JP6637439B2 - 抗ox40抗体及び使用方法 - Google Patents
抗ox40抗体及び使用方法 Download PDFInfo
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- JP6637439B2 JP6637439B2 JP2016559908A JP2016559908A JP6637439B2 JP 6637439 B2 JP6637439 B2 JP 6637439B2 JP 2016559908 A JP2016559908 A JP 2016559908A JP 2016559908 A JP2016559908 A JP 2016559908A JP 6637439 B2 JP6637439 B2 JP 6637439B2
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Description
本出願は、それぞれその全体が参照によって本明細書に組み込まれる2014年3月31日出願の米国仮特許出願第61/973,193号;2014年5月6日出願の同第61/989,448号;2014年10月31日出願の同第62/073,873号;及び2014年11月14日出願の同第62/080,171号の優先権を主張する。
ASCIIテキストファイルでの下記の送信内容は、その全体が参照によって本明細書に組み込まれる:配列表のコンピュータ読み込み可能な形式(CRF)(ファイル名:146392029140SEQLIST.txt、記録日:2015年3月26日、サイズ:143KB)。
本発明は、抗OX40抗体及びその使用方法に関する。
OX40(CD34、TNFRSF4、及びACT35としても公知)は、腫瘍壊死因子受容体スーパーファミリーのメンバーである。OX40は、ナイーブT細胞上では構成的に発現されないが、T細胞受容体(TCR)の結合後に誘発される。OX40のリガンドであるOX40Lは、抗原提示細胞上で主に発現される。OX40は、活性化CD4+T細胞、活性化CD8+T細胞、メモリーT細胞、及び調節性T細胞によって高度に発現される。OX40シグナル伝達は、CD4及びCD8T細胞に同時刺激シグナルを示し、細胞増殖、生存、エフェクター機能、及び遊走の増強につながり得る。OX40シグナル伝達はまた、メモリーT細胞の発生及び機能を増強する。
免疫機能不全の内容における「機能不全」という用語は、抗原刺激に対して免疫応答性が低減した状態を指す。
(a)アミノ酸残基26〜32(L1)、50〜52(L2)、91〜96(L3)、26〜32(H1)、53〜55(H2)、及び96〜101(H3)において生じる超可変ループ(Chothia and Lesk,J.Mol.Biol.196:901〜917(1987));
(b)アミノ酸残基24〜34(L1)、50〜56(L2)、89〜97(L3)、31〜35b(H1)、50〜65(H2)、及び95〜102(H3)において生じるCDR(Kabat et al.,Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD(1991));
(c)アミノ酸残基27c〜36(L1)、46〜55(L2)、89〜96(L3)、30〜35b(H1)、47〜58(H2)、及び93〜101(H3)において生じる抗原コンタクト(MacCallum et al.J.Mol.Biol.262:732−745(1996));及び
(d)HVRアミノ酸残基46〜56(L2)、47〜56(L2)、48〜56(L2)、49〜56(L2)、26〜35(H1)、26〜35b(H1)、49〜65(H2)、93〜102(H3)、及び94〜102(H3)を含む、(a)、(b)、及び/または(c)の組合せ
が含まれる。
別段に示さない限り、可変ドメインにおけるHVR残基及び他の残基(例えば、FR残基)は、本明細書において上記のKabat et al.に従ってナンバリングされる。
一実施形態では、HVR残基は、図11A〜Iまたは本明細書の他の箇所において特定されるものを含む。
100×分数X/Y
(式中、Xは、配列アライメントプログラムALIGN−2によって、そのプログラムのA及びBのアライメントにおいて完全な一致としてスコア化されたアミノ酸残基の数であり、Yは、B中のアミノ酸残基の総数である)。アミノ酸配列Aの長さがアミノ酸配列Bの長さと等しくない場合、Bに対するAのアミノ酸配列同一性%は、Aに対するBのアミノ酸配列同一性%と等しくはならないことは分かるであろう。別段に特に述べない限り、本明細書において使用するすべてのアミノ酸配列同一性%値は、直前の段落において記載したとおり、ALIGN−2コンピュータプログラムを使用して得られる。
DIQMTQSPSSLSASVGDRVTITC(配列番号189)−L1−WYQQKPGKAPKLLIY(配列番号190)−L2−GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(配列番号191)−L3−FGQGTKVEIK(配列番号192)の各々の少なくとも一部またはすべてを含む。
一態様では、本発明は、一部では、様々なOX40結合薬の特定に基づく。ある種の実施形態では、ヒトOX40に結合する抗体(例えば、アゴニスト抗体)を提供する。本発明の抗体は、例えば、OX40発現及び/または活性に関連するがん及び他の障害の診断または処置に有用である。
一態様では、本発明は、ヒトOX40に結合する単離抗体を提供する。
ある種の実施形態では、本明細書において提供する抗体は、≦1μM、≦100nM、≦10nM、≦1nM、≦0.1nM、≦0.01nM、または≦0.001nM(例えば、10−8M以下、例えば、10−8M〜10−13M、例えば、10−9M〜10−13M)の解離定数(Kd)を有する。
ある種の実施形態では、本明細書において提供する抗体は、抗体断片である。抗体断片には、限定されないが、Fab、Fab’、Fab’−SH、F(ab’)2、Fv、及びscFv断片、ならびに下記の他の断片が含まれる。ある種の抗体断片の概説については、Hudson et al.Nat.Med.9:129−134(2003)を参照されたい。scFv断片の概説については、例えば、Pluckthun,in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,(Springer−Verlag,New York),pp.269−315(1994)を参照されたい;また、WO93/16185;及び米国特許第5,571,894号及び同第5,587,458号を参照されたい。サルベージ受容体結合エピトープ残基を含み、増大したin vivo半減期を有するFab及びF(ab’)2断片の考察については、米国特許第5,869,046号を参照されたい。
ある種の実施形態では、本明細書において提供する抗体は、キメラ抗体である。ある種のキメラ抗体は、例えば、米国特許第4,816,567号;及びMorrison et al.,Proc.Natl.Acad.Sci.USA、81:6851−6855(1984))において記載されている。一例では、キメラ抗体は、非ヒト可変領域(例えば、マウス、ラット、ハムスター、ウサギ、またはサルなどの非ヒト霊長類に由来する可変領域)及びヒト定常領域を含む。さらなる例では、キメラ抗体は、クラスまたはサブクラスが親抗体のそれから変更されている「クラススイッチされた」抗体である。キメラ抗体には、それらの抗原結合断片が含まれる。
ある種の実施形態では、本明細書において提供する抗体は、ヒト抗体である。ヒト抗体は、当技術分野で公知の様々な技術を使用して生産することができる。ヒト抗体は、一般に、van Dijk and van de Winkel,Curr.Opin.Pharmacol.5:368−74(2001)、及びLonberg,Curr.Opin.Immunol.20:450−459(2008)において記載されている。
本発明の抗体は、所望の活性(複数可)を有する抗体についてコンビナトリアルライブラリをスクリーニングすることによって単離してもよい。例えば、ファージディスプレイライブラリを生成し、そのようなライブラリを、所望の結合特性を保有する抗体についてスクリーニングするための様々な方法が当技術分野で公知である。そのような方法は、例えば、Hoogenboom et al. in Methods in Molecular Biology 178:1−37(O’Brien et al.,ed.,Human Press,Totowa,NJ,2001)において概説され、さらに、例えば、McCafferty et al.,Nature 348:552−554;Clackson et al.,Nature 352:624−628(1991);Marks et al.,J.Mol.Biol.222:581−597(1992);Marks and Bradbury,in Methods in Molecular Biology 248:161−175(Lo,ed.,Human Press,Totowa,NJ,2003);Sidhu et al.,J.Mol.Biol.338(2):299−310(2004);Lee et al.,J.Mol.Biol.340(5):1073−1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467−12472(2004);及びLee et al.,J.Immunol.Methods 284(1−2):119−132(2004)において記載されている。
ある種の実施形態では、本明細書において提供する抗体は、多重特異性抗体、例えば、二重特異性抗体である。多重特異性抗体は、少なくとも2つの異なる部位について結合特異性を有するモノクローナル抗体である。ある種の実施形態では、結合特異性の一方は、OX40についてのものであり、他方は、任意の他の抗原についてのものである。ある種の実施形態では、二重特異性抗体は、OX40の2つの異なるエピトープに結合してもよい。二重特異性抗体を使用して、細胞傷害性薬物を、OX40を発現する細胞に限局させてもよい。二重特異性抗体は、全長抗体または抗体断片として調製することができる。
ある種の実施形態では、本明細書において提供する抗体のアミノ酸配列変異体を企図する。例えば、抗体の結合親和性及び/または他の生物学的特性を改善することが望ましいことがある。抗体のアミノ酸配列変異体は、適切な修飾を、抗体をコードするヌクレオチド配列中に導入することによって、またはペプチド合成によって調製してもよい。そのような修飾には、例えば、抗体のアミノ酸配列からの残基の欠失、及び/または抗体のアミノ酸配列への残基の挿入、及び/または抗体のアミノ酸配列内での残基の置換が含まれる。欠失、挿入、及び置換の任意の組合せを作製して、最終構築物に到達することができるが、ただし、その最終構築物が、所望の特性、例えば、抗原結合性を保有することを条件とする。
ある種の実施形態では、1つまたは複数のアミノ酸置換を有する抗体変異体を提供する。置換型変異誘発についての対象部位には、HVR及びFRが含まれる。保存的置換を表Aにおいて、「好ましい置換」の見出しの下に示す。より実質的な変化を表Aにおいて、「例示的な置換」の見出しの下に提供し、またアミノ酸側鎖クラスを参照して下記にさらに記載する。アミノ酸置換を対象抗体に導入し、産物を、所望の活性、例えば、保持/改善された抗原結合、減少した免疫原性、または改善されたADCC若しくはCDCについて、スクリーニングしてもよい。
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)塩基性:His、Lys、Arg;
(5)鎖配向に影響を及ぼす残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe。
ある種の実施形態では、本明細書において提供する抗体を、抗体がグリコシル化される程度を上昇または低下させるように変化させる。抗体へのグリコシル化部位の付加または欠失は、1つまたは複数のグリコシル化部位が作成または除去されるように、アミノ酸配列を変化させることによって、好都合に遂行してもよい。
ある種の実施形態では、1つまたは複数のアミノ酸修飾を、本明細書において提供する抗体のFc領域に導入し、それによってFc領域変異体を生成してもよい。Fc領域変異体は、1つまたは複数のアミノ酸位置にアミノ酸修飾(例えば、置換)を含む、ヒトFc領域配列(例えば、ヒトIgG1、IgG2、IgG3、またはIgG4 Fc領域)を含んでもよい。
ある種の実施形態では、抗体の1個または複数個の残基がシステイン残基で置換されている、システイン操作された抗体、例えば、「チオMab」を作成することが望ましいことがある。特定の実施形態では、置換残基は、抗体のアクセス可能な部位において生じる。それらの残基をシステインで置換することによって、反応性のチオール基はそれによって、抗体のアクセス可能な部位に位置付けられ、それを使用して、抗体を、薬物部分またはリンカー−薬物部分などの他の部分にコンジュゲートさせて、本明細書においてさらに記載するとおりのイムノコンジュゲートを作成してもよい。ある種の実施形態では、次の残基のうちの任意の1個または複数個をシステインで置換してもよい:軽鎖のV205(Kabatナンバリング)、重鎖のA118(EUナンバリング)、及び重鎖Fc領域のS400(EUナンバリング)。システイン操作された抗体を、例えば、米国特許第7,521,541号において記載されているとおりに生成してもよい。
ある種の実施形態では、本明細書において提供する抗体を、当技術分野で公知であり、容易に入手可能な追加の非タンパク質性部分を含有するようにさらに修飾してもよい。抗体の誘導体化に適した部分には、限定されないが、水溶性ポリマーが含まれる。水溶性ポリマーの非限定的な例には、限定されないが、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールのコポリマー、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ−1,3−ジオキソラン、ポリ−1,3,6−トリオキサン、エチレン/無水マレイン酸コポリマー、ポリアミノ酸(ホモポリマーまたはランダムコポリマーのいずれか)、及びデキストランまたはポリ(n−ビニルピロリドン)ポリエチレングリコール、プロプロピレン(propropylene)グリコールホモポリマー、プロリプロピレン(prolypropylene)オキシド/エチレンオキシドコポリマー、ポリオキシエチル化ポリオール(例えば、グリセロール)、ポリビニルアルコール、ならびにそれらの混合物が含まれる。ポリエチレングリコールプロピオンアルデヒドは、水中でのその安定性によって、製造において利点を有し得る。ポリマーは、任意の分子量のものであってもよく、分岐していても非分岐であってもよい。抗体に付着したポリマーの数は、様々であってもよく、1つを超えるポリマーが付着される場合、それらは、同じ分子または異なる分子であり得る。一般に、誘導体化に使用されるポリマーの数及び/または種類は、限定されないが、改善される抗体の特定の特性または機能、抗体誘導体が規定の条件下で療法において使用されるかどうかなどを含む考察に基づいて、決定することができる。
抗体を、例えば、米国特許第4,816,567号において記載されているとおり、組換え法及び組成物を使用して生産してもよい。一実施形態では、本明細書に記載の抗OX40抗体をコードする単離核酸を提供する。そのような核酸は、抗体のVLを含むアミノ酸配列及び/またはVHを含むアミノ酸配列(例えば、抗体の軽鎖及び/または重鎖)をコードし得る。さらなる実施形態では、そのような核酸を含む1種または複数種のベクター(例えば、発現ベクター)を提供する。さらなる実施形態では、そのような核酸を含む宿主細胞を提供する。そのような一実施形態では、宿主細胞は、(1)抗体のVLを含むアミノ酸配列及び抗体のVHを含むアミノ酸配列をコードする核酸を含むベクター、または(2)抗体のVLを含むアミノ酸配列をコードする核酸を含む第1のベクター、及び抗体のVHを含むアミノ酸配列をコードする核酸を含む第2のベクターを含む(例えば、それらで形質転換されている)。一実施形態では、宿主細胞は、真核性、例えば、チャイニーズハムスター卵巣(CHO)細胞またはリンパ系細胞(例えば、Y0、NS0、Sp20細胞)である。一実施形態では、抗OX40抗体を作製する方法であって、上記で提供したとおりの抗体をコードする核酸を含む宿主細胞を、抗体の発現に適した条件下で培養することと、任意選択的に、抗体を宿主細胞(または宿主細胞培養培地)から回収することとを含む方法を提供する。
本明細書において提供する抗OX40抗体は、それらの物理/化学特性及び/または生物学的活性について、当技術分野で公知の様々なアッセイによって、特定され、スクリーニングされ、または特徴付けられてもよい。
一態様では、本発明の抗体を、その抗原結合活性について、例えば、ELISA、ウェスタンブロットなどの公知の方法によって試験する。OX40結合を、当技術分野で公知の方法を使用して決定してもよく、例示的な方法を本明細書において開示する。一実施形態では、結合を、ラジオイムノアッセイを使用して測定する。例示的なラジオイムノアッセイを実施例において例示する。OX40抗体をヨウ化し、固定濃度のヨウ化抗体及び漸減濃度の系列希釈された未標識OZ X40抗体を含有する競合反応混合物を調製する。OX40を発現する細胞(例えば、ヒトOX40で安定的にトランスフェクトされたBT474細胞)を、反応混合物に添加する。インキュベーションの後に、細胞を洗浄して、遊離ヨウ化OX40抗体を、細胞に結合したOX40抗体から分離する。結合したヨウ化OX40抗体のレベルを、例えば、細胞に関連した放射能をカウントすることによって決定し、結合親和性を、標準的な方法を使用して決定する。別の実施形態では、表面発現OX40(例えば、T細胞サブセット上)に結合するOX40抗体の能力を、フローサイトメトリーを使用して評価する。末梢白血球を得(例えば、ヒト、カニクイザル、ラット、またはマウスから)、細胞を血清でブロッキングする。標識されたOX40抗体を系列希釈法で添加し、T細胞も、T細胞サブセットを特定するために染色する(当技術分野で公知の方法を使用)。試料のインキュベーション及び洗浄の後に、細胞を、フローサイトメーターを使用して分類し、データを、当技術分野で周知の方法を使用して分析する。別の実施形態では、OX40結合を、表面プラスモン共鳴を使用して分析してもよい。例示的な表面プラスモン共鳴方法は、実施例において例示する。
一態様では、生物学的活性を有する抗OX40抗体をそこから特定するためのアッセイを提供する。生物学的活性には、例えば、OX40への結合(例えば、ヒト及び/またはカニクイザルOX40への結合)、OX40媒介性シグナル伝達の増大(例えば、NFkB−媒介性転写の増大)、ヒトOX40を発現する細胞(例えば、T細胞)の枯渇、ADCC及び/または食作用による、ヒトOX40を発現する細胞の枯渇、例えばエフェクターT細胞増殖の増大及び/またはエフェクターT細胞によるサイトカイン産生(例えば、ガンマインターフェロン)の増大によるTエフェクター細胞機能(例えば、CD4+エフェクターT細胞)の増強、例えばメモリーT細胞増殖の増大及び/またはメモリーT細胞によるサイトカイン産生(例えば、ガンマインターフェロン)の増大によるメモリーT細胞機能(例えば、CD4+メモリーT細胞)の増強、調節性T細胞機能の阻害(例えば、エフェクターT細胞機能(例えば、CD4+エフェクターT細胞機能)のTreg抑制の低下による)、ヒトエフェクター細胞への結合が含まれ得る。in vivo及び/またはin vitroでそのような生物学的活性を有する抗体も提供する。
本発明はまた、1種または複数種の細胞傷害性薬剤、例えば、化学療法薬若しくは薬物、成長阻害薬、毒素(例えば、タンパク質毒素、細菌、真菌、植物、若しくは動物由来の酵素活性毒素、またはその断片)、または放射性同位体にコンジュゲートされた本明細書の抗OX40抗体を含むイムノコンジュゲートを提供する。
ある種の実施形態では、本明細書において提供する抗OX40抗体はいずれも、生体試料中のOX40の存在を検出するために有用である。「検出すること」という用語は、本明細書において使用する場合、定量または定性検出を包含する。ある種の実施形態では、生体試料は、細胞または組織、例えば、腫瘍(例えば、NSCLCまたは乳房腫瘍)の試料を含む。
本明細書に記載のとおりの抗OX40抗体の医薬製剤は、所望の程度の純度を有するそのような抗体を、1種または複数種の任意選択的な薬学的に許容される担体(Remington’s Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))と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調製される。薬学的に許容される担体は一般に、用いられる投薬量及び濃度で、受容者に対して非毒性であり、それらには、限定されないが:リン酸塩、クエン酸塩、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;防腐剤(塩化オクタデシルジメチルベンジルアンモニウムなど;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;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、もしくは免役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、もしくはリシンなどのアミノ酸;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炭水化物;EDTAなどのキレート化剤;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;金属複合体(例えば、Zn−タンパク質複合体);ならびに/また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。本明細書における例示的な薬学的に許容される担体には、可溶性の中性活性ヒアルロニダーゼ糖タンパク質(sHASEGP)などの介在性(insterstitial)薬物分散剤、例えば、rHuPH20(HYLENEX(登録商標)、Baxter International,Inc.)などのヒト可溶性PH−20ヒアルロニダーゼ糖タンパク質がさらに含まれる。rHuPH20を含む、ある種の例示的なsHASEGP及び使用方法は、米国特許出願公開第2005/0260186号及び同第2006/0104968号において記載されている。一態様では、sHASEGPは、コンドロイチナーゼなどの1種または複数種の追加のグリコサミノグリカナーゼと組み合わされる。
本明細書において提供する抗ヒトOX40抗体のいずれも、治療方法において使用され得る。
である。一部の実施形態では、IDOアンタゴニストは、INCB24360である。一部の実施形態では、IDOアンタゴニストは、Indoximod(1−メチル−トリプトファンのD異性体)である。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、抗体−薬物コンジュゲートと併せて投与してもよい。一部の実施形態では、抗体−薬物コンジュゲートは、メルタンシンまたはモノメチルオーリスタチンE(MMAE)を含む。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、抗NaPi2b抗体−MMAEコンジュゲート(DNIB0600A、RG7599、またはリファスツズマブ・ベトチン(lifastuzumab vedotin)としても公知)と併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、トラスツズマブ・エムタンシン(T−DM1、ado−トラスツズマブ・エムタンシン、またはKADCYLA(登録商標)(Genentech)としても公知)と併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、抗MUC16抗体−MMAEコンジュゲート、DMUC5754Aと併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、抗MUC16抗体−MMAEコンジュゲート、DMUC4064Aと併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、エンドセリンB受容体(EDNBR)をターゲティングする抗体−薬物コンジュゲート、例えば、MMAEとコンジュゲートした、EDNBRに対する抗体と併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、リンパ球抗原6複合体、ローカスE(locus E)(Ly6E)をターゲティングする抗体−薬物コンジュゲート、例えば、MMAEとコンジュゲートした、Ly6Eに対する抗体(DLYE5953Aとしても公知)と併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、ポラツズマブ・ベドチンと併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、CD30をターゲティングする抗体−薬物コンジュゲートと併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、ADCETRIS(ブレンツキシマブ・ベドチンとしても公知)と併せて投与してもよい。一部の実施形態では、抗ヒトOX40アゴニスト抗体を、ポラツズマブ・ベドチンと併せて投与してもよい。
本発明の別の態様では、上記の障害の処置、防止、及び/または診断に有用な材料を含有する製品を提供する。製品は、容器、及び容器上か、またはそれに随伴するラベルまたは添付文書を含む。適切な容器には、例えば、ボトル、バイアル、シリンジ、静脈内用溶液バッグなどが含まれる。容器は、様々な材料、例えば、ガラスまたはプラスチックから形成されていてよい。容器は、組成物だけか、または状態の処置、防止、及び/もしくは診断に有効である別の組成物と組み合わせられている組成物を保持し、滅菌アクセスポート(例えば、容器は、皮下注射針で穴開けされ得るストッパーを備えた静脈内用溶液バッグまたはバイアルであってよい)を有してもよい。組成物中の少なくとも1種の活性薬剤は、本発明の抗体である。ラベルまたは添付文書は、組成物が、選択された状態の処置に使用されることを表示する。さらに、製品は、(a)本発明の抗体を含む組成物を中に含む第1の容器;及び(b)さらなる細胞傷害性薬または別段の治療薬を含む組成物を中に含む第2の容器を含んでもよい。本発明のこの実施形態における製品は、組成物が、特定の状態を処置するために使用することができることを表示する添付文書をさらに含んでもよい。あるいは、または加えて、製品は、薬学的に許容される緩衝液、例えば、注射用静菌水(BWFI)、リン酸緩衝生理食塩水、リンゲル液、及びデキストロース溶液を含む第2(または第3)の容器をさらに含んでもよい。これは、他の緩衝液、希釈剤、フィルター、針、及びシリンジを含む、商業的及び使用者の見地から望ましい他の材料をさらに含んでもよい。
表面プラスモン共鳴:Biacore 3000 装置(GE Healthcare)で表面プラスモン共鳴(SPR)を使用して、抗OX40抗体の結合反応速度を測定した。製造者が提供するプロトコルを使用して、アミンベースのカップリングによって、CM5センサーチップ上に抗ヒトFc(GE Healthcare)を固定化した。抗OX40抗体は、300〜400共鳴単位(RU)のレベルで捕捉された。ヒトOX40(Sino Biological Inc)に対して、抗体結合を測定した。18.75〜300nMまたは6.25〜200nMの範囲を有するhuOX40の2倍濃度系列を、実験のために使用した。30μl/分の流速、25℃の温度で、10mM HEPES、pH7.4、150mM NaCl、及び0.005%Tween 20の泳動緩衝液を用い、2分の注入時間を使用して、OX40の結合についてのセンサーグラムを記録した。注入の後に、抗体からのリガンドの分離を、泳動緩衝液中で600秒間にわたってモニターした。結合サイクルの合間に、3M塩化マグネシウム40μlの注入で、表面を再生させた。泳動緩衝液のみを含有したブランクを差し引いた後に、1:1 Langmuir結合モデルを、製造者が供給するソフトウェアで使用して、抗OX40抗体へのOX40の結合について観察されたセンサーグラムを分析して、反応速度及び結合定数を算出した。
OX40アゴニスト抗体は、ナノモル未満の親和性でヒトOX40と結合した。表面プラスモン共鳴分析を使用して、ヒトOX40への抗OX40抗体結合の結合反応速度を測定した。Biacoreによって測定した場合に、ヒト化抗体1A7の変異体は、ヒトOX40に対して高い親和性結合を示した。この分析の結果を、表2において示す。
表2:ヒトOX40へのヒト化抗OX40抗体1A7変異体結合の反応速度定数
表4:ヒトOX40へのヒト化抗OX40抗体1D2変異体結合の反応速度定数
表5:mab 1A7.gr.1の変異体に導入した変異
表6:ヒトOX40への抗OX40 1A7変異体結合の反応速度定数
表7:mab 3C8.gr.5の変異体に導入した変異
表8:ヒトOX40への抗OX40 3C8安定性変異体結合についての反応速度定数
表9:ヒトOX40への抗OX40 1A7.gr.1アラニンスキャン変異体結合の反応速度定数(置換アラニンに下線が付されている)
[訳者注:下記表で[ ]で囲まれている配列箇所は、PCT/US2015/023432では、下線が引かれた文字である。]
表10:ヒトOX40への抗OX40 3C8.gr.5アラニンスキャン変異体結合の反応速度定数(アラニン置換に下線が付されている)
[訳者注:下記表で[ ]で囲まれている配列箇所は、PCT/US2015/023432では、下線が引かれた文字である。]
表11 組換えヒトOX40を発現するBT−474細胞へのmab 1A7.gr.1結合の平衡結合分析
表12:ヒト及びカニクイザルT細胞へのMab 1A7.gr.1結合
1. 抗体:精製抗ヒトOX40(PE)(クローンACT35)、マウスIgG1(PE)、抗ヒトCD3(クローンSP34)、抗ヒトCD4(FITC)、抗ヒトCD25(PE)、抗ヒトCD45RA(APC)、抗ヒトCD3−APC、及び精製マウス抗ヒトCD11b抗体は、BD biosciencesから購入した。アレムツズマブ(Campath)は、Genzymeから購入した。抗ヒトCD52(APC)は、Sigmaから購入した。ヤギ抗マウスIgG Alexa Fluor 647は、Invitrogenから購入した。抗ヒトCD127(eFluor 450)及びラット抗マウスOX40(PE、クローンOX86)は、eBiosciencesから購入した。抗ヒトOX40抗体IA7gr1、リツキシマブ(キメラ抗CD20、IgG1)及び抗HSV糖タンパク質D(抗gD抗体、ヒトIgG1)は、Genentechで生成した。抗ヒトIgG(PE)は、BD Biosciencesから購入した。ヒトCD4 Isolation Kit IIは、Miltenyi Biotechからのものであった。ヒトNK Isolationキットは、Stem Cell Technologyから購入した。
Mab 1A7.gr.1は、CD4+ナイーブT細胞のTreg抑制を阻害した:本発明者らは、Treg細胞へのOX40アゴニスト抗体の結合によるOX40架橋結合が、ナイーブT細胞増殖を阻害するそれらの能力を阻害するかどうかを試験した。ナイーブCD4+T細胞増殖は、1A7.gr1の不在下で抗CD3架橋結合によって誘発された。ナイーブT細胞培養物へのTreg細胞の添加は、抗CD3誘発性ナイーブT細胞増殖を抑制した。mAb 1A7.gr.1での処理は、調節性T細胞の抑制機能を阻害した(n=3、図6)。フローサイトメトリー分析によって低CFSE集団をモニターすることによって、ナイーブT細胞増殖を測定した。この結果は、mAb 1A7.gr.1がTreg細胞の抑制機能を阻害することを実証した。
OX40L及び抗OX40結合競合アッセイ。抗ヒトOX40抗体1A7gr1を、Alexa Fluor647にコンジュゲートさせた。ヒトOX40L−フラッグ及びヒトDR5−フラッグタンパク質は、Genentechで生成した。Alexa Fluor 555にコンジュゲートした抗フラッグ抗体は、Cell Signaling(カタログ番号3768)から購入した。トランスジェニックHut78−hOX40細胞(Hut78−hOX40、ヒトT細胞系、ヒトOX40発現のためにレトロウイルスで形質導入)を培養し、完全RPMI培地(RPMI−1640、10%FBS(熱不活化)/Pen/strep/グルタミン/非必須アミノ酸/55uM βMEで補充)中、37℃/5%CO2インキュベーターで維持した。
滴定実験は、抗ヒトOX40mab 1A7gr1が用量依存的にHut78−hOX40細胞に結合し、最大結合の70%が約200ng/mLの抗体で観察されることを実証した(図12A)。この濃度を、競合実験のために選択した。OX40L−フラッグはまた、Hut78−hOX40細胞への用量依存的結合を実証した(図12B)。
マウスにおける抗OX40の薬物動態(PK)評価。雌のB6.CB17−Prkdcscid/SzJマウス(n=12動物/群)に、0日目に、1A7.gr1 IgG1(MOXR0916)の単回静脈内注射を1mg/kgまたは10mg/kgで与えた。各マウスに、5mL/kg(1mg/kg用量は、0.2mg/mLの濃度であり;10mg/kg用量は、2mg/mLの濃度であった)の用量体積を与えた。投与後5分目;1、3、8、及び24時間目;ならびに2、4、7、10、14、21、及び28日目に、心臓穿刺(1動物当たり3時点;1時点当たり3動物)によって、各動物から血液試料(125〜150μL)を収集した。研究のために投与前試料を収集しなかった。試料を、血清分離管を備えた管に収集し、下記のとおり処理した。
カニクイザルにおけるパイロット4週間毒性研究。ビヒクル(10mM酢酸ヒスチジン、6%スクロース、0.02%Tween20、pH5.8)または1A7.gr1 IgG1を、0.01、0.3、または10mg/kg/用量で、雄のカニクイザルに静脈内投与した。投与計画は、2週間毎に1回で3回の投与であった(1、15、及び29日目に投与)。終末検死を、最後の投与の3日後に行った。安全性エンドポイントには:臨床観察及び毎日の観察、臨床病理、凝固、検尿、肉眼及び顕微鏡による分析、毒物動態(TK)、及び抗治療抗体(ATA)力価が含まれた。薬力学的(PD)分析には、血清サイトカイン、T細胞活性化/増殖/枯渇、及びOX40受容体占有率が含まれた。
パイロット毒性研究
この研究の目的は、2週毎に1回(1、15、及び29日目)、合計3回の投与で静脈内注射を介してカニクイザルに投与した場合の抗OX40(1A7.gr1 IgG1)の毒性、毒物動態プロファイル、及び薬力学を評価することであった。
GLP毒性研究の目的は、0、0.5、5、及び30mg/kg/用量で静脈内投与されたカニクイザルにおいて、研究日1、15、29、43日目に、続いて、無投与の42日目(回復期間)に、1A7.gr1の毒性を決定することであった。
Claims (41)
- (1)(a)DSYMS(配列番号2)のアミノ酸配列を含むHVR−H1;(b)DMYPDNGDSSYNQKFRE(配列番号3)のアミノ酸配列を含むHVR−H2;及び(c)APRWYFSV(配列番号4)のアミノ酸配列を含むHVR−H3を含む重鎖可変ドメイン(VH);並びに
(2)(d)RASQDISNYLN(配列番号5)のアミノ酸配列を含むHVR−L1;(e)YTSRLRS(配列番号6)のアミノ酸配列を含むHVR−L2;及び(f)QQGHTLPPT(配列番号7)のアミノ酸配列を含むHVR−L3を含む軽鎖可変ドメイン(VL)を含む、ヒトOX40に結合する抗体。 - ヒトOX40に結合する抗体が抗ヒトOX40アゴニスト抗体である、請求項1に記載の抗体。
- ヒトOX40及びカニクイザルOX40と結合する、請求項1又は2に記載の抗体。
- 2週間にわたる40℃での処理の後に安定している、請求項1〜3のいずれか1項に記載の抗体。
- VHドメインが、配列番号56のアミノ酸配列に対し、少なくとも90%の配列同一性を有する、請求項1〜4のいずれか1項に記載の抗体。
- VHドメインが、配列番号56のアミノ酸配列に対し、少なくとも95%の配列同一性を有する、請求項5に記載の抗体。
- VHドメインが、配列番号56のアミノ酸配列を含む、請求項5に記載の抗体。
- VLドメインが、配列番号57のアミノ酸配列に対し、少なくとも90%の配列同一性を有する、請求項1〜7のいずれか1項に記載の抗体。
- VLドメインが、配列番号57のアミノ酸配列に対し、少なくとも95%の配列同一性を有する、請求項8に記載の抗体。
- VLドメインが配列番号57のアミノ酸配列を含む、請求項8に記載の抗体。
- VHドメインが配列番号56のアミノ酸配列を含み、かつVLドメインが配列番号57のアミノ酸配列を含む、請求項1〜4のいずれか1項に記載の抗体。
- Fab、Fab’、Fab’−SH、F(ab’)2、Fv、及びscFv断片からなる群から選択される抗体断片である、請求項1〜11のいずれか1項に記載の抗体。
- ヒトIgG1 Fc領域をさらに含む、請求項1〜11のいずれか1項に記載の抗体。
- モノクローナル抗体である、請求項1〜11のいずれか1項に記載の抗体。
- ヒト化抗体である、請求項1〜14のいずれか1項に記載の抗体。
- 請求項1〜15のいずれか1項に記載の抗体をコードする単離核酸。
- 請求項16に記載の核酸を含む宿主細胞。
- 請求項17に記載の宿主細胞を培養して、抗体が産生されるようにすることを含む、抗体を生産する方法。
- 宿主細胞から抗体を回収することをさらに含む、請求項18に記載の方法。
- 細胞傷害性薬物又は標識にコンジュゲートされた請求項1〜15のいずれか1項に記載の抗体を含むイムノコンジュゲート。
- 請求項1〜15のいずれか1項に記載の抗体、及び薬学的に許容される担体を含む組成物。
- 緩衝液、界面活性剤、及び糖を含む、請求項21に記載の組成物。
- 10mg/mL〜100mg/mLの抗体、0.01%〜0.1%(w/v)の界面活性剤、100mM〜320mMの糖、1mM〜50mMのヒスチジン緩衝液を含み、pHが5.0〜6.0である、請求項21に記載の組成物。
- 10mg/mL〜100mg/mLの抗体、0.01%〜0.1%(w/v)の界面活性剤、100mM〜150mMの糖、1mM〜25mMのヒスチジン緩衝液を含み、pHが5.0〜6.0である、請求項21に記載の組成物。
- 50mg/mL〜75mg/mLの抗体、0.01%〜0.1%(w/v)の界面活性剤、110mM〜130mMの糖、20mM〜30mMのヒスチジン緩衝液を含み、pHが5.0〜6.0である、請求項21に記載の組成物。
- 10mg/mL〜100mg/mLの抗体、0.02%〜0.06%(w/v)のポリソルベート、100mM〜320mMのスクロース、1mM〜50mMのヒスチジン緩衝液を含み、pHが5.0〜6.0である、請求項21に記載の組成物。
- 60mg/mLの抗体、0.03%(w/v)のポリソルベート、120mMのスクロース、20mMの酢酸ヒスチジン緩衝液を含み、pHが5.5である、請求項21に記載の組成物。
- 有効量の請求項1〜15のいずれか1項に記載の抗体又は請求項21に記載の組成物を含む、がんを有する個体を処置するための医薬。
- 抗体又は組成物が追加の治療剤と共に投与される、請求項28に記載の医薬。
- 追加の治療剤が化学療法薬を含む、請求項29に記載の医薬。
- 追加の治療剤がPD−1軸結合アンタゴニストを含む、請求項29に記載の医薬。
- PD−1軸結合アンタゴニストがPD−L1結合アンタゴニストである、請求項31に記載の医薬。
- PD−L1結合アンタゴニストが抗PD−L1抗体である、請求項32に記載の医薬。
- PD−1軸結合アンタゴニストがPD−1結合アンタゴニストである、請求項31に記載の医薬。
- PD−1結合アンタゴニストが抗PD−1抗体である、請求項34に記載の医薬。
- 抗PD−1抗体がニボルマブ又はペムブロリズマブである、請求項35に記載の医薬。
- がんが、乳がん、肺がん、黒色腫、腎臓細胞がん、膀胱がん、結腸直腸がん、及び卵巣がんからなる群から選択される、請求項28〜36のいずれか1項に記載の医薬。
- がんが三種陰性乳がんである、請求項28〜36のいずれか1項に記載の医薬。
- がんが非小細胞肺がんである、請求項28〜36のいずれか1項に記載の医薬。
- がんが尿路のがんである、請求項28〜36のいずれか1項に記載の医薬。
- がんを処置するための医薬の製造における、請求項1〜15のいずれか1項に記載の抗体の使用。
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