JP7058219B2 - Cd3及びpsmaに結合するヘテロ二量体抗体 - Google Patents
Cd3及びpsmaに結合するヘテロ二量体抗体 Download PDFInfo
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Description
本出願は、2015年12月7日出願の米国仮出願第62/264,261号及び2016年4月19日出願の同第62/324,823号に対して優先権を主張し、これらは、参照によりそれらの全体が明確に組み込まれる。
本出願をより完全に理解し得るために、いくつかの定義を以下に示す。そのような定義は、文法的に等価であるものを包含することを意図する。
CD3及び腫瘍抗原標的を共捕捉する二重特異性抗体は、T細胞を再配向化して標的腫瘍細胞を攻撃し溶解するために、設計され使用されてきた。例には、CD3及び腫瘍抗原を一価で捕捉するBiTE及びDART形式が含まれる。CD3ターゲティング手法が相当な見込みを示した一方、そのような治療の共通の副作用は、サイトカインの関連する産生であり、毒性サイトカイン放出症候群につながることが多い。二重特異性抗体の抗CD3結合ドメインが、すべてのT細胞を捕捉するため、高サイトカイン産生CD4 T細胞サブセットが補充される。その上、CD4 T細胞サブセットは、制御性T細胞を含み、その補充及び拡大は、免疫抑制に潜在的につながり、長期の腫瘍抑制に悪影響を有し得る。さらに、これらの形式は、Fcドメインを含有せず、患者において非常に短い血清半減期を示す。
本発明は、CD3及びPSMAに結合する二重特異性抗体、一般には、治療用抗体の生成に関する。以下に論じられるように、「抗体」という用語が、一般に使用される。本発明において用途を見出す抗体は、本明細書に記載されるいくつかの形式で使用でき、伝統的な抗体、ならびに以下に記載される抗体の誘導体、断片、及び模倣体が含まれる。
いくつかの実施形態では、抗体は、異なる種由来の混合物であり得、例えば、キメラ抗体及び/またはヒト化抗体である。一般に、「キメラ抗体」及び「ヒト化抗体」の両方が、2つ以上の種由来の領域を組み合わせる抗体を指す。例えば、「キメラ抗体」は、伝統的に、マウス(または場合によってはラット)由来の可変領域(複数可)、及びヒト由来の定常領域(複数可)を含む。「ヒト化抗体」は、一般に、ヒト抗体においてみられる配列と交換された可変ドメインフレームワーク領域を有する非ヒト抗体を指す。一般に、ヒト化抗体では、CDRを除き、抗体全体が、ヒト起源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内は除いて、そのような抗体と同一である。CDRのいくつか、またはすべては、非ヒト生物起源の核酸によってコードされており、抗体を創出するためにヒト抗体可変領域のベータシートフレームワークへ移植され、その特異性は、移植されたCDRによって決定される。そのような抗体の創出は、例えば、WO92/11018、Jones,1986,Nature 321:522-525、Verhoeyen et al.,1988,Science 239:1534-1536において説明されており、これらはすべて、参照により完全に組み込まれる。対応するドナー残基に対して選択されたアクセプターフレームワーク残基の「復帰突然変異(Backmutation)」が、初期移植構築物において消失した親和性を回復するために必要であることが多い(US5530101、US5585089、US5693761、US5693762、US6180370、US5859205、US5821337、US6054297、US6407213、これらはすべて、参照により完全に組み込まれる)。ヒト化抗体は、免疫グロブリンの定常領域の少なくとも一部も最適に含み、これは、典型的には、ヒト免疫グロブリンのものであり、したがって、典型的には、ヒトFc領域を含む。ヒト化抗体は、遺伝学的に操作された免疫系を有するマウスを使用して生成させることもできる。Roque et al.,2004,Biotechnol.Prog.20:639-654が、参照により完全に組み込まれる。