JP5010281B2 - Epcamに対する二重特異性抗体を含む薬学的組成物 - Google Patents
Epcamに対する二重特異性抗体を含む薬学的組成物 Download PDFInfo
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Description
(a)SEQ ID NO:80、SEQ ID NO:84、SEQ ID NO:88、SEQ ID NO:92、およびSEQ ID NO:96のいずれかに示されるアミノ酸配列;
(b)SEQ ID NO:79、SEQ ID NO:83、SEQ ID NO:87、SEQ ID NO:91、およびSEQ ID NO:95に示される核酸配列によってコードされるアミノ酸配列;
(c)ストリンジェントなハイブリダイゼーション条件下で(b)において定義される核酸配列の相補鎖とハイブリダイズする核酸配列によってコードされるアミノ酸配列;
(d)(b)および(c)のいずれか一方のヌクレオチド配列に対する遺伝コードの結果としての縮重である核酸配列によってコードされるアミノ酸配列。
(a)SEQ ID NO:82、SEQ ID NO:86、SEQ ID NO:90、SEQ ID NO:94、およびSEQ ID NO:98のいずれかに示されるアミノ酸配列;
(b)SEQ ID NO:81、SEQ ID NO:85、SEQ ID NO:89、SEQ ID NO:93、およびSEQ ID NO:97に示される核酸配列によってコードされるアミノ酸配列;
(c)ストリンジェントなハイブリダイゼーション条件下で(b)において定義される核酸配列の相補鎖とハイブリダイズする核酸配列によってコードされるアミノ酸配列;
(d)(b)および(c)のいずれか一方のヌクレオチド配列に対する遺伝コードの結果としての縮重である核酸配列によってコードされるアミノ酸配列。
からなる群より選択されるCD3特異的抗体に由来する。これらのCD3特異的抗体は当技術分野において周知であり、とりわけ、Tunnacliffe (1989), Int. Immunol. 1, 546-550において記載されている。より好ましい態様において、このCD3特異的ドメインのこのVHおよびVL領域はOKT-3(上記に定義されかつ記載される)に由来する。なおより好ましくは(および添付の実施例において例証されるように)、このVH領域およびVL領域は、Traunecker (1991), EMBO J. 10, 3655-3659によって記載されたCD3分子についての特異性を有する抗体/抗体誘導体であるか、またはそれに由来する。本発明に従って、このVHおよびVL領域は、他のTCRサブユニットの文脈において(例えば、ヒトCD3-ε鎖についてトランスジェニックであるマウス細胞において)ヒトCD3-ε鎖を特異的に認識することが可能である抗体/抗体誘導体などに由来する。これらのトランスジェニックマウス細胞は、ネイティブなまたはほぼネイティブなコンホメーションでヒトCD3-ε鎖を発現する。従って、CD3-ε鎖特異的抗体に由来するVHおよびVL領域は、本発明に従って最も好ましく、この(親の)抗体は、TCR複合体の文脈において提示されるヒトCD3の、ネイティブもしくはほぼネイティブな構造を反映するエピトープ、またはコンホメーションエピトープを特異的に結合することが可能であるはずである。このような抗体は、Tunnacliffe (1989)によって「グループII」抗体として分類されてきた。Tunnacliffe (1989)によるさらなる分類は、CD3に対して指向される「グループI」および「グループIII」の抗体の定義を含む。「グループI」抗体は、UCHT1と同様に、組換えタンパク質として、および細胞表面上でTCRの一部として発現されたCD3-εを認識する。従って、「グループI」抗体は、CD3-ε鎖に高度に特異的である。対照的に、本発明で好ましい「グループII」抗体は、他のTCRサブユニットと結合しているネイティブなTCR複合体中でのみ、CD3-ε鎖を認識する。理論に拘束されることはないが、本発明の文脈において、「グループII」抗体においては、TCR含量がCD3-ε鎖の認識のための必要であることが仮定される。ε鎖と結合されるCD3-γ鎖およびδ鎖もまた、「グループII」抗体の結合に関与する。3つ全てのサブユニットが免疫レセプターチロシン活性化モチーフ(ITAM)を発現し、これは、タンパク質チロシンに基づくキナーゼによってチロシンリン酸化され得る。この理由のために、グループII抗体は、CD3-ε鎖、γ鎖、およびδ鎖を介してT細胞シグナル伝達を誘導し、CD3-ε鎖を介してT細胞シグナル伝達を選択的に誘導するグループI抗体と比較してより強力なシグナルをもたらす。さらに、治療的適用のためには、強力なT細胞シグナル伝達の誘導が望ましいので、本発明の薬学的組成物中に含まれる二重特異性単鎖構築物において利用されるVH(抗CD3)/VL(抗CD3)領域(またはその部分)は、好ましくは、ヒトCD3に対して指向される抗体に由来し、かつTunnacliffe (1989)前掲による「グループII」に分類される。
