JP6425730B2 - Pd−1に対するヒト抗体 - Google Patents
Pd−1に対するヒト抗体 Download PDFInfo
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- JP6425730B2 JP6425730B2 JP2016548008A JP2016548008A JP6425730B2 JP 6425730 B2 JP6425730 B2 JP 6425730B2 JP 2016548008 A JP2016548008 A JP 2016548008A JP 2016548008 A JP2016548008 A JP 2016548008A JP 6425730 B2 JP6425730 B2 JP 6425730B2
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Description
別段具体的に示されない限り、本明細書において用いられる用語「抗体」は、2つの免疫グロブリン重鎖、および2つの免疫グロブリン軽鎖を含む抗体分子(すなわち、「完全抗体分子」)、ならびにその抗原結合フラグメントを包含することは理解されるだろう。本明細書において用いられる用語、抗体の「抗原結合部分」、抗体の「抗原結合フラグメント」などは、任意の天然に生じる、酵素的に得られる、合成された、または遺伝子操作された、抗原に特異的に結合して複合体を形成するポリペプチドもしくは糖タンパク質を含む。本明細書において用いられる用語、抗体の「抗原結合フラグメント」、または「抗体フラグメント」は、PD−1に特異的に結合する能力を保持する抗体の1つまたはそれ以上のフラグメントを指す。抗体フラグメントは、Fabフラグメント、F(ab’)2フラグメント、Fvフラグメント、dAbフラグメント、CDRを含有するフラグメント、または単離されたCDRを含む。ある種の実施形態において、用語「抗原結合フラグメント」は、多特異性抗原結合分子のポリペプチドフラグメントを指す。かかる実施形態において、用語「抗原結合フラグメント」は、例えば、PD−1に特異的に結合するPD−L1の細胞外ドメインを含む。抗体の抗原結合フラグメントは、例えば、タンパク質消化、または抗体可変および(場合により)定常ドメインをコードするDNAの操作および発現を伴う組み換え遺伝子操作技術のような任意の適切な標準的技術を用いて、完全抗体分子から得ることができる。かかるDNAは公知であり、および/または例えば、市販の供給源、DNAライブラリー(例えば、ファージ−抗体ライブラリーを含む)から容易に入手可能であるか、もしくは合成される。DNAは、配列決定され、化学的に、または分子生物学技術を用いることにより操作されて、例えば、1つもしくはそれ以上の可変および/もしくは定常ドメインが適切な配置に配置されるか、またはコドンが導入されるか、システイン残基が作製されるか、アミノ酸が修飾されるか、付加されるか、もしくは欠損される。
遺伝子導入マウスにおいてヒト抗体を作製する方法は、当該分野で公知である。任意のかかる公知の方法を、本発明の文脈において用いて、PD−1に特異的に結合するヒト抗体が作られる。
本発明の抗PD−1抗体および抗体フラグメントは、記載される抗体のものと異なるが、PD−1に結合する能力を保持する、アミノ酸配列を有するタンパク質を包含する。かかる変異体抗体および抗体フラグメントは、親配列と比較された場合、アミノ酸の1つまたはそれ以上の付加、欠失、または置換を含むが、記載される抗体のものと実質的に等価物である生物学的活性を示す。同様に、本発明のDNA配列をコードする抗体は、開示される配列と比較された場合、ヌクレオチドの1つまたはそれ以上の付加、欠失、または置換を含むが、本発明の抗体または抗体フラグメントに実質的な生物学的等価物である抗体または抗体フラグメントをコードする配列を含む。
本発明のある種の実施形態によると、例えば、中性pHと比較して酸性pHにおいて、FcRn受容体への抗体結合を増強するか、もしくは損なう1つまたはそれ以上の変異を含むFcドメインを含む抗PD−1抗体が提供される。例えば、本発明は、FcドメインのCH2またはCH3領域における変異を含む抗PD−1抗体を含み、ここで、変異は、酸性環境において(例えば、pHが約5.5〜約6.0の範囲にあるエンドソームにおいて)、FcRnに対するFcドメインの親和性を増大させる。かかる変異は、動物に投与される場合、抗体の血清半減期の増大をもたらす。かかるFc修飾の非限定的な例は、例えば、250位(例えば、EもしくはQ);250位および428位(例えば、LもしくはF);252位(例えば、L/Y/F/W、もしくはT)、254位(例えば、S、もしくはT)、ならびに256位(例えば、S/R/Q/E/D、もしくはT)における修飾;または428位および/もしくは433位(例えば、H/L/R/S/P/Q、もしくはK)および/もしくは434位(例えば、A、W、H、F、もしくはY[N434A、N434W、N434H、N434F、もしくはN434Y])における修飾;または250位および/もしくは428位における修飾;または307位もしくは308位(例えば、308F、V308F)、および434位における修飾を含む。