JP6087503B2 - ヒト抗pd−1、pd−l1、及びpd−l2抗体とその用途 - Google Patents
ヒト抗pd−1、pd−l1、及びpd−l2抗体とその用途 Download PDFInfo
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Description
この出願は、その全体を出典明示によりここに援用する2008年9月26日出願の米国仮出願第61/100534号の優先権の利益を請求する。
ループ カバット AbM Chothia 接触
−−− −−− −−− −−−− −−−−
L1 L24-L34 L24-L34 L24-L34 L30-L36
L2 L50-L56 L50-L56 L50-L56 L46-L55
L3 L89-L97 L89-L97 L89-L97 L89-L96
H1 H31-H35B H26-H35B H26-H32,33又は34 H30-H35B (Kabat番号付)
H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia番号付)
H2 H50-H65 H50-H58 H52-H56 H47-H58
H3 H95-H102 H95-H102 H95-H102 H93-H101
「フレームワーク」又は「FR」残基は、ここで定義するHVR残基以外の可変ドメイン残基である。
遺伝コード
アラニン(Ala, A) GCA, GCC, GCG, GCT
アルギニン(Arg, R) AGA, ACG, CGA, CGC, CGG, CGT
アスパラギン(Asn, N) AAC, AAT
アスパラギン酸 (Asp, D) GAC, GAT
システイン(Cys, C) TGC, TGT
グルタミン酸(Glu, E) GAA, GAG
グルタミン(Gln, Q) CAA, CAG
グリシン(Gly, G) GGA, GGC, GGG, GGT
ヒスチジン(His, H) CAC, CAT
イソロイシン(Ile, I) ATA, ATC, ATT
ロイシン(Leu, L) CTA, CTC, CTG, CTT, TTA, TTG
リジン(Lys, K) AAA, AAG
メチオニン(Met, M) ATG
フェニルアラニン(Phe, F) TTC, TTT
プロリン(Pro, P) CCA, CCC, CCG, CCT
セリン(Ser, S) AGC, AGT, TCA, TCC, TCG, TCT
スレオニン(Thr, T) ACA, ACC, ACG, ACT
トリプトファン(Trp, W) TGG
チロシン(Tyr, Y) TAC, TAT
バリン(Val, V) GTA, GTC, GTG, GTT
終止シグナル(末端) TAA, TAG, TGA
ここに記載された発明の態様及び実施態様は態様及び実施態様「からなる」及び/又は「から本質的になる」ことを含むものと理解される。
本発明の様々な態様を以下のサブセクションで更に詳細に記載する。
本発明の一態様は、本発明のポリペプチド(例えば図2−7のもの)又はその生物学的に活性な部分をコードする単離された核酸分子、並びにこれらポリペプチドをコードする核酸分子を同定するためのハイブリダイゼーションプローブとしての使用に十分な核酸断片及び核酸分子の増幅又は変異のためのPCRプライマーとして使用するための断片に関する。ここで使用される場合、「核酸分子」なる用語は、DNA分子(例えばcDNA又はゲノムDNA)及びRNA分子(例えばmRNA)及びヌクレオチドアナログを使用して生産されるDNA又はRNAのアナログを含むものである。核酸分子は一本鎖又は二本鎖でありうるが、好ましくは二本鎖DNAである。
本発明の一態様は、本発明の単離されたポリペプチド(ここに記載された抗体及びその抗原結合断片、及び図2−7のものを含む)、及びその生物学的に活性な部分に関する。一実施態様では、本発明のポリペプチド(例えば、図2−7のもの)、及びその生物学的に活性な部分は、標準的なタンパク質精製技術によって細胞又は組織源から単離することができる。他の実施態様では、本発明のポリペプチド (例えば、図2−7のもの)、及びその生物学的に活性な部分は組換えDNA技術によって生産される。別法では、本発明のポリペプチド (例えば、図2−7のもの)、及びその生物学的に活性な部分は標準的なペプチド合成技術を使用して化学的に合成することができる。