非ヒト抗体のヒト化及び再形成のための様々な技術及び方法が、当該技術分野でよく知られている(Tsurushita&Vasquez,2004,Humanization of Monoclonal Antibodies,Molecular Biology of B Cells,533-545,Elsevier Science(USA)、及びそこで引用される参照文献を参照のこと。これらはすべて、参照により完全に組み込まれる)。ヒト化の方法には、限定されないが、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.USA 88:4181-4185、O’Connor et al.,1998,Protein Eng 11:321-8において説明される方法が含まれ、これらはすべて、参照により完全に組み込まれる。非ヒト抗体可変領域の免疫原性を低下させるヒト化または他の方法には、例えば、Roguska et al.,1994,Proc.Natl.Acad.Sci.USA 91:969-973において説明されるような表面再構成法(resurfacing method)が含まれ、参照により完全に組み込まれる。
したがって、いくつかの実施形態では、本発明は、ヘテロ二量体抗体を形成するために自己組織化する2つの異なる重鎖変異体Fcドメイン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、ホモ二量体を除去してヘテロ二量体形成及び/または精製を可能にするためにヘテロ二量体変異体を利用する様々な形式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。
いくつかの実施形態では、ヘテロ二量体の形成は、立体変異体の追加によって促進され得る。すなわち、それぞれの重鎖におけるアミノ酸を変更することによって、同一Fcアミノ酸配列を有するホモ二量体の形成と比較して、異なる重鎖が、会合してヘテロ二量体構造を形成する可能性が高くなる。好適な立体変異体は、図10に含まれる。
一般に、当業者に理解されるように、pI変異体には2つの一般的なカテゴリー:タンパク質のpIを増加させるもの(塩基性の変更)、及びタンパク質のpIを減少させるもの(酸性の変更)が存在する。本明細書に記載されるように、これらの変異体の組み合わせはすべて実施することができる、すなわち、一方の単量体が、野生型、または野生型と顕著に異なるpIを示さない変異体であり得、他方は、より塩基性、またはより酸性であり得る。あるいは、それぞれの単量体が、1つは、より塩基性へ、1つは、より酸性へと変更される。
抗体に基づくヘテロ二量体の場合では、例えば、単量体のうちの少なくとも1つが、重鎖ドメインに加えて軽鎖を含む場合、pI変異体を軽鎖に作ることもできる。軽鎖のpIを低下させるためのアミノ酸置換には、限定されないが、K126E、K126Q、K145E、K145Q、N152D、S156E、K169E、S202E、K207E、及び軽鎖のC末端におけるペプチドDEDEの追加が含まれる。定常ラムダ軽鎖に基づくこのカテゴリーにおける変更には、R108Q、Q124E、K126Q、N138D、K145T、及びQ199Eでの1つ以上の置換が含まれる。加えて、軽鎖のpIの増加も可能である。
加えて、本発明の多くの実施形態が、1つのIgGアイソタイプから別のものへの、特定位置でのpIアミノ酸の「取り込み」に依存しており、したがって、変異体へ導入される不要な免疫原性の可能性を低下または除去している。これらのいくつかは、米国公開第2014/0370013号の図21に示され、参照により本明細書に組み込まれる。すなわち、IgG1は、高いエフェクター機能を含む様々な理由のため、治療用抗体のための共通のアイソタイプである。しかしながら、IgG1の重定常領域は、IgG2よりも高いpIを有する(8.10対7.31)。特定位置で、IgG2残基を、IgG1主鎖へ導入することによって、得られる単量体のpIは低下(または増加)し、付加的に血清半減期の長期化を示す。例えば、IgG1は、位置137にグリシン(pI5.97)を有し、IgG2は、グルタミン酸(pI3.22)を有する。つまり、グルタミン酸の取り込みは、得られるタンパク質のpIに影響を与える。以下に記載されるように、いくつかのアミノ酸置換は、一般に、変異体抗体のpIに顕著な影響を与えることが必要とされている。しかしながら、以下に論じられるように、IgG2分子における変更でさえ、血清半減期の増加を可能にすることに留意するべきである。