(a)SEQ ID NO:2、4、8、10、12、14、16、18、20、30、36、39、42、44、46、48、50、52、54、56、58、および60のいずれかに示されるアミノ酸配列;
(b)SEQ ID NO:1、3、7、9、11、13、15、17、19、29、35、38、41、43、45、47、49、51、53、55、57、および59のいずれかに示される核酸配列によってコードされるアミノ酸配列;
(c)ストリンジェントなハイブリダイゼーション条件下で(b)において定義される核酸配列の相補鎖とハイブリダイズする核酸配列によってコードされるアミノ酸配列;
(d)(b)および(c)のいずれか一方のヌクレオチド配列に対する遺伝コードの結果としての縮重である核酸配列によってコードされるアミノ酸配列。
(a)本明細書中に定義される二重特異性単鎖抗体構築物のアミノ酸配列、好ましくは、SEQ ID NO:2、4、8、10、12、14、16、18、20、30、36、39、42、44、46、48、50、52、54、56、58、および60のいずれかに示されるアミノ酸配列を含む成熟型タンパク質をコードするヌクレオチド配列;
(b)SEQ ID NO:1、3、7、9、11、13、15、17、19、29、35、38、41、43、45、47、49、51、53、55、57、および59のいずれかに示されるDNA配列を含むか、またはこの配列からなるヌクレオチド配列;
(c)ストリンジェントなハイブリダイゼーション条件下で(b)において定義される核酸配列の相補鎖とハイブリダイズするヌクレオチド配列;
(d)(a)または(b)のヌクレオチド配列によってコードされるアミノ酸配列の1個または数個のアミノ酸の置換、欠失、および/または付加の手段によって、(a)または(b)のヌクレオチド配列によってコードされるタンパク質に由来するタンパク質をコードするヌクレオチド配列;
(e)(a)または(b)のヌクレオチド配列によってコードされるアミノ酸配列に対して、少なくとも60%同一であるアミノ酸配列を有するタンパク質をコードするヌクレオチド配列;
(f)(a)から(e)のいずれか1つのヌクレオチド配列に対する遺伝コードの結果としての縮重である核酸配列。
列挙された核酸分子およびベクターは、直接的導入のために、またはリポソーム、もしくはウイルスベクター(例えば、アデノウイルス、レトロウイルス)を介する細胞への導入のために設計され得る。好ましくは、この細胞は生殖系列細胞、胚性細胞、または卵細胞、またはそれらから由来する細胞であり、最も好ましくは、幹細胞である。胚性幹細胞の例は、とりわけ、Nagy, Proc. Natl. Acad. Sci. USA 90 (1993), 8424-8428において記載されている幹細胞であり得る。
種々の構造およびドメイン配置にある抗CD3および抗EpCAMを含む多数の構築物を生成した。抗体3-1の抗EpCAM VHおよびVL可変ドメインをSEQ ID NO:79、80、81、82に、3-5をSEQ ID NO:83、84、85、86に、4-1をSEQ ID NO:87、88、89、90に、4-7をSEQ ID NO:91、92、93、94に、および5-10をSEQ ID NO:95、96、97、98に示す。これらの構築物を表1に要約する。
1.1.1 抗CD3 PCR産物の調製
a) もともとの18アミノ酸リンカーを有する抗CD3構築物(SEQ ID NO:1、2、3および4)
18アミノ酸リンカーを含むN末端のもともとの抗CD3(SEQ ID NO:70)を、CD19xCD3構築物(Loeffler A et al. Blood 2000 95:2098-103)をテンプレートとして、および以下のプライマー
を使用してPCRによって得た。
18アミノ酸リンカーを含むN末端のもともとの抗CD3(SEQ ID NO:70)およびCysからSerへの変異を、CD19x抗CD3(C→S変異)構築物をテンプレートとして、およびプライマーCD3 VH BsrGIおよびCD3 VL BspEI(SEQ ID NO:5および6)を使用してPCRによって得た。Cys-Ser変異を有するCDRH3配列をSEQ ID NO:78に示す。
15アミノ酸標準(G4S)3リンカー(SEQ ID NO:99)を含むN末端抗CD3を、CD19xCD3(Loeffler A et al. Blood 2000 95:2098-103)をテンプレートとしてPCRによって得た。抗CD3 VH領域および抗CD3 VL領域を、以下のプライマー