ここに記載されたPD−1、PD−L1、又はPD−L2に対する抗体は、ここに記載され又は当該分野で知られている任意の方法によって産生させることができる。本発明のモノクローナル抗体 (例えば、ヒト抗体)は、様々な既知の技術、例えばKohler及びMilstein, Nature 256: 495 (1975)によって記載された標準的な体細胞ハイブリダイゼーション技術を使用して産生させることができる。体細胞ハイブリダイゼーション法は原理的には好ましいが、モノクローナル抗体を産生させるための他の技術、例えば、Bリンパ球のウイルス又は癌化、ヒト抗体遺伝子のライブラリーを使用するファージディスプレイ技術を用いることができる。
(1)ヒトPD−1、PD−L1、又はPD−L2への結合;
(2)PD−1へのEH12.2H7の、PD−L1への29E.2A3の、又はPD−L2への24F.10C12の結合の阻害;
(3)ヒトPD−1への結合と、結合したPD−1のPD−1リガンド(例えば、PD−L1及び/又はPD−L2)に結合する能力の阻害;
(4)ヒトPD−L1への結合と、結合したPD−L1のPD−L1リガンド(例えば、PD−1及び/又はB7−1)に結合する能力の阻害;
(5)ヒトPD−L2への結合と、結合したPD−L2のPD−L2リガンド(例えば、PD−1)に結合する能力の阻害
のような、本発明の抗体の他の機能的性質のその保持について選択することができる。
EH12.2H7重鎖可変領域
QVQLQQSGAELAKPGASVQMSCKASGYSFTSSWIHWVKQRPGQGLEWIGYIYPSTGFTEYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARWRDSSGYHAMDYWGQGTSVTVSS(配列番号:76)
EH12.2H7軽鎖可変領域
DIVLTQSPASLTVSLGQRATISCRASQSVSTSGYSYMHWYQQKPGQPPKLLIKFGSNLESGIPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIK(配列番号:77)
29E.2A3重鎖可変領域
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYVNPFNDGTKYNEMFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARQAWGYPWGQGTLVTVSA(配列番号:78)
29E.2A3軽鎖可変領域
DIVLTQSPASLAVSLGQRATISCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPARFSGSGSGTDFSLTIHPVEEDDIAMYFCQQSRRVPYTFGGGTKLEIK(配列番号:79)
24F.10C12重鎖可変領域
QVQLQQSAAELARPGASVKMSCKASGYTFTGYTMHWVKQRPGQGLEWIGYINPRSGYTEYNQKFKDKTTLTADKSSSTAYMQLSSLTSEDSAVYYCARPWFAYWGQGTLVTVSA(配列番号:80)
24F.10C12軽鎖可変領域
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLELK(配列番号:81)
本発明の他の態様は、一又は複数の本発明のポリペプチド (例えば、図2-7) (又はその一部)をコードする一つ、二つ又はそれ以上の核酸分子を含むベクター、好ましくは発現ベクターに関する。ここで使用される場合、「ベクター」なる用語は、それが結合した他の核酸を輸送することができる核酸分子を意味する。ベクターの一つのタイプは、更なるDNAセグメントがライゲートされうる円形の二本鎖DNAストランドDNAループを意味する「プラスミド」である。ベクターの他のタイプは、更なるDNAセグメントがウイルスゲノム中にライゲートされうるウイルスベクターである。ある種のベクターはそれらが導入される宿主細胞中において自律増殖可能である(例えば、細菌の複製起点を有する細菌ベクター及びエピソーム哺乳動物ベクター)。他のベクター(例えば、非エピソーム哺乳動物ベクター)が宿主細胞中への導入時に宿主細胞のゲノム中に組み込まれ、それによって宿主ゲノムに沿って複製される。更に、ある種のベクターは、それらが作用可能に結合した遺伝子の発現を指向しうる。そのようなベクターは「発現ベクター」とここでは称される。一般に、組換えDNA技術において利用できる発現ベクターはしばしばプラスミドの形態である。本明細書において、「プラスミド」と「ベクター」は、プラスミドがベクターの最も一般的に使用される形態であるので、交換可能に使用されうる。しかしながら、本発明は、均等な機能を呈する、例えばウイルスベクター(例えば複製欠損レトロウイルス、アデノウイルス及びアデノ随伴ウイルス)のような発現ベクターのそのような他の形態を含むものである。
