JP2017536829A - Cd3および腫瘍抗原に結合するヘテロ二量体抗体 - Google Patents
Cd3および腫瘍抗原に結合するヘテロ二量体抗体 Download PDFInfo
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Abstract
Description
本願は、35U.S.C.§119(e)の下で、2014年11月26日に出願された米国仮特許出願第62/085,117号明細書、2014年11月26日に出願された米国仮特許出願第62/084,908号明細書、2014年11月26日に出願された米国仮特許出願第62/085,027号明細書、2014年11月26日に出願された米国仮特許出願第62/085,106号明細書、2015年5月8日に出願された米国仮特許出願第62/159,111号明細書、2015年11月4日に出願された米国仮特許出願第62/251,005号明細書および2015年11月4日に出願された米国仮特許出願第62/250,971号明細書(これらのすべては、その中の図、説明文および特許請求の範囲に関する特定の参照とともに、その全体が参照により本明細書中に明示的に援用される)に対する優先権を主張する。
本願がより十分に理解され得るように、幾つかの定義が以下に示される。かかる定義は、文法的均等物を包含することが意図される。
CD3および腫瘍抗原標的に共会合する二重特異性抗体は、T細胞が標的化腫瘍細胞を攻撃し、溶解するように再誘導するように設計され、用いられている。例として、CD3および腫瘍抗原に一価的に会合する、BiTEおよびDART形式が挙げられる。CD3を標的化する手法がかなり有望であることを示している一方、かかる治療法に共通の副作用は、有毒なサイトカイン放出症候群をもたらすことが多い、それに関連するサイトカイン産生である。二重特異性抗体の抗CD3結合ドメインがすべてのT細胞に会合することから、高いサイトカイン産生性のCD4 T細胞サブセットが動員される。さらに、CD4 T細胞サブセットは、動員および増殖が潜在的には免疫抑制をもたらし、長期腫瘍抑制に対する負の影響を有し得るような制御性T細胞を含む。さらに、これらの形式は、Fcドメインを有することなく、患者における極めて短い血清半減期を示す。
本発明は、2つの異なる抗原、例えば、CD3および標的腫瘍抗原、例えばCD20、CD38およびCD123に結合し、また一般に治療抗体である二重特異性抗体の作製に関する。下記に考察されるように、用語「抗体」が一般に用いられる。本発明において用途が見出される抗体は、従来の抗体、ならびに本明細書に記載の抗体誘導体、断片および模倣物を含む、本明細書に記載のような幾つかの形式を取り得る。
一部の実施形態では、抗体は、異なる種からの混合体、例えばキメラ抗体および/またはヒト化抗体であり得る。一般に、「キメラ抗体」および「ヒト化抗体」の両方は、2つ以上の種に由来する領域を組み合わせた抗体を指す。例えば、「キメラ抗体」は、従来、マウス(または場合によりラット)由来の可変領域と、ヒト由来の定常領域とを含む。「ヒト化抗体」は、一般に、可変ドメインフレームワーク領域を、ヒト抗体に見出される配列と交換された非ヒト抗体を指す。一般に、ヒト化抗体では、CDRを除く全抗体が、ヒト由来のポリヌクレオチドによってコードされるか、またはそのCDR内を除いて、かかる抗体と同一である。非ヒト生物に由来する核酸によって一部または全部がコードされるCDRが、ヒト抗体可変領域のβシートフレームワーク内に移植されて抗体が作出され、移植されたCDRによってその特異性が決定される。かかる抗体の作出は、例えば、国際公開第92/11018号、Jones,1986,Nature 321:522−525、Verhoeyen et al、1988,Science 239:1534−1536(すべてが全体として参照により援用される)に記載されている。最初の移植構築物において失われた親和性を回復するため、選択されたアクセプターフレームワーク残基の対応するドナー残基への「逆変異」が必要であることが多い(米国特許第5530101号明細書、米国特許第5585089号明細書、米国特許第5693761号明細書、米国特許第5693762号明細書、米国特許第6180370号明細書、米国特許第5859205号明細書、米国特許第5821337号明細書、米国特許第6054297号明細書、米国特許第6407213号(すべてが全体として参照により援用される))。ヒト化抗体はまた、最適には、免疫グロブリンの定常領域(典型的にはヒト免疫グロブリンの定常領域)の少なくとも一部を含むことになり、したがって、典型的にはヒトFc領域を含むことになる。ヒト化抗体はまた、遺伝子操作された免疫系を有するマウスを用いて作製され得る。Roque et al.,2004,Biotechnol.Prog.20:639−654(全体として参照により援用される)。非ヒト抗体をヒト化および再形成するための様々な技術および方法が当該技術分野で周知である(Tsurushita&Vasquez,2004,Humanization of Monoclonal Antibodies,Molecular Biology of B Cells,533−545,Elsevier Science(USA)、およびその中に引用される参考文献(すべてが全体として参照により援用される)を参照)。ヒト化方法は、限定はされないが、Jones et al.,1986,Nature 321:522−525;Riechmann et al.,1988;Nature 332:323−329;Verhoeyen et al.,1988,Science,239:1534−1536;Queen et al.,1989,Proc Natl Acad Sci,USA 86:10029−33;He et al.,1998,J.Immunol.160:1029−1035;Carter et al.,1992,Proc Natl Acad Sci USA 89:4285−9,Presta et al.,1997,Cancer Res.57(20):4593−9;Gorman et al.,1991,Proc.Natl.Acad.Sci.USA88:4181−4185;O’Connor et al.,1998,Protein Eng 11:321−8(すべてが全体として参照により援用される)に記載される方法を含む。ヒト化方法、または非ヒト抗体可変領域の免疫原性を低下させる他の方法は、Roguska et al.,1994,Proc.Natl.Acad.Sci.USA 91:969−973(全体として参照により援用される)に記載のような表面再処理方法を含んでもよい。一実施形態では、親抗体は、当該技術分野で公知のように親和性成熟されている。ヒト化および親和性成熟には、例えば米国特許出願第11/004,590号明細書に記載されるような構造に基づく方法を用いてもよい。抗体可変領域をヒト化および/または親和性成熟させるため、限定はされないが、Wu et al.,1999,J.Mol.Biol.294:151−162;Baca et al.,1997,J.Biol.Chem.272(16):10678−10684;Rosok et al.,1996,J.Biol.Chem.271(37):22611−22618;Rader et al.,1998,Proc.Natl.Acad.Sci.USA 95:8910−8915;Krauss et al.,2003,Protein Engineering 16(10):753−759(すべてが全体として参照により援用される)に記載される方法を含む、選択に基づく方法を用いてもよい。限定はされないが、米国特許出願第09/810,510号明細書;Tan et al.,2002,J.Immunol.169:1119−1125;De Pascalis et al.,2002,J.Immunol.169:3076−3084(すべてが全体として参照により援用される)に記載される方法を含む、他のヒト化方法は、CDRの一部分のみの移植を伴う場合がある。