によって別々に増幅した。PCR産物によって導入された重複する相補的配列を、引き続く融合PCRの間に15アミノ酸(G4S)3(1文字アミノ酸コード)(SEQ ID NO:99)リンカーのコード配列を形成するために使用した。この増幅段階を、プライマー対CD3 VH BsrGI(SEQ ID NO:5)およびCD3 VL BspEI(SEQ ID NO:6)を用いて実行した。
18アミノ酸リンカー(SEQ ID NO:70)を含むN末端のもともとの抗CD3、または15アミノ酸の標準(G4S)3リンカー(SEQ ID NO:99)を含むN末端のもともとの抗CD3を制限酵素BsrGIおよびBspE1で切断し、続いて、EcoRI/BsrGIフラグメントとして真核生物分泌シグナル(リーダーペプチド)のアミノ酸配列を含むbluescript KSベクター(Stratagene, La Jolla, CA)にクローニングした。EcoRIおよびBspEIを用いるこの構築物の切断後、リーダーペプチドを有するそれぞれの抗CD3 scFvを含む得られるDNAフラグメントを、pEFDHFR中にc末端EpCAM結合部分3-1(SEQ ID NO:79〜82)、4-7(SEQ ID NO:91〜94)、または5-10(SEQ ID NO:95〜98)を含むEcoRI/BspEI切断プラスミドにクローニングした。pEFDHFRはMack et al. Proc. Natl. Sci. USA 92 (1995) 7021-7025に記載された。
15アミノ酸の標準リンカー(SEQ ID NO:99)を含むVLVH方向にあるC末端抗EpCAM抗体4-7(SEQ ID NO:91〜94)をPCRによって得た。4-7 VH領域および4-7 VL領域を以下のプライマー
によって別々に増幅した。PCR産物に導入された重複する相補性配列を、引き続く融合PCRの間に15アミノ酸(G4S)3(1文字アミノ酸コード)リンカー(SEQ ID NO:99)のコード配列を形成するために使用した。この増幅段階を、プライマー対4-7 VL BspEI FORおよび4-7 VH SalI REV(SEQ ID NO:100、SEQ ID NO:24)を用いて実行した。
によって別々に増幅した。PCR産物に導入された重複する相補性配列を、引き続く融合PCRの間に15アミノ酸(G4S)3リンカー(SEQ ID NO:99)のコード配列を形成するために使用した。この増幅段階を、プライマー対5-10 VL BspEI FORおよび5-10 VH SalI REV(SEQ ID NO:25、SEQ ID NO:28)を用いて実行した。
配列決定による二重特異性単鎖をコードする配列の確認後、真核生物発現のために、このプラスミドをDHFR欠損CHO細胞にトランスフェクトした。DHFR欠損CHO細胞における真核生物タンパク質発現は、Kaufmann R.J. (1990) Methods Enzymol. 185, 537-556において記載されているように実行した。次いで、トランスフェクトされた細胞を拡大し、1リットルの上清を産生した。二重特異性単鎖分子の発現および結合はFACS分析によって確認した。この目的のために、EpCAMポジティブヒト胃癌細胞株KatoIII(American Type Culture Collection(ATCC) Manassas, VA 20108 USAから入手、ATCC番号:HTB-103)を使用した。抗CD3部分の結合はJurkat細胞(ATCC TIB 152)上で実証した。
1.2.1 抗EpCAMx抗CD3構築物のクローニング
構築物3-5x抗CD3(SEQ ID NO:29、30)のクローニング
VH-VL方向にあるC末端3-5を、3-5x抗CD3(SEQ ID NO:29)分子の構築のためにPCRによって得た。フラグメントIおよびIIを、プライマー対me 81(SEQ ID NO:31)/me 90(SEQ ID NO:34)およびme 83(SEQ ID NO:32)/me 84(SEQ ID NO:33)をそれぞれ使用して、PCRによって増幅した。ホットスタートPCRを、Roche DiagnosticsのExpand High Fidelity Systemを使用して行った。増幅のために20サイクル(94℃/30秒間;60℃/1分間;72℃/1分間)使用し、続いて1サイクル(72℃3分間)使用した。
VH-VL方向にあるC末端3-1を、3-1x抗CD3(SEQ ID NO:35)分子の構築のためにPCRによって得た。フラグメントIおよびIIを、プライマー対me 91a(SEQ ID NO:37)/me 90(SEQ ID NO:34)およびme 83(SEQ ID NO:32)/me 84(SEQ ID NO:33)をそれぞれ使用して、PCRによって増幅した。PCRを上記のように実行した。