更に他の態様では、本発明は、PD−1、PD−L1、又はPD−L2に特異的に結合するヒトモノクローナル抗体を発現することが可能な、トランスジェニック及び導入染色体非ヒト動物、例えばトランスジェニック又は導入染色体マウスを提供する。特定の実施態様では、本発明は、PD−1、PD−L1、又はPD−L2抗原及び/又はPD−1、PD−L1、又はPD−L2を発現する細胞で免疫化されたときにマウスがヒト抗 PD−1、PD−L1、又はPD−L2抗体を生産するように、ヒト重鎖導入遺伝子を含むゲノムを有するトランスジェニック又は導入染色体マウスを提供する。ヒト重鎖導入遺伝子は、当該分野でよく知られた方法に従って、トランスジェニックマウス、例えばHuMAbの場合のように、マウスの染色体DNA中に組み込むことができる。別法では、ヒト重鎖導入遺伝子は、国際公開第02/43478号に記載されているように導入染色体(例えばKM)マウスの場合のように、染色体外に維持されうる。そのようなトランスジェニック及び導入染色体マウスは、V−D−J組換え及びアイソタイプスイッチングを受けることによって、PD−1、PD−L1、又はPD−L2に対するヒトモノクローナル抗体の複数のアイソタイプ(例えば、IgG、IgA及び/又はIgE)を製造することができる。アイソタイプスイッチングは、例えば古典的な又は非古典的なアイソタイプスイッチングによって生じうる。
(1)未再編成の重鎖及び再編成の軽鎖免疫グロブリン導入遺伝子を含むトランスジェニック動物;
(2)未再編成の重鎖及び未再編成の軽鎖免疫グロブリン導入遺伝子を含むトランスジェニック動物;
(3)再編成の重鎖及び未再編成の軽鎖免疫グロブリン導入遺伝子を含むトランスジェニック動物;及び
(4)再編成の重鎖及び再編成の軽鎖免疫グロブリン導入遺伝子を含むトランスジェニック動物。
他の態様では、本発明は、例えば細胞毒素、薬剤(例えば免疫抑制剤)又は放射性同位体などの療法用部分にコンジュゲートされたヒトPD−1、PD−L1、又はPD−L2抗体を特徴とする。細胞毒素にコンジュゲートされると、これらの抗体コンジュゲートは、「免疫毒素」と称される。細胞毒素又は細胞傷害剤には、細胞に有害な(例えば細胞を死滅させる)あらゆる薬剤が含まれる。例には、タキソール、サイトカラシンB、グラミシジンB、エチジウムブロミド、エメチン、マイトマイシン、エトポシド、テノポシド、ビンクリスチン、ビンブラスチン、コルヒチン、ドキソルビシン、ダウノルビシン、ジヒドロキシアントラシンジオン、ミトキサントロン、ミトラマイシン、アクチノマイシンD、1−デヒドロテストステロン、グルココルチコイド、プロカイン、テトラカイン、リドカイン、プロプラノロール、及びピューロマイシン、並びにそのアナログ又はホモログが含まれる。治療剤には、限定されるものではないが、代謝拮抗剤(例えばメトトレキセート、6−メルカプトプリン、6−チオグアニン、シタラビン、5−フルオロウラシル、デカルバジン)、アルキル化剤(例えばメクロレタミン、チオエパ(thioepa)、クロラムブシル、メルファラン、カルムスチン(BSNU)及びロムスチン(CCNU)、シクロトスファミド(cyclothosphamide)、ブスルファン、ジブロモマンニトール、ストレプトゾトシン、マイトマイシンC、及びシス−ジクロロジアミン白金(II)(DDP)、シスプラチン)、アントラサイクリン(例えばダウノルビシン(先のダウノマイシン)及びドキソルビシン)、抗生物質(例えばダクチノマイシン(先のアクチノマイシン)、ブレオマイシン、ミトラマイシン、及びアントラマイシン(AMC))、及び有糸分裂阻害剤(例えばビンクリスチン及びビンブラスチン)が含まれる。本発明の抗体を、放射性同位体、例えば放射性ヨウ素にコンジュゲートして、関連疾患、例えば癌の治療のための細胞傷害性放射性薬剤を生成することも可能である。
他の態様では、本発明は、薬学的に許容可能な担体と共に処方されて、本発明のモノクローナル抗体、又はその抗原結合部分(例えば抗原結合断片)の一又は組合せを含む組成物、例えば薬学的組成物を提供する。一実施態様では、組成物は、本発明の複数(例えば二以上)の単離されたヒト抗体の組合せを含む。好ましくは、組成物の抗体の各々は、 PD−1、PD−L1、及び/又はPD−L2の区別される予め選択されたエピトープに結合する。