したがって、一部の実施形態では、本発明は、ヘテロ二量体Fcドメインおよびヘテロ二量体抗体を形成するために自己組織化することになる、2つの異なる重鎖変異体のFc配列の使用に依存するヘテロ二量体抗体を提供する。
本発明は、ヘテロ二量体の形成および/またはホモ二量体からの精製を可能にするヘテロ二量体変異体を利用する、種々の形式でのヘテロ二量体抗体を含むヘテロ二量体タンパク質を提供する。
一部の実施形態では、ヘテロ二量体の形成は、立体変異体の付加により促進され得る。すなわち、各重鎖内のアミノ酸を改変することにより、異なる重鎖が会合し、同じFcアミノ酸配列を有するホモ二量体を形成するよりもヘテロ二量体構造を形成する可能性が高い。好適な立体変異体は図29に含まれる。
一般に、当業者によって理解されるように、pI変異体には2つの一般的なカテゴリー、すなわちタンパク質のpIを増加させるもの(塩基性変化)およびタンパク質のpIを低下させるもの(酸性変化)がある。本明細書に記載のように、これらの変異体のあらゆる組み合わせを設けることができ、一方の単量体は、野生型、または野生型と有意に異なるpIを呈しない変異体であってもよく、また他方は、より塩基性またはより酸性のいずれかであり得る。あるいは、各単量体は変化を受け、より塩基性になるものと、より酸性になるものがある。
抗体に基づくヘテロ二量体の場合、例えば少なくとも1つの単量体が重鎖ドメインに加えて軽鎖を含む場合、pI変異体はまた、軽鎖内で作製され得る。軽鎖のpIを低下させるためのアミノ酸置換として、限定はされないが、K126E、K126Q、K145E、K145Q、N152D、S156E、K169E、S202E、K207Eおよび軽鎖のC末端でのペプチドDEDEの付加が挙げられる。定常λ軽鎖に基づくこのカテゴリーにおける変化は、R108Q、Q124E、K126Q、N138D、K145TおよびQ199Eでの1つ以上の置換を含む。さらに、軽鎖のpIを増加させることもできる。
さらに、本発明の多くの実施形態は、あるIgGアイソタイプから別のIgGアイソタイプへの、特定の位置でのpIアミノ酸の「組み込み」に依存しており、そうすることで、不要な免疫原性が変異体に導入される可能性を減少させるかまたは排除する。これらの幾つかが米国特許出願公開第2014/0370013号明細書(本明細書で参照により援用される)の図21に示される。すなわち、高いエフェクター機能を含む様々な理由のために、IgG1は、治療抗体のための一般的なアイソタイプである。しかし、IgG1の重定常領域は、IgG2の重定常領域よりも高いpIを有する(8.10対7.31)。IgG1骨格の特定の位置にIgG2残基を導入することにより、結果として得られる単量体のpIが低下し(または増加し)、加えて血清半減期の延長を呈する。例えば、IgG1は137位にグリシン(pI5.97)を有し、IgG2はグルタミン酸(pI3.22)を有する。グルタミン酸を組み込むことは、結果として得られるタンパク質のpIに影響を与えることになる。後述するように、幾つかのアミノ酸置換が一般に、変異体抗体のpIに著しい影響を与えることが要求される。しかし、後に考察されるように、たとえIgG2分子における変化であっても血清半減期の延長を可能にすることは注目されるべきである。
各単量体のpIは、変異体重鎖定常ドメインのpIと、変異体重鎖定常ドメインおよび融合パートナーを含む全単量体のpIとに依存し得る。したがって、一部の実施形態では、pIの変化は、米国特許出願公開第2014/0370013号明細書の図19におけるチャートを用いて、変異体重鎖定常ドメインに基づいて計算される。本明細書で考察されるように、いずれの単量体を改変するかは一般に、Fvおよびスキャフォールド領域に特有のpIによって決定される。あるいは、各単量体のpIを比較することもできる。
pI変異体が単量体のpIを低下させる場合、それらはインビボでの血清保持を改善するというさらなる利益を有し得る。
pIアミノ酸変異体に加えて、限定はされないが、1つ以上のFcγR受容体への結合性の改変、FcRn受容体への結合性の改変などを含む、種々の理由から作製され得る有用なFcアミノ酸修飾が幾つか存在する。
したがって、FcγR受容体の1つ以上への結合を改変するために作製され得る有用なFc置換が幾つか存在する。結合の増強および結合の低下をもたらす置換は有用であり得る。例えば、Fc RIIIaへの結合の増強が一般に、ADCC(抗体依存性細胞傷害;FcγRを発現する非特異的な細胞傷害性細胞が標的細胞上の結合抗体を認識し、続いて標的細胞の溶解を引き起こす細胞媒介性反応)の増加をもたらすことは知られている。同様に、FcγRIIb(阻害性受容体)への結合の低下は、一部の環境下で同様に有利であり得る。本発明において用途が見出されるアミノ酸置換は、米国特許出願第11/124,620号明細書(特に図41)、米国特許出願第11/174,287号明細書、米国特許出願第11/396,495号明細書、米国特許出願第11/538,406号明細書(これらのすべては、その全体において、また特にその中で開示された変異体について、参照により本明細書中に明示的に援用される)において列挙されるものを含む。用途が見出される特定の変異体として、限定はされないが、236A、239D、239E、332E、332D、239D/332E、267D、267E、328F、267E/328F、236A/332E、239D/332E/330Y、239D、332E/330L、243A、243L、264A、264Vおよび299Tが挙げられる。
同様に、機能的変異体の別のカテゴリーが、「FcγR切断変異体」または「Fcノックアウト(FcKOまたはKO)」変異体である。これらの実施形態では、一部の治療用途において、追加的な作用機序を回避するため、1つ以上もしくはすべてのFcγ受容体(例えば、FcγR1、FcγRIIa、FcγRIIb、FcγRIIIaなど)へのFcドメインの正常な結合を低下させるかまたは除去することが望ましい。すなわち、例えば多数の実施形態では、特にCD3に一価的に結合する二重特異性抗体の使用において、ADCC活性を除去するかまたは有意に低下させるため、FcγRIIIaの結合を切断することが一般に望ましく、ここでFcドメインの1つは1つ以上のFcγ受容体切断変異体を含む。これらの切断変異体は図31に示され、各々は独立的かつ任意選択的に含められ得るかまたは除外され得、好ましい態様では、G236R/L328R、E233P/L234V/L235A/G236del/S239K、E233P/L234V/L235A/G236del/S267K、E233P/L234V/L235A/G236del/S239K/A327G、E233P/L234V/L235A/G236del/S267K/A327GおよびE233P/L234V/L235A/G236delからなる群から選択される切断変異体が用いられる。本明細書で参照される切断変異体がFcγR結合を切断するが、一般にFcRn結合を切断しないことは注目されるべきである。
当業者によって理解されるように、列挙された(歪曲および/またはpI変異体を含む)ヘテロ二量体化変異体のすべては、それらの「鎖状態」または「単量体区画」を保持する限り、任意の方法で任意選択的かつ独立的に組み合わせることができる。さらに、これらの変異体のすべては、ヘテロ二量体化形式のいずれかに組み合わせることができる。
当業者によって理解され、後により十分に考察されるように、本発明のヘテロ二量体融合タンパク質は、一般に図1で示されるように、多種多様な立体配置を取り得る。一部の図面は「シングルエンド」立体配置を表し、ここでは、分子の一方の「アーム」に対して1種の特異性が存在し、他方の「アーム」に対して異なる特異性が存在する。他の図面は「デュアルエンド」立体配置を表し、ここでは分子の「最上部」に少なくとも1種の特異性が存在し、分子の「底部」に1つ以上の異なる特異性が存在する。したがって、本発明は、異なる第1の抗原および第2の抗原と共会合する新規な免疫グロブリン組成物を対象とする。
本発明に特定用途が見出される1つのヘテロ二量体スキャフォールドは、図1A、AおよびBに示されるような「三重F」または「ボトルオープナー」スキャフォールド形式である。この実施形態では、抗体の一方の重鎖は一本鎖Fv(後に定義されるような「scFv」)を有し、他方の重鎖は可変重鎖および軽鎖を含む「レギュラーな」FAb形式である。この構造は、ボトルオープナーとのおおまかな視覚的類似性があることから、本明細書で「三重F」形式(scFv−FAb−Fc)または「ボトルオープナー」形式と称される場合がある(図1を参照)。2つの鎖は、後により十分に説明されるように、ヘテロ二量体抗体の形成を促進する定常領域(例えば、Fcドメイン、CH1ドメインおよび/またはヒンジ領域)におけるアミノ酸変異体の使用により結合される。
本発明に特定用途が見出される1つのヘテロ二量体スキャフォールドは、図1に示されるmAb−Fv形式である。この実施形態では、同形式は、「余分な」可変重鎖ドメインの一方の単量体へのC末端付着および「余分な」可変軽鎖ドメインの他方の単量体へのC末端付着の使用に依存することにより、第3の抗原結合ドメインを形成し、ここで2つの単量体のFab部分はTTAに結合し、また「余分な」scFvドメインはCD3に結合する。
本発明に特定用途が見出される1つのヘテロ二量体スキャフォールドは、図1に示されるmAb−Fv形式である。この実施形態では、同形式は、単量体の一方へのscFvのC末端付着の使用に依存することにより、第3の抗原結合ドメインを形成し、ここで2つの単量体のFab部分はTTAに結合し、また「余分な」scFvドメインはCD3に結合する。したがって、第1の単量体は、scFv可変軽鎖ドメイン、scFvリンカーおよびscFv可変重鎖ドメインを含むC末端に共有結合されたscFvを有する、第1の重鎖(可変重鎖ドメインおよび定常ドメインを含む)を含む。この実施形態では、TTAに結合する2つの同一のFabを形成するため、重鎖と会合する、可変軽鎖ドメインおよび定常軽鎖ドメインを含む共通軽鎖がさらに用いられる。本明細書中の実施形態の多くに関して、これらの構築物は、本明細書で所望され、記載されるように、歪曲変異体、pI変異体、切断変異体、追加的なFc変異体などを含む。
本発明に特定用途が見出される1つのヘテロ二量体スキャフォールドは、図1に示されるCentral−scFv形式である。この実施形態では、同形式は、挿入されたscFvドメインの使用に依存することにより、第3の抗原結合ドメインを形成し、ここで2つの単量体のFab部分はTTAに結合し、また「余分な」scFvドメインはCD3に結合する。scFvドメインがFcドメインと単量体の一方のCH1−Fv領域との間に挿入されることで、第3の抗原結合ドメインが提供される。
本発明に特定用途が見出される1つのヘテロ二量体スキャフォールドは、図1に示されるCentral−Fv形式である。この実施形態では、同形式は、挿入されたscFvドメインの使用に依存することにより、第3の抗原結合ドメインを形成し、ここで2つの単量体のFab部分はTTAに結合し、また「余分な」scFvドメインはCD3に結合する。scFvドメインは、Fcドメインと単量体のCH1−Fv領域との間に挿入されることで、第3の抗原結合ドメインが提供され、ここで各単量体はscFvの成分を有する(例えば、一方の単量体は可変重鎖ドメインを含み、他方は可変軽鎖ドメインを含む)。
本発明に特定用途が見出される1つのヘテロ二量体スキャフォールドは、図1に示される単一アームCentral−scFv形式である。この実施形態では、一方の単量体がFcドメインのみを含む一方、他方の単量体では挿入されたscFvドメインが用いられることにより、第2の抗原結合ドメインを形成する。この形式では、Fab部分がTTAに結合しかつscFvがCD3に結合するかまたはその逆のいずれかである。scFvドメインは、Fcドメインと単量体の一方のCH1−Fv領域との間に挿入される。
本発明はまた、当該技術分野で公知でありかつ図1に示されるような二重scFv形式を提供する。
本発明の二重特異性抗体は、2つの異なる抗原結合ドメイン、すなわちCD3に結合するもの(一般に一価的)、および標的腫瘍抗原に結合するもの(本明細書中で「TTA」と称される場合がある)を有する。好適な標的腫瘍抗原として、限定はされないが、CD20、CD38、CD123;ROR1、ROR2、BCMA;PSMA;SSTR2;SSTR5、CD19、FLT3、CD33、PSCA、ADAM17、CEA、Her2、EGFR、EGFR−vIII、CD30、FOLR1、GD−2、CA−IX、Trop−2、CD70、CD38、メソセリン、EphA2、CD22、CD79b、GPNMB、CD56、CD138、CD52、CD74、CD30、CD123、RON、ERBB2、およびEGFRが挙げられる。