それぞれの単量体のpIは、変異体重鎖定常ドメイン及び融合パートナーを含む、変異体重鎖定常ドメイン及び総単量体のpIに依存し得る。したがって、いくつかの実施形態では、米国公開第2014/0370013号の図19中のチャートを使用して、変異体重鎖定常ドメインに基づいて、pIの変化が計算される。本明細書で論じられるように、どの単量体を操作するかは、一般に、Fv及び骨格領域の固有pIによって決定される。あるいは、それぞれの単量体のpIを、比較することができる。
pI変異体が、単量体のpIを減少させる場合、インビボにおける血清保持の改善という利点が追加され得る。
pIアミノ酸変異体に加えて、様々な理由から実施することのできる、いくつかの有用なFcアミノ酸改変が存在し、限定されないが、1つ以上のFcγR受容体に対する結合の変更、FcRn受容体に対する結合の変更などが含まれる。
したがって、FcγR受容体のうちの1つ以上に対する結合を変えるために作製することができるいくつかの有用なFc置換が存在する。結合の増加及び結合の減少をもたらす置換が有用であり得る。例えば、FcγRIIIaに対する結合の増加は、一般に、ADCC(抗体依存性細胞媒介細胞傷害性。これは、細胞が媒介する反応であって、FcγRを発現する非特異性である細胞傷害性の細胞が、標的細胞上の結合した抗体を認識し、その後に標的細胞の溶解を引き起こす反応である)の増加をもたらすことが知られている。同様に、FcγRIIb(抑制性受容体)に対する結合の減少も、状況によっては、有益であり得る。本発明において用途を見出すアミノ酸置換には、USSN11/124,620(特に図41)、11/174,287、11/396,495、11/538,406において記載されるものが含まれ、これらはすべて参照によりその全体、及び特に、そこで開示される変異体に関して明確に本明細書に組み込まれる。用途を見出す特定の変異体には、限定されないが、236A、239D、239E、332E、332D、239D/332E、267D、267E、328F、267E/328F、236A/332E、239D/332E/330Y、239D、332E/330L、243A、243L、264A、264V、及び299Tが含まれる。
同様に、機能性変異体の別のカテゴリーは、「FcγR消去変異体」または「Fcノックアウト(FcKOもしくはKO)」変異体である。こうした実施形態では、いくつかの治療用途のため、Fcγ受容体(例えば、FcγR1、FcγRIIa、FcγRIIb、FcγRIIIaなど)のうちの1つ以上またはすべてに対するFcドメインの通常の結合を低下または除去して、作用の付加的な機構を回避することが望ましい。すなわち、例えば、多くの実施形態では、特にCD3を一価で結合する二重特異性抗体の使用において、FcγRIIIa結合を消去して、ADCC活性を排除、または著しく低下させることが一般に望ましい。Fcドメインのうちの1つは、1つ以上のFcγ受容体消去変異体を含む。これらの消去変異体は、図12に示され、それぞれは、G236R/L328R、E233P/L234V/L235A/G236del/S239K、E233P/L234V/L235A/G236del/S267K、E233P/L234V/L235A/G236del/S239K/A327G、E233P/L234V/L235A/G236del/S267K/A327G、及びE233P/L234V/L235A/G236delからなる群から選択される消去変異体を利用する好ましい態様と共に独立かつ任意選択で含むか、または除外することができる。本明細書において参照される消去変異体が、一般に、FcRn結合ではなくFcγR結合を消去することに留意するべきである。
当業者により理解されるように、列挙されるヘテロ二量体化変異体(歪曲及び/またはpI変異体を含む)のすべては、その「鎖性」または「単量体区分(monomer partition)」が保持される限り、任意選択かつ独立して、任意の方法で組み合わせることができる。加えて、これらの変異体のすべてが、ヘテロ二量体化形式のいずれかに組み入れることができる。