(抗体の誘導体及びコンジュゲートを含む)ここに記載の抗体及び抗体を含む組成物は、(例えば免疫応答の上方又は下方調節による)様々なインビトロ及びインビボ診断及び治療用途に使用することができる。例えば、PD−1又はB7−1に結合するPD−1リガンドは阻害性シグナルを伝達する。よって、PD−1とPD−1リガンド間、又はPD−1リガンドとB7ポリペプチドの間の相互作用の調節が免疫応答の調節を生じる。PD−1リガンドはまたT細胞を同時刺激しうる。よって、一実施態様では、PD−1リガンドとPD−1又はB7間の相互作用をブロックする抗体は、阻害性シグナルを防止しうる。一実施態様では、PD−1リガンドの同時刺激シグナルをブロックする抗体は、免疫細胞に対する同時刺激シグナルをブロックする。更に、PD−L2のライゲーションはサイトカイン分泌及び樹状細胞の生存を誘導しうる。よって、PD−L2ライゲーションをブロックする抗体は樹状細胞の生存を阻害し、樹状細胞によるサイトカイン発現を低減させ、これらのメカニズムを通じて免疫応答を阻害しうる。特に、ここに記載された抗体は、例えばKeir等(2008) Annu. Rev. Immunol. 26:677;Sharpe等, (2007) Nat. Immunol. 8:239;Freeman等(2007) J. Exp. Med. 10:2223(各々はその全体が出典明示によりここに援用される)において検討されているように、PD−1、PD−L1、及び/又はPD−L2により媒介される特定の症状に関連した診断、予後、予防、及び治療応用に有用である。
皮膚筋炎、円板状エリテマトーデス、グッドパスチャー症候群、橋本甲状腺炎、突発性副腎萎縮症、突発性 血小板減少症、インスリン依存性糖尿病、ランバート・イートン症候群、ルポイド肝炎、リンパ球減少症の幾つかの症例、混合性結合組織病、類天疱瘡、天疱瘡尋常性、悪性貧血、水晶体起因性ブドウ膜炎、結節性多発動脈炎、多腺性自己免疫症候群、原発性胆汁性肝硬変、原発性硬化性胆管炎、レイノー症候群、再発性多発性軟骨炎、シュミット症候群、限局型全身性強皮症(又は クレスト症候群)、交感性眼炎、全身性エリテマトーデス、高安動脈炎、側頭動脈炎、甲状腺中毒症、b型インスリン抵抗性、潰瘍性大腸炎及びウェゲナー肉芽腫症)の診断、予後、予防、及び治療応用(例えば治療し、疾患の発症又は進行を遅延させる)に有用である。
本発明の一態様は、(例えばPD−1、PD−L1、又はPD−L2の機能を調節する抗体のような)同時刺激を調節することにより免疫応答を調節するための本発明の抗体の使用方法に関する。このような方法は、細胞ベース及び非細胞ベースのアッセイを含むスクリーニングアッセイを利用する。一実施態様では、アッセイは、PD−1リガンド及びPD−1の相互作用を調節する抗体を同定するための方法を提供する。他の実施態様では、アッセイは、PD−1リガンドとB7ポリペプチド間の相互作用を調節する抗体を同定するための方法を提供する。
一態様では、本発明は、望まれない又は所望の度合いが少ない免疫応答に関連した疾患又は症状を被験者において予防する方法に関する。本発明の抗体又は方法での治療から恩恵を受ける疾患に対してリスクがある被験者は、例えば当該分野で知られている診断又は予後アッセイの何れか又は組合せによって同定することができる。予防的抗体の投与は、望まれない又は所望の度合いが少ない免疫応答に関連した徴候の現れの前に起こりうる。治療に使用される適切な抗体は、臨床的適応に基づいて決定することができ、例えばここに記載されたスクリーニングアッセイを使用して、同定することができる。
本発明の他の側面は、例えば、PD−1及びPD−1リガンド及び/又はPD−1リガンド及びB7ポリペプチドの間の相互作用を調節することにより、免疫応答を調節する治療方法に関する。例えば、PD−1及びPD−1リガンド間、又はPD−1リガンド及びB7ポリペプチド間の相互作用の調節は免疫応答の調節を生じる。よって、一実施態様では、PD−1及びPD−1リガンド間の相互作用をブロックする抗体は、阻害性シグナル伝達を防止しうる。PD−1リガンドはまたT細胞中の同時刺激シグナルを亢進しうる。よって、他の実施態様では、PD−1リガンドが同時刺激シグナルをもたらすことを防止する抗体はT細胞同時刺激を阻害しうる。
PD−1リガンドの阻害機能をアップレギュレートするか、又は同時刺激をダウンレギュレートして免疫応答をダウンレギュレートするための本発明の多くの実施態様が存在する。ダウンレギュレーションは、既に進行している免疫応答を阻害するか又はブロックする形態であり得、あるいは免疫応答の誘導を妨害することを含みうる。活性化された免疫細胞の機能は、免疫細胞応答をダウンレギュレートするか、あるいは免疫細胞において特異的アネルギーを誘導するか、又はその双方によって阻害することができる。