TNFRSF13C(BAFF R)、TNFRSF14(HVEM ATAR、HveA、LIGHT R、TR2)、TNFRSF16(NGFR p75NTR)、TNFRSF17(BCMA)、TNFRSF18(GITR AITR)、TNFRSF19(TROY TAJ、TRADE)、TNFRSF19L(RELT)、TNFRSF1A(TNF RI CD120a、p55−60)、TNFRSF1B(TNF RII CD120b、p75−80)、TNFRSF26(TNFRH3)、TNFRSF3(LTbR TNF RIII、TNFCR)、TNFRSF4(OX40 ACT35、TXGP1 R)、TNFRSF5(CD40 p50)、TNFRSF6(Fas Apo−1、APT1、CD95)、TNFRSF6B(DcR3 M68、TR6)、TNFRSF7(CD27)、TNFRSF8(CD30)、TNFRSF9(4−1BB CD137、ILA)、TNFRSF21(DR6)、TNFRSF22(DcTRAIL R2 TNFRH2)、TNFRST23(DcTRAIL R1TNFRH1)、TNFRSF25(DR3 Apo−3、LARD、TR−3、TRAMP、WSL−1)、TNFSF10(TRAIL Apo−2リガンド、TL2)、TNFSF11(TRANCE/RANKリガンドODF、OPGリガンド)、TNFSF12(TWEAK Apo−3リガンド、DR3リガンド)、TNFSF13(APRIL TALL2)、TNFSF13B(BAFF BLYS、TALL1、THANK、TNFSF20)、TNFSF14(LIGHT HVEMリガンド、LTg)、TNFSF15(TL1A/VEGI)、TNFSF18(GITRリガンドAITRリガンド、TL6)、TNFSF1A(TNF−aコネクチン、DIF、TNFSF2)、TNFSF1B(TNF−b LTa、TNFSF1)、TNFSF3(LTb TNFC、p33)、TNFSF4(OX40リガンドgp34、TXGP1)、TNFSF5(CD40リガンド CD154、gp39、HIGM1、IMD3、TRAP)、TNFSF6(FasリガンドApo−1リガンド、APT1リガンド)、TNFSF7(CD27リガンド CD70)、TNFSF8(CD30リガンド CD153)、TNFSF9(4−1BBリガンド CD137リガンド)、TP−1、t−PA、Tpo、TRAIL、TRAIL R、TRAIL−R1、TRAIL−R2、TRANCE、トランスフェリング受容体、TRF、Trk、TROP−2、TSG、TSLP、腫瘍関連抗原CA125、腫瘍関連抗原発現ルイスY関連炭水化物、TWEAK、TXB2、Ung、uPAR、uPAR−1、ウロキナーゼ、VCAM、VCAM−1、VECAD、VE−カドヘリン、VE−カドヘリン−2、VEFGR−1(flt−1)、VEGF、VEGFR、VEGFR−3(flt−4)、VEGI、VIM、ウイルス抗原、VLA、VLA−1、VLA−4、VNRインテグリン、ヴォン・ヴィレブランド因子、WIF−1、WNT1、WNT2、WNT2B/13、WNT3、WNT3A、WNT4、WNT5A、WNT5B、WNT6、WNT7A、WNT7B、WNT8A、WNT8B、WNT9A、WNT9A、WNT9B、WNT10A、WNT10B、WNT11、WNT16、XCL1、XCL2、XCR1、XCR1、XEDAR、XIAP、XPD、ならびにホルモンおよび成長因子に対する受容体に属するタンパク質、サブユニット、ドメイン、モチーフ、および/またはエピトープを含む実質的に任意の抗原は、本明細書中の免疫グロブリンによって標的化してもよい。
本発明は、本発明の二重特異性抗体をコードする核酸組成物をさらに提供する。当業者によって理解されるように、核酸組成物は、ヘテロ二量体タンパク質の形式およびスキャフォールドに依存することになる。したがって、例えば形式が、例えば三重F形式(例えば、FcドメインおよびscFvを含む第1のアミノ酸単量体、重鎖および軽鎖を含む第2のアミノ酸単量体)として3つのアミノ酸配列を必要とする場合、発現のため、3つの核酸配列が1つ以上の発現ベクターに組み込まれ得る。同様に、一部の形式(例えば、図1に開示されるような二重scFv形式)では2つの核酸のみが必要であり、さらにそれらは1つもしくは2つの発現ベクターに挿入され得る。
本発明の組成物は、作製されると、幾つかの適用において用途が見出される。CD20、CD38およびCD123はすべて、多数の造血器腫瘍および様々な造血器腫瘍由来の細胞株において制御されず、そのため、本発明のヘテロ二量体抗体は、がん、例えば限定はされないがすべてのB細胞リンパ腫および白血病、例えば限定はされないが、非ホジキンリンパ腫(NHL)、バーキットリンパ腫(BL)、多発性骨髄腫(MM)、B慢性リンパ性白血病(B−CLL)、BおよびT急性リンパ性白血病(ALL)、T細胞リンパ腫(TCL)、急性骨髄性白血病(AML)、ヘアリー細胞白血病(HCL)、ホジキンリンパ腫(HL)、慢性リンパ性白血病(CLL)、非ホジキンリンパ腫、および慢性骨髄性白血病(CML)の治療に用途が見出される。
本発明に従って用いられる抗体の製剤は、貯蔵のため、凍結乾燥製剤または水溶液の形態で、所望される純度を有する抗体を任意選択的な薬学的に許容できる担体、賦形剤もしくは安定剤と混合することによって調製される(Remington’s Pharmaceutical Sciences 16th edition,Osol,A.Ed.[1980])。許容できる担体、賦形剤、または安定剤は、用いられる用量および濃度でレシピエントに対して非毒性であり、リン酸塩、クエン酸塩、および他の有機酸などの緩衝液;アスコルビン酸およびメチオニンを含む抗酸化剤;保存料(例えば、オクタデシルジメチルベンジル塩化アンモニウム;塩化ヘキサメトニウム;塩化ベンザルコニウム、塩化ベンゼトニウム;フェノール、ブチルもしくはベンジルアルコール;メチルもしくはプロピルパラベンなどのアルキルパラベン;カテコール;レソルシノール;シクロヘキサノール;3−ペンタノール;およびm−クレゾール);低分子量(約10残基未満)ポリペプチド;タンパク質、例えば血清アルブミン、ゼラチン、または免疫グロブリン;ポリビニルピロリドンなどの親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、もしくはリジンなどのアミノ酸;単糖、二糖、および他の糖類、例えばグルコース、マンノース、もしくはデキストリン;EDTAなどのキレート剤;スクロース、マンニトール、トレハロースもしくはソルビトールなどの糖類;ナトリウムなどの塩形成対イオン;金属錯体(例えば、Zn−タンパク質錯体);および/またはツイーン(商標)、プルロニック(商標)もしくはポリエチレングリコール(PEG)などの非イオン性界面活性剤を含む。
本発明の抗体および化学療法剤は、公知の方法、例えばボーラスとしての静脈内投与に従い、または長期間にわたる持続注入により、筋肉内、腹腔内、大脳脊髄内、皮下、関節内、滑液嚢内、くも膜下腔内、経口、局所、または吸入経路により、被験者に投与される。抗体の静脈内または皮下投与が好ましい。
本発明の方法では、疾患もしくは状態に対して正の治療応答を提供するような治療法が用いられる。「正の治療応答」は、疾患もしくは状態における改善、および/または疾患もしくは状態に関連した症状における改善が意図される。例えば、正の治療応答であれば、疾患における以下の改善、すなわち、(1)腫瘍性細胞数の減少;(2)腫瘍性細胞死の増加;(3)腫瘍性細胞生存の阻害;(5)腫瘍成長の阻害(すなわち、ある程度の緩徐化、好ましくは停止);(6)患者生存率の増加;および(7)疾患もしくは状態に関連した1つ以上の症状からの部分的緩和のうちの1つ以上を指すことになる。
実施例1:代替形式
二重特異体の産生