当業者によって理解され、以下により完全に論じられるように、本発明のヘテロ二量体融合タンパク質は、一般に、図1に示されるように、幅広い種類の立体配置をとることができる。いくつかの図は、分子の一方の「アーム」上に1種類の特異性、及びもう一方の「アーム」上に異なる特異性がある「シングルエンド化(single ended)」立体配置を示す。他の図は、分子の「上部」に少なくとも1種類の特異性、及び分子の「下部」に1つ以上の異なる特異性がある「二重エンド化(dual ended)」立体配置を示す。したがって、本発明は、異なる第1及び第2の抗原を共捕捉する新規の免疫グロブリン組成物を対象とする。
本発明において特に用途が見出される1つのヘテロ二量体骨格は、「三重F」または図1Aに示される「ボトルオープナー」骨格形式である。この実施形態では、抗体の一方の重鎖は、単鎖Fv(以下に定義される「scFv」)を含み、もう一方の重鎖は、「定型的な(regular)」FAb形式であって、可変重鎖及び軽鎖を含む。この構造は、本明細書において「三重F」形式(scFv-FAb-Fc)、またはボトルオープナーにおおよそ視覚的に類似している(図1を参照されたい)ことから「ボトルオープナー」形式と称されることがある。以下により完全に記載されるように、2つの鎖は、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、及び/またはヒンジ領域)において、アミノ酸変異体を使用することによって一緒にまとめられている。
本発明において特定の用途を見出す1つのヘテロ二量体骨格は、図1に示されるmAb-Fv形式である。この実施形態では、形式は、一方の単量体への「余分な」可変重ドメインのC末端付加、及びもう一方の単量体への「余分な」可変軽ドメインのC末端付加の使用に依存し、したがって、第3の抗原結合ドメインを形成し、2つの単量体のFab部分は、PSMAに結合し、「余分な」Fvドメインは、CD3に結合する。
本発明において特定の用途を見出す1つのヘテロ二量体骨格は、図1に示されるmAb-scFv形式である。この実施形態では、形式は、単量体のうちの1つへのscFvのC末端付加の使用に依存し、したがって、第3の抗原結合ドメインを形成し、2つの単量体のFab部分は、PSMAに結合し、「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、第1の重鎖(可変重ドメイン及び定常ドメインを含む)を含み、C末端共有結合されたscFvは、いずれの配向で(vh1-CH1-ヒンジ-CH2-CH3-[任意選択のリンカー]-vh2-scFvリンカー-vl2またはvh1-CH1-ヒンジ-CH2-CH3-[任意選択のリンカー]-vl2-scFv linker-vh2)、scFv可変軽ドメイン、scFvリンカー、及びscFv可変重ドメインを含む。この実施形態は、PSMAに結合する2つの同一Fabを形成するために重鎖に関連する、可変軽ドメイン及び定常軽ドメインを含む共通の軽鎖をさらに利用する。本明細書の実施形態の多くに関して、これらの構築物には、本明細書で所望され記載される歪曲変異体、pI変異体、消去変異体、追加のFc変異体などが含まれる。
本発明において特定の用途を見出す1つのヘテロ二量体骨格は、図1に示される中心scFv形式である。この実施形態では、形式は、挿入scFvドメインの使用に依存し、したがって、第3の抗原結合ドメインを形成し、2つの単量体のFab部分は、PSMAに結合し、「余分な」scFvドメインは、CD3に結合する。scFvドメインは、単量体のうちの1つのFcドメインとCH1-Fv領域との間に挿入され、したがって、第3の抗原結合ドメインを提供する。
本発明において特定の用途を見出す1つのヘテロ二量体骨格は、図1に示される中心Fv形式である。この実施形態では、形式は、挿入scFvドメインの使用に依存し、したがって、第3の抗原結合ドメインを形成し、2つの単量体のFab部分は、PSMAに結合し、「余分な」Fvドメインは、CD3に結合する。scFvドメインは、単量体のFcドメインとCH1-Fv領域との間に挿入され、したがって、第3の抗原結合ドメインを提供し、各単量体は、Fvの成分を含有する(例えば、一方の単量体は、可変重ドメインを含み、もう一方は、可変軽ドメインを含む)。