治療的にまた有用であるのは、免疫応答をアップレギュレートする手段としての、PD−1リガンドとPD−1又はB7−1との相互作用の遮断である。免疫応答のアップレギュレーションは、存在する免疫応答の亢進又は最初の免疫応答の誘発の形態をとりうる。例えば、主題の組成物及び方法を使用する免疫応答の増強は、微生物(例えば、細菌、ウイルス、又は寄生虫)での感染の場合に有用である。一実施態様では、PD−1とのPD−1リガンドの相互作用をブロックする抗体が免疫応答を亢進させるために使用される。そのような抗体(例えば、PD−1へのPD−L1の結合をブロックする非活性化抗体)は、抗体のアップレギュレーション及び細胞媒介性応答が有益である状況において治療的に有用である。例示的な疾患は、疱疹又は帯状疱疹などのウイルス性皮膚疾患を含み、その場合、そのような薬剤が皮膚に局所的に送達されうる。また、インフルエンザ、感冒及び脳炎のような全身性ウイルス性疾患は、このような薬剤の全身投与によって軽減されるかもしれない。
マウスEH12.2H7、29E.2A3及び24F.10C12 V領域の構造モデルを、Swiss Pdbを使用して製造し、抗体の結合特性に対して必須かもしれないマウスV領域中の重要な「制限」アミノ酸を同定するために分析した。カバット及びChothia双方の定義で定義されるCDR残基を含む、CDRs内に含まれる残基のみが重要であると考えた。
抗原 複合VH配列 複合VK配列
PD−1 図2(A−E) 図3(A−D)
PD−L1 図4(A−E) 図5(A−D)
PD−L2 図6(A−E) 図7(A−D)
最初の変異体1複合ヒト抗体VH及びVK領域遺伝子を、完全長合成V領域を得るためにアニールし、ライゲートさせ、PCR増幅させた一連のオーバーラップするオリゴヌクレオチドを使用して、EH12.2H7、29E.2A3及び24F.10C12に対して合成した(図2A、図3A、図4A、図5A、図6A及び図7A)。各複合ヒト抗体に対して、最初の変異体1を鋳型として使用し、長いオーバーラップするオリゴヌクレオチド及びPCRを使用して、次の配列変異体を構築した。ついで、その構築した変異体を発現ベクター中に直接クローニングし(図1)、その配列を確認した。
PD−1シグナル伝達経路は中程度のTCR/CD28同時刺激シグナルを阻害し、サイトカイン生産がT細胞増殖を減少させることなく低減された。TCR/CD28同時刺激シグナルが弱くされているので、PD−1経路が優勢であり、サイトカイン生産における大きな減少に増殖の減少が伴う。従って、本発明の複合ヒト抗体を使用するPD−L1又はPD−L2との相互作用の阻害によるPD−1経路の阻害がT細胞活性化を亢進させることを確認するために、混合リンパ球反応(MLRs)を実施する。
リンパ球性脈絡髄膜炎ウイルス(LCMV)の様々な株に感染したマウスを使用して、CD8 T細胞機能に対する慢性的ウイルス感染の効果を研究する。LCMV Armstrong株は、8日以内に除去され、後に高度に機能的な休止メモリーCD8 T細胞の長命の集団を残す急性感染を引き起こす。LCMV Cl−13株は、これに対して、3ヶ月まで続くウイルス血症によって特徴付けられる持続感染を宿主に樹立する。
持続感染中のT細胞応答をブーストさせるための一つのアプローチ法は治療用ワクチン接種である。このアプローチ法の原理は、内在性抗原が慢性ウイルス感染中において最適な又は免疫原性の形で提示され得ないこと、またワクチンの形態で抗原を提供することによりウイルス特異的T及びB細胞に対してより効果的な刺激をもたらしうることである。慢性的LCMVモデルを使用して、マウスに治療用ワクチン(VVGP33)としてLCMV GP33エピトープを発現する組換えワクシニアウイルスを投与し、これが幾らかの慢性的に感染したマウスにおいてCD8 T細胞応答の中程度の亢進を生じる。この治療用ワクチン接種には、本発明の複合ヒト抗PD−1抗体、抗PD−L1抗体及び/又は抗PD−L2抗体が組み合わされる。LCMV特異的T細胞応答が、何れかの治療だけの場合と比較してより大きなレベルまでブーストされ、併用治療の効果が相加的以上のものとなることが予想される。
チンパンジーは、ヒトにおけるHCV持続のモデルを提供する。長寿命のウイルス持続を生じるT細胞免疫の欠損は、HCV特異的CD4+ヘルパーT細胞及び損なわれたか又は改変されたCD8エフェクターT細胞活性の欠損の双方を含む。持続的に感染させられたチンパンジーを、本発明の複合ヒト抗PD−1抗体、抗PD−L1抗体及び/又は抗PD−L2抗体で処置する。組換え構造的及び組換え非構造的HCVタンパク質を使用してワクチン接種と組み合わせた阻害性経路の遮断の効力、及びこのような方策がウイルス特異的メモリーT細胞の頻度及び寿命を向上させうるか否かが決定される。T細胞免疫の欠損は、持続的に感染したヒト及びチンパンジーにおいて専らHCV特異的である。ついで、抗ウイルス活性は、これらの分子によるシグナル伝達を遮断するヒト化モノクローナル抗体をチンパンジーに送達することによって回復されうる。