抗CD38×抗CD3二重特異体の模式図を図1に示す。抗CD38×抗CD3二重特異体の代替形式としてのアミノ酸配列を図39〜図43に列挙する。二重特異性の発現にとって必要とされる3本の鎖をコードするDNAを、遺伝子合成(Blue Heron Biotechnology,Bothell,Wash.)により作製し、標準の分子生物学技術を用いて発現ベクターpTT5にサブクローニングした。部位特異的変異誘発(QuikChange,Stratagene,Cedar Creek,Tex.)または追加的な遺伝子合成およびサブクローニングのいずれかを用いて置換を導入した。発現のため、HEK293E細胞にDNAを遺伝子導入し、得られたタンパク質を、プロテインA親和性(GE Healthcare)および陽イオン交換クロマトグラフィーを用いて上清から精製した。プロテインAアフィニティー精製後の収率を図35に示す。陽イオン交換クロマトグラフィー精製を、50mM MESの洗浄/平衡化緩衝液(pH6.0)および50mM MESの溶出緩衝液(pH6.0+1M NaCl直線勾配)を有するHiTrap SP HPカラム(GE Healthcare)を用いて実施した(クロマトグラムについては図36を参照)。
抗CD38×抗CD3二重特異体を、CD38+RPMI8266骨髄腫細胞株の再誘導されたT細胞細胞傷害性(RTCC)についてインビトロで特徴付けた。10kのRPMI8266細胞を、500kのヒトPBMCとともに24時間インキュベートした。RTCCを、図示のようにLDH蛍光により測定した(図37を参照)。
再誘導されたT細胞細胞傷害性
抗CD38×抗CD3 Fab−scFv−Fc二重特異体を、CD38+RPMI8266骨髄腫細胞株の再誘導されたT細胞細胞傷害性(RTCC)についてインビトロで特徴付けた。40kのRPMI8266細胞を、400kのヒトPBMCとともに96時間インキュベートした。RTCCを、図示のようにフローサイトメトリーにより測定した(図44を参照)。CD69、Ki−67、およびPI−9のCD4+およびCD8+T細胞発現についてもフローサイトメトリーにより特徴付けたが、それを図45に示す。
−23日目、NOD重症複合免疫不全γ(NSG)マウス5匹からなる4つの群の各々に、5×106のRPMI8226TrS腫瘍細胞(多発性骨髄腫、ルシフェラーゼを発現する)を静脈内尾静脈注射により移植した。0日目、マウスの腹腔内に10×106のヒトPBMCを移植した。0日目のPBMCの移植後、被験物を毎週(0、7日目)、図4に表示される用量レベルで腹腔内注射により投与する。試験設計を図46にさらにまとめる。腫瘍成長を、インビボイメージングシステム(IVIS(登録商標))を用いて全フラックス/マウスを測定することにより監視した。XmAb13551およびXmAb15426の両方は、実質的な抗腫瘍効果を示した(図47および図48を参照)。
カニクイザルに抗CD38×抗CD3二重特異体を単回用量で与えた。抗RSV×抗CD3二重特異性対照も含めた。用量レベルは、(3つの独立試験において)20μg/kgのXmAb13551(n=2)、0.5mg/kgのXmAb15426(n=3)、3mg/kgのXmAb14702(n=3)、または3mg/kgのXmAb13245(抗RSV×抗CD3対照、n=3)であった。抗CD38×抗CD3二重特異体は、末梢血中のCD38+細胞を迅速に枯渇させた(図49を参照)。抗CD38×抗CD3二重特異体は、CD69の発現による測定の通り、T細胞活性化をもたらした(図50を参照)。IL−6の血清レベルも測定した(図51を参照)。XmAb13551と比べて、XmAb15426がCD38+細胞の枯渇の持続時間延長とT細胞活性化およびIL−6産生のレベル低下とを有したことは注目すべきである。
Claims (72)
- a)第1の単量体であって、
i)第1の重鎖であって、
1)第1の可変重鎖ドメイン;
2)第1のFcドメインを含む第1の定常重鎖;ならびに
3)scFv可変軽鎖ドメイン、scFvリンカーおよびscFv可変重鎖ドメインを含み、ドメインリンカーを用いて前記FcドメインのC末端に共有結合されたscFv、
を含む第1の重鎖
含む第1の単量体と;
b)第2の可変重鎖ドメイン、および、第2のFcドメインを含む第2の定常重鎖、を含む、第2の重鎖を含む第2の単量体と;
c)可変軽鎖ドメインおよび定常軽鎖ドメインを含む共通軽鎖と
を含み、
前記第1および前記第2のFcドメインは、S364K/E357Q:L368D/K370S;L368D/K370S:S364K;L368E/K370S:S364K;T411T/E360E/Q362E:D401K;L368D/K370S:S364K/E357LおよびK370S:S364K/E357Qからなる群から選択されるアミノ酸置換のセットを有し、
前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインは第1の標的腫瘍抗原(TTA)に結合し、
前記第2の可変重鎖ドメインおよび前記可変軽鎖ドメインは前記第1のTTAに結合し、かつ
前記scFvはヒトCD3(配列番号XX)に結合する、
ヘテロ二量体抗体。 - 前記scFvが、配列番号XX(scFv13551)、配列番号XX(scFv15426)、配列番号XX(scFv13423)および配列番号XX(scFv14702)からなる群から選択されるポリペプチド配列を有する、請求項1に記載のヘテロ二量体抗体。
- 前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインが、CD19、CD20およびCD123からなる群から選択されるTTAに結合する、請求項1または2に記載のヘテロ二量体抗体。
- a)第1の単量体であって、
i)第1の重鎖であって、
1)第1の可変重鎖ドメイン;
2)第1のFcドメインを含む第1の定常重鎖ドメイン;および
3)ドメインリンカーを用いて前記第1のFcドメインのC末端に共有結合された第1の可変軽鎖ドメイン
を含む第1の重鎖
を含む第1の単量体と;
b)第2の単量体であって、
i)第2の可変重鎖ドメイン;
ii)第2のFcドメインを含む第2の定常重鎖ドメイン;および
iii)前記第2の可変重鎖ドメインがドメインリンカーを用いて前記第2のFcドメインのC末端に共有結合されている、第3の可変重鎖ドメイン
を含む第2の単量体と;
c)可変軽鎖ドメインおよび定常軽鎖ドメインを含む共通軽鎖と
を含み、
前記第1および前記第2のFcドメインは、S364K/E357Q:L368D/K370S;L368D/K370S:S364K;L368E/K370S:S364K;T411T/E360E/Q362E:D401K;L368D/K370S:S364K/E357LおよびK370S:S364K/E357Qからなる群から選択されるアミノ酸置換のセットを有し、
前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインは第1のTTAに結合し、
前記第2の可変重鎖ドメインおよび前記可変軽鎖ドメインは前記TTAに結合し、かつ
前記第2の可変軽鎖ドメインおよび前記第3の可変重鎖ドメインはCD3に結合する、ヘテロ二量体抗体。 - 前記scFvが、配列番号XX(scFv13551)、配列番号XX(scFv15426)、配列番号XX(scFv13423)および配列番号XX(scFv14702)からなる群から選択されるポリペプチド配列を有する、請求項4に記載のヘテロ二量体抗体。