本発明において特定の用途を見出す1つのヘテロ二量体骨格は、図1に示されるワンアーム化中心scFv形式である。この実施形態では、一方の単量体は、Fcドメインのみを含み、もう一方の単量体は、挿入scFvドメインを使用し、したがって、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、PSMAに結合し、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、単量体のうちの1つのFcドメインとCH1-Fv領域との間に挿入される。
本発明はまた、当該技術分野で知られ、図1に示される二重scFv形式も提供する。具体的には、本発明は、二重scFv形式を提供し、抗CD3 scFv配列は、図2~図7に示されるとおりである。
本発明において特定の用途を見出す1つのヘテロ二量体骨格は、図1に示される共通の軽鎖形式である。この実施形態では、第1の単量体は、第1の可変重ドメイン、及び第1のFcドメインを含む第1の定常重ドメインを含む、第1の重鎖を含む。第2の単量体は、第2の可変重ドメイン、及び第2のFcドメインを含む第2の定常重鎖を含む。第1及び第2の単量体のそれぞれは、可変軽ドメイン及び定常軽ドメインを含む共通の軽鎖に関連する。本明細書の実施形態の多くに関して、これらの構築物には、本明細書で所望され記載される歪曲変異体、pI変異体、消去変異体、追加のFc変異体などが含まれる。
本発明において特定の用途を見出す1つのヘテロ二量体骨格は、図1に示される二重特異性形式である。この実施形態では、第1の単量体は、第1の可変重ドメイン、及び第1のFcドメインを含む第1の定常重ドメインを含む、第1の重鎖を含む。第2の単量体は、第2の可変重ドメイン、及び第2のFcドメインを含む第2の定常重鎖を含む。第1及び第2の単量体のそれぞれは、可変軽ドメイン及び定常軽ドメインを含む軽鎖(すなわち、それぞれ、第1の軽鎖及び第2の軽鎖)に関連する。本明細書の実施形態の多くに関して、これらの構築物には、本明細書で所望され記載される立体変異体(例えば、ノブイントゥホール変異体)、歪曲変異体、pI変異体、消去変異体、追加のFc変異体などが含まれる。
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。当業者により理解されるように、核酸組成物は、ヘテロ二量体タンパク質の形式及び骨格に依存する。したがって、例えば、形式が、三重F形式などのために3つのアミノ酸配列を必要とするとき(例えば、Fcドメイン及びscFvを含む第1のアミノ酸単量体、重鎖及び軽鎖を含む第2のアミノ酸単量体)、3つの核酸配列は、発現のための1つ以上の発現ベクターに組み込まれ得る。同様に、いくつかの形式(例えば、図1に開示されるものなどの二重scFv形式)2つの核酸のみが必要とされ、再度それらは、1つまたは2つの発現ベクターに加えられ得る。
一旦作製されると、本発明の組成物は、限定されないが、前立腺癌を含む、PSMAを発現または過剰発現する癌の治療を含むいくつかの用途に用途を見出す。
本発明に従って使用する抗体の製剤は、所望の純度を有し、任意選択で、医薬的に許容可能な担体、賦形剤、または安定剤(Remington’s Pharmaceutical Sciences 16th edition,Osol,A.Ed.[1980])と共に抗体を混合することによって、凍結乾燥製剤または水溶液の形態で、貯蔵のために調製される。許容可能な担体、賦形剤、または安定剤は、用いられる投与量及び濃度で、レシピエントに対して非毒性であり、リン酸、クエン酸、及び他の有機酸などの緩衝剤、アスコルビン酸及びメチオニンを含む抗酸化剤、保存剤(オクタデシルジメチルベンジルアンモニウムクロリド、ヘキサメトニウムクロリド、ベンザルコニウムクロリド、ベンゼトニウムクロリド、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、レゾルシノール、シクロヘキサノール、3-ペンタノール、及びm-クレゾールなど)、低分子量(約10残基未満)ポリペプチド、血清アルブミン、ゼラチン、もしくは免疫グロブリンなどのタンパク質、ポリビニルピロリドンなどの親水性重合体、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、及びグルコース、マンノース、もしくはデキストリンを含む他の糖質、EDTAなどのキレート物質、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、ナトリウムなどの塩形成対イオン、金属複合体(例えば、亜鉛-タンパク質複合体)、ならびに/またはTWEEN(商標)、PLURONICS(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が含まれる。