慢性サル免疫不全ウイルス(SIV)感染中におけるPD−1の遮断の免疫回復の可能性をマカクにおいて試験した。SIVに感染した14匹のインディアンアカゲザル(Macaca mulatta)を研究した。8匹のマカクを早期の慢性段階に使用し、SIV251の200の50%組織培養感染用量(TCID50)で静脈内感染させた。6匹のマカクを後期慢性段階に使用し、3匹をSIV251で直腸内的に感染させ、3匹をSIV239で静脈内的に感染させた。RDb11を除いて、全てのマカクがMamu B08及びMamu B17アレルに対して陰性であった。RDb11はMamu B17アレルに対して陽性であった。
SIV Gag特異的CD8 T細胞の増殖能についての、EH−12.2H7から誘導されたヒト化抗PD−1抗体及び29E.2A3から誘導されたヒト化抗PD−L1抗体の効果をインビトロで試験した。ヒト化抗PD−1抗体は、配列番号:28の重鎖可変領域配列と配列番号:32の軽鎖可変領域配列を有している。ヒト化抗PD−L1抗体は、配列番号:35の重鎖可変領域配列と、配列番号:42の軽鎖可変領域配列を有している。ヒト化抗体の重鎖定常領域は、抗体が二量体を形成するようにSer228からProへの変異(CPSCPからCPPCPへ)を有するヒトIgG4由来であり、軽鎖定常領域はヒトκ軽鎖定常領域である。Ser228に対するアミノ酸番号付けはEU番号付けシステムによる。Aalberse等, Immunology 105:9-19, 2002を参照のこと。SIV感染マカク(感染後3ヶ月から1.5年)から得られたPBMCをカルボキシフルオセイン二酢酸スクシンイミジルエステル(CFSE)を染色し、遮断抗体の存在下又は不在下で6日間、SIV Gagペプチドプールか又は培養培地の何れかで刺激した。刺激の終わりに、細胞を表面CD3及びCD8、及び細胞内Ki−67に対して染色した。ついで、細胞をFACS Caliburで獲得し、Flowjoソフトウェアを使用して分析した。リンパ球を散乱に基づいて同定した後、CD8 T細胞(CD3+、CD8+)をKi−67及びCFSEに対する同時染色に対して分析した。Ki−67+、CFSE低細胞を増殖細胞として同定した。
CFSE標識肝内リンパ球(2×106)を、10年を越えてHCVの遺伝子型1aH77株で慢性的に感染させられたチンパンジー1564から単離した。肝内リンパ球を、操作されないままか又は全HCVポリタンパク質をスパンするオーバーラップペプチドでパルスした(遺伝子型1aH77株)4×106の照射された自己CD8枯渇PBMCと共に6日間、共培養した。細胞を、抗PD−L1遮断抗体(10μg/ml,0日目及び2日目に添加)を伴ってまた伴わないで、L−グルタミン及び10%FCSが補填されたRPMI培地で培養した。ヒト化抗PD−L1抗体は、配列番号:35の重鎖可変領域及び配列番号:42の軽鎖可変領域配列を有する。ヒト化抗体の重鎖定常領域は、抗体が二量体を形成するようにSer228からProへの変異(CPSCPからCPPCPへ)を有するヒトIgG4由来であり、軽鎖定常領域はヒトκ軽鎖定常領域である。Ser228に対するアミノ酸番号付けはEU番号付けシステムによる。Aalberse等, Immunology 105:9-19, 2002を参照のこと。6日目に、細胞をCD8−PerCP、A0701/P7(758)−PE四量体、PD−1−Alexa647、CD4−Alexa700、CD14−Alexa700、CD16−Alexa700、CD19−Alexa700、及びライブ/デッドブルーで染色した。試料はBD LSRIIフローサイトメーターで獲得し、データを、FlowJoソフトウェアを使用して解析した。
ここに述べた全ての刊行物、特許、及び特許出願は、あたかも各個々の刊行物、特許又は特許出願が出典明示により特にかつ個々に援用されるべきことが示されるように、出典明示によりその全体がここに援用される。矛盾する場合、ここでの定義を含む本出願が優先する。
当業者であれば、ここに記載された発明の特定の実施態様に対する多くの均等物を認識し又は常套的なものに過ぎない実験を使用して確認できるであろう。そのような均等物は次の特許請求の範囲によって包含されるものである。
Claims (49)
- a)配列番号:34−38からなる群から選択される重鎖可変領域配列;及び
b)配列番号:39−42からなる群から選択される軽鎖可変領域配列
を含む、単離された抗体又はその抗原結合断片であって、
ここで、単離された抗体、又はその抗原結合断片が、配列番号:4のアミノ酸配列を有するPD−L1タンパク質に結合し、かつ単離された抗体、又はその抗原結合断片が、ヒト化、又は複合である単離された抗体又はその抗原結合断片。 - a)配列番号:35又は37を含む重鎖可変領域配列;及び