- 前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインが、CD19、CD20およびCD123からなる群から選択されるTTAに結合する、請求項4または5に記載のヘテロ二量体抗体。
- a)第1の単量体であって、
i)第1の重鎖であって、
1)第1の可変重鎖ドメイン;
2)第1のCH1ドメインおよび第1のFcドメインを含む第1の定常重鎖;ならびに
3)scFv可変軽鎖ドメイン、scFvリンカーおよびscFv可変重鎖ドメインを含み、ドメインリンカーを用いて前記CH1ドメインのC末端と前記第1のFcドメインのN末端との間で共有結合されたscFv
を含む第1の重鎖
を含む第1の単量体と;
b)第2の可変重鎖ドメイン、および第2のFcドメインを含む第2の定常重鎖を含む、第2の重鎖を含む第2の単量体と;
c)可変軽鎖ドメインおよび定常軽鎖ドメインを含む共通軽鎖と
を含み、
前記第1および前記第2のFcドメインは、S364K/E357Q:L368D/K370S;L368D/K370S:S364K;L368E/K370S:S364K;T411T/E360E/Q362E:D401K;L368D/K370S:S364K/E357LおよびK370S:S364K/E357Qからなる群から選択されるアミノ酸置換のセットを有し、
前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインは第1のTTAに結合し、
前記第2の可変重鎖ドメインおよび前記可変軽鎖ドメインは前記TTAに結合し、かつ
前記scFvはヒトCD3に結合する、
ヘテロ二量体抗体。 - 前記scFvが、配列番号XX(scFv13551)、配列番号XX(scFv15426)、配列番号XX(scFv13423)および配列番号XX(scFv14702)からなる群から選択されるポリペプチド配列を有する、請求項7に記載のヘテロ二量体抗体。
- 前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインが、CD19、CD20およびCD123からなる群から選択されるTTAに結合する、請求項7または8に記載のヘテロ二量体抗体。
- a)第1の単量体であって、
i)第1の重鎖であって、
1)第1の可変重鎖ドメイン;
2)第1のFcドメインを含む第1の定常重鎖ドメイン;および
3)前記第2の可変軽鎖ドメインがドメインリンカーを用いて前記第1の定常重鎖ドメインのCH1ドメインのC末端と前記第1のFcドメインのN末端との間で共有結合されている、第1の可変軽鎖ドメイン
を含む第1の重鎖
を含む第1の単量体と;
b)第2の単量体であって、
i)第2の可変重鎖ドメイン;
ii)第2のFcドメインを含む第2の定常重鎖ドメイン;および
iii)前記第2の可変重鎖ドメインがドメインリンカーを用いて前記第2のFcドメインのC末端に共有結合されている、第3の可変重鎖ドメイン
を含む第2の単量体と;
c)可変軽鎖ドメインおよび定常軽鎖ドメインを含む共通軽鎖と
を含み、
前記第1および前記第2のFcドメインは、S364K/E357Q:L368D/K370S;L368D/K370S:S364K;L368E/K370S:S364K;T411T/E360E/Q362E:D401K;L368D/K370S:S364K/E357LおよびK370S:S364K/E357Qからなる群から選択されるアミノ酸置換のセットを有し、
前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインは第1のTTAに結合し、
前記第2の可変重鎖ドメインおよび前記可変軽鎖ドメインは前記TTAに結合し、かつ
前記第2の可変軽鎖ドメインおよび前記第3の可変重鎖ドメインはヒトCD3に結合する、
ヘテロ二量体抗体。 - 前記scFvが、配列番号XX(scFv13551)、配列番号XX(scFv15426)、配列番号XX(scFv13423)および配列番号XX(scFv14702)からなる群から選択されるポリペプチド配列を有する、請求項10に記載のヘテロ二量体抗体。
- 前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインが、CD19、CD20およびCD123からなる群から選択されるTTAに結合する、請求項10または11に記載のヘテロ二量体抗体。
- a)第1の単量体であって、
i)第1の重鎖であって、
1)第1の可変重鎖ドメイン;
2)第1のCH1ドメインおよび第1のFcドメインを含む第1の定常重鎖;ならびに
3)scFv可変軽鎖ドメイン、scFvリンカーおよびscFv可変重鎖ドメインを含み、ドメインリンカーを用いて前記CH1ドメインのC末端と前記第1のFcドメインのN末端との間で共有結合されたscFv
を含む第1の重鎖
を含む第1の単量体と;
b)第2のFcドメインを含む第2の単量体と;
c)可変軽鎖ドメインおよび定常軽鎖ドメインを含む軽鎖と
を含み、
前記第1および前記第2のFcドメインは、S364K/E357Q:L368D/K370S;L368D/K370S:S364K;L368E/K370S:S364K;T411T/E360E/Q362E:D401K;L368D/K370S:S364K/E357LおよびK370S:S364K/E357Qからなる群から選択されるアミノ酸置換のセットを有し、
前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインは第1の抗原に結合し、
前記scFvは第2の抗原に結合する、
ヘテロ二量体抗体。 - 前記scFvが、配列番号XX(scFv13551)、配列番号XX(scFv15426)、配列番号XX(scFv13423)および配列番号XX(scFv14702)からなる群から選択されるポリペプチド配列を有する、請求項13に記載のヘテロ二量体抗体。
- 前記第1の可変重鎖ドメインおよび前記可変軽鎖ドメインが、CD19、CD20およびCD123からなる群から選択されるTTAに結合する、請求項13または14に記載のヘテロ二量体抗体。
- a)配列GSSTGAVTTSNYAN(配列番号XX)を有するvlCDR1、配列GTNKRAP(配列番号XX)を有するvlCDR2、および配列ALWYSNHWV(配列番号XX)を有するvlCDR3を含む可変軽鎖ドメインと;
b)配列TYAMN(配列番号XX)を有するvhCDR1、配列RIRSKANNYATYYADSVKG(配列番号XX)を有するvhCDR2、および配列HGNFGDSYVSWFAY(配列番号XX)を有するvhCDR3を含む可変重鎖ドメインと
を含む抗CD3抗体結合ドメイン。 - scFvである、請求項16に記載の抗CD3抗体結合ドメイン。
- 前記可変軽鎖ドメインが配列L1.47(配列番号XX)を有し、かつ前記可変重鎖ドメインが配列H1.32(配列番号XX)を有する、請求項16または17に記載の抗CD3抗体結合ドメイン。
- 前記scFvが配列H1.32_L1.47(配列番号XX)を有する、請求項18に記載の抗CD3抗体結合ドメイン。