VH-VL方向にあるC末端4-1を、4-1x抗CD3(SEQ ID NO:38、39)分子の構築のためにPCRによって得た。フラグメントIおよびIIを、プライマー対me 92a(SEQ ID NO:40)/me 90(SEQ ID NO:34)およびme 83(SEQ ID NO:32)/me 84(SEQ ID NO:33)をそれぞれ使用して、PCRによって増幅した。PCRを、60℃のアニーリング温度で上記のように実行した。
VH-VL方向にあるC末端4-7を、4-7x抗CD3(SEQ ID NO:41、42)分子の構築のためにPCRによって得た。フラグメントIおよびIIを、プライマー対me 81(SEQ ID NO:31)/me 90(SEQ ID NO:34)およびme 83(SEQ ID NO:32)/me 84(SEQ ID NO:33)をそれぞれ使用して、PCRによって増幅した。PCRを、60℃のアニーリング温度で上記のように実行した。
VH-VL方向にあるC末端5-10を、5-10x抗CD3(SEQ ID NO:43、44)分子の構築のためにPCRによって得た。フラグメントIおよびIIを、プライマー対me 92a(SEQ ID NO:40)/me 90(SEQ ID NO:34)およびme 83(SEQ ID NO:32)/me 84(SEQ ID NO:33)をそれぞれ使用して、PCRによって増幅した。PCRを、60℃のアニーリング温度で上記のように実行した。
DHFR遺伝子を欠くCHO細胞を、10%ウシ胎仔血清(Life Technologies、65℃で30分間熱不活化)で、およびHT(ヒポキサンチンおよびチミジン;Life Technologies、カタログ番号:41065-012)で補充したαMEM培地(Life Technologies、カタログ番号:32561)中に維持した。細胞を、pEF-dHFR-3-1x抗CD3(SEQ ID NO:35、36)、pEF-dHFR-3-5x抗CD3(SEQ ID NO:29、30)、pEF-dHFR-4-1x抗CD3(SEQ ID NO:38、39)、pEF-dHFR-4-7x抗CD3(SEQ ID NO:41、42)、およびpEF-dHFR-5-10x抗CD3(SEQ ID NO:43、44)、で、製造業者によって提供される指示書に従ってLipofectamine 2000キット(Invitrogen;カタログ番号11668-019)を使用してトランスフェクトした。48時間後、細胞を、トランスフェクトされた細胞を選択培地(熱不活化した10%透析胎仔ウシ血清(Life Technologies)を含むαMEM培地(カタログ番号:32561))に移すことによって選択に供した。2〜3週間の選択後、細胞を、2リットルの組織培養ローラーボトル(Falcon(カタログ番号:353068;Becton Dickinson Labware))中で、二重特異性分子の産生のために8〜9日間(500mlの選択培地中で)増殖させた。この組織培養培地を4℃で10分間、300g(1300rpm)で遠心分離して、細胞および細胞破壊片を除去した。分泌された二重特異性分子を含む上清を、さらなる分析まで-20℃で保存した。
本発明の二重特異性抗EpCAMx抗CD3単鎖構築物の結合強度を分析するために、以下の結合アッセイを実行した。
抗EpCAMおよび抗CD3を含む二重特異性単鎖構築物を精製するために、CHO-EpCAM細胞を、HiClone(登録商標)CHO改変DMEM培地(HiQ)を含むローラーボトル中で、収集前7日間増殖させた。細胞を遠心分離によって取り除き、発現されたタンパク質を含む上清を-20℃で保存した。
抗CD3および抗EpCAMを含む構築物の生物活性を試験するために、FACSに基づく細胞毒性試験を実行した。
本発明の構築物の優れた結合アフィニティーを示すために、この構築物および先行技術の抗EpCAM構築物(M79)x抗CD3のKD値を決定した。
従来のM79xCD3構築物およびHD70xCD3構築物と、NXDモチーフを有する構築物の生物活性を比較するために、以下の細胞毒性アッセイを実行した。
Claims (15)
- 二重特異性単鎖抗体構築物を含む、対象における腫瘍性疾患の予防、治療、または寛解のために用いられる薬学的組成物であって、該二重特異的単鎖抗体構築物が、以下からなる群より選択されるアミノ酸配列を含む、組成物:
(a) SEQ ID NOs: 2, 4, 8,10, 12, 14, 16, 18, 20, 30, 36, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58および60のいずれかに示されるアミノ酸配列;
(b) SEQ ID NOs : 1, 3, 7, 9, 11,13, 15, 17, 19, 29, 35, 38, 41, 43, 45, 47, 49, 51, 53, 55, 57 および 59に示される核酸配列によってコードされるアミノ酸配列;
(c)(b)のヌクレオチド配列に対する遺伝コードの結果としての縮重である核酸配列によってコードされるアミノ酸配列。 - 二重特異性単鎖抗体構築物が、SEQ ID NO:2、18、36、および44のいずれかに示されるアミノ酸配列からなる群から選択されるアミノ酸配列を含む、請求項1記載の薬学的組成物。
- 請求項1または2に定義される二重特異性単鎖抗体構築物をコードする核酸配列を含む、対象における腫瘍性疾患の予防、治療、または寛解のために用いられる薬学的組成物。
- 請求項3に定義される核酸配列を含むベクターを含む、対象における腫瘍性疾患の予防、治療、または寛解のために用いられる薬学的組成物。
- ベクターが、請求項3に定義される核酸配列に作動可能に連結されている調節配列をさらに含む、請求項4記載の薬学的組成物。
- ベクターが発現ベクターである、請求項4または5記載の薬学的組成物。
- 請求項4から6のいずれかに定義されるベクターで形質転換またはトランスフェクトされた宿主を含む、対象における腫瘍性疾患の予防、治療、または寛解のために用いられる薬学的組成物。
- 免疫エフェクター細胞のための活性化シグナルを提供することが可能であるタンパク質性化合物をさらに含む、請求項1から7のいずれか一項記載の薬学的組成物。
- 薬学的組成物が37℃以上で熱安定性である、請求項1から8のいずれか一項記載の薬学的組成物。
- 請求項1または2に定義される二重特異性単鎖抗体構築物の発現を可能にする条件下で請求項7に定義される宿主を培養する工程、および該培養から産生した二重特異性単鎖抗体構築物を回収する工程を含む、請求項1から9のいずれか一項記載の薬学的組成物の産生のための方法。
- 腫瘍性疾患の予防、治療、または寛解のための薬学的組成物の調製のための、請求項1または2に定義される二重特異性単鎖抗体構築物、請求項3に定義される核酸配列、請求項4から6のいずれかに定義されるベクター、および/または請求項7に定義される宿主の使用。
- 腫瘍性疾患が上皮癌または微小残存癌である、請求項11記載の使用。
- 対象がヒトである、請求項1から9のいずれか一項記載の薬学的組成物。
- 腫瘍性疾患が上皮癌または微小残存癌である、請求項1から9および13のいずれか一項記載の薬学的組成物。
- 請求項1または2に定義される二重特異性単鎖抗体構築物、請求項3に定義される核酸配列、請求項4から6のいずれかに定義されるベクター、請求項7に定義される宿主、および/または請求項10に記載される方法によって産生される薬学的組成物を含む、対象における腫瘍性疾患の予防、治療、または寛解のために用いられるキット。
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US8513417B2 (en) | 2007-01-31 | 2013-08-20 | Kyushu University, National University Corporation | Method for synthesis of nitroxyl radical |
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JP2007530435A (ja) | 2007-11-01 |
WO2004106383A1 (en) | 2004-12-09 |
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EP1629013A1 (en) | 2006-03-01 |
RU2005137325A (ru) | 2006-09-10 |
US7919089B2 (en) | 2011-04-05 |
AU2004242847A1 (en) | 2004-12-09 |
BRPI0410338A (pt) | 2006-05-30 |
CA2522894C (en) | 2013-06-25 |
CA2522894A1 (en) | 2004-12-09 |
US20110256137A1 (en) | 2011-10-20 |
EP1629013B1 (en) | 2018-01-24 |
KR20060015602A (ko) | 2006-02-17 |
AU2004242847B2 (en) | 2011-06-09 |
US20070081993A1 (en) | 2007-04-12 |
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