b)配列番号:39、40又は42を含む軽鎖可変領域配列
を含む、請求項1に記載の単離された抗体又は抗原結合断片。 - 単離された抗体又はその抗原結合断片が配列番号:78を含む重鎖可変領域配列及び配列番号:79を含む軽鎖可変領域配列を含む抗体のFc−PD−L1への結合を阻害する、請求項1又は2に記載の単離された抗体又は抗原結合断片。
- 単離された抗体又はその抗原結合断片がPD−L1媒介シグナルを阻害する、請求項1から3の何れか一項に記載の単離された抗体又は抗原結合断片。
- a)配列番号:25−28からなる群から選択される重鎖可変領域配列;及び
b)配列番号:30−33からなる群から選択される軽鎖可変領域配列
を含む、単離された抗体又はその抗原結合断片であって、
ここで、単離された抗体、又はその抗原結合断片が、配列番号:2のアミノ酸配列を有するPD−1タンパク質に結合し、かつ単離された抗体、又はその抗原結合断片が、ヒト化、又は複合である単離された抗体又はその抗原結合断片。 - a)配列番号:27又は28を含む重鎖可変領域配列;及び
b)配列番号:32又は33を含む軽鎖可変領域配列
を含む、請求項5に記載の単離された抗体又は抗原結合断片。 - 単離された抗体又は抗原結合断片が配列番号:76を含む重鎖可変領域配列及び配列番号:77を含む軽鎖可変領域配列を含む抗体のFc−PD−1への結合を阻害する、請求項5又は6に記載の単離された抗体又は抗原結合断片。
- 単離された抗体又は抗原結合断片がPD−1媒介シグナルを阻害する、請求項5から7の何れか一項に記載の単離された抗体又は抗原結合断片。
- a)配列番号:43−46からなる群から選択される重鎖可変領域配列;及び
b)配列番号:48−51からなる群から選択される軽鎖可変領域配列
を含む、単離された抗体又はその抗原結合断片であって、
ここで、単離された抗体、又はその抗原結合断片が、配列番号:6のアミノ酸配列を有するPD−L2タンパク質に結合し、かつ単離された抗体、又はその抗原結合断片が、ヒト化、又は複合である単離された抗体又はその抗原結合断片。 - a)配列番号:44又は46からなる群から選択される重鎖可変領域配列;及び
b)配列番号:49−51からなる群から選択される軽鎖可変領域配列
を含む、請求項9に記載の単離された抗体又はその抗原結合断片。 - 単離された抗体又は抗原結合断片が配列番号:80を含む重鎖可変領域配列及び配列番号:81を含む軽鎖可変領域配列を含む抗体のFc−PD−L2への結合を阻害する、請求項9又は10に記載の単離された抗体又はその抗原結合断片。
- 単離された抗体又は抗原結合断片がPD−L2媒介シグナルを阻害する、請求項9から11の何れか一項に記載の単離された抗体又は抗原結合断片。
- ポリペプチドをコードする単離された核酸であって、ポリペプチドが配列番号:25−28、30−46及び48−51からなる群から選択される配列を含む単離された核酸。
- 請求項1から12の何れか一項に記載の抗体又は抗原結合断片をコードする単離された核酸。
- 請求項13又は14に記載の単離された核酸を含むベクター。
- 請求項13又は14に記載の核酸を含む宿主細胞。
- 核酸によってコードされる抗体又は抗原結合断片を産生する請求項16に記載の宿主細胞。
- 請求項13又は14に記載の核酸を含むトランスジェニック非ヒト動物。
- 消耗したT細胞を再活性化させる方法に用いるための、請求項1から4の何れか一項に記載の抗体又はその抗原結合断片を含む医薬であって、前記方法はT細胞集団を有効量の前記医薬に接触させることを含み、少なくとも幾らかのT細胞がPD−L1を発現する、医薬。
- 消耗したT細胞を再活性化させる方法に用いるための、請求項5から8の何れか一項に記載の抗体又はその抗原結合断片を含む医薬であって、前記方法はT細胞集団を有効量の前記医薬に接触させることを含み、少なくとも幾らかのT細胞がPD−1を発現する、医薬。
- 消耗したT細胞を再活性化させる方法に用いるための、請求項9から12の何れか一項に記載の抗体又はその抗原結合断片を含む医薬であって、前記方法は細胞集団を有効量の前記医薬に接触させることを含み、少なくとも幾らかの細胞がPD−L2を発現する、医薬。
- 接触工程がインビトロで実施される請求項19から21の何れか一項に記載の医薬。
- 接触工程がエキソビボで実施される請求項19から21の何れか一項に記載の医薬。
- 接触工程がインビボで実施される請求項19から21の何れか一項に記載の医薬。