- 請求項19に記載のscFvをコードする核酸組成物。
- 請求項20に記載の核酸組成物を含む発現ベクター。
- 請求項21に記載の発現ベクターを含む宿主細胞。
- a)配列GSSTGAVTTSNYAN(配列番号XX)を有するvlCDR1、配列GTNKRAP(配列番号XX)を有するvlCDR2、および配列ALWYSNHWV(配列番号XX)を有するvlCDR3を含む可変軽鎖ドメインと;
b)配列TYAMN(配列番号XX)を有するvhCDR1、配列RIRSKYNNYATYYADSVKG(配列番号XX)を有するvhCDR2、および配列HGNFGDEYVSWFAY(配列番号XX)を有するvhCDR3を含む可変重鎖ドメインと
を含む抗CD3抗体結合ドメイン。 - scFvである、請求項23に記載の抗CD3抗体結合ドメイン。
- 前記可変軽鎖ドメインが配列L1.47(配列番号XX)を有し、かつ前記可変重鎖ドメインが配列H1.89(配列番号XX)を有する、請求項23または24に記載の抗CD3抗体結合ドメイン。
- 前記scFvが配列H1.89_L1.47(配列番号XX)を有する、請求項23に記載の抗CD3抗体結合ドメイン。
- 請求項26に記載のscFvをコードする核酸組成物。
- 請求項27に記載の核酸組成物を含む発現ベクター。
- 請求項28に記載の発現ベクターを含む宿主細胞。
- a)配列GSSTGAVTTSNYAN(配列番号XX)を有するvlCDR1、配列GTNKRAP(配列番号XX)を有するvlCDR2、および配列ALWYSNHWV(配列番号XX)を有するvlCDR3を含む可変軽鎖ドメインと;
b)配列TYAMN(配列番号XX)を有するvhCDR1、配列RIRSKYNNYATYYADSVKG(配列番号XX)を有するvhCDR2、および配列HGNFGDPYVSWFAY(配列番号XX)を有するvhCDR3を含む可変重鎖ドメインと
を含む抗CD3抗体結合ドメイン。 - scFvである、請求項30に記載の抗CD3抗体結合ドメイン。
- 前記可変軽鎖ドメインが配列L1.47(配列番号XX)を有し、かつ前記可変重鎖ドメインが配列H1.90(配列番号XX)を有する、請求項30または31に記載の抗CD3抗体結合ドメイン。
- 前記scFvが配列H1.90_L1.47(配列番号XX)を有する、請求項30に記載の抗CD3抗体結合ドメイン。
- 請求項33に記載のscFvをコードする核酸組成物。
- 請求項34に記載の核酸組成物を含む発現ベクター。
- 請求項35に記載の発現ベクターを含む宿主細胞。
- a)配列GSSTGAVTTSNYAN(配列番号XX)を有するvlCDR1、配列GTNKRAP(配列番号XX)を有するvlCDR2、および配列ALWYSNHWV(配列番号XX)を有するvlCDR3を含む可変軽鎖ドメインと;
b)配列TYAMN(配列番号XX)を有するvhCDR1、配列RIRSKYNNYATYYADSVKG(配列番号XX)を有するvhCDR2、および配列HGNFGDSYVSWFDY(配列番号XX)を有するvhCDR3を含む可変重鎖ドメインと
を含む抗CD3抗体結合ドメイン。 - scFvである、請求項37に記載の抗CD3抗体結合ドメイン。
- 前記可変軽鎖ドメインが配列L1.47(配列番号XX)を有し、かつ前記可変重鎖ドメインが配列H1.33(配列番号XX)を有する、請求項37または38に記載の抗CD3抗体結合ドメイン。
- 前記scFvが配列H1.33_L1.47(配列番号XX)を有する、請求項38に記載の抗CD3抗体結合ドメイン。
- 請求項38に記載のscFvをコードする核酸組成物。
- 請求項41に記載の核酸組成物を含む発現ベクター。
- 請求項42に記載の発現ベクターを含む宿主細胞。
- a)配列GSSTGAVTTSNYAN(配列番号XX)を有するvlCDR1、配列GTNKRAP(配列番号XX)を有するvlCDR2、および配列ALWYSNHWV(配列番号XX)を有するvlCDR3を含む可変軽鎖ドメインと;
b)配列TYAMS(配列番号XX)を有するvhCDR1、配列RIRSKYNNYATYYADSVKG(配列番号XX)を有するvhCDR2、および配列HGNFGDSYVSWFAY(配列番号XX)を有するvhCDR3を含む可変重鎖ドメインと
を含む抗CD3抗体結合ドメイン。 - scFvである、請求項44に記載の抗CD3抗体結合ドメイン。
- 前記可変軽鎖ドメインが配列L1.47(配列番号XX)を有し、かつ前記可変重鎖ドメインが配列H1.31(配列番号XX)を有する、請求項44または45に記載の抗CD3抗体結合ドメイン。
- 前記scFvが配列H1.31_L1.47(配列番号XX)を有する、請求項46に記載の抗CD3抗体結合ドメイン。
- 請求項47に記載のscFvをコードする核酸組成物。
- 請求項48に記載の核酸組成物を含む発現ベクター。
- 請求項49に記載の発現ベクターを含む宿主細胞。
- a)第1の単量体であって、
i)第1のFcドメイン;ならびに
ii)scFv可変軽鎖ドメイン、scFvリンカーおよびscFv可変重鎖ドメインを含み、ドメインリンカーを用いて前記FcドメインのN末端に共有結合された抗CD3 scFv
を含む第1の単量体と;
b)第2の単量体であって、
i)重鎖可変ドメイン;および
ii)第2のFcドメインを含む重鎖定常ドメイン
を含む重鎖を含む第2の単量体と;
c)可変軽鎖ドメインおよび可変軽定常ドメインを含む軽鎖と
を含み、
前記抗CD3 scFvは、抗CD3H1.32_L1.47(配列番号XX)、抗CD3H1.89_L1.47(配列番号XX)、抗CD3H1.90_L1.47(配列番号XX)および抗CD3H1.33_L1.47(配列番号XX)からなる群から選択され、かつ
前記重可変ドメインおよび前記軽可変ドメインはTTAに結合する、
ヘテロ二量体抗体。 - 前記TTAがCD19、CD20およびCD123からなる群から選択される、請求項51に記載のヘテロ二量体抗体。
- a)配列RASWSVSYIH(配列番号XX)を有するvlCDR1、配列ATSNLAS(配列番号XX)を有するvlCDR2、および配列QQWTHNPPT(配列番号XX)を有するvlCDR3を含む可変軽鎖ドメインと;
b)配列SYNMH(配列番号XX)を有するvhCDR1、配列AIYPGNGATSYSQKFQG(配列番号XX)を有するvhCDR2、および配列SYYMGGDWYFDV(配列番号XX)を有するvhCDR3を含む可変重鎖ドメインと
を含む抗CD20抗体結合ドメイン。 - 前記可変軽鎖ドメインが配列C2B8L1.113(配列番号XX)を有し、かつ前記可変重鎖ドメインが配列C2B8H1.202(配列番号XX)を有する、請求項53に記載の抗CD20抗体結合ドメイン。
- 請求項53に記載の結合ドメインをコードする核酸組成物。
- 請求項55に記載の核酸組成物を含む発現ベクター。
- 請求項56に記載の発現ベクターを含む宿主細胞。
- a)配列RASSSVSYIH(配列番号XX)を有するvlCDR1、配列ATSNLAS(配列番号XX)を有するvlCDR2、および配列QQWTSNPPT(配列番号XX)を有するvlCDR3を含む可変軽鎖ドメインと;
b)配列SYNMH(配列番号XX)を有するvhCDR1、配列AIYPGNGDTSYNQKFQG(配列番号XX)を有するvhCDR2、および配列STYYGGDWYFNV(配列番号XX)を有するvhCDR3を含む可変重鎖ドメインと
を含む抗CD20抗体結合ドメイン。 - 前記可変軽鎖ドメインが配列C2B8L1(配列番号XX)を有し、かつ前記可変重鎖ドメインが配列C2B8H1(配列番号XX)を有する、請求項58に記載の抗CD20抗体結合ドメイン。
- 請求項58に記載の結合ドメインをコードする核酸組成物。
- 請求項60に記載の核酸組成物を含む発現ベクター。
- 請求項61に記載の発現ベクターを含む宿主細胞。
- a)第1の単量体であって、
i)第1のFcドメイン;ならびに
ii)scFv可変軽鎖ドメイン、scFvリンカーおよびscFv可変重鎖ドメインを含み、ドメインリンカーを用いて前記FcドメインのN末端に共有結合された抗CD3 scFv
を含む第1の単量体と;
b)第2の単量体であって、
i)重鎖可変ドメイン;および
ii)第2のFcドメインを含む重鎖定常ドメイン
を含む重鎖を含む第2の単量体と;
c)可変軽鎖ドメインおよび可変軽定常ドメインを含む軽鎖と
を含み、
前記可変軽鎖ドメインは、配列RASSSVSYIH(配列番号XX)を有するvlCDR1、配列ATSNLAS(配列番号XX)を有するvlCDR2、および配列QQWTSNPPT(配列番号XX)を有するvlCDR3を含み、かつ
前記可変重鎖ドメインは、配列SYNMH(配列番号XX)を有するvhCDR1、配列AIYPGNGDTSYNQKFQG(配列番号XX)を有するvhCDR2、および配列STYYGGDWYFNV(配列番号XX)を有するvhCDR3を含む、
ヘテロ二量体抗体。 - a)第1の単量体であって、
i)第1のFcドメイン;ならびに
ii)scFv可変軽鎖ドメイン、scFvリンカーおよびscFv可変重鎖ドメインを含み、ドメインリンカーを用いて前記FcドメインのN末端に共有結合された抗CD3 scFv
を含む第1の単量体と;
b)第2の単量体であって、
i)重鎖可変ドメイン;および
ii)第2のFcドメインを含む重鎖定常ドメイン
を含む重鎖を含む第2の単量体と;
c)可変軽鎖ドメインおよび可変軽定常ドメインを含む軽鎖と
を含み、
前記可変軽鎖ドメインは、配列RASSSVSYIH(配列番号XX)を有するvlCDR1、配列ATSNLAS(配列番号XX)を有するvlCDR2、および配列QQWTSNPPT(配列番号XX)を有するvlCDR3を含み、かつ
前記可変重鎖ドメインは、配列SYNMH(配列番号XX)を有するvhCDR1、配列AIYPGNGDTSYNQKFQG(配列番号XX)を有するvhCDR2、および配列STYYGGDWYFNV(配列番号XX)を有するvhCDR3を含む、
ヘテロ二量体抗体。 - a)第1の単量体であって、
i)第1のFcドメイン;ならびに
ii)scFv可変軽鎖ドメイン、scFvリンカーおよびscFv可変重鎖ドメインを含み、ドメインリンカーを用いて前記FcドメインのN末端に共有結合された抗CD3 scFv
を含む第1の単量体と;
b)第2の単量体であって、
i)重鎖可変ドメイン;および
ii)第2のFcドメインを含む重鎖定常ドメイン
を含む重鎖を含む第2の単量体と;
c)可変軽鎖ドメインおよび可変軽定常ドメインを含む軽鎖と
を含み、
前記可変軽鎖ドメインは、配列KSSQSLLNTGNQKNYLT(配列番号XX)を有するvlCDR1、配列WASTRES(配列番号XX)を有するvlCDR2、および配列QNDYSYPYT(配列番号XX)を有するvlCDR3を含み、かつ
前記可変重鎖ドメインは、配列DYYMK(配列番号XX)を有するvhCDR1、配列DIIPSNGATFYNQKFKG(配列番号XX)を有するvhCDR2、および配列SHLLRASWFAY(配列番号XX)を有するvhCDR3を含む、
ヘテロ二量体抗体。 - XENP15049、XENP15051;XENP15050、XENP13676、XENP14696、XENP15629、XENP15053、XENP15630、XENP15631、XENP15632、XENP15633、XENP15634、XENP15635、XENP15636、XENP15638、XENP15639、XENP13677、XENP14388、XENP14389、XENP14390、XENP14391、XENP14392、XENP14393、XENP16366、XENP16367、XENP16368、XENP16369、XENP16370、XENP16371、XENP16372、XENP16373、XENP16375、XENP16376およびXENP16377からなる群から選択されるヘテロ二量体抗体。
- XENP15049、XENP15051;XENP15050、XENP13676、XENP14696、XENP15629、XENP15053、XENP15630、XENP15631、XENP15632、XENP15633、XENP15634、XENP15635、XENP15636、XENP15638、XENP15639、XENP13677、XENP14388、XENP14389、XENP14390、XENP14391、XENP14392、XENP14393、XENP16366、XENP16367、XENP16368、XENP16369、XENP16370、XENP16371、XENP16372、XENP16373、XENP16375、XENP16376およびXENP16377からなる群から選択されるヘテロ二量体抗体をコードする3つの核酸を含む核酸組成物。
- 発現ベクター組成物であって、それぞれ核酸を含有する3つの発現ベクターを含み、それにより、前記3つの発現ベクターは、XENP15049、XENP15051;XENP15050、XENP13676、XENP14696、XENP15629、XENP15053、XENP15630、XENP15631、XENP15632、XENP15633、XENP15634、XENP15635、XENP15636、XENP15638、XENP15639、XENP13677、XENP14388、XENP14389、XENP14390、XENP14391、XENP14392、XENP14393、XENP16366、XENP16367、XENP16368、XENP16369、XENP16370、XENP16371、XENP16372、XENP16373、XENP16375、XENP16376およびXENP16377からなる群から選択されるヘテロ二量体抗体をコードする、発現ベクター組成物。
- 請求項67に記載の核酸組成物を含む宿主細胞。
- 請求項68に記載の発現ベクター組成物を含む宿主細胞。
- 請求項66に記載のヘテロ二量体抗体を作製する方法であって、請求項69または70に記載の宿主細胞を前記抗体が発現される条件下で培養するステップと、前記抗体を回収するステップとを含む、方法。
- がんを治療する方法であって、請求項66に記載のヘテロ二量体抗体を、それを必要とする患者に投与するステップを含む、方法。
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