鏈CDR3之胺基酸序列可相較於SEQ ID NO:7。
如本文所揭示及請求,SEQ ID NOs.1-8敘述之序列包含「保守性序列修飾」,亦即不顯著影響或改變由核苷酸序列編碼或含有該胺基酸序列的抗體之結合特性之胺基酸序列修飾。此等保守性序列修飾包含胺基酸取代、添加及刪除。可利用此項技藝中已知之標準技術(例如定點突變及PCR-傳介之突變),於SEQ ID NOs:1-8或其編碼核酸中引入修飾。保守性胺基酸取代包含其中胺基酸殘基被具有相似側鏈之胺基酸殘基置換者。此項技藝中已界定具有相似側鏈之胺基酸殘基家族。彼等家族包含具有鹼性側鏈(例如,離胺酸、精胺酸、組胺酸)、酸性側鏈(例如,天冬胺酸、麩胺酸)、未帶電荷之極性側鏈(例如,甘胺酸、天冬醯胺、麩胺醯胺、絲胺酸、蘇胺酸、酪胺酸、半胱胺酸、色胺酸)、非極性側鏈(例如,丙胺酸、顯胺酸、白胺酸、異白胺酸、脯胺酸、苯丙胺酸、甲硫胺酸)、β-分支側鏈(例如,蘇胺酸、纈胺酸、異白胺酸)及芳族側鏈(例如,酪胺酸、苯丙胺酸、色胺酸、組胺酸)之胺基酸。因此,人類抗-αV抗體中之預測非必需胺基酸殘基較佳為被得自相同側鏈家族之其他胺基酸殘基置換。
本發明之至少一抗體以對至少一個αV次單元蛋白質、次單元、片段、部分或其任何組合具專一性之至少一專一抗原決定部位進行結合。該至少一個抗原決定部位可包含至少一個抗體結合區域(其包含該蛋白質之至少一部分),該抗原決定部位較佳為由該蛋白質之至少一細胞外、可溶、親水性、外部或細胞質部分構成。該至少一專一抗原決定部位可包含至少1至3個胺基酸之至少一胺基酸序列與SEQ ID NO:9鄰接胺基酸整個專一部分之任何組合。
如先前所述,本發明亦有關包含實質上與本文所述胺基酸序列相同的序列之胺基酸之抗體、抗原-結合片段、免疫球蛋白鏈與CDRs。較佳為,此等抗體或抗原-結合片段及包含此等鏈或CDRs之抗體可以高親和性(例如,小於或等於約10- 9
M之KD
)結合人類α-V次單元。實質上與本文所述序列相同之胺基酸序列包括含有保守性胺基酸取代、以及胺基酸刪除及/或嵌入之序列。
功能上必需之本發明抗-α-V次單元抗體中之胺基酸可利用此項技藝中已知之方法,例如定點突變或丙胺酸-掃描突變[例如,Ausubel,文獻同上,Chapters 8,15;Cunningham and Wells,Science 244:1081-1085(1989)]予以鑑定。後一程序於分子中之每一殘基引入單一丙胺酸突變。然後測試所得突變體分子之生物活性,例如,惟不限於至少一個α-V次單元中和活性。對抗體結合具關鍵性之位點亦可利用結構分析法例如結晶、核磁共振或光親和性標記法[Smith,et al.,J.Mol.Biol.224:899-904(1992)及de Vos,et al,Science 255:306-312(1992)]予以鑑定。
用以製造根據本發明化合物DM1、DM3與DM4及相關之活化類美登素(圖1)之起始化合物,美登素醇,可利用還原切割法,以自天然來源單離之美登素天然C-3酯[Kupchan et al.,J.Amer.Chem.Soc.97,5294(1975)]製備。-40℃下,於四氫呋喃中之試劑氫化三甲氧鋁鋰特別適用於此步驟。其他天然類美登素酯類亦可有利地藉由在培養液中培養經建造以產生美登素醇、美登納新(maytanacine)或C-3美登素醇酯類例如美登素醇丙酸酯之屬於土壤絲菌屬(美國專利案4,151,042)或束絲放線菌屬(Actinosynnema spp.
)之微生物,自培養液抽取化合物供進一步純化而產生。此項技藝中已知用於製造抗體類美登素接合體之許多連接基包括例如二硫化物基團、硫醚基團、酸不穩定基團、光不穩定基團、肽酶不穩定胜肽連接劑、或可為酸不穩定或酯酶可切割之酯類。
如美國專利案5,208,020之教示,以含甲基二硫基或其他經保護之硫基之羧酸(包括例如N-甲基-N-[3-(甲基二硫基)-1-酮基丙基]-L-丙胺酸)酯化美登素醇或類似物,產生對應之含二硫鍵結之類美登素。如WO03096782之教示,於產生含有D-及L-醯基側鏈之二非鏡像異構物之情形下,該等非鏡像異構物類美登素酯類可容易地利用此項技藝中已知之方法分離,將較不符合需求之D-丙胺醯基類似物異構物產物還原以回收美登素醇。以二硫蘇糖醇還原性切割該二硫鍵結基團,得到對應之含硫醇之類美登素,其可容易地經由二硫或硫醚鍵結連接於細胞結合劑。硫醇-類美登素可利用HPLC予以純化(使用C18管柱,逆相模式,以水-乙腈溶洗)。
二官能偶聯試劑
一般已知使用二官能劑製備兩個物質之接合體(其中至少一者含有蛋白質或多肽),俾使其價偶聯接合體成分;接合分子中之胺基通常用於接合反應。二官能蛋白偶聯劑包括N-琥珀醯亞胺基-(2-吡啶基二硫基)丙酸酯(SPDP)、琥珀醯亞胺基-4-(N-馬來醯亞胺基甲基)環己烷-1-甲酸酯、亞胺四氫噻吩(IT)、亞胺酯類之二官能衍生物例如己二醯亞胺酸二甲酯.HCl、活性酯類例如辛二酸二琥珀醯亞胺酯、醛類例如戊二醛、雙-疊氮基化合物例如雙(對疊氮基苯甲醯基)己二胺、雙-重氮鎓衍生物例如雙-(對重氮鎓苯甲醯基)伸乙二胺)、二異氰酸酯類(例如2,6-二異氰酸伸甲苯酯)、及雙活性氟化合物例如1,5-二氟-2,4-二硝基苯)。SPDP為供此目的之最常用試劑,許多其他N-琥珀醯亞胺基-(2-吡啶基二硫基)-、N-琥珀醯亞胺基-(5-硝基-2-吡啶基二硫基)-或N-琥珀醯亞胺基-(4-吡啶基二硫基)-短鏈鏈烷酸已被證實有用。圖2顯示常用二官能連接劑之結構及其化學縮寫。
活化抗體與硫醇化類美登素之接合
CNTO 95-類美登素接合體之製備係採用先前敘述並概述於圖3之方法(Chari et al.,Cancer Res.52:127-131,1992及美國專利案5,208,020)。此程序中,抗體係於連接劑對抗體比在5至10:1之範圍下,使用二官能連接劑進行修飾,於抗體胺基酸側鏈引入二硫吡啶基。利用G25凝膠過濾層析法分離活化抗體與殘留連接劑。純化後,連接劑對抗體比小於5至10:1,典型地在3至5:1之範圍內,並利用252奈米與280奈米處之吸光率予以測定。於較所測得連接劑莫耳過量下,添加活化硫醇-類美登素。接合後,再利用G25分級排除層析法純化該混合物而獲得大量產物。
於替代方法中,主要係利用使帶有反應性酯之類美登素與未先行化學活化處理之抗-整合蛋白抗體反應之單一步驟製備抗-整合蛋白抗體類美登素接合體。類美登素之反應性酯可為N-琥珀醯亞胺基、N-磺酸琥珀醯亞胺基、N-酞醯亞胺基、N-磺酸酞醯亞胺基、2-二硝苯基、4-二硝苯基、2,4-二硝苯基、3-磺醯基-4-二硝苯基或3-羧基-4-二硝苯基酯。此方法見述於公告案WO2002098883,其內容併入本文以資參考。
本發明抗體可投與有其需要之對象,以預防、治療、處理或改善癌症或其一或多種症狀。本發明抗體亦可組合一或多種其他療法[較佳為用以預防、處理或治療癌症之療法(包括惟不限於下文列舉之預防劑或治療劑)]投與有其需要之對象,以預防、治療、處理或改善癌症或其一或多種症狀。於特定具體實例中,本發明提供用於預防、治療、處理或改善癌症或其一或多種症狀之方法,該方法包括投與有其需要之對象預防或治療有效劑量之含本發明抗-αV抗體接合體之調配物。於另一具體實例中,本發明提供用於預防、治療或改善癌症或其一或多種症狀之方法,該方法包括投與有其需要之對象預防或治療有效劑量之本發明抗-αV抗體接合體,結合預防或治療有效之一或多種療法(例如,手術、放射療法、或投與抗-αV抗體接合體以外之治療劑)。本發明之抗體接合體可作為第一、第二、第三或第四線癌症治療用。本發明提供用於治療或改善對象之一或多種癌症症狀之方法。再者,本發明藉由投與本發明抗-αV抗體接合體而提供用於預防已治療之病患癌症復發且無疾病活性之方法。
可利用本發明涵蓋的方法治療之癌症包含,惟不限於,瘤、腫瘤、轉移、或其特徵為未經控制之細胞生長之任何疾病或失調症。此癌症可為原發性或轉移性癌症;其癌細胞可表現或不表現αV次單元整合蛋白。於較佳具體實例中,根據本發明方法處理、治療或改善之癌症為表現整合蛋白αV次單元之癌症且已轉移至病患體內之其他位置或器官或具有轉移潛力者。可利用本發明涵蓋方法治療的癌症之詳細實例包含,惟不限於,頭、頸、眼、口、喉嚨、食道、胸、骨骼、肺臟、結腸、直腸、胃、前列腺、乳房、卵巢、腎臟、肝臟、胰臟、及腦等癌症。附加之癌症包含,惟不限於:白血病例如惟不限於急性白血病、急性淋巴性白血病、急性骨髓性白血病例如骨髓母細胞性、前骨髓性、骨髓單核細胞性、單核細胞性、紅白血病性白血病與骨髓發育不良症候群、慢性白血病例如惟不限於慢性骨髓性(顆粒細胞性)白血病、慢性淋巴性白血病、髮狀細胞性白血病;真性紅血球增多症;淋巴瘤例如惟不限於何杰金氏症(Hodgkin’s disease)、非何杰金氏淋巴瘤;骨髓瘤例如多發性骨髓瘤、非分泌性骨髓瘤、骨質硬化性骨髓瘤、漿細胞白血病、單一性漿細胞瘤與髓外漿細胞瘤;瓦登挫氏(Waldenstrom’s)巨球蛋白血症;骨癌及結締組織肉瘤例如骨骼肉瘤、骨髓瘤骨症、骨肉瘤、軟骨肉瘤、依汶氏(Ewing’s)肉瘤、佩吉特氏(Paget’s)骨症、惡性巨細胞腫瘤、骨纖維肉瘤、脊索瘤、骨膜肉瘤、軟-組織肉瘤、血管肉瘤(hemangiosarcoma)、纖維肉瘤、卡波西氏(Kaposi’s)肉瘤、平滑肌肉瘤、脂肪肉瘤、淋巴管肉瘤、神經鞘瘤、橫紋肌肉瘤、關節滑膜肉瘤;腦瘤例如惟不限於神經膠質瘤、星細胞瘤、非神經膠質腫瘤、聽神經纖維瘤、顱咽管瘤、神經管母細胞瘤、腦膜瘤、松果體瘤、松果體母細胞瘤、原發性腦淋巴瘤;乳癌包括腺癌與腺管內癌、及乳頭狀乳癌;腎上腺癌包括嗜鉻細胞瘤與腎上腺皮質癌;甲狀腺癌;胰臟癌;腦垂體癌;眼癌惟不限於眼黑色素瘤、脈絡膜黑色素瘤、睫狀體黑色素瘤、與視網膜母細胞瘤;陰道癌;外陰癌;子宮頸癌;子宮癌惟不限於子宮內膜癌與子宮肉瘤;卵巢癌;食道癌及其他頭頸部癌例如惟不限於鱗狀癌、腺癌、黏液類上皮癌、腺鱗狀癌、肉瘤、黑色素瘤、漿細胞瘤、疣狀癌、與燕麥細胞(小型細胞)癌;胃癌;結腸癌;直腸癌;肝癌例如肝細胞癌肝母細胞癌、膽囊癌;膽管癌;肺癌例如非小型細胞肺癌、鱗狀細胞癌(表皮樣癌)、腺癌、大細胞癌與小細胞肺癌;睪丸癌、絨毛癌(卵黃囊瘤)、前列腺癌;陰莖癌;口腔癌惟不限於鱗狀細胞癌;基底細胞癌;唾腺癌;腎細胞癌與其他腎臟癌;及膀胱癌惟不限於過渡細胞癌(此等疾病之綜述,參閱DeVita,V.T.,Hellman,S.,& Rosenberg,S.A.Cancer:Principles and practice of oncology.Philadelphia:J.B.Lippincott Company;6th Edition,2001)。癌變前症狀亦可利用本發明方法與組成物治療。此等癌症包括惟不限於濾泡型淋巴瘤、具p53突變之癌症、乳房、前列腺與卵巢之激素依存性腫瘤、及癌前病變例如家族性多發腺瘤性息肉症、及骨髓發育不良症候群。
於較佳具體實例中,根據本發明方法預防、處理、治療或改善之癌症係選自前列腺癌、乳癌、骨癌、黑色素瘤、肺癌與卵巢癌。於另一具體實例中,根據本發明方法預防、處理、治療或改善之癌症係選自轉移性腫瘤包括,惟不限於,已經或可能轉移至骨骼之腫瘤(非限制實例為已轉移或具有轉移至骨骼潛力之前列腺癌、乳癌與肺癌)、已經或可能轉移至肺部之腫瘤、已經或可能轉移至腦部之腫瘤、及已經或可能轉移至病患之其他器官或組織之腫瘤。