- 持続感染に罹患している患者を治療するための、請求項1から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- ウイルス感染に罹患している患者を治療するための、請求項1から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- ウイルス感染が、サイトメガロウイルス、エプスタイン・バーウイルス、B型肝炎、C型肝炎ウイルス、ヘルペスウイルス、ヒト免疫不全ウイルス、ヒトTリンパ球向性ウイルス、リンパ球性脈絡髄膜炎ウイルス、呼吸器多核体ウイルス、及び/又はライノウイルスからなる群から選択される請求項26に記載の医薬。
- 細菌感染に罹患している患者を治療するための、請求項1から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 細菌感染が、ヘリコバクター、マイコバクテリア、ポルフィロモナス、及びクラミジアからなる群から選択される請求項28に記載の医薬。
- 蠕虫感染に罹患している患者を治療するための、請求項1から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 蠕虫が、住血吸虫及び条虫類からなる群から選択される請求項30に記載の医薬。
- 原虫感染に罹患している患者を治療するための、請求項1から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 原虫感染が、メキシコリーシュマニア及びマラリア原虫からなる群から選択される請求項32に記載の医薬。
- 癌に罹患している患者を治療するための、請求項1から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 癌が、固形腫瘍、血液癌、膀胱癌、脳癌、乳癌、結腸癌、胃(gastric)癌、神経膠腫、頭部癌、白血病、肝臓癌、肺癌、リンパ腫、骨髄腫、頸部癌、卵巣癌、メラノーマ、膵臓癌、腎臓癌、唾液腺癌、胃(stomach)癌、胸腺上皮性癌、及び甲状腺癌からなる群から選択される請求項34に記載の医薬。
- PD−L1を過剰発現する癌に罹患している患者を治療するための、請求項1から4の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 単離された抗体が抗体媒介性細胞傷害性を誘導する請求項36に記載の医薬。
- 抗体が抗体誘導細胞傷害性を増大させるように修飾されている請求項37に記載の医薬。
- 抗体が、毒素及び造影剤からなる群から選択される薬剤にコンジュゲートされている請求項38に記載の医薬。
- PD−L2を過剰発現する癌に罹患している患者を治療するための、請求項9から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 単離された抗体が抗体媒介性細胞傷害性を誘導する請求項40に記載の医薬。
- 抗体が抗体誘導細胞傷害性を増大させるように修飾されている請求項41に記載の医薬。
- 抗体が、毒素及び造影剤からなる群から選択される薬剤にコンジュゲートされている請求項42に記載の医薬。
- 喘息に罹患している患者を治療するための、請求項9から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 炎症性疾患に罹患している患者を治療するための、請求項1から4及び9から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 炎症性疾患が、急性播種性脳脊髄炎、アジソン病、強直性脊椎炎、抗リン脂質抗体症候群、自己免疫性溶血性貧血、自己免疫性肝炎、関節炎、ベーチェット病、水疱性類天疱瘡、セリアック病、シャーガス病、クローン病、皮膚筋炎、1型糖尿病、グッドパスチャー症候群、移植片対宿主病、グレーブス病、ギラン・バレー症候群、橋本病、高IgE症候群、特発性血小板減少性紫斑病、エリテマトーデス、多発性硬化症、重症筋無力症、天疱瘡、悪性貧血、多発性筋炎、原発性胆汁性肝硬変、乾癬、関節リウマチ、シェーグレン症候群、側頭動脈炎、血管炎、及びウェゲナー肉芽腫症からなる群から選択される請求項45に記載の医薬。
- 移植片拒絶に罹患している患者を治療するための、請求項1から4及び9から12の何れか一項に記載の抗体又はその抗原結合断片を含有する医薬。
- 移植片拒絶が、臓器拒絶反応、骨髄移植拒絶反応、及び/又は骨髄非破壊的骨髄移植拒絶反応からなる群から選択される請求項47に記載の医薬。
- 請求項1から12の何れか一項に記載の抗体又は抗原結合断片を製造する方法において、抗体又は抗原結合断片を産生する細胞を培養し、細胞により製造された抗体又は抗原結合断片を回収することを含む方法。
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