本発明の抗体物質及び化学療法物質は、ボーラスとしての静脈内投与、または一定期間にわたる継続注入によるなどの既知の方法に従って、筋肉内経路、腹腔内経路、脳脊髄内(intracerobrospinal)、皮下経路、関節内経路、関節滑液嚢内経路、くも膜下腔内、口腔、局所、または吸入経路によって、対象に投与される。抗体の静脈内投与または皮下投与が好ましい。
本発明の方法において、療法は、疾患または状態に関する有益な治療応答を提供するために使用される。「有益な治療応答」は、疾患もしくは状態における改善、及び/または疾患もしくは状態と関連する症状における改善を意図する。例えば、有益な治療応答は、疾患における下記の改善のうちの1つ以上を指すであろう。(1)新生細胞数の減少、(2)新生細胞死の増加、(3)新生細胞の生存阻害、(5)腫瘍成長の阻害(例えば、ある程度の鈍化、好ましくは停止)、(6)患者生存率の増加、及び(7)疾患または状態と関連する1つ以上の症状のある程度の緩和。
抗PSMA×抗CD3二重特異性体のアミノ酸配列を図9及び21A~Dに列記する。二重特異性発現のために必要とされる3つの鎖をコードするDNAを、遺伝子合成(Blue Heron Biotechnology,Bothell,Wash.)により生成し、発現ベクターpTT5に標準的な分子生物学的技術を使用してサブクローニングした。置換を、部位特異的な突然変異誘発(QuikChange,Stratagene,Cedar Creek,Tex.)または追加の遺伝子合成及びサブクローニングのいずれかを使用して導入した。DNAを、発現のためのHEK293E細胞にトランスフェクトし、得られたタンパク質を、プロテインA親和性(GE Healthcare)及びカチオンイオン交換クロマトグラフィーを使用して上清から精製した。カチオンイオン交換クロマトグラフィー精製を、50mM MES、pH6.0の洗浄/平衡緩衝剤及び50mM MES、pH6.0+1M NaCl直線勾配の溶離緩衝剤を用いるHiTrap SP HPカラム(GE Healthcare)を使用して実施した。
抗PSMA×抗CD3二重特異性体を、PSMA+LNCaP前立腺癌細胞株への細胞表面結合及びその再配向化T細胞の細胞傷害性(RTCC)に関して、インビトロで特徴付けした。(図16及び23)アッセイの詳細は図の説明文に示される。これらの図に示されるように、対象抗PSMA×抗CD3抗体XENP14484及びXENP19722は、インビトロにおいてLNCaP前立腺癌細胞に結合し、RTCC殺傷を媒介することができたが、抗RSV対照XENP13245は、PSMAまたはRTCCを示さなかった。
カニクイザル(n=3)に、XENP14484(抗PSMA×抗CD3、30μg/kg)またはXENP13245(抗RSV×CD3、3mg/kg)のいずれかを単回投与した。CD4+T細胞の辺縁趨向及びCD69 MFIによる活性化は、フローサイトメトリーによって調べられた。IL-6血清レベルは、ELISAによって調べられた(図17A)。加えて、CD8+T細胞の辺縁趨向及びCD69 MFIによる活性化は、フローサイトメトリーによって調べられ、TNFα血清レベルは、ELISAによって調べられた(図17B)。これらの図に示されるように、T細胞の応答及びサイトカイン放出症候群(CRS)は、サルにおいて、抗PSMA×抗CD3抗体による標的細胞の会合に依存する。
カニクイザルカニクイザル(n=3)に、0.06mg/kgのXENP14484(高CD3親和性)または1mg/kgのXENP19722(低CD3親和性)のいずれかの単回静脈内(i.v.)用量を投与した。図24に示されるように、XENP14484及びXENP19722抗体は、異なるCD3親和性を有するにも関わらず、類似するT細胞の辺縁趨向及び活性化(CD4+(上のパネル)及びCD8+(中央のパネル))を示す。しかしながら、T細胞活性化における類似性にも関わらず、CD3に対して低親和性を有するXENP19722が、CD3に対して高親和性を有するXENP14484と比較して、より少ないサイトカイン放出症候群(CRS)を誘導した(図24、下のパネル)。そのようなより低いCD3親和性は、より高い用量レベルにおいてもサイトカイン放出の低減と相関する。そのため、抗PSMA二重特異性体の効力は、T細胞を補充するその能力を調整することによって調節することができる。