已知用於、或已用於或目前一直用於預防、治療、處理或改善癌症或其一或多種症狀之任何藥劑或療法(例如,化學療法、放射療法、荷爾蒙療法、及/或生物療法或免疫療法)可與根據本文所述之本發明抗-αV抗體接合體組合使用。治療或預防劑包含,惟不限於,胜肽、多肽、蛋白質、融合蛋白、核酸分子、小分子、模擬劑、合成藥物、無機分子、與有機分子。此類藥劑(亦即,抗癌劑)之實例包含,惟不限於,細胞毒素、血管新生抑制劑、與免疫調節劑及用以提供解除疼痛或抵消一或多種治療劑之有害效應之藥劑(例如用以降低糖皮質激素之高血鈣效應之雙膦酸鹽)。
生物免疫調節劑包含:抗-T細胞受體抗體例如抗-CD3抗體(例如Nuvion(Protein Design Labs)、OKT3[Johnson & Johnson)、或抗-CD20抗體Rituxan(IDEC)]、抗-CD52抗體[例如CAMPATH 1H(Ilex)]、抗-CD11a抗體[例如Xanelim(Genentech)];抗-細胞激素或抗-細胞激素受體抗體與拮抗劑例如抗-IL-2受體抗體[Zenapax(Protein Design Labs)]、抗-LL-6受體抗體[例如MRA(Chugai)]、與抗-IL-12抗體[CNTO 1275(Centocor)]、抗-TNFα抗體[Remicade(Centocor)]或TNF受體拮抗劑[Enbrel(Immunex)]、抗-IL-6抗體[BE8(Diaclone)與CNTO328(Centocor)]、及免疫專一性地結合於腫瘤相關抗原[例如,搓杜滋美(trastuzimab,Genentech)]之抗體。
血管新生抑制劑(亦即,抗-血管新生劑)包含,惟不限於,血管阻斷素(胞漿素原片段);抗血管新生抗凝血素III;血管酶(angiozyme)。雙膦酸鹽包含,惟不限於,阿倫膦酸鹽(alendronate)、氯膦酸鹽(clodronate)、羥乙膦酸鹽(etidronate)、伊班膦酸鹽(ibandronate)、帕米膦酸鹽(pamidronate)、利塞膦酸鹽(risedronate)、替魯膦酸鹽(tiludronate)、與唑來膦酸鹽(zoledronate)。
可用於根據本發明方法的抗癌劑之詳細實例包含,惟不限於:5-氟尿嘧啶;阿西維辛(acivicin);阿地白介素(aldesleukin);六甲嘧胺(altretamine);胺基導眠能(aminoglutethimide);安吖啶(amsacrine);阿那曲唑(anastrozole);蒽黴素(anthramycin);天冬醯胺酶;氮雜替汀(azacitidine);阿扎替派(azetepa);含氮黴素(azotomycin);巴馬司他(batimastat);比卡魯胺(bicalutamide);硫酸博來黴素(bleomycin);布奎那(brequinar)鈉;溴匹利明(bropirimine);白血福恩(busulfan);卡鉑錠(carboplatin);卡氮芥(carmustine);鹽酸卡如比辛(carubicin);卡折勒新(carzelesin);塞地芬果(cedefingol);苯丁酸氮芥(chlorambucil);西蘿黴素(cirolemycin);順鉑錠(cisplatin);克拉屈濱(cladribine);甲磺酸克里斯妥(crisnatol);環磷醯胺;阿糖胞苷;氮烯咪胺;更生黴素;鹽酸道諾紅黴素;地西他濱(decitabine);右奧馬鉑(dexormaplatin);地扎胍寧(deza鳥嘌呤);甲磺酸地扎胍寧;地濟光(diaziquone);多西他賽(docetaxel);小紅莓;鹽酸小紅莓;卓洛西芬(droloxifene);檸檬酸卓洛西芬;丙酸卓莫諾隆(dromostanolone);杜佐黴素(duazomycin);依達曲沙(edatrexate);鹽酸依氟鳥胺酸(eflornithine);恩洛鉑(enloplatin);恩普胺酯(enpromate);依匹洛啶(epipropidine);鹽酸依匹紅菌素(epirubicin);爾布蘿唑(erbulozole);鹽酸依索紅菌素(esorubicin);雌莫司汀(estramustine);磷酸雌莫司汀鈉;依他硝唑(etanidazole);依托泊苷(etoposide);磷酸依托泊苷;法扎拉濱(fazarabine);芬瑞亭奈(fenretinide);5-氟脫氧尿苷(floxuridine);磷酸氟達拉濱(fludarabine);氟脲嘧啶;氟西他濱(flurocitabine);磷奎酮(fosquidone);磷崔辛(fostriecin)鈉;吉西他濱(gemcitabine);鹽酸吉西他濱;羥基脲;鹽酸依達紅菌素(idarubicin);異環磷醯胺(ifosfamide);伊莫福新(ilmofosine);介白素II(包括基因重組介白素II、或rIL2)、干擾素α-2a;干擾素α-2b;干擾素α-m;干擾素α-n3;干擾素β-I a;干擾素γ-I b;異丙鉑(iproplatin);鹽酸伊立替康(irinotecan);乙酸蘭瑞泰(lanreotide);來曲唑(letrozole);乙酸白脯利特(leuprolide);鹽酸里蘿唑(liarozole);洛美曲索(lometrexol)鈉;洛莫司汀(lomustine);鹽酸洛索杉聰(losoxantrone);馬索蘿酚(masoprocol);氮芥鹽酸鹽;乙酸甲地孕酮;乙酸美倫孕酮(melengestrol);苯丙胺酸氮芥;美諾立爾(menogaril);巰基嘌呤;胺甲喋呤;胺甲喋呤鈉;美托普林(metoprine);米得派(meturedepa);絲裂黴素;米托司培(mitosper);米托坦(mitotane);鹽酸米托蒽醌(mitoxantrone);黴酚酸;諾考達唑(nocodazole);奧馬鉑(ormaplatin);紫杉醇;培門冬酶(pegaspargase);甲基絲裂黴素;潑尼莫司汀(prednimustine);鹽酸甲基苄肼;嘌呤黴素;羅谷亞胺(rogletimide);鹽酸沙芬果(safingol);司莫司汀(semustine);二甲二苯四氮烯;司帕弗塞(sparfosate)鈉;稀疏黴素;螺莫司汀(spiromustine);螺鉑(spiroplatin);鏈黴黑素;鏈佐星(streptozocin);磺氯苯(sulofenur);塔里索黴素(talisomycin);替加氟(tegafur);鹽酸替洛杉聰(teloxantrone);替莫泊芬(temoporfin);替尼泊苷(teniposide);替羅昔隆(teroxirone);睪丸內酯;噻米普林(thiamiprine);硫代鳥嘌呤;thiotepa;塞替派(tiazofurin);替拉扎明(tirapazamine);拓樸替康(topotecan);三甲曲沙(trimetrexate);葡糖醛酸三甲曲沙;曲普瑞林(triptorelin);尿嘧啶芥;尿烷亞胺;伐普(vapreotide);維替泊芬(verteporfn);硫酸長春花鹼;硫酸長春新鹼;長春地辛(vindesine);硫酸長春地辛;硫酸長春匹定(vinepidine);硫酸長春甘酯(vinglycinate);硫酸環氧長春鹼(vinleurosine);酒石酸長春瑞濱(vinorelbine);硫酸異長春鹼(vinrosidine);硫酸長春利定(vinzolidine);伏氯唑(vorozole);折尼鉑(zeniplatin);淨司他汀(zinostatin);鹽酸佐柔比星(zorubicin)。
本發明亦涵蓋投與本發明抗體組合放射治療(包括使用x-射線、γ-射線及其他輻射來源)以破壞癌症細胞。於較佳具體實例中,放射治療係給與外部放射線照射或遠隔體外治療,其中放射係自遠距來源指揮。於其他較佳具體實例中,放射治療係給與內部治療或近接治療,其中放射來源置於身體內側靠近癌細胞或腫瘤團。
於特定具體實例中,罹患乳癌病患係投與預防或治療有效量之本發明抗-αV抗體接合體,並組合投與預防或治療有效量之一或多種用於乳癌治療之其他藥劑,包括惟不限於:小紅莓、依匹紅菌素、小紅莓與環磷醯胺(AC)之組合物、環磷醯胺、小紅莓與5-氟尿嘧啶之組合物(CAP)、環磷醯胺、依匹紅菌素與5-氟尿嘧啶之組合物(CEF)、或其他藥劑例如赫賽汀(Herceptin)、他莫昔芬(tamoxifen)、紫杉醇或剋癌易(taxotere)。
於特定具體實例中,罹患前列腺癌病患係投與預防或治療有效量之本發明抗-αV抗體接合體,並組合投與預防或治療有效量之一或多種用於前列腺癌治療之其他藥劑,包括惟不限於外部放射線照射療法;組織間植入放射性同位素亦即,錸、鈀、或銥;白脯利特或其他LHRH促效劑;非類固醇性抗雄激素[氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺)、類固醇性抗雄激素[乙酸環丙氯地孕酮(cyproterone)]、白脯利特與氟他胺之組合物、雌激素例如DES、炔雌醇;低劑量潑尼松(prednisone)、或被記述對於症狀及減少PSA量產生增進之其他化學療法。
於特定具體實例中,罹患卵巢癌病患係投與預防或治療有效量之本發明抗-αV抗體接合體,並組合預防或治療有效量之一或多種用於卵巢癌治療之其他藥劑,包括惟不限於:腹膜腔內放射療法、例如3 2
P治療;腹部及骨盆總體放射療法、順鉑錠、紫杉醇(Taxol)或多西他賽(Taxotere)與順鉑錠或卡鉑之組合物、環磷醯胺與順鉑錠之組合物、環磷醯胺與卡鉑之組合物、5-FU與甲醯四氫葉酸之組合物、依托泊苷、微脂體小紅莓、吉西他濱、異環磷醯胺、六甲基蜜胺(HMM)、或拓樸替康。
於特定具體實例中,罹患腫瘤轉移性至骨骼之病患係投與預防或治療有效量之本發明抗-αV抗體接合體,並組合預防或治療有效量之一或多種用於骨骼轉移性腫瘤治療之其他藥劑,包括惟不限於:治療潛在惡性腫瘤所用之藥劑或療法,例如供轉移至骨骼之前列腺癌或乳癌用之激素抑制劑、具有趨骨性金屬放射性同位素(鍶-89與釤-153)之放射療法或化學放射療法、及雙膦酸鹽(例如帕米膦酸鹽或阿倫膦酸鹽)。
癌症療法與其劑量、投與途徑及推薦用法為此項技藝中已知及已見述於文獻例如Physician’s Desk Reference(第57版,2003),頃可經由向PDRElectronic Library,Thomson Micromedex,Greenwood Village,Colorado(Edition 2004)網路訂閱獲得。
本發明抗-αV抗體接合體可投與有其需要之對象,以預防、管理、治療或改善炎性疾病或其一或多種症狀。本發明抗體亦可組合一或多種其他療法[較佳為用於預防、處理、治療或改善有其需要之對象之炎性疾病(包括惟不限於下文列舉之預防或治療劑),以預防、管理、治療或改善其炎性疾病或其一或多種症狀之療法]投與。
可利用本發明涵蓋的方法治療之炎性疾病包含,惟不限於,氣喘、腦炎、炎性腸道疾病、慢性阻塞性肺疾(COPD)、過敏性疾病、敗血性休克、肺纖維化、未分化之脊椎關節病變、未分化之關節病變、關節炎、骨關節炎、脊椎關節病變[例如牛皮癬性關節炎、僵直性脊椎炎、萊特氏症候群(反應性關節炎)]、炎性溶骨症、威爾森氏症(Wilson's disease)及由於慢性病毒或細菌感染之慢性炎症。此外,自體免疫疾病與炎性病變相關。
本發明提供預防、處理、治療或改善炎性疾病或其一或多種症狀之方法,該方法包括投與有其需要之對象本發明之抗-αV抗體接合體及一或多種療法(例如除了免疫專一性地與αV整合蛋白結合以外之其他抗體或抗體片段預防劑或治療劑)。已知用於、或已用於或目前一直用於預防、處理、治療或改善炎性疾病或其一或多種症狀之任何藥劑或療法可與根據本文所述之本發明抗-αV抗體接合體組合使用。此等藥劑之實例包含,惟不限於,免疫調節劑、抗血管新生劑、抗炎劑與TNFα拮抗劑。
可與本發明抗-αV抗體接合體組合投與罹患炎性疾病對象之免疫調節劑之詳細實例包含,胺甲喋呤、來氟米特(leflunomide)、環磷醯胺、癌得星(cytoxan)、奴蘭(nuran)、環孢靈A、二甲胺四環素、硫唑嘌呤、抗生素[例如FK506(他克莫司(tacrolimus))]、甲基氫化潑尼松(MP)、皮質類固醇、類固醇、黴酚酸酯腸溶劑、雷帕黴素(rapamycin)[西羅莫司(sirolimus)]、來氟米特、抗-T細胞受體抗體[例如Orthoclone OKT3(Johnson & Johnson)、Nuvion(Protein Design Labs)、或抗-CD20抗體[Rituxan(IDEC)]、抗-CD52抗體[例如CAMPATH 1H(Ilex)]、抗-IL-2受體抗體[例如Zenapax(Protein Design Labs)]、抗-IL6(CNTO 328,Centocor)或抗-IL-6受體抗體(MRA,Chugai)、抗-IL-12抗體(CNTO 1275,Centocor)、抗-IFN抗體、抗-TNF抗體、抗-IL-1抗體及IL-1α/β拮抗劑。
可與本發明抗-αV抗體接合體組合投與罹患炎性疾病對象之TNFα拮抗劑之實例包含蛋白質、多肽、胜肽、融合蛋白、抗體(及其抗原-結合片段)例如免疫專一性地結合於TNFα之抗體、核酸分子(例如反義分子或三螺旋體)、有機分子、無機分子、及封阻、降低、抑制或中和TNFα之功能、活性及/或表現之小分子。TNFα拮抗劑之實例包含:因福昔單抗(infliximab)(REMICADE;Centocor)、D2E7(HUMARA;Abbott Laboratories/Knoll Pharmaceuticals Co.,Mt.Olive,N.J.)、CDP571亦為所謂HUMICADE與CDP-870(均為Celltech/Pharmacia,Slough,U.K.產品)、TNF-R1(Amgen)、恩特西普(etanercept)(ENBREL;Immunex)、及受體TNFR超級家族其他成員之抑制劑。本發明涵蓋之其他TNF拮抗劑包含,惟不限於,已知封阻TNFα產生與抗-p38 MAPK劑之IL-10。
可與本發明抗-αV抗體接合體組合投與罹患炎性疾病對象之抗炎劑之非限制實例包含非類固醇性抗炎藥物(NSAIDs)、類固醇性抗炎藥物、β-促效劑、抗膽鹼能劑、與甲基黃嘌呤類。NSAIDs之實例包含,惟不限於,阿斯匹靈、異丁苯丙酸、塞勒昔布(celecoxib)(CELEBREX)、待克菲那(diclofenac)(VOLTAREN)、依托度酸(etodolac)(IODINE)、非諾洛芬(fenoprofen)(NALFON)、消炎痛(INDOCIN)、酮洛勒(ketoralac)(TORADOL)、奧沙普(oxaprozin)(DAYPRO)、萘丁美酮(nabumentone)(RELAFEN)、舒林酸(sulindac)(CLINORIL)、四苯醯吡咯乙酸(TOLECTIN)、羅非昔布(rofecoxib)(VIOXX)、萘普生(naproxen)(ALEVE,NAPROSYN)、酮洛芬(ketoprofen)(ACTRON)與萘丁美酮(nabumetone)(RELAFEN)。此等NSAIDs藉由抑制環氧酶酵素(例如COX-1及/或COX-2)而作用。類固醇性抗炎藥物之實例包含,惟不限於,糖皮質激素、地塞米松(dexamethasone)(DECADRON)、可體松(cortisone)、氫化可體松(hydrocortisone)、潑尼松(DELTASONE)、氫化潑尼松、與曲安西隆(triamcinolone)。
於特定具體實例中,罹患骨關節炎之病患係投與預防或治療有效量之本發明抗-αV抗體接合體組合用以預防、治療、處理或改善骨關節炎之其他藥劑或療法,包括惟不限於:止痛劑例如乙醯胺酚、非那西汀(phenacetin);與曲馬多(tramadol)、NSAIDs例如阿斯匹靈、二氟苯柳酸、待克菲那(diclofenac)、依托度酸、菲那密酸鹽(fenamates)、非諾洛芬、氟吡洛芬(flurbiprofen)、異丁苯丙酸、消炎痛、酮洛芬、柳酸甲酯、奈布滅痛(nebumetone)、萘普辛(naproxen)、奧沙普、保泰松(phenylbutazope)、吡羅昔康(piroxicam)、舒林酸、與四苯醯吡咯乙酸;環氧酶(Cox)-2-專一性抑制劑(CSIs)例如塞勒昔布與羅非昔布;關節內或關節周圍注射例如糖皮質激素或生技藥物之儲存製劑,及玻尿酸之關節內注射。本發明抗-αV抗體接合體亦可組合其他非藥物措施以預防、治療、處理及改善骨關節炎,彼等措施包括惟不限於:骨關節炎關節注洗、減少關節罹患;施加熱或冷至受疾病侵襲之關節;辣椒素霜劑;運動與其他物理治療、及關節置換術。
於特定具體實例中,罹患類風濕性關節炎之病患係投與預防或治療有效量之本發明抗-αV抗體接合體組合用以預防、治療、處理及改善類風濕性關節炎之其他藥劑或療法包括NSAIDs、止痛劑、及用於骨關節炎述及之CSIs。此外,可同時或於投與本發明抗-αV抗體之前或之後使用之其他療法例如每月一次脈衝輸送高劑量糖皮質激素、或關節內糖皮質激素;緩和疾病之抗風濕藥物(DMARDs)包括胺甲喋呤、金化合物(例如Auranofin)、D-青黴胺、抗瘧藥物(例如氯奎)、與柳酸磺胺吡啶(sulfasalazine);TNFα中和劑例如恩特西普與因福昔單抗;免疫抑制劑與胞毒劑不限於硫唑嘌呤、來氟米特、環孢靈、與環磷醯胺;及外科手術介入例如關節造形術、全關節置換、重建手手術、打開或關節鏡滑膜切除術、與腕關節早期腱滑膜切除術;外部介入例如各種矯正與協助裝置、與其他物理療法;及膳食補充品例如增加ω-3脂肪酸(例如花生五烯酸)。
於特定具體實例中,罹患慢性阻塞性肺疾(COPD)之病患係投與預防或治療有效量之本發明抗-α V抗體接合體組合用以預防、治療、處理及改善COPD之其他藥劑或療法,包括惟不限於:支氣管擴張劑包括惟不限於短效及長效型β-腎上腺素能促效劑例如舒喘寧、吡布特羅(pirbuterol)、特布塔林(terbutalin)、與奧西那林(metaproterenol)、口服緩釋型舒喘寧與吸入型史立穩(salmeterol);抗膽鹼能藥物例如異丙托溴銨(ipratropium bromide)、及茶鹼與其衍生物;糖皮質激素;氧氣;肺移植;肺容量縮減手術;氣管插管、使用呼吸器;每年一次之流感疫苗與肺炎球菌疫苗接種;運動;及戒煙。
於特定具體實例中,罹患肺纖維化之病患係投與預防或治療有效量之本發明抗-αV抗體接合體組合有效量之一或多種用於肺纖維化治療之其他藥劑,包括惟不限於:氧氣;皮質類固醇;胞毒藥物(環磷醯胺或硫唑嘌呤);支氣管擴張劑包括惟不限於短效及長效型β-腎上腺素能促效劑、抗膽鹼能藥物、茶鹼與其衍生物);及抗組織胺藥物[二苯海拉明(diphenhydramine)與苯吡拉明(doxylamine)]。
於特定具體實例中,罹患氣喘病患係投與預防或治療有效量之本發明抗-αV抗體接合體組合有效量之一或多種用於氣喘治療之其他藥劑,包括惟不限於:腎上腺素能興奮劑(其實例包含,惟不限於,兒茶酚胺類例如腎上腺素、異丙基腎上腺素、與新異丙腎上腺素;間苯二酚類例如奧西那林、特布塔林、與芬忒醇;水楊醇類例如舒喘靈(salbutamol);甲基黃嘌呤類包括茶鹼與其各種鹽類;抗膽鹼能藥物包括硫酸阿托品(atropine)、甲基硝酸阿可潘(akopine)、與異丙托溴銨;糖皮質激素;肥大細胞安定劑色甘酸鈉與奈多羅米(nedocromil)鈉;白三烯素改良劑Zileuton、扎魯司特(zafirlukast)與孟魯司特(montelukast);免疫抑制劑包括胺甲喋呤;及乙醯基半胱胺酸。
於特定具體實例中,罹患過敏症之病患係投與預防或治療有效量之本發明抗-αV抗體接合體組合有效量之一或多種用於過敏症治療之其他藥劑,包括惟不限於:色甘酸;抗組織胺藥物;擬交感神經作用藥物(α-腎上腺素能與β-腎上腺素能藥物二者);茶鹼與其衍生物;糖皮質激素;及過敏原注射免疫脫敏處理。
本發明抗-αV抗體接合體可投與有其需要之對象,以預防、管理、治療或改善自體免疫疾病或其一或多種症狀。本發明抗-αV抗體接合體亦可組合一或多種其他療法[較佳為用以預防、處理或治療自體免疫疾病(包括惟不限於下文列舉之預防劑或治療劑)投與有其需要之對象,以預防、管理、治療或改善自體免疫疾病或其一或多種症狀之療法。於特定具體實例中,本發明提供用於預防、處理、治療或改善自體免疫疾病或其一或多種症狀之方法,該方法包括投與有其需要之對象預防或治療有效劑量之本發明液體調配物。於另一具體實例中,本發明提供用於預防、處理、治療或改善自體免疫疾病或其一或多種症狀之方法,該方法包括投與有其需要之對象預防或治療有效劑量之本發明液體調配物及預防或治療有效劑量之免疫專一性地結合於αV整合蛋白之抗體或抗體片段以外之一或多種治療劑(例如,預防劑或治療劑)。
本發明提供用於處理、治療或改善以習知療法難治其自體免疫疾病的對象之此等自體免疫疾病或其一或多種症狀之方法,該方法包括投與該對象預防或治療有效劑量之本發明抗體。本發明亦提供用於處理、治療或改善以現行單一療法難治其自體免疫疾病的對象之此等自體免疫疾病或其一或多種症狀之方法,該方法包括投與該對象預防或治療有效劑量之本發明抗-αV抗體接合體及預防或治療有效劑量之免疫專一性地結合於αV整合蛋白之抗體或抗體片段以外之一或多種治療劑(例如,預防劑或治療劑)。本發明亦提供藉由投與本發明抗-αV抗體接合體組合任何其他治療,針對已證明其他療法難治而未再進行彼等治療之病患,處理、治療或改善其自體免疫疾病或其一或多種症狀之方法。本發明亦提供用於處理或治療自體免疫疾病之替代方法,其中另一療法已證明或可能證實對已接受治療的對象毒性太大,亦即,導致不可接受或不能忍受之副作用。
特別是,本發明提供用於處理或治療自體免疫疾病之替代方法,其中病患對其他療法有抵抗力。再者,本發明提供用於防止已利用投與本發明抗-αV抗體接合體治療且無疾病活性之病患再發生自體免疫疾病之方法。
自體免疫疾病係於無搏鬥之外來物質下,由於錯誤地攻擊自身,身體之正常防禦免疫系統對其本身組織引起傷害,免疫系統即觸發免疫反應。不同的自體免疫疾病以不同方式侵襲身體:例如,罹患多發性硬化症之個體,腦部受侵襲;罹患克隆氏症(Crohn’s disease)之個體,腸道受侵襲;罹患類風濕性關節炎之個體,許多關節之滑膜、骨骼與軟骨受侵襲。隨著自體免疫疾病進展,可能造成一或多種身體組織遭破壞、器官不正常生長(可能伴隨該器官或組織之新血管生成)、或器官功能產生變化。自體免疫疾病可能只侵襲一種器官或組織,也可能侵襲許多器官與組織。常見被自體免疫疾病侵襲之器官與組織包括紅血球細胞、血管、結締組織、內分泌腺(例如甲狀腺或胰臟)、肌肉、關節、與皮膚。可利用本發明方法治療之自體免疫疾病實例包含,惟不限於,斑禿、僵直性脊椎炎、抗磷脂症候群、自體免疫艾廸生氏症(Addison’s disease)腎上腺自體免疫疾病、自體免疫溶血性貧血、自體免疫肝炎、自體免疫卵巢炎與睪丸炎、自體免疫血小板減少症、貝賽特氏症(Behcet’s disease)、大皰性類天皰瘡、心肌病變、口炎性腹瀉-皮膚炎、慢性疲勞免疫功能障礙症候群(CFIDS)、慢性炎性脫髓鞘性多發性神經病變、Churg-Strauss症候群、瘢痕性類天皰瘡、CREST症候群、冷凝素症、克隆氏症、盤狀狼瘡、本態性混合型冷凝球蛋白症、纖維肌痛-纖維肌炎、腎絲球腎炎、葛瑞芙氏症(Graves’ disease)、格林-巴里(Guillain-Barre)症候群、橋本氏甲狀腺炎、自發性肺纖維化、自發性血小板減少症、紫斑症(ITP)、IgA神經病變、幼年型關節炎、扁平苔癬、紅斑性狼瘡、梅尼爾氏症(Meniere’s disease)、混合性結締組織疾病、多發性硬化症、1型或免疫傳介之糖尿病、重症肌無力、尋常型天皰瘡、惡性貧血、結節性多動脈炎、多發性軟骨炎、多發性腺體症候群、風濕性多肌痛、原發性無γ球蛋白血症、原發性膽汁硬化症、牛皮癬、牛皮癬性關節炎、雷諾氏(Raynauld’s)現象、賴透氏(Reiter’s)症候群、類風濕性關節炎、類肉瘤症、硬皮症、修格連氏(Sjogren’s)症候群、僵直人症候群、全身紅斑性狼瘡、紅斑性狼瘡、高安氏動脈炎、顳動脈炎/巨細胞動脈炎、潰瘍性結腸炎、葡萄膜炎、血管炎例如疱疹樣皮膚炎血管炎、白斑症、與韋格內氏(Wegener’s)肉芽腫症。
自體免疫療法及其劑量、投與途徑及推薦用法為此項技藝中已知及已見述於文獻例如Physician’s Desk Refererce(第56版,2002及第57版,2003)。
本發明提供預防、處理、治療或改善自體免疫疾病或其一或多種症狀之方法,該方法包括投與有其需要之對象本發明抗-αV抗體接合體及免疫專一性地結合於αV整合蛋白之抗體或抗體片段以外之一或多種治療劑(例如,預防劑或治療劑)。已知用於、或已用於或目前一直用於預防、處理、治療或改善自體免疫疾病或其一或多種症狀之任何藥劑或療法可與根據本文所述之本發明抗-αV抗體接合體組合使用。此等藥劑之實例包含,惟不限於,免疫調節劑、抗炎劑與TNFα拮抗劑。可與本發明抗-αV抗體接合體組合使用以預防、處理、治療或改善自體免疫疾病之免疫調節劑、抗炎劑與TNFα拮抗劑之詳細實例如上文所揭示。
於特定具體實例中,罹患多發性硬化症(MS)之病患係投與預防或治療有效量之本發明抗-αV抗體接合體組合用以預防、治療、處理及改善MS之其他藥劑或療法,包括惟不限於:IFN-β1b(Betaseron)與IFN-α2a(Avonex);乙酸格拉雷美(glatiramer)(Copaxone);米托蒽醌;胺甲喋呤;環磷醯胺;靜脈內免疫球蛋白;糖皮質激素;甲基氫化潑尼松;2-氯脫氧腺苷(克拉屈濱);氯苯胺丁酸(經口或經由留置導管進行鞘內注射);鹽酸環苯扎林(cycloenzaprine);鹽酸氯硝西畔(clonazepam);可樂寧(clonidine);卡馬西平(carbamazepine);加巴噴丁(gabapentin);阿米替林(amitriptyline);捕癎酮(primidone);昻丹司瓊(ondansetron);異煙肼;羥布托寧(oxybutynin);托特羅定(tolterodine);丙胺太林(propantheline);貝膽鹼(bethanecol);鹽酸特拉唑新(terazosin);檸檬酸西地那非(sildenafil);金剛胺;匹莫林(pemoline);高劑量維生素;乳清酸鈣;更昔洛韋(gancyclovir);抗生素;與血漿置換術。
於特定具體實例中,罹患牛皮癬病患係投與預防或治療有效量之本發明抗-αV抗體接合體組合用以預防、治療、處理及改善牛皮癬之其他藥劑或療法,包括局部含類固醇之製劑;焦油(Estar、Psorigel、Fototar霜劑);局部維生素D類似物例如卡泊三烯(calcipotriene)軟膏;具或不具補骨脂素之紫外光;胺甲喋呤;環孢靈;柳酸磺胺吡啶;及合成類視黃類。
於特定具體實例中,罹患克隆氏症病患係投與預防或治療有效量之本發明抗-αV抗體組合用以預防、治療、處理及改善克隆氏症之其他藥劑或療法,包括惟不限於:止瀉藥[洛哌丁胺(loperamide)、具有阿托品之氰苯哌酯、消膽胺或可列替泊(colestipol)];抗抽搐藥物(丙胺太林、二環胺、或莨菪鹼);5-胺基柳酸劑(柳酸磺胺吡啶、美沙拉明(mesalamine)(Asacol)及其緩釋型(Pentasa);皮質類固醇;用於風濕性疾病之免疫調節藥物-硫唑嘌呤、巰基嘌呤、環孢靈、與胺甲喋呤;抗生素;TNF抑制劑包括恩特西普與因福昔單抗;免疫抑制劑包括他克莫司、黴酚酸、與酞胺哌啶酮;營養療法;使用成分營養膳食(例如,Vivonex 4週)之腸道治療;及全靜脈營養療法。
於特定具體實例中,罹患紅斑性狼瘡之病患係投與預防或治療有效量之本發明抗-αV抗體組合用以預防、治療、處理及改善紅斑性狼瘡之其他藥劑或療法,包括惟不限於:抗瘧藥物(包括,惟不限於,羥基氯奎);糖皮質激素(例如,可使用低劑量、或高劑量靜脈內脈衝療法);免疫抑制劑與免疫調節劑包括環磷醯胺、苯丁酸氮芥、與硫唑嘌呤、胺甲喋呤及黴酚酸;雄激素類固醇[包括惟不限於達那唑(danazol)];及抗凝血劑(包括惟不限於苄丙酮香豆素)。
本發明接合體亦用於治療非惡性增殖性疾病,尤其是彼等涉及血管新生者。已知血管新生除了具備使腫瘤生長與轉移之能力外,為許多病理狀況[例如眼睛疾病包括視網膜病變,及皮膚疾病包括牛皮癬與卡波西氏(Kaposi’s)肉瘤症]之可能致因。
此等非致癌性血管新生依存疾病之代表性實例包含角膜新血管生成、肥厚性疤痕與蟹足腫、增殖性糖尿病性視網膜病變、類風濕性關節炎、動靜脈畸形(如上述)、動脈粥樣硬化斑塊與缺血性心臟疾病、傷口延緩癒合、血友病性關節、接合不全之骨折、Osler-Weber症候群、牛皮癬、尋常型天皰瘡、貝賽特氏症候群、急性呼吸窘迫症候群(ARDS)、化膿性肉芽腫、硬皮症、沙眼、經血過多(如上述)及血管沾粘。
本發明提供抗-αV-類美登素接合體之穩定調配物,其較佳為水性磷酸鹽緩衝鹽液或混合鹽溶液,以及適用於醫藥或獸醫用途之保存溶液與含有防腐劑之調配物,及多用途之保存調配物,於醫藥上可接受之調配物中包括至少一種抗-αV-類美登素接合體。
較佳之防腐劑包含選自下述組群者:酚、間甲酚、對甲酚、鄰甲酚、氯甲酚、苄醇、對羥苯甲酸酯類(甲酯、乙酯、丙酯、丁酯等)、氯化苄烷銨、氯化苄乙氧銨、脫氫乙酸鈉與硫柳汞、或其混合物。
呈本文所述之穩定或保存調配物或溶液之至少一種抗-αV-類美登素接合體可根據本發明,經由多種遞送方法包括SC或TM注射;經皮膚、肺部、經黏膜、移植、滲透幫浦、藥匣、微幫浦、或此項技藝中悉知且為熟習此項技藝人士可察知之其他方式投與病患。
於投與CNTO 95-類美登素之較佳方法中,藥物係自備有藥用軟袋之先行安置之導管,經靜脈內給與。裝於20毫升單一用途瓶中之CNTO 95-美登素由ImmunoGen,Inc.(Cambridge,MA)提供。各瓶於主要由磷酸二氫鉀(0.57毫克/毫升)、磷酸二氫鈉單水合物(0.20毫克/毫升)、磷酸一氫鈉(0.555毫克/毫升)、與氯化鈉(8.16毫克/毫升)在純水(USP)中組成之緩衝溶液(pH 6.5±0.5)中,含有濃度為0.05至約2.0毫克/毫升之蛋白質。於徐徐滴入劑量容積至藥用軟袋中後,使醫藥產品通過低蛋白質-結合5-μ濾器預過濾兩次,製備8小時內,經由在管線中之0.22微米濾投與病患。注射後,該i.v.管線必須以流體沖洗,以確保藥物劑量之完全遞送。
根據先前於人類病患使用Mab-類美登素接合體之經驗,利用該靜脈內方法,每隔3週可給與22至295毫克/M2
不等之劑量(J Clin Oncol.21:211-222,2003)。
本發明包含含有用於治療上文敘述的疾病之包括抗-αV-類美登素接合體的物質、容器及插入該容器中或與其結合之標籤或包裝之製造物件。該製造物件較佳為含有包含至少一種抗-αV-類美登素接合體之溶液與視需要在水性稀釋劑中之指定緩衝劑及/或防腐劑之至少一個小瓶,其中該包裝材料包含指示該等溶液可保持一段時間之標籤。本發明進一步包含一種製造物件,其包含包裝材料、含有呈凍乾形式之至少一種抗-αV-類美登素接合體之第一小瓶、及含有指定緩衝劑或防腐劑的水性稀釋劑之第二小瓶,其中該包裝材料包含一標籤,其上指示從事者或病患如何於水性稀釋劑中再組成該至少一種抗-αV-類美登素接合體以形成溶液。
適當容器包含,例如,瓶子、小瓶、注射器等。該等容器可由多種材質(例如玻璃或塑膠)形成。該容器可具有無菌存取埠(例如該容器可為靜脈內溶液袋或具有可被皮下注射針刺破的塞子之小瓶)。
組成物中之至少一種活性劑為抗-αV抗體類美登素接合體。標籤或包裝內插物指示該組成物係用於治療選定之症狀,例如癌症。本文之包裝內插物可指示,該抗體或組成物係用於治療對於如本文概述用於專一性疾病與診斷之標準照料無反應或反應不足之癌症。於其他具體實例中,包裝內插物可指示,該抗體-類類美登素接合體或組成物可用於治療轉移性癌症、前列腺癌、乳癌或大腸直腸癌。
於以一般術語敘述本發明後,茲於下述具體實例中,進一步揭示本發明之具體實例。
抗-αV整合蛋白抗體CNTO95之製備詳述於PCT公告案WO 02/12501與U.S.公告號2003/040044,均併入本文以資參考。詳言之,人類Mab CNTO 95係藉由使用自人類胎盤純化獲得之αVβ3整合蛋白免疫處理(CBA/J x C57/BL6/J,GenPharm Internatiinal)F2雜交小鼠而產生。此抗體由人類可變區及IgG1 κ恒定區組成。CNTO95之製造方法及所需特性先前已見述於WO0212501與Trikha,et al.2004,Int.J.Cancer 110(3):326-335。
使用表現人類免疫球蛋白而不表現小鼠IgM或Ig κ之得自GenPharm International之基因轉殖小鼠。彼等小鼠含有進行V(D)J接合、重鏈類轉換及體細胞突變而產生人類免疫球蛋白序列目錄之人類轉殖基因序列(Taylor et al.,International Immunology 6:579-591(1993))。輕鏈轉殖基因部分係衍生自包含幾乎一半胚細胞人類V區域之酵母人造染色體菌株。除了數個VH基因外,重鏈(HC)轉殖基因編碼人類μ與人類γ1(Lonberg et al.,Nature 368:856-859(1994))及/或γ3恒定區域。於免疫處理及融合程序中,使用衍生自HC012基因型排列之小鼠以產生用於製備本發明接合體之抗-αV單株抗體。
如WO0212501所述,使用於緩衝鹽液中之OTG(辛基硫葡萄糖苷,得自Pierce)萃取表現αVβ3整合蛋白之人類胎盤(以碎肉機打碎)或M21人類黑色素瘤細胞。
以相同容積之完全Freund氏佐劑乳化彼等製劑,於第0及第14天,用以免疫處理15至17週大之經手術閹割之公小鼠(GenPharm,Foster City,CA);於第28、48、及56天,於不完全Freund氏佐劑中進行。三天後,自使用固相EIA版式顯示抗αVβ3力價為1:1280之小鼠獲取脾細胞。以鼠類骨髓癌細胞(SP2/0)對存活脾細胞1:1之比率進行融合。使用EIA微量盤測定法或EIA捕獲測定法篩選融合瘤上澄液,將選定之抗體產生株擴大,並再測試所需性質。
如WO0212501所述,使用於緩衝鹽液中之OTG(辛基硫葡萄糖苷,得自Pierce)萃取表現αVβ3整合蛋白之人類胎盤(以碎肉機打碎)或M21人類黑色素瘤細胞。以相同容積之完全Freund氏佐劑乳化彼等製劑,於第0及第14天,用以免疫處理15至17週大之經手術閹割之公小鼠(GenPharm,Foster City,CA);於第28、48、及56天,於不完全Freund氏佐劑中進行。三天後,自使用固相EIA版式顯示抗αVβ3力價為1:1280之小鼠獲取脾細胞。以鼠類骨髓癌細胞(SP2/0)對存活脾細胞1:1之比率進行融合。使用EIA微量盤測定法或EIA捕獲測定法篩選融合瘤上澄液,將選定之抗體產生株擴大,並再測試所需性質。
ELISA分析證實,得自兩個融合瘤之純化抗體,C371A(亦稱為Mab CNTO 95)與C372A,以濃度依存方式結合αVβ3。於C372A與CNTO 95濃度分別為0.07與0.7微克/毫升時,達成50%之結合。以相同之測定法,抗-αIIβ3抗體,c7E3 IgG,於0.07微克/毫升顯示50%最大結合。
為了確定CNTO95之獨特專一性,乃使用下述鼠類抗體進行競爭結合(或互補)測定:m7E3 IgG、抗-αVβ3(LM609株,Chemicon)、抗-αVβ5(P1F6株,Gibco)、抗-β3(Chemicon,AMAC)、或抗-αV(VNR139株,Gibco)等抗體;結果證明CNTO 95結合不為所測試之其他抗體共有之抗原決定部位。
針對諸純化整合蛋白與受體(其於使用125-I CNTO 95的各種細胞株上表現)結合之結合親和性值進行比較。A375S2與M21細胞表現αv
β3
與αv
β5
二者,HT-29細胞表現αv
β5
。為了比較,乃使用能結合整合蛋白之其他單株抗體。使用多重複之多批次抗體,於各情形下,從飽和結合曲線計算Kd。於αv
β3
塗覆盤上,CNTO 95平均KD
為2.1±1.33 x 10- 1 0
M;阿昔單抗(abciximab)平均Kd為2.5±1.46 x 10- 1 0
M。αv
β5
上之CNTO 95平均KD
為2.5±1.04 x 10- 1 1
M。於αv
β5
塗覆盤上,阿昔單抗未顯示結合及劑量反應。
如圖4所示,於裸鼠中,以CNTO 95給藥抑制人類黑色素腫瘤生長。於第26天,相較於對照組處理動物之腫瘤,CNTO 95抑制大約80%腫瘤生長。此模式中,CNTO 95由於不結合小鼠整合蛋白而不與宿主新生血管相互作用,暗示單僅封阻表現人類腫瘤之整合蛋白即可抑制小鼠之腫瘤生長,與抗血管新生效應無關。
有關大鼠之研究,6-7週大之母裸大鼠係購自Harlan。以A375.S2細胞(3 x 106
)自皮下接種於20隻大鼠之腰窩部位(第1天)。第4天,將大鼠隨機分成2組。一組i.v注射CNTO 95(10毫克/公斤,於PBS中),另一組接受同功型-相配之對照組IgO(10毫克/公斤);之後,每週一次持續用藥至第46天(總共6劑)。每週兩次,以測徑器測量腫瘤,利用公式(長x寬2
)/2計算腫瘤體積。同時每週記錄體重一次。
於大鼠中,CNTO 95能封阻大鼠血管新生整合蛋白及表現人類腫瘤細胞之整合蛋白。相較於同功型-相配之人類IgG對照組單株抗體(圖5),每週以10毫克/公斤CNTO 95治療之罹患腫瘤之裸大鼠,腫瘤生長降低。於第46天之前,相較於對照組-處理之裸大鼠,以CNTO 95處理者,其最終腫瘤大小顯著地減少(p=0.0007)。
概括而言,CNTO 95為完全人類單株抗體,由多項功能測定證明,其以獨特專一性、抗體親抗原性及活性結合整合蛋白αV族成員,顯示其於試管內及活體內中和整合蛋白受體αVβ3與αVβ5之生物效應。CNTO 95於試管內抑制腫瘤及內皮細胞二者之黏著、遷移、增殖與侵襲,並證明結合及封阻多個αV整合蛋白受體比單獨封阻單一整合蛋白更有效。此外,CNTO 95於活體內抑制血管新生及腫瘤生長。人類黑色素腫瘤之生長於小鼠模式中藉由封阻腫瘤細胞整合蛋白;於大鼠模式中藉由組合封阻腫瘤細胞與宿主血管新生整合蛋白而顯著減少,突顯出於抗腫瘤效力上標靶導向多個細胞標點之潛在重要性。
試管內模式結果證明CNTO 95具有強力之抗血管新生性質,抑制內皮細胞黏著、增殖、遷移及毛細血管快速生長。此外,CNTO 95封阻大鼠Matrigel模式中受bFGF與M21黑色素瘤細胞二者,及靈長類血管新生模式中受bFGF刺激之血管新生。於齧齒類模式及新穎之非人類靈長類模式(食蟹獼猴)中,CNTO 95展現強力之抗血管新生作用。
除了封阻血管新生內皮上之整合蛋白,抑制腫瘤細胞本身的整合蛋白功能之能力亦減少腫瘤生長。許多αV整合蛋白被暗示於腫瘤細胞生物學上扮演關鍵角色。於CNTO 95不與宿主整合蛋白交叉反應之小鼠異種移植模式中,以CNTO 95處理明顯抑制v3/5-陽性黑色素惡性腫瘤之生長。
CNTO 95最重要的特徵之一為其完全人類本質。由於其為完全人類,因此CNTO 95較不可能引起病患之免疫反應。再者,由於CNTO 95不僅可結合αVβ3與αVβ5,亦可結合其他αV整合蛋白(例如αVβ6與αVβ1),因此具有抑制多種整合蛋白-傳介的情況之潛力。
使用如所述之二官能連接劑開始製備硫醇化美登素之抗體接合體,以供進一步之生物測試。
供接合用之CNTO 95抗體由Centocor提供,總共供應大約20毫克/毫升(260毫克)CNTO 95。將抗體透析入緩衝液A(50 mM KPi、50 mM NaCl、2 mM EDTA pH6.5)中,然後使其濃度成為8毫克/毫升(於95%緩衝液A、5% ETOH中)。抗體以6.5倍莫耳過量之SPP修飾,引入接合藥物用之連接劑,以形成CNTO 95-SS-Py,其中S-Py為2-巰基吡啶。利用G25凝膠過濾層析法移除殘留之SPP。測得連接劑對抗體比率為4.7。以對連接劑1.7倍莫耳過量之DM1(MW=737.5克/莫耳)修飾該Ab-SS-Py接合體,使用3.2/毫升(於97%緩衝液A、3%二甲基乙醯胺中)之抗體濃度。接合後,接合體於G25上進行再層析(使用PBS,pH 6.5為緩衝液)。所得接合體每莫耳CNTO-95:[Ab]=2.59毫克/毫升含有3.2莫耳DM1,[DM1]=38.3微克/毫升。根據過濾物質於252與280奈米處之吸光率讀數進行計算,使用消光係數:280奈米之Ab=224,000 M- 1
cm- 1
,280奈米之DM1=5700 M- 1
cm- 1
;252奈米之Ab=82,880 M- 1
cm- 1
及252奈米之DM1=26,790 M- 1
cm- 1
。
利用非還原性SDS-PAGE、SEC HPLC及利用ELISA測定對αVβ3與αVβ5蛋白之結合親和性,進行產物分析。由PAGE,產物於160 kDa附近有顯著帶,亦可見較微弱之較低分子量帶。由SEC HPLC分析,溶洗出單體(18.8’)之接合體溶離份為96%,約4%接合體呈較高分子量物種(16.2’)被溶洗出。利用吸光率對濃度作圖計算結合親和性,得到CNTO95之表觀Kd為3.0 e-11 M及接合體對αVβ5之Kd為3.5 e-11 M。此二物質對αVβ3之表觀Kd大約3.0 e-9。
使用如圖2所示之二官能連接劑及圖3概述之類似方式,製備其他批次之CNTO95-SPP-DM1與接合於DM4之CNTO 95及同法接合、標靶導向非人類抗原,F105,之不恰當抗體。彼等製劑之特性如下文所述:CNTO95-SPP-DM1(CNTO 364)之製備
如下述使用SPP連接劑將單株抗體CNTO95接合於類美登素DM1:使270.6毫克CNTO95接合於3.7毫克DM1,所得98毫升接合體以2.74毫克/毫升(於PBS中,pH 6.5)濃度貯存於2℃至8℃;由吸光率測得DM1濃度為37.6微克/毫升;因此,每莫耳CNTO95之DM1比率為2.98(1微克DM1等當量於68.9微克接合之CNTO95抗體);由HPLC測得此製劑為具有0.59%游離藥物之96.3%單體。
CNTO95-SPP-DM1(CNTO 364)之製備
如下述使用SPP連接劑將單株抗體CNTO95接合於類美登素DM1:使104毫克CNTO95接合於1.82毫克DM1,所得26毫升接合體以3.65毫克/毫升(於PBS中,pH 6.5)接合之CNTO95-SPP-DM1抗體濃度貯存於2℃至8℃;由吸光率測得DM1濃度為70.07微克/毫升;因此,此製劑含有每莫耳CNTO95對3.80莫耳DM1之比率(1微克DM1等當量於57.2微克接合之CNTO95抗體);由HPLC測得此製劑為具有1.61%游離藥物之93.4%單體。
CNTO95-SPP-DM1(CNTO 364)之製備
如下述使用SPP連接劑將單株抗體CNTO95接合於類美登素DM1:使228毫克CNTO95接合於4.13毫克DM1,所得102毫升接合體以2.24毫克/毫升(於PBS中,pH 6.5)接合之CNTO95-SPP-DM1抗體濃度貯存於2℃至8℃;由吸光率測得DM1濃度為40.53微克/毫升;因此,此製劑含有每莫耳CNTO95對3.93莫耳DM1之比率(1微克DM1等當量於55.3微克接合之CNTO95抗體);由HPLC測得此製劑為具有1.00%游離藥物之94.7%單體。
CNTO95-SSNPB-DM4(CNTO 365)之製備
如下述使用SSNPB連接劑將單株抗體CNTO95接合於類美登素DM4:使121毫克CNTO95接合於2.18毫克DM4,所得34毫升接合體以3.25毫克/毫升(於PBS中,pH 6.5)濃度貯存於2℃至8℃;由吸光率測得DM4濃度為64.11微克/毫升;因此,每莫耳抗體之DM4比率為3.57(1微克DM4等當量於55.6微克接合之CNTO95抗體);由HPLC測得此製劑為具有3.23%游離藥物之95.4%單體。
CNTO95-SSNPP-DM4(CNTO 366)之製備
如下述使用SSNPP連接劑將單株抗體CNTO95接合於類美登素DM4:使101毫克CNTO95接合於1.45毫克DM4,所得30毫升接合體以3.07毫克/毫升(於PBS中,pH 6.5)抗體濃度貯存於2℃至8℃;由吸光率測得DM4濃度為48.39微克/毫升;因此,此製劑中每莫耳CNTO95具有2.95莫耳DM4(1微克DM4等當量於69.5微克接合之CNTO95抗體);由HPLC測得此製劑為具有1.18%游離藥物之85.9%單體。
CNTO95-SPDB-DM4(CNTO 365)之製備
如下述使用SPDB連接劑將單株抗體CNTO95接合於類美登素DM4:使228.5毫克CNTO95接合於4.37毫克DM4,所得104.5毫升接合體以2.19毫克/毫升(於PBS中,pH 6.5)接合之CNTO95-SPDB-DM4抗體濃度貯存於2℃至8℃;由吸光率測得DM4濃度為41.84微克/毫升;因此,此製劑中每莫耳CNTO95具有3.92莫耳DM4(1微克DM4等當量於52.3微克接合之CNTO95抗體);由HPLC測得此製劑為具有0.55%游離藥物之93.6%單體。
CNTO95-SPDB-DM4(CNTO 365)之製備
如下述使用SPDB連接劑將單株抗體CNTO95接合於類美登素DM4:使309毫克CNTO95接合於5.4毫克DM4,所得130.7毫升接合體以2.36毫克/毫升(於PBS中,pH 6.5)接合之CNTO95-SPDB-DM4抗體濃度貯存於2℃至8℃;由吸光率測得DM4濃度為41.2微克/毫升;因此,此製劑中每莫耳CNTO95具有3.57莫耳DM4(1微克DM4等當量於57.5微克接合之CNTO95抗體);由HPLC測得此製劑為具有0.40%游離藥物之93.8%單體。
CNTO95-SPP-DM1(CNTO 364)之製備
如下述使用SPP連接劑將單株抗體CNTO95接合於類美登素DM1:使270.6毫克CNTO95接合於3.7毫克DM1,所得接合體以2.74毫克/毫升(於PBS中,pH 6.5)濃度貯存於2℃至8℃;由吸光率測得DM1濃度為37.6微克/毫升;因此,此製劑含有每莫耳CNTO95對2.98莫耳DM1之比率(1微克DM1等當量於68.9微克接合之CNTO95抗體);由HPLC測得此製劑為具有0.59%游離藥物之96.3%單體。
CNTO95-SPP-DM1(CNTO 364)之製備
如下述使用SPP連接劑將單株抗體CNTO95接合於類美登素DM1:使245毫克F105接合於4.28毫克DM1,所得91.5毫升接合體以2.68毫克/毫升(於PBS中,pH 6.5)接合之F105-SPP-DM1抗體濃度貯存於2℃至8℃;由吸光率測得DM1濃度為46.76微克/毫升;因此,此製劑含有每莫耳F105對3.79莫耳DM1之比率(1微克DM1等當量於57.3微克接合之F105抗體);由HPLC測得此製劑為具有2.44%游離藥物之90.3%單體。
CNTO95-SPP-DM4(CNTO 366)之製備
如下述使用SPP連接劑將單株抗體CNTO95接合於類美登素DM4:使76.7毫克CNTO95接合於1.10毫克DM4,所得35毫升接合體以2.19毫克/毫升(於PBS中,pH 6.5)接合之CNTO95-SPP-DM4抗體濃度貯存於2℃至8℃;由吸光率測得DM4濃度為31.5微克/毫升;因此,此製劑含有每莫耳CNTO95對2.96莫耳DM4之率(1微克DM4等當量於69.4微克接合之CNTO95抗體);由HPLC測得此製劑為具有1.14%游離藥物之97.3%單體。
F105-SSNPB-DM4之製備
如下述使用SSNPB連接劑將單株抗體F105接合於類美登素DM4:使106毫克F105接合於1.84毫克DM4,所得25毫升接合體以3.85毫克/毫升(於PBS中,pH 6.5)濃度貯存於2℃至8℃;由吸光率測得DM4濃度為73.45微克/毫升;因此,每莫耳抗體之DM4比率為3.57(1微克DM4等當量於57.5微克接合之F105抗體);由HPLC測得此製劑為具有1.92%游離藥物之85.1%單體。
F105-SSNPB-DM4之製備
如下述使用SSNPB連接劑將單株抗體F105接合於類美登素DM4:使106毫克F105接合於1.84毫克DM4,所得30毫升接合體以3.46毫克/毫升(於PBS中,pH 6.5)濃度貯存於2℃至8℃;由吸光率測得DM4濃度為57.93微克/毫升;因此,每莫耳抗體之DM4比率為3.32(1微克DM4等當量於65.4微克接合之F105抗體);由HPLC測得此製劑為具有1.85%游離藥物之88.8%單體。
F105-SSNPP-DM4之製備
如下述使用SSNPP連接劑將單株抗體F105接合於類美登素DM4:使105毫克F105接合於1.76毫克DM4,所得28毫升接合體以3.41毫克/毫升(於PBS中,pH 6.5)濃度貯存於2℃至8℃;由吸光率測得DM4濃度為62.87微克/毫升;因此,此製劑中每莫耳F105含有3.45莫耳DM4(1微克DM4等當量於59.4微克接合之F105抗體);由HPLC測得此製劑為具有3.75%游離藥物之85.9%單體。
F105-SPDB-DM4之製備
如下述使用SPDB連接劑將單株抗體F105接合於類美登素DM4:使230.5毫克F105接合於4.12毫克DM4,所得104.5毫升接合體以2.21毫克/毫升(於PBS中,pH 6.5)濃度貯存於2℃至8℃;由吸光率測得DM4濃度為39.41微克/毫升;因此,此製劑中每莫耳F105含有3.66莫耳DM4(1微克DM4等當量於56.0微克接合之F105抗體);由HPLC測得此製劑為具有0.65%游離藥物之89.2%單體。
概括而言,係合成下述物質供進一步分析(表6)。
測試結合於活細胞之CNTO95-類美登素接合體之能力與親和性。
材料與方法CNTO 95,Centocor批次#95-VF30A03-1,20毫克/毫升,於PBS中;CNTO 364(CNTO 95-SPP-DM1),ImmunoGen批次#1806-164,37.6毫克/毫升DM1,2.74毫克/毫升接合抗體,內毒素含量<0.1 EU/毫克;CNTO 365(CNTO 95-SPDB-DM4),ImmunoGen批次#2020-78,41.2毫克/毫升DM4,2.36毫克/毫升接合抗體,內毒素含量<0.1 EU/毫克;CNTO 366(CNTO95-SPP-DM4),ImmunoGen批次#2020-48,31.5毫克/毫升DM4,2.19毫克/毫升接合抗體,內毒素含量<0.1 EU/毫克。
細胞:HT29人類結腸癌與A549人類肺癌細胞均得自ATCC及維持於補充10%胎牛血清(FBS)之αMEM中。A2780人類卵巢癌細胞係得自National Cancer Institute。於含10% FBS之RPMI 1640培養基中培養A2780細胞。獲取細胞,清洗,使其懸浮於不含血清之DMEM中,相繼於冰上以經系列稀釋之CNTO 95、CNTO 364、CNTO 365與CNTO 366及FITC-標記之抗-人類抗體(10毫克/毫升)培育60分鐘。缺乏一次抗體或以同功型相配抗體取代一次抗體作為負對照組。立即使用FACS Scan II流式細胞儀(Becton Dickinson,Mountain View,CA)分析細胞。使用非線性迴歸,以GraphPad Prism軟體分析數據,決定50%最大結合之濃度(表7)。於多數情形下,有效結合常數之變化小於兩倍。
於試管內測試CNTO95-類美登素接合體殺害腫瘤細胞之經時能力。
CNTO 364(CNTO 95-SPP-DM1),ImmunoGen批次#1806-164,37.6微克/毫升DM1,2.74毫克/毫升接合抗體,內毒素含量<0.1 EU/毫克。CNTO 365(CNTO 95-SPDB-DM4),ImmunoGen批次#2020-78,41.2微克/毫升DM4,2.36毫克/毫升接合抗體,內毒素含量<0.1 EU/毫克。CNTO 366(CNTO95-SPP-DM4),ImmunoGen批次#2020-48,31.5微克/毫升DM4,2.19毫克/毫升接合抗體,內毒素含量<0.1 EU/毫克。
37℃,5% CO2
存在下,於補充10% FBS之αMEM中培養人類HT29人類結腸癌及人類非小型細胞肺癌細胞A549(ATCC)。將細胞接種入白色96槽組織培養盤(5000個細胞/槽)之培養基中,培育16小時。添加免疫接合體之系列稀釋液至各適當盤(0-20微克/毫升)。於37℃培育組織培養盤96小時。根據廠商指示進行ATPLIte測定。使用非線性迴歸,以GraphPad Prism軟體分析數據(表8),以決定由發光度測定之於一半最大細胞數時之濃度。
本實驗乃研究CNTO 364相較於CNTO95之對後階段s.c.A375.S2人類黑色素瘤細胞之效力。
CNTO 95-DM1由ImmunoGen,Inc.製備,Lot # 1716-74B,貯液濃度:2.59毫克/毫升。5毫克/公斤CNTO 95-DM1等當量於74微克/公斤DM1。CNTO 95係得Centocor,批次#5380-027,貯液濃度=20毫克/毫升。人類IgG-DM1:ChromPure人類IgG得自Jackson ImmunoResearch Laboratories。人類IgGDM1由ImmunoGen,Inc.製備,批次#1762-50,貯液濃度2.8毫克/毫升。5毫克/公斤此接合體等當量於76微克/公斤DM1。美登素:ImmunoGen,批次#1710-121,貯液濃度=16.38微克/毫升(於PBS中,pH 6.5)。以PBS將美登素貯液稀釋至15及7.5微克/毫升。PBS:ImmunoGen,pH 6.5。A375.S2人類黑色素瘤細胞係購自ATCC,於Centocor Cell Biology Services進行繼代培養及冷凍貯存。
以A375.S2人類黑色素瘤細胞對九週齡無胸腺裸大鼠進行皮下接種。於第14天,當平均腫瘤體積達到250-300立方毫米時,將動物隨機分成9/10組,開始進行治療。靜脈注射CNTO 95-DM1及適當之對照組化合物(第一週隔天注射,共注射三次,其後於第11、14、16、21及28天每週注射一次,注射兩週)。記錄腫瘤大小及體重。圖6顯示裸鼠中人類黑色素瘤腫瘤體積之經時變化。腫瘤體積以平均值+/- SEM(n=9或10)表示。箭頭指示靜脈內藥物注射。星號指示一隻未反應之動物由於其腫瘤體積超過1500立方毫米而犧牲。於第35天,犧牲所有動物。腫瘤體積以平均值+/- SEM(n=9或10)表示。箭頭指示靜脈內藥物投與。於此實驗中,5毫克/公斤之CNTO95-DM1封阻腫瘤生長且降低平均腫瘤體積,而10毫克/公斤之CNTO95則無效果。
第二個大鼠實驗,於第14天平均腫瘤體積達到250立方毫米。將動物隨機分組,第14天進行第一次靜脈投與給藥。接著於同週之第16與18天注射,其後於第23及31天每週注射一次。第35天犧牲所有動物。5毫克/公斤CNTO 95-DM1導使無胸線母大鼠之A375.S2人類黑色素瘤異種移植物完全復原(圖7)。對照組化合物包括PBS、游離CNTO 95、不恰當之抗體-DM1接合體、游離美登素、及游離CNTO 95加游離美登素則未顯示任何明顯效果。
本實驗乃研究CNTO 364相較於CNTO95之對後階段s.c.HT29人類結腸癌之效力。
CNTO 364,ImmunoGen批次#1806-50,蛋白質濃度2.53毫克/毫升,DM1濃度41.8毫克/毫升,DM1對CNTO 95之比率,每莫耳CNTO 95為3.6莫耳DM1。使用PBS或抗體F105-DM1作為對照組;F105-DM1,ImmunoGen批次#1806-44,蛋白質濃度2.2毫克/毫升,DM1濃度38.3毫克/毫升,DM1對F105之比率,每莫耳F105為3.8莫耳DM1。所有測試物件均已測試內毒素污染,LAL值低於1.0 EU/毫克。表現avb3、avb5、與avb6整合蛋白之HT29人類結腸癌細胞株係得自Centocor之細胞庫。測得此細胞株不含黴漿菌及細菌劑。於37℃,5% CO2
存在下,在補充10% FBS、1%丙酮酸鹽、與1% MEM非必需胺基酸之αMEM中培養細胞。
此研究中使用得自Harlan Laboratories(Indianapolis,IN)之70隻無胸線母大鼠。以5x106
個HT29細胞自大鼠後腰窩部位(背側,離肋骨下緣尾端大約0.5吋及離背脊0.5吋處)進行皮下注射(25 x106
個細胞/毫升,0.2毫升)。每天(工作日)監測所有大鼠之可觸摸腫瘤之外觀。依個別腫瘤體積將動物分級成為七個組別,每組9隻動物(表9)。所有組別之起始平均腫瘤體積介於250-260立方毫米之間。
分組當天(第0天),將動物稱重,以對照組抗體F105-DM1(25毫克/公斤)或CNTO 364(3、6、10、15或25毫克/公斤)進行靜脈注射。所有測試及對照組物件均給與每100克體重1毫升之容積。3、6、及10毫克/公斤CNTO 364組依q7dx5藥程進行i.v.投與。15毫克/公斤之CNTO 364組於第7、14、及35天給藥。25毫克/公斤CNTO 364與25毫克/公斤F105-DM1組於第7及14天給藥。後二組由於體重明顯喪失(相較於第0天超過10%),根據IACUC指導方針使其安樂死(圖8)。
每週記錄腫瘤體積測量值兩次。使用測徑器測量腫瘤長與寬,單位為毫米。以公式V=(長x寬x寬)/2計算腫瘤體積(立方毫米)。使用未配對t-試驗,以GraphPad Prism軟體進行統計分析。
CNTO 364以劑量依存方式抑制已確定的結腸癌腫瘤之生長(圖9)。依q7dx5給藥程序之10毫克/公斤CNTO 364,於9隻動物中,產生3個完全腫瘤復原及2個部分復原(圖10)。第7、14及35天使用15毫克/公斤CNTO 364之治療,於9隻罹患腫瘤動物中,產生4個完全復原及4個部分復原。PBS對照組實驗於移植腫瘤細胞35天後終止(平均腫瘤體積超過5000立方毫米)。此時,10毫克/公斤與15毫克/公斤CNTO 364治療組相對於PBS對照組之腫瘤體積差異具有<0.0001之P值(使用二尾未配對t試驗)。
25毫克/公斤CNTO 364與25毫克/公斤F105-DM1二者之二連續注射均具毒性,產生無法接受之體重喪失(圖8)。然而,25毫克/公斤CNTO 364之單次注射使平均腫瘤體積在4000立方毫米以上之後階段HT29人類結腸癌腫瘤完全復原(未示出)。
進行此研究以評估CNTO 95-DM1接合體對罹患A549人類肺癌的無胸線母大鼠之活體內效力。CNTO 95在Centocor(Malvern,PA)製備,DM1之接合由ImmunoGen(Cambridge,MA)執行。CNTO 364為實例1敘述之CNTO95-SPP-DM1。
於含10% FBS之MEMα中培養人類肺癌細胞株A549(ATCC),在不含血清之αMEM中製備供皮下移植於無胸線大鼠中之細胞。
無胸線母大鼠(6週齡,Harlan Laboratory,Indianapolis,IN)後腰窩部位(背側,離肋骨下緣尾端大約0.5吋及離背脊0.5吋處)以5x106
個細胞進行皮下移植(25 x106
個細胞/毫升,0.2毫升)。當平均腫瘤體積達到250立方毫米時,將具有相似平均腫瘤體積之動物分成數個劑量組(表10),於腫瘤細胞注射後第17及29天進行靜脈給藥。
表10
每週記錄腫瘤體積測量值兩次。使用電子Vernier測徑器測量腫瘤長與寬,單位為毫米。以公式V=(長x寬x寬)/2計算腫瘤體積(立方毫米)。腫瘤體積以平均值+/- SEM(n=6)表示。將彼等結果對時間作圖,圖12,其中箭頭指示靜脈內藥物注射時間。使用體重作為耐受度指標(圖11)亦顯示此研究使用之CNTO 364藥程可為動物所忍受,於第一次用藥後,初始體重只產生3%之體重短暫喪失。
使用95%信賴區間,以GraphPad Prism 4軟體(GraphPad software,Inc.,San Diego,CA)進行使用Bonferroni試驗之單因子變異數分析(ANOVA)。參照圖12:第1組,PBS;第2組,15毫克/公斤之F105-DM1;第3組,15毫克/公斤之CNTO 364;第4組,單只CNTO 95,15毫克/公斤;第5組,15毫克/公斤之CNTO 95加260毫克/公斤之美登素;第6組,單只美登素,260毫克/公斤。多種比較係藉由使用Bonferroni試驗之單因子變異數分析(ANOVA)測定P值。*
P<0.05,CNTO 364 v.s.F105-DM1,CNTO 95加美登素或單只美登素;* *
P<0.01,CNTO 364 v.s.單只CNTO 95;* * *
P<0.001,CNTO 364 v.s.PBS。
使DM1接合於CNTO 95,一種大分子,可能藉由延長DM1之活體內半衰期而改變DM1之藥物動力學性質。為了排除此可能性,乃於此研究中包含不恰當抗體F105-DM1免疫接合體以確定CNTO 95-DM1接合體之活性是否具CNTO 95-依存性。由於CNTO 95係抗血管新生與抗腫瘤化合物,DM1為胞毒劑,抗腫瘤活性有可能係由於游離CNTO 95與游離DM1之單純加成效應。因此,游離CNTO 95,游離CNTO 95加游離美登素,及游離美登素用藥組別均涵蓋於對照組。如圖13所示,15毫克/公斤之CNTO 364消除依qx12dx2藥程的六個腫瘤A549肺癌腫瘤異種移植物之六個。於F105-DM1組觀察到一個完全腫瘤復原;於CNTO 95加美登素組觀察到兩個。彼等結果證明CNTO 95-DM1免疫接合體,CNTO 364,於A549肺癌腫瘤復原中之優越性。依此藥程以CNTO364治療之動物顯示短暫的皮膚毒性及體重喪失,無明顯的嚴重毒性跡象。
選擇於免疫障礙大鼠中使用皮下移植HT29人類結腸癌腫瘤-衍生細胞之後階段腫瘤模式來檢測用以製備CNTO 95免疫接合體的各種鍵結之耐受性及效力。
CNTO 95-SPP-DM1(CNTO 364)、CNTO 95-SSNPB-DM4(CNTO 365)、CNTO 95-SSNPP-DM4(CNTO 366)、及彼等之Mab F105對等物均由ImmunoGen(Cambridge,MA)製備。一百隻無胸線母大鼠(4-6週)係得自Harlan Laboratories。
於37℃,5% CO2
存在下,將人類HT29(ATCC)培養於補充10% FBS之αMEM中。製備濃度為每毫升不含血清之αMEM中有二千五百萬個細胞之細胞供接種用。無胸線母大鼠後腰窩部位(背側,離肋骨下緣尾端大約0.5吋及離背脊0.5吋處)以5x106
個HT29細胞進行皮下接種(25x106
個細胞/毫升,0.2毫升)。每週檢測所有大鼠之腫瘤外觀兩次。根據平均腫瘤體積(各組大約250立方毫米)將動物分為13組,每組6隻動物。分組當天(第7天),各組接受如表11所列之其初始劑量。免疫接合體之劑量係根據各接合體中之DM1或DM4內容計算。L及H分別代表175及350微克/公斤DM1或DM4。所有測試物件均給與1毫升/100克體重之容積。除了第11組係於第7天僅接受一次劑量外,所有其他組別均於第7及第21天給藥。使用腫瘤體積作為效力指標(圖14A & B);使用體重變化(圖15A & B)監偵耐受性。所有測量均以組別平均值+/- SEM(n=6)表示。
表11
如圖14B所示,注射350微克/公斤DM4 CNTO 365及F105-SSNPB-DM4之動物於第一次給藥後喪失大於10%之最初體重。因此,此二組別於注射一次後即停止給藥。>10%之體重喪失屬短暫性,動物於停止治療10天內即告恢復。其餘組別於第7及21天均給藥,除了高劑量CNTO 364組喪失10%以上體重外,未觀察到明顯的體重喪失。其他實驗中,依此藥程使用CNTO 364均未見明顯之體重喪失。如圖14B所示,高劑量CNTO 365之單次注射,於6隻動物中,4隻獲得已確定sc人類HT29結腸癌之完全復原。高劑量(350微克/公斤DM1)CNTO 364及低劑量(175微克/公斤DM4)CNTO 365亦使預先形成之結腸癌腫瘤復原(各組分別於6隻動物中有2隻)或明顯抑制HT29結腸癌腫瘤生長。然而,低劑量(175微克/公斤DM1)CNTO 364與高低二劑量之CNTO 366對於腫瘤大小均無任何明顯效果。彼等結果暗示,於此腫瘤異種移植模式中,依q14dx2藥程進行靜脈時,CNTO 365比CNTO 364及CNTO 366具有更佳之潛力與功效。
本發明亦可以如前文詳細說明及實例特別敘述以外之方法實施乃顯見之事。
依照上文之教示,本發明之許多修飾與變化均屬可能,且隸屬隨附申請專利範圍之內。
圖1
顯示具有較佳形式之硫醇化類美登素醯胺類之化學結構;DM1、DM3與DM4如備註。
圖2
顯示本發明較佳二官能連接劑試劑之化學結構及其化學縮寫。
圖3
係顯示製備本發明抗體-類美登素接合體之合成方法之反應圖式。
圖4
係顯示裸小鼠中人類黑色素惡性腫瘤經時體積變化及投與CNTO 95之效果之圖式。小鼠經皮下接種A375.S2細胞(3x106
個),三天後開始進行CNTO 95或對照組用藥。每週三次,使用CNTO 95或賦形劑,以10毫克/公斤之劑量經腹膜內處理小鼠。各數據點為得自10隻罹患腫瘤動物之平均腫瘤體積(±SEM)。於第26天,相較於對照組處理之動物,每週給與三次CNTO 95顯著地抑制腫瘤之生長(P=0.0005)。
圖5
係顯示裸大鼠中人類黑色素惡性腫瘤經時體積變化及投與CNTO 95之效果之圖式。大鼠經皮下接種A375.S2細胞(3x106
個),三天後開始進行CNTO 95或對照組治療。每週一次,使用CNTO 95或賦形劑,以10毫克/公斤之劑量經靜脈內處理小鼠。各數據點為得自9隻罹患腫瘤動物之平均腫瘤體積(±SEM)。
圖6
係顯示裸小鼠中A375.S2人類黑色素瘤細胞經時生長情形之圖式。腫瘤體積以平均值+/- SEM(n=9或10)表示。箭頭指示靜脈內藥物注射。星號指示一隻未反應之動物由於其腫瘤體積超過1500立方毫米而犧牲。
圖7
係顯示無胸腺裸大鼠中人類A375.S2黑色素瘤細胞生長之圖式。第14天,當平均腫瘤體積達到250立方毫米時,將動物隨機分組,投與第一個劑量。於第35天,犧牲所有動物。腫瘤體積以平均值+/- SEM(n=9或10)表示。箭頭指示靜脈內投與藥物之天數。
圖8
係顯示於植入腫瘤後第7天及其後每隔7天(X5)以3、6、或10毫克/公斤CNTO 364;第7及14天以25毫克/公斤CNTO364或F105-DM1;及於第7、14與35天以15毫克/公斤CNTO364注射罹患腫瘤之小鼠之總體重經時變化之圖式。
圖9
係顯示如圖8之相同動物腫瘤體積經時變化之圖式。
圖10
係顯示如圖8所述所有動物組別個別腫瘤體積之圖式。
圖11
係罹患皮下人類A549人類肺癌腫瘤並以15毫克/公斤CNTO 364處理或以對照組處理之裸大鼠經時體重平均值+/- SEM(n=6)之圖式。箭頭指示靜脈內藥物注射之時間。
圖12
係顯示於無胸線母大鼠中,人類A549人類肺癌腫瘤生長之圖式。CNTO 364(15毫克/公斤)處理使無胸線母大鼠中已確立之A549人類肺癌腫瘤復原。
圖13
係顯示以15毫克/公斤CNTO364或對照組物質處理之無胸線母大鼠中,人類A549人類肺癌腫瘤生長研究結束時,個別腫瘤重量之散佈圖。水平線段代表各研究組別之中值。
圖14A & B
係顯示罹患HT29人類結腸腫瘤細胞並以CNTO 364(CNTO95-SPP-DM1)、CNTO 365(CNTO95-SSNPB-DM4)、與CNTO 366(CNTO95-SSNPP-DM4)處理之大鼠平均腫瘤體積經時變化之圖形。A.