1つの実施形態において、修飾は、428L(例えば、M428L)、ならびに434S(例えば、N434S)修飾;428L、259I(例えば、V259I)、ならびに308F(例えば、V308F)修飾;433K(例えば、H433K)、ならびに434(例えば、434Y)修飾;252、254、ならびに256(例えば、252Y、254T、および256E)修飾;250Q、ならびに428L修飾(例えば、T250Q、およびM428L);ならびに307、ならびに/または308修飾(例えば、308F、もしくは308P)を含む。なお別の実施形態において、修飾は、265A(例えば、D265A)、および/または297A(例えば、N297A)修飾を含む。
一般に、本発明の抗体は、PD−1に結合することにより機能する。本発明は、可溶性単量体または二量体PD−1分子を高親和性で結合する抗PD−1抗体およびその抗原結合フラグメントを含む。例えば、本発明は、例えば、本明細書における実施例3において定義されるアッセイフォーマットを用いて、表面プラズモン共鳴により測定される、(例えば、25℃において、または37℃において)約50nM未満のKDで単量体PD−1に結合する抗体および抗体の抗原結合フラグメントを含む。ある種の実施形態において、抗体またはその抗原結合フラグメントは、例えば、本明細書における実施例3において定義されるアッセイフォーマット、もしくは実質的に類似のアッセイを用いて、表面プラズモン共鳴により測定される、約40nM未満、約30nM未満、約20nM未満、約10nM未満、約5nM未満、約2nM未満、もしくは約1nM未満のKDで単量体PD−1に結合する。
本発明のある種の実施形態によると、抗PD−1抗体は、ヒトPD−1に結合するが、他の種由来のPD−1に結合しない。あるいは、本発明の抗PD−1抗体は、ある種の実施形態において、ヒトPD−1、および1つまたはそれ以上の非ヒト種由来のPD−1に結合する。例えば、本発明の抗PD−1抗体は、ヒトPD−1に結合し、マウス、ラット、モルモット、ハムスター、スナネズミ、ブタ、ネコ、イヌ、ウサギ、ヤギ、ヒツジ、ウシ、ウマ、ラクダ、カニクイザル、マーモセット、アカゲザル、もしくはチンパンジーPD−1のうちの1つもしくはそれ以上に結合するか、または結合しない。ある種の実施形態において、本発明の抗PD−1抗体は、ヒトおよびカニクイザルPD−1に、同一の親和性で、または異なる親和性で結合するが、ラットおよびマウスPD−1に結合しない。
本発明は、例えば、細胞外(IgV様)ドメイン、膜貫通型ドメイン、ならびに免疫受容体チロシンベースの阻害モチーフ(ITIM)および免疫受容体チロシンベースのスイッチモチーフ(ITSM)を含有する細胞内ドメインを含むPD−1分子の1つまたはそれ以上のドメイン内で見出される1個またはそれ以上のアミノ酸と相互作用する、抗PD−1抗体を含む。抗体が結合するエピトープは、PD−1分子の前述のドメインのいずれかに位置する、3個またはそれ以上(例えば、3個、4個、5個、6個、7個、8個、9個、10個、11個、12個、13個、14個、15個、16個、17個、18個、19個、20個もしくはそれ以上)のアミノ酸の単一の連続配列からなる(例えば、ドメインにおける直線エピトープ)。あるいは、エピトープは、PD−1分子の前述のドメインのいずれかまたは両方に位置する、多数の非連続アミノ酸(もしくはアミノ酸配列)からなる(例えば、立体構造エピトープ)。
本発明は、細胞毒素、またはがんを処置するための化学療法剤のような、治療部分に結合したヒト抗PD−1モノクローナル抗体(「免疫複合体」)を包含する。本明細書において用いられる用語「免疫複合体」は、細胞毒素、放射性剤、サイトカイン、インターフェロン、標的もしくはレポーター部分、酵素、毒素、ペプチドもしくはタンパク質、もしくは治療剤に化学的または生物学的に結合される抗体を指す。抗体は、その標的に結合することができる限り、分子に沿った任意の位置において、細胞毒素、放射性剤、サイトカイン、インターフェロン、標的もしくはレポーター部分、酵素、毒素、ペプチド、または治療剤に結合される。免疫複合体の例は、抗体薬物複合体、および抗体と毒素の融合タンパク質を含む。1つの実施形態において、剤は、PD−1に対する第2の異なる抗体である。ある種の実施形態において、抗体は、腫瘍細胞、またはウイルス性に感染した細胞に特異的な剤に結合される。抗PD−1抗体に結合される治療部分のタイプは、処置されるべき条件、および達成されるべき所望の治療効果を考慮する。免疫複合体を形成させるのに適切な剤の例は、当該分野で公知であり、例えば、WO05/103081を参照。
本発明の抗体は、単特異性、二重特異性、または多特異性である。多特異性抗体は、1つの標的ポリペプチドの異なるエピトープに特異的であるか、または1つより多くの標的ポリペプチドに特異的な抗原結合ドメインを含有する。例えば、Tuttら、1991年、J.Immunol.147:60〜69頁;Kuferら、2004年、Trends Biotechnol.22:238〜244頁を参照。
本発明は、本発明の抗PD−1抗体またはその抗原結合フラグメントを含む治療組成物を提供する。治療組成物は、本発明に従い、輸送、デリバリー、寛容の好転などをもたらすよう製剤に取り込まれる、適切な担体、賦形剤、および他の剤と共に投与される。多数の適切な製剤は、全ての医薬化学者に公知の処方書:Remington’s Pharmaceutical Sciences、Mack Publishing Company、Easton、PAにおいて見出される。これらの製剤は、例えば、粉末、ペースト、軟膏、ジェル、ワックス、油、脂質、脂質(陽イオンまたは陰イオン)含有ベシクル(例えば、LIPOFECTIN(商標))、DNA結合体、無水吸収ペースト、水中油型および油中水型エマルジョン、エマルジョンカルボワックス(種々の分子量のポリエチレングリコール)、半固体ジェル、ならびにカルボワックスを含有する半固体混合物を含む。Powellら、「Compendium of excipients for parenteral formulations」PDA(1998年)J Pharm Sci Technol52:238〜311頁も参照。
本発明の抗体は、とりわけ、PD−1発現、シグナル伝達、もしくは活性に関連するか、もしくはそれにより仲介される、もしくはPD−1とPD−1リガンド(例えば、PD−L1、もしくはPD−L2)との間の相互作用を遮断すること、もしくはそうでなければPD−1活性および/もしくはシグナル伝達を阻害することにより処置可能な、任意の疾患または障害の処置、予防、および/または改善に有用である。例えば、本発明は、処置を必要とする患者に、本明細書において記載される抗PD−1抗体(もしくは抗PD−1抗体を含む医薬組成物)を投与することによる、がん(腫瘍成長阻害)、慢性ウイルス感染症、および/または自己免疫疾患を処置する方法を提供する。本発明の抗体は、がん、自己免疫疾患、もしくはウイルス感染症のような疾患、もしくは障害、もしくは状態の処置、予防、および/もしくは改善するのに、ならびに/またはかかる疾患、障害、もしくは状態に関連する少なくとも1つの症状を改善するのに有用である。本明細書において記載される処置の方法の文脈において、抗PD−1抗体は、単独療法として(すなわち、唯一の治療剤として)、または1つもしくはそれ以上のさらなる治療剤(その例は、本明細書において他の場所で記載される)との併用で投与される。
併用療法は、本発明の抗PD−1抗体、および本発明の抗体、または本発明の抗体の生物学的に活性なフラグメントと有利に組み合わされる、任意のさらなる治療剤を含む。
本発明のある種の実施形態によると、複数回用量の抗PD−1抗体(または抗PD−1抗体、および本明細書において言及される、さらなる治療上活性な剤のいずれかの併用を含む医薬組成物)は、定義される時間経過に渡り、対象に投与される。本発明のこの態様による方法は、対象に、複数回用量の本発明の抗PD−1抗体を連続して投与することを含む。本明細書において用いられる「連続して投与すること」は、それぞれの用量の抗PD−1抗体が、対象に、時間における異なる点において、例えば、予め決定された間隔(例えば、時間、日、週、または月)により隔てられた異なる日において投与されることを意味する。本発明は、患者に、単回開始用量の抗PD−1抗体、続いて、1つまたはそれ以上の2次用量の抗PD−1抗体、場合により、続いて、1つまたはそれ以上の3次用量の抗PD−1抗体を連続して投与することを含む方法を含む。抗PD−1抗体は、0.1mg/kg〜100mg/kgの間の用量において投与される。
本発明の抗PD−1抗体を用いて、例えば、診断の目的のため、試料中のPD−1が検出され、および/または測定される。ある実施形態は、がん、自己免疫疾患、もしくは慢性ウイルス感染症のような疾患もしくは障害を検出するためのアッセイにおいて、1つまたはそれ以上の本発明の抗体の使用を考慮する。PD−1についての典型的な診断アッセイは、例えば、患者から得た試料を、本発明の抗PD−1抗体と接触させることを含み、ここで、抗PD−1抗体は、検出可能な標識もしくはレポーター分子で標識されるか、または患者試料からPD−1を選択的に単離するための捕捉リガンドとして用いられる。あるいは、未標識の抗PD−1抗体は、検出可能に標識されたそれ自体である2次抗体と組み合わせた診断適用において用いられる。検出可能な標識またはレポーター分子は、3H、14C、32P、35S、もしくは125Iのようなラジオアイソトープ;フルオレセインイソチオシアネート、もしくはローダミンのような蛍光もしくは化学発光部分;またはアルカリホスファターゼ、β−ガラクトシダーゼ、西洋ワサビペルオキシダーゼ、もしくはルシフェラーゼのような酵素である。試料中のPD−1を検出または測定するために用いられる特異的な典型的アッセイは、酵素結合免疫吸着アッセイ(ELISA)、ラジオイムノアッセイ(RIA)、および蛍光活性化細胞分取(FACS)を含む。
C93S変更を有するGenBank受託NP_005009.2(配列番号327)のおよそアミノ酸25〜170の範囲にあるPD−1のフラグメントを用いて、PD−1に対するヒト抗体を作製した。免疫応答を刺激するためのアジュバントと共に、ヒト免疫グロブリン重鎖およびカッパー軽鎖可変領域をコードするDNAを含むVELOCIMMUNE(登録商標)マウスに、免疫原を直接的に投与した。PD−1特異的イムノアッセイにより、抗体免疫応答をモニターした。所望の免疫応答を達成したら、脾細胞を回収し、マウスミエローマ細胞と融合させて生存能を保持し、ハイブリドーマ細胞株を形成させた。ハイブリドーマ細胞株をスクリーニングし、選択して、PD−1特異的抗体を産生する細胞株を同定した。この技術、および上で記載した免疫原を用いて、いくつかの抗PD−1キメラ抗体(すなわち、ヒト可変ドメインおよびマウス定常ドメインを有する抗体)を得て;この方法で作製した典型的な抗体を、H1M7789N、H1M7799N、H1M7800N、H2M7780N、H2M7788N、H2M7790N、H2M7791N、H2M7794N、H2M7795N、H2M7796N、およびH2M7798Nと命名した。
表1には、選択した本発明の抗PD−1抗体の重鎖および軽鎖可変領域、ならびにCDRのアミノ酸配列識別名を記載する。対応する核酸配列識別名を表2に記載する。
Biacore 4000またはBiacore T200機器におけるリアルタイム表面プラズモン共鳴バイオセンサーアッセイを用いて、精製した抗PD1抗体への抗原結合について、結合ならびに解離速度定数(それぞれ、kaおよびkd)、平衡解離定数、ならびに解離半減期(それぞれ、KDおよびt1/2)を決定した。Biacoreセンサー表面を、ポリクローナルウサギ抗マウス抗体(GE、番号BR−1008−38)、またはモノクローナルマウス抗ヒトFc抗体(GE、番号BR−1008−39)のいずれかで誘導体化して、それぞれ、マウスFcまたはヒトFcいずれかと共に発現させた、およそ100〜900RUの抗PD−1モノクローナル抗体を捕捉した。抗PD−1抗体への結合について試験したPD−1試薬は、C末端のmyc−myc−ヘキサヒスチジンタグと共に発現させた組み換えヒトPD−1(hPD−1−MMH;配列番号321)、C末端のmyc−myc−ヘキサヒスチジンタグと共に発現させた組み換えカニクイザルPD−1(MfPD−1−MMH;配列番号322)、C末端のマウスIgG2a Fcタグと共に発現させた組み換えヒトPD−1二量体(hPD−1−mFc;配列番号323)、またはC末端のヒトIgG1 Fcと共に発現させた組み換えヒトPD−1二量体(hPD1−hFc;配列番号324)、およびmFcを有するサルPD−1(配列番号329)を含んでいた。Biacore 4000における流速30μL/分、またはBiacore T200における流速50μL/分において、抗PD−1モノクローナル抗体捕捉表面に渡り、200nM〜3.7nMの範囲にある異なる濃度のPD−1試薬を注入した。捕捉したモノクローナル抗体へのPD−1試薬の結合を、3〜5分間モニターし、一方、抗体からのそれらの解離を、HBSTランニングバッファー(0.01M HEPES pH7.4、0.15M NaCl、3mM EDTA、0.05%v/v 界面活性剤P20)において7〜10分間モニターした。25℃および37℃において実験を行った。データを処理し、Scrubber 2.0c曲線近似ソフトウェアを用いて1:1結合モデルに近似させることにより、動力学的結合(ka)および解離(kd)速度定数を決定した。次に、動力学的速度定数から、KD(M)=kd/ka、およびt1/2(分)=[ln2/(60*kd)]として、結合解離平衡定数(KD)、ならびに解離半減期(t1/2)を計算した。25℃および37℃において、異なるPD−1試薬に結合する異なる抗PD−1モノクローナル抗体についての結合動力学的パラメーターを、表4〜11において表にした。
リガンド、PD−L1受容体へのヒトPD−1結合を遮断する抗PD−1抗体の能力を、3種の競合的サンドイッチELISAフォーマットを用いて測定した。C末端のヒトFcタグ(hPD−L1−hFc;配列番号325)もしくはC末端のマウスFcタグ(hPD−L1−mFc;配列番号326)いずれかと共に発現させたヒトPD−L1細胞外ドメインの部分を含む二量体ヒトPD−L1タンパク質、またはC末端のヒトFcタグ(hPD−L2−hFc;R&D Systems、番号1224−PL)と共に産生させたヒトPD−L2細胞外領域を含む二量体ヒトPD−L2を、PBS中2μg/mLの濃度にて、96ウェルマイクロタイタープレートにおいて、一晩、4℃において別々にコートした。PBS中0.5%(w/v) BSA溶液を用いて、非特異的結合部位を続いて遮断した。第1の競合フォーマットにおいて、抗体の最終濃度が0〜200nMの範囲になるように、C末端のマウスFcタグ(hPD−1−mFc;配列番号323)と共に発現させたヒトPD−1細胞外ドメインを含む、1.5nMの一定濃度の二量体ヒトPD−1タンパク質を、抗PD−1抗体またはアイソタイプ対照抗体の連続希釈液に加えた。第2の競合フォーマットにおいて、C末端のヒトFcタグと共に発現させた、ヒトPD−1細胞外ドメイン(biot−hPD−1−hFc;配列番号323)を含む、200pMの一定濃度の二量体ビオチン化ヒトPD−1タンパク質を、0〜50nMの範囲にある最終抗体濃度において、抗PD−1抗体またはアイソタイプ対照の連続希釈液に同様に加えた。第3の競合フォーマットにおいて、100pMの一定濃度の二量体hPD−1−mFcタンパク質を、0〜100nMの範囲にある最終抗体濃度において、抗PD−1抗体またはアイソタイプ対照の連続希釈液に同様に加えた。次に、これらの抗体とタンパク質複合体を、1時間、室温(RT)においてインキュベートした(incubated)。1.5nM一定のhPD−1−mFcとの抗体とタンパク質複合体を、hPD−L1−hFcでコートしたマイクロタイタープレートに移し、200pM一定のbiot−hPD−1−hFcとの抗体とタンパク質複合体を、hPD−L1−mFcコートプレートに移し、100pM一定のhPD−1−mFcとの抗体とタンパク質複合体を、hPD−L2−hFcでコートしたマイクロタイタープレートに移した。1時間RTにおいてインキュベートした後、ウェルを洗浄し、プレートに結合したhPD−1−mFcを、西洋ワサビペルオキシダーゼ(HRP)(Jackson ImmunoResearch Inc.、番号115−035−164)が結合した抗mFcポリクローナル抗体で検出し、プレートに結合したbiot−hPD−1−hFcを、HRP(Thermo Scientific、番号N200)が結合したストレプトアビジンで検出した。試料をTMB溶液(BD Biosciences、番号51−2606KC、および番号51−2607KC)で発展させて、比色分析反応を生じさせ、次に、色の発生を1M 硫酸の添加により安定化させ、その後、VictorX5プレートリーダーにおいて450nmにおける吸光度を測定した。Prism(商標)ソフトウェア(GraphPad)のS状用量応答モデルを用いて、データ解析を行った。ヒトPD−L1またはPD−L2へのヒトPD−1結合の50%を低減するのに必要とされる抗体の濃度として定義される、計算したIC50値を、遮断有効性の指標として用いた。用量曲線から決定した、プレート上のヒトPD−L1またはPD−L2へのヒトPD−1の結合を完全に遮断する抗体の能力の測定値として、パーセント最大遮断を計算した。このパーセント最大遮断は、抗PD−1抗体を含有しないヒトPD−1の試料(0%遮断)について観察したシグナルと、HRPが結合した2次抗体単独(100%遮断)由来のバックグラウンドシグナルの間の相違と比較した、それぞれの抗体について最高の試験濃度の存在下で観察したシグナルにおける低減率を、100%から引くことにより、計算した。
いずれかのOctet Red96バイオセンサー機器(Fortebio Inc.)においてリアルタイム生体層インターフェロメトリーアッセイを用いて、またはBiacore3000機器においてリアルタイム表面プラズモン共鳴バイオセンサーアッセイを用いて、異なる抗PD−1モノクローナル抗体による、ヒトPD−1のヒトPD−L1への結合に対する阻害を研究した。
Octet RED384バイオセンサー(Pall ForteBio Corp.)におけるリアルタイムの標識を含まないバイオ層インターフェロメトリーアッセイを用いて、抗PD−1モノクローナル抗体間の結合競合を決定した。全体の実験を、25℃において、0.01M HEPES pH7.4、0.15M NaCl、3mM EDTA、0.05%v/v 界面活性剤Tween−20、0.1mg/mL BSA(Octet HBS−ETバッファー)中、速度1000rpmにてプレートを振盪しながら行った。2つの抗体が、C末端のmyc−myc−ヘキサヒスチジンタグと共に組換え発現させたヒトPD−1(hPD−1−MMH;配列番号321)上のそれぞれのエピトープへの結合について、互いに競合することができるかを評価するために、5分間、50μg/mL hPD−1−MMH溶液を含有するウェルにチップを沈めることにより、抗ペンタ−His抗体でコートしたOctetバイオセンサーチップ(Pall ForteBio Corp.、番号18−5079)上におよそ0.1nMのhPD−1−MMHをまず捕捉させた。次に、50μg/mL mAb−1の溶液を含有するウェルに5分間沈めることにより、抗原により捕捉したバイオセンサーチップを、1次抗PD−1モノクローナル抗体(以後、mAb−1として言及)で飽和させた。次に、50μg/mL 2次抗PD−1モノクローナル抗体(以後、mAb−2として言及)の溶液を含有するウェルに、バイオセンサーチップを続いて浸した。実験の工程毎の間にOctet HBS−ETバッファー中でバイオセンサーチップを洗浄した。実験の経過中、リアルタイムの結合応答をモニターし、工程毎の終わりの結合応答を記録した。mAb−1と予め複合体を形成させたhPD−1−MMHに対するmAb−2結合の応答を比較し、異なる抗PD−1モノクローナル抗体の競合的/非競合的行為を決定した。結果を表17において要約した(*自己競合するmAb2は挙げなかった)。
全長ヒトPD−1(受託番号 NP_005009.2のアミノ酸1〜289)で安定的に遺伝子導入したヒト胎児由来腎臓細胞株(HEK293;ATCC、番号CRL−1573)(HEK293/hPD−1)への抗PD−1抗体の結合を、FACSにより決定した。
抗原提示細胞(APC)上の主要組織適合複合体クラスIまたはIIタンパク質により提示された特異的ペプチドを認識するT細胞受容体(TcR)を刺激することにより、T細胞活性化は起きる。活性化TcRは次にシグナル伝達現象のカスケードを開始させるがこれは、活性化因子−タンパク質1(AP−1)、活性化T細胞の核因子(NFAT)、または活性化B細胞の核因子カッパー−軽鎖−エンハンサー(NFκb)のような転写因子により駆動されるレポーター遺伝子によりモニターすることができる。T細胞応答は、T細胞上で恒常的または誘導的いずれかで発現する共受容体の会合を介して調節される。1つのかかる受容体は、PD−1、T細胞活性の負の調節因子である。PD−1は、そのリガンド、PD−L1と相互作用し、APCまたはがん細胞を含む標的細胞上で発現し、ホスファターゼをTcRシグナロソームに動員させ、正のシグナル伝達の抑制をもたらすことにより、阻害性シグナルを送るよう作用する。
関連インビボモデルにおいて、選択した数の本発明の抗PD−1抗体の効果を決定するために、腫瘍細胞の皮下注射を含み、異なる日に開始した3つのMC38.ova腫瘍成長研究を、75% C57/Bl6/25% 129株バックグラウンドにおいて、マウスPD−1の細胞外ドメイン(PD−1 HumInマウス)の代わりにヒトPD−1の細胞外ドメインの発現についてホモ接合性であるマウスにおいて行った。
早期処置腫瘍モデルを開発し、抗PD−1抗体とVEGFアンタゴニストの併用の効能を試験した。このモデルにおいて、腫瘍移植の直後に、併用療法を投与した。実験はまた、抗PD−L1抗体単独、およびVEGFアンタゴニストとの併用においても用いた。この実験において用いた抗PD−1抗体は、ラットIgG2bを有する抗マウスPD−1クローン「RPMI−14」(Bio X Cell、West Lebanon、NH)であった。この実験において用いたVEGFアンタゴニストは、アフリベルセプトであった(「VEGF−trap」、または「VEGFR1R2−FcΔC1(a)」としても公知の、VEGF受容体ベースのキメラ分子、この全ての記載を本明細書において他の場所で提供した)。この実験において用いた抗PD−L1抗体は、マウスIgG2aを有する、US20100203056A1(Genentech、Inc.)による抗体「YW243.55S70」のVH/VL配列を有する抗PD−L1モノクローナル抗体であり、マウスPD−L1と交差反応性であった。
これは、進行した悪性腫瘍を有する患者における、抗PD−1抗体単独、または放射線療法、シクロホスファミド、もしくは両方との併用での用量増大研究である。この実施例において用いた典型的な抗PD−1抗体(「mAb」)は、配列番号162のHCVR、および配列番号170のLCVRを含んでいた。
研究の一番目の目的は、進行した悪性腫瘍を有する患者において、安全性、忍容性、単独療法としてまたは標的化放射線との併用でIV投与したmAbのDLT(これが主要な腫瘍切除療法よりむしろ免疫刺激として役立つことを有する目的で)、少ない用量のシクロホスファミド(調節性T細胞応答を阻害することを示した療法)、または両方を特徴付けることである。
別々の、標準3+3つの用量増大コホートにおいて(単独療法、放射線療法との併用、シクロホスファミドとの併用、ならびに放射線療法およびシクロホスファミドとの併用における)、安全性を評価する。放射線、シクロホスファミド、または両方との併用療法の選択は、スポンサーと相談して個々の患者のための療法の最善の選択の治験責任医師による評価に基づく。放射線療法コホートに登録されるためには、患者は、安全に照射することができ、想定される限定的な対症的用量での放射線が医薬上適切であると考えられる病変を有し、応答評価に適切な少なくとも1つの他の病変を有していなければならない。患者は、選択した処置についてのコホートにおいて空きがある場合に限り、登録することを認める。
患者は最大48週の処置を受け、その後、24週の追跡期間をとる。患者は、48週の処置期間が完了するまで、または疾患の進行、受け入れられない毒性、同意の撤回、もしくは別の研究撤回基準のミーティングまで、処置を受ける。最短24週の処置後、確認した完了応答(CR)を有する患者は、処置を中断し、全ての関連研究評価(例えば、効能評価)を続けることを選択してもよい。最短24週の処置後、3つの逐次腫瘍評価について変化していない、安定した疾患(SD)または部分的応答(PR)の腫瘍負荷評価を有する患者も、処置を中断し、全ての関連研究評価(例えば、効能評価)を続けることを選択してもよい。
この研究のための標的集団は、標準的療法の候補者ではない、進行した悪性腫瘍を有する患者、標準的療法を受けることを望まない患者、または臨床上の利点をもたらす利用可能な療法が予期されない患者;ならびに治癒不可能である悪性腫瘍を有する患者、および標準的療法に応答しなかった患者、もしくは標準的療法にも関わらず腫瘍進行を示した患者を含む。
無菌の単回使用バイアル中の液体として、mAbを供給する。それぞれのバイアルは、25mg/mLの濃度のmAb10mLを取り出すのに十分な容量を含有する。用量調整の指示を、研究参照マニュアルにおいて提供する。外来において、30分のIV注入として設定して、mAbを投与する。それぞれの患者の用量は、個々の体重に依存する。それぞれのサイクル、10%以上の体重における変化に合わせて、mAbの用量を調節しなければならない。単独、ならびに放射線および、またはシクロホスファミドとの併用で、mAbを投与する。
外来において、48週間14日毎に、30分に渡るIV注入により設定して、mAbを投与する(すなわち、56日サイクルの1日、15±3、29±3、および43±3)。割り当てるべき計画した単独療法治療計画は:(i)48週間14日毎の30分間に渡る1mg/kgIV注入;(ii)48週間14日毎の30分間に渡る3mg/kg注入;(iii)48週間14日毎の30分間に渡る10mg/kg注入;および(iv)48週間14日毎の30分間に渡る0.3mg/kg注入(MTDは1mg/kg未満であると決定したなら)を含み得る。
処方を通じて、併用の放射線療法およびシクロホスファミドを供給し、それらの使用、用量、用量改変、低減、または遅延、ならびにそれらの使用をもたらす任意の潜在的AEを、mAbのものと共に追跡する。
・48週間14日毎の30分間に渡る1mg/kg mAb注入、加えて30Gyの放射線療法(6Gy×5回/週;mAbの最初の投薬後所定の1週間、好ましくは、連日)
・48週間14日毎の30分間に渡る1 mg/kg mAb注入、加えて27Gyの放射線療法(9Gy×3回/週;mAbの最初の投薬後所定の1週間、好ましくは、連日ではない)
・48週間14日毎の30分間に渡る3mg/kg mAb注入、加えて30Gyの放射線療法(6Gy×5回/週;mAbの最初の投薬後所定の1週間、好ましくは、連日)
・48週間14日毎の30分間に渡る3mg/kg mAb注入、加えて27Gyの放射線療法(9Gy×3回/週;mAbの最初の投薬後所定の1週間、好ましくは、連日ではない)を含み得る。
・計4回の投薬のための14日毎(第1の56日サイクルの−1、14、28、および42日)の200mg/m2のシクロホスファミド、加えて
・48週間14日毎の30分間に渡る3mg/kg mAb注入(但し、MTD未満の3mg/kgの単独療法用量;3mg/kgがMTDより高い場合、用量は1mg/kgである)。
・計4回の投薬のための14日毎(第1の56日サイクルの−1、14、28、および42日)の200mg/m2のシクロホスファミド、加えて
・27Gyの放射線療法(9Gy×3回/週;mAbの最初の投薬後所定の1週間、好ましくは、連日ではない)、または
30Gyの放射線療法(6Gy×5回/週;mAbの最初の投薬後所定の1週間、好ましくは、連日)、加えて
・48週間14日毎の30分間に渡る3mg/kg mAb注入(但し、MTD未満の3mg/kgの単独療法用量;3mg/kgがMTDより高い場合、用量は1mg/kgである)。
1次変数:1次安全性変数は、48週の処置を通じた、DLTの発生率、処置により出現した副作用(TEAE)の発生率および重症度、ならびに異常な検査知見を含む。
・mAbの血清濃度、および薬物動態(PK)
・指標についての適切な基準を用いて評価した抗腫瘍活性:
・コンピュータ断層撮影(CT)、もしくは磁気共鳴画像法(MRI)により測定した、固形腫瘍における応答評価基準(RECIST)
・RECIST測定が標準的でない特定の腫瘍について、他の評価基準も用いるべきである。
・RECIST測定に適用した免疫関連応答基準(irRC)。
全てのケースにおいて、irRCは、疾患の進行(PD)、SD、CR、またはPRを決定するための管理ツールである。情報の目的のため、標準的RECISTデータも集める。
・抗mAb抗体。
研究の適格性を決定する、またはベースラインの集団を特徴付ける目的のためのスクリーンングにおいて、以下の方法を行う:(i)血清β−HCG(結果は、最初の投薬前72時間以下でなければならない);(ii)達成した腫瘍材料の回収:患者が所定のインフォームドコンセントを得た後、任意の利用可能な既に回収した腫瘍サンプル(sample)を提供するため用意することを患者に尋ねる;(iii)脳MRI:先の60日において行っていなければ、スクリーニングにおいて、脳MRIが必要とされる;および(iv)胸部x線:先の60日において行っていなければ、スクリーニングにおいて、胸部x線が必要とされる。
有害事象(AE)は、研究薬物との因果関係があることもないこともある、研究薬物を投与した患者におけるあらゆる有害な医学的出来事である。それ故、AEは、研究薬物と関連するとみなされるか否かに関わらず、あらゆる好ましくなく、かつ意図しないサイン(異常な検査室知見を含む)、症状、または研究薬物の使用に時間的に関連する疾患である。AEはまた、研究薬物の使用に時間的に関連する、既存の状態のいかなる悪化(すなわち、頻度および/または強度における任意の臨床上有意な変化)も含む。原因となる悪性腫瘍の進行は、原因となるがん(時間経過、影響を受けた器官などを含む)の典型的な進行パターンと明確に一致するなら、AEとみなさない。症状が、原因となる悪性腫瘍の進行に排他的に起因すると決定されず、または研究下の疾患について予期される進行パターンに適合しなかったなら、進行の臨床症状をAEとして報告する。
研究用量増大は、用量レベル毎に3人から6人の患者が割り当てられる従来の3+3設計に基づく。研究において登録した患者の正確な数は、プロトコールにより定義されているDLTを観察した数、その時点で定義されている用量レベルを拡大する、またはより少ない用量レベルでの公のさらなるコホートを開始する必要性に依存する。用量増大において次のコホートに必要な開始時登録を行った後、その処置についてMTD未満の従前のコホートのそれぞれへの登録を、(増大中に既に拡大していなければ)計6人の患者まで拡大する。
Claims (10)
- ヒトプログラム細胞死1(PD−1)タンパク質に特異的に結合する、単離されたヒトモノクローナル抗体またはその抗原結合フラグメントであって、
該抗体またはその抗原結合フラグメントは、配列番号162の重鎖可変領域(HCVR)配列内に含まれる、3つの重鎖相補性決定領域(CDRs)(HCDR1、HCDR2およびHCDR3);および配列番号170の軽鎖可変領域(LCVR)配列内に含まれる、3つの軽鎖CDRs(LCDR1、LCDR2およびLCDR3)を含む、
上記単離された抗体またはその抗原結合フラグメント。 - 以下の:
(a)配列番号164のアミノ酸配列を有するHCDR1ドメイン;
(b)配列番号166のアミノ酸配列を有するHCDR2ドメイン;
(c)配列番号168のアミノ酸配列を有するHCDR3ドメイン;
(d)配列番号172のアミノ酸配列を有するLCDR1ドメイン;
(e)配列番号174のアミノ酸配列を有するLCDR2ドメイン;および
(f)配列番号176のアミノ酸配列を有するLCDR3ドメイン;
を含む、請求項1に記載の単離された抗体またはその抗原結合フラグメント。 - 抗体またはその抗原結合フラグメントは、配列番号162/170のHCVR/LCVRアミノ酸配列対を含む、請求項2に記載の単離された抗体またはその抗原結合フラグメント。
- 抗体またはその抗原結合フラグメントは、以下の特性:
(a)25℃における競合サンドイッチELISAアッセイにおいて測定される3nM未満のIC50でPD−L1へのヒトPD−1タンパク質結合を遮断する;
(b)37℃における表面プラズモン共鳴アッセイにおいて測定される50nM未満の結合解離平衡定数(KD)で単量体ヒトPD−1に結合する;
(c)25℃における表面プラズモン共鳴アッセイにおいて12nM未満のKDで単量体ヒトPD−1に結合する;
(d)25℃における表面プラズモン共鳴アッセイにおいて8.5nM未満のKDで単量体カニクイザルPD−1に結合する;
(e)25℃における表面プラズモン共鳴アッセイにおいて測定される6.3分より長い解離半減期(t1/2)で単量体ヒトPD−1に結合する;および
(f)37℃における表面プラズモン共鳴アッセイにおいて測定される0.9分より長い解離半減期(t1/2)で単量体ヒトPD−1に結合する;
のうちの1つまたはそれ以上を有する、請求項2に記載の単離された抗体またはその抗原結合フラグメント。 - 抗体またはその抗原結合フラグメントは、重鎖および軽鎖を含み、ここで重鎖は配列番号330のアミノ酸配列を含む、請求項4に記載の単離された抗体またはその抗原結合フラグメント。
- 抗体またはその抗原結合フラグメントは、重鎖および軽鎖を含み、ここで軽鎖は配列番号331のアミノ酸配列を含む、請求項4に記載の単離された抗体またはその抗原結合フラグメント。
- 抗体またはその抗原結合フラグメントは、配列番号330/331の重鎖/軽鎖アミノ酸配列対を含む、請求項6に記載の単離された抗体またはその抗原結合フラグメント。
- 請求項1に記載のPD−1に結合する単離されたヒトモノクローナル抗体またはその抗原結合フラグメント、および薬学的に許容し得る担体または希釈剤を含む、医薬組成物。
- ヒトプログラム細胞死1(PD−1)タンパク質に特異的に結合する、単離されたヒトモノクローナル抗体またはその抗原結合フラグメントであって、
該抗体またはその抗原結合フラグメントは、配列番号162のアミノ酸配列を含む重鎖可変領域(HCVR)、および配列番号170のアミノ酸配列を含む軽鎖可変領域(LCVR)を含む、
上記単離された抗体またはその抗原結合フラグメント。 - ヒトプログラム細胞死1(PD−1)タンパク質に特異的に結合する、単離されたヒトモノクローナル抗体またはその抗原結合フラグメントであって、
該抗体またはその抗原結合フラグメントは、配列番号330のアミノ酸配列を含む重鎖、および配列番号331のアミノ酸配列を含む軽鎖を含む、
上記単離された抗体またはその抗原結合フラグメント。
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