Claims (10)
- a)第1の単量体であって、
i)第1のFcドメインと、
ii)第1の可変重ドメイン、scFvリンカー、及び第1の可変軽ドメインを含む抗CD3 scFvであって、前記scFvが、ドメインリンカーを使用して前記FcドメインのN末端に共有結合されている、抗CD3 scFvと、
を含む、第1の単量体と、
b)重鎖を含む第2の単量体であって、
i)第2の可変重ドメインと、
ii)第2のFcドメインを含む重定常ドメインと、を含む、第2の単量体と、
c)第2の可変軽ドメイン及び定常軽ドメインを含む軽鎖と、を含み、
前記第1の可変重ドメインが配列番号10のアミノ酸配列を含み、前記第1の可変軽ドメインが配列番号14のアミノ酸配列を含み、
前記第2の可変重ドメインが配列番号110のアミノ酸配列を含み、前記第2の可変軽ドメインが配列番号106のアミノ酸配列を含む、ヘテロ二量体抗体。 - 前記第1の単量体が配列番号125のアミノ酸配列を含み、前記第2の単量体が配列番号124のアミノ酸配列を含み、前記軽鎖が配列番号126のアミノ酸配列を含む、請求項1に記載のヘテロ二量体抗体。
- 前記第1のFcドメイン及び前記第2のFcドメインが、S364K/E357Q:L368D/K370S、L368D/K370S:S364K、L368E/K370S:S364K、T411T/E360E/Q362E:D401K、L368D/K370S:S364K/E357L、及びK370S:S364K/E357Qからなる群から選択される1セットの変異体を含む、請求項1に記載のヘテロ二量体抗体。
- 前記scFvリンカーが、荷電リンカーである、請求項1に記載のヘテロ二量体抗体。
- 前記重鎖定常ドメインが、アミノ酸置換N208D/Q295E/N384D/Q418E/N421Dを更に含む、請求項3に記載のヘテロ二量体抗体。
- 前記第1及び第2のFcドメインが、アミノ酸置換E233P/L234V/L235A/G236del/S267Kを含む、請求項5に記載のヘテロ二量体抗体。
- ヘテロ二量体抗体をコードする核酸組成物であって、
a)請求項1に記載の前記第1の単量体をコードする第1の核酸と、
b)請求項1に記載の前記第2の単量体をコードする第2の核酸と、
c)請求項1に記載の前記軽鎖をコードする第3の核酸と、を含む、核酸組成物。 - 請求項7に記載の核酸組成物を含む、発現ベクター組成物。
- 請求項7に記載の核酸組成物又は請求項8に記載の発現ベクター組成物を含む、宿主細胞。
- ヘテロ二量体抗体を作製する方法であって、前記抗体が発現される条件下で請求項9に記載の宿主細胞を培養することと、前記抗体を回収することと、を含む、方法。
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EP3387013B1 (en) | 2022-06-08 |
CA3007030A1 (en) | 2017-06-15 |
AU2016365742A1 (en) | 2018-06-21 |
CN108699136B (zh) | 2022-03-18 |
KR20180085800A (ko) | 2018-07-27 |
US10227410B2 (en) | 2019-03-12 |
CN108699136A (zh) | 2018-10-23 |
WO2017100372A1 (en) | 2017-06-15 |
EP3387013A1 (en) | 2018-10-17 |
IL259834A (en) | 2018-07-31 |
JP2019500862A (ja) | 2019-01-17 |
US11623957B2 (en) | 2023-04-11 |
US20200216559A1 (en) | 2020-07-09 |
US20170320947A1 (en) | 2017-11-09 |
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