PBS對照組及使用相同程序與試劑接合於硫醇化類美登素之不恰當抗體,F105,於第7及21天進行10毫克/公斤之注射。B.
PBS對照組及如前述之接合抗體,於第7及21天進行20毫克/公斤之注射,惟CNTO365組別於第7天接受單次注射。
圖15A & B
係顯示如圖14所述之罹患HT29腫瘤之大鼠體重平均值變化之圖形。
<110> 森托克公司(Centocor,Inc.) 崔克漢(Trikha,Mohit) 陳其明(Qiming,Chen) <120> 抗-整合蛋白免疫接合體,方法及用途<130> CEN 50?? <140> TBD <141> 2004-11-04 <160> 9 <170> PatentIn version 3.3 <210> 1 <211> 5 <212> PRT <213> 智人<400> 1<210> 2 <211> 17 <212> PRT <213> 智人<400> 2<210> 3 <211> 10 <212> PRT <213> 智人<400> 3<210> 4 <211> 11 <212> PRT <213> 智人<400> 4<210> 5 <211> 7 <212> PRT <213> 智人<400> 5<210> 6 <211> 8 <212> PRT <213> 智人<400> 6<210> 7 <211> 119 <212> PRT <213> 智人<400> 7 <210> 8 <211> 108 <212> PRT <213> 智人<400> 8<210> 9 <211> 1048 <212> PRT <213> 智人<400> 9
Claims (38)
- 一種具下式之抗體-藥物接合體,[C-L] m -A I 式中A係人類αV整合蛋白專一性抗體,其中該抗體能被表現該αV整合蛋白之細胞內化,且該抗體包含SEQ ID NOS:1、2、及3所示之所有CNTO95重鏈互補決定區(CDR)胺基酸序列及SEQ ID NOS:4、5、及6所示之所有CNTO95輕鏈CDR胺基酸序列;C係細胞毒素,係選自類美登素(maytansinoids)、硝礦黴素(calicheamicins)、依波西隆(epothilones)、狄可德莫(discodermolide)、愛柳洛平(eleuthrobins)、多拉司丁(dolastatins)、隱花植物素(cryptophycins)、喜樹鹼、利索新(rhizoxin)及紫杉烷衍生物所組成之群組;L係結合抗體與細胞毒素之連接基,其進一步含有可被細胞內環境成分切割之鍵結,且該可切割之化學鍵結係選自二硫鍵、硫醚、酯或胜肽鍵所組成之組群;及m代表連接於該抗體的細胞毒素分子之平均數,其為1至10之整數。
- 根據申請專利範圍第1項之抗體-藥物接合體,其中該抗體分子對胺基酸序列SEQ ID NO:9內之抗原決定部位具專一性。
- 如申請專利範圍第1項之抗體-藥物接合體,其中該抗體係人類、人類化、或嵌合型抗體。
- 根據申請專利範圍第1項之抗體-藥物接合體,其中該可切割之化學鍵結為二硫鍵。
- 根據申請專利範圍第1項之抗體-藥物接合體,其中該胞毒劑對腫瘤細胞生長具有10-9 M或更小之一半最大抑制值(IC50或GI50)之彼等其他化合物。
- 根據申請專利範圍第5項之抗體-藥物接合體,其中該胞毒劑係類美登素。
- 根據申請專利範圍第6項之抗體-藥物接合體,其中係使用醯基化之胺基酸(該醯基帶有經保護之硫氫基)使類美登素於C-3、C-14、C-15、或C-20處酯化,其中鄰接經保護之硫氫基的醯基之碳原子具有一或兩個取代基,該等取代基係選自:CH3 、C2 H5 、具有1至10個碳原子之直鏈烷基或烯基、具有3至10個碳原子之分支鏈或環狀烷基或烯基、苯基、經取代之苯基、雜環芳基、雜環烷基、或H;及其中醯基於羰基官能基與硫原子之間具有至少兩個碳原子之直鏈鏈長。
- 根據申請專利範圍第6項之抗體-藥物接合體,其中該類美登素係N2’ -脫乙醯基-美登素之硫醇化衍生物。
- 根據申請專利範圍第8項之抗體-藥物接合體,其中N2’ -脫乙醯基-美登素之衍生物係經由具下式之基團連接於抗體分子:-SCH2 CH2 -CO-、-S-CH2 CH2 CH2 CH2 -CO-、-S-CH(CH3 )CH2 CH2 -CO-、或-S-C(CH3 )2 CH2 CH2 -CO-基。
- 如申請專利範圍第1項之抗體-藥物接合體,其中連接於抗體分子的胞毒殘基之平均數介於3與4之間。
- 一種具下式之抗體-藥物接合體,
- 如申請專利範圍第11項之抗體-藥物接合體,其中n=2,R與R2二者為甲基,Z為氫及p為3。
- 一種製造根據申請專利範圍第1項之接合體之方法,該方法包括下述步驟:(a)於對人類αV整合蛋白具專一性之抗體分子中,引入一或多個游離或經保護之硫醇基;(b)使步驟(a)之抗體分子與對細胞具毒性之化合物(IC50值為10-9 M或更小)反應,該化合物具有一或多個二硫基或硫醇基;及(c)回收所得接合體。
- 如申請專利範圍第13項之方法,其中該毒性化合物為類美登素。
- 如申請專利範圍第13或14項之方法,其中係使用(2-吡啶基)-3-二硫基丙酸N-羥基琥珀醯亞胺酯(SPDP)、(2-吡啶基)-4-二硫基戊酸N-羥基琥珀醯亞胺酯(SPP)、或(2-吡啶基)-4-二硫基丁酸N-羥基琥珀醯亞胺酯(SPDB),以於抗體分子中引入游離或經保護之硫醇基。
- 一種醫藥組成物,其包含根據申請專利範圍第1至12項之任一項之接合體及醫藥上可接受之載劑、稀釋劑、或賦形劑。
- 一種根據申請專利範圍第1至12項之任一項之接合體於製備用於治療癌症之醫藥組成物之用途。
- 一種於有其需要的病患治療癌症之醫藥組成物,其包含治療有效量之根據申請專利範圍第1至12項之任一項之接合體,其中該癌症為乳腺癌、肺腺癌、胰腺癌、結腸腺癌、腎細胞癌、或胃腺癌。
- 根據申請專利範圍第1至12項中任一項之於有其需要的病患治療癌症之醫藥組成物,其中該癌症為頭頸部鱗狀細胞癌、食道鱗狀細胞癌、肺鱗狀細胞癌癌、皮膚鱗狀細胞癌、或子宮頸鱗狀細胞癌。
- 一種醫藥組成物,係使用根據申請專利範圍第1至12項之任一項之接合體治療或預防癌症轉移擴散,其包含治療有效量之根據申請專利範圍第1至12項之任一項之接合體。
- 一種用於抑制有其需要的哺乳動物癌細胞生長之醫藥組成物,其包含有效量之防止CNTO 95結合於表現人類αVβ3整合蛋白的活細胞之根據申請專利範圍第1至12項之任一項之抗體-藥物接合體,以抑制該癌細胞於該哺乳動物中之生長。
- 根據申請專利範圍第21項之醫藥組成物,其中抗體-藥物接合體係經靜脈內投與。
- 根據申請專利範圍第22項之醫藥組成物,其中抗體-藥物接合體係以0.05毫克/公斤至12.0毫克/公斤體重之量投與。
- 根據申請專利範圍第21項之醫藥組成物,其中哺乳動物為人類病患。
- 一種抑制有其需要的哺乳動物血管新生依存疾病之醫藥組成物,該方法包含有效量之防止CNTO 95結合於表現人類αVβ3整合蛋白的活細胞之根據申請專利範圍第1至12項之任一項之單株抗體-藥物接合體,以抑制該血管新生,其中該血管新生-依存疾病係選自下述組群之疾病:癌症轉移、血管瘤、血管纖維瘤、糖尿病性視網膜病變、早產兒視網膜病變、新生血管性青光眼、血管新生誘發之角膜疾病、退化斑、黃斑病變、眼翳、視網膜衰退、水晶體後纖維組織增生、顆粒性結膜炎、牛皮癬、毛細血管擴張症、化膿性肉芽腫、脂漏性皮膚炎、痤瘡與關節炎。
- 根據申請專利範圍第25項之醫藥組成物,其中該單株抗體-藥物接合體用於治療選自下述組群之血管新生性皮膚疾病:牛皮癬、靜脈曲張性潰瘍、痤瘡、酒糟鼻、疣、濕疹、血管瘤、與淋巴血管新生。
- 根據申請專利範圍第25項之醫藥組成物,其中該單株抗體-藥物接合體用於治療涉及角膜或視網膜新血管生成之疾病。
- 一種用於改善有其需要的哺乳動物之炎性疾病之醫藥組成物,其包含有效量之防止CNTO 95結合於表現人類αVβ3整合蛋白的活細胞之根據申請專利範圍第1至 12項之任一項之單株抗體-藥物接合體,以改善選自下述組群之該炎性疾病之一或多種症狀:類風濕性關節炎、黃斑病變、牛皮癬、糖尿病性視網膜病變。
- 如申請專利範圍第16至28項之任一項之醫藥組成物,其中抗體-藥物接合體係組合第二治療或預防劑或物理療法投與。
- 一種製造物件,其包含根據申請專利範圍第1至12項之任一項之接合體組成物與容器,及進一步包含包裝內插物或標籤,指示該組成物可用於治療特徵為表現αV整合蛋白的細胞之疾病。
- 根據申請專利範圍第30項之製造物件,其中該包裝內插物指示該組成物可用於治療癌症。
- 一種具有下式之抗體-藥物接合體,
- 一種具有下式之抗體-藥物接合體,
- 根據申請專利範圍第32或33項之抗體-藥物接合體,其中至少一重鏈可變區序列包含SEQ ID NOS:7所示之CNTO95重鏈可變區序列。
- 根據申請專利範圍第32或33項之抗體-藥物接合體,其中至少一輕鏈可變區序列包含SEQ ID NOS:8所示之CNTO95輕鏈可變區序列。
- 根據申請專利範圍第32或33項之抗體-藥物接合體,其中該抗體包含SEQ ID NOS:7所示之CNTO95重鏈可變區及SEQ ID NOS:8所示之CNTO95輕鏈可變區。
- 根據申請專利範圍第32或33項之抗體-藥物接合體,其中該抗體為單株抗體CNTO95。
- 一種具有下式之抗體-藥物接合體,
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