JP2023051947A - がんの治療及び診断方法 - Google Patents
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Abstract
Description
腫瘍微小環境内のCD8+T細胞コンパートメントに焦点を当てた研究では、治療された患者のかなりの部分、大まかに30%において明らかな臨床上の利益があるにもかかわらず、抗PD-1免疫療法の作用機序をこれまで明らかにできなかった。研究は主にCD8+T細胞に焦点を当てているが、最近、マイクロサテライト不安定腫瘍における腫瘍浸潤性CD4+T細胞が、マイクロサテライト安定腫瘍におけるよりも高いレベルのPD-1を発現することが観察された(Llosa及びCruise, Cancer discovery 5(1): 43-51 (2015))。加えて、メラノーマにおいて、腫瘍浸潤性CD4+T細胞はしばしば変異した抗原を認識する(Linnemann及びvan Buuren, Nature medicine 21(1): 81-85 (2015))。これらの研究と一致して、結腸直腸がん及びメラノーマの動物モデルにおいて実施された実験では、MHCクラスII拘束性T細胞応答が腫瘍制御において重要な役割を果たしうること(Kreiter等, Nature 520(7549): 692-696 (2015))、腫瘍反応性CD4+T細胞が細胞傷害性能力を発達させ、大きな樹立腫瘍を根絶しうること(Quezada等, J Exp. Med., 207(3): 637-650 (2010))が実証された。ここで報告された研究の前には、PD-1遮断薬、例えば抗PD-1抗体がヒトがんの状況においてCD4+T細胞に影響を及ぼすかどうか、また如何にして影響を及ぼすかは知られていなかった。
一態様では、本発明は、個体におけるがんを治療するか又はがんの進行を遅らせるための方法であって、治療有効量のPD-1軸結合アンタゴニストを患者に投与することを含み、患者から得られた血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上であると決定されている、方法を特徴とする。
発明を詳細に説明する前に、この発明は、特定の組成物又は生物系(当然、変わりうる)に限定されるものではないことが理解されるべきである。また、ここで使用される専門用語は、特定の実施態様を説明するためだけのものであり、限定することを意図するものではないことが理解されるべきである。
種々の治験薬、例えばチオプラチン、PS-341、フェニルブチレート、ET-18-OCH3、又はファルネシルトランスフェラーゼ阻害剤(L-739749、L-744832);ポリフェノール、例えばケルセチン、レスベラトロール、ピセタノール、没食子酸エピガロカテキン、テアフラビン、フラバノール、プロシアニジン、ベツリン酸及びその誘導体;オートファジー阻害剤、例えばクロロキン;デルタ-9-テトラヒドロカンナビノール(ドロナビノール、MARINOL(登録商標));ベータ-ラパコン;ラパコール;コルヒチン;ベツリン酸;アセチルカンプトテシン、スコポレクチン(scopolectin)、及び9-アミノカンプトテシン);ポドフィロトキシン;テガフール(UFTORAL(登録商標));ベキサロテン(TARGRETIN(登録商標));ビスホスホネート、例えばクロドロネート(例えば、BONEFOS(登録商標)又はOSTAC(登録商標))、エチドロネート(DIDROCAL(登録商標))、NE-58095、ゾレドロン酸/ゾレドロネート(ZOMETA(登録商標))、アレンドロネート(FOSAMAX(登録商標))、パミドロネート(AREDIA(登録商標))、チルドロネート(SKELID(登録商標))、又はリセドロネート(ACTONEL(登録商標));及び上皮増殖因子受容体(EGF-R);ワクチン、例えばTHERATOPE(登録商標)ワクチン;ペリフォシン、COX-2阻害剤(例えばセレコキシブ又はエトリコキシブ)、プロテオソーム阻害剤(例えばPS341);CCI-779;ティピファニブ(R11577);オラフェニブ(orafenib)、ABT510;Bcl-2阻害剤、例えばオブリメルセンナトリウム(GENASENSE(登録商標));ピクサントロン;ファルネシルトランスフェラーゼ阻害剤、例えば、ロナファーニブ(SCH6636、SARASARTM);及び上記の何れかの薬学的に許容可能な塩、酸、又は誘導体;並びに上記の二つ以上の組み合わせ、例えばCHOP(シクロホスファミド、ドキソルビシン、ビンクリスチン、及びプレドニゾロンの併用療法の略記);及びFOLFOX(5-FU及びロイコボリンと組み合わせたオキサリプラチン(ELOXATINTM)を用いた治療レジメンの略記)がまた含まれる。
ここに提供されるものは、治療有効量のPD-1軸結合アンタゴニストを患者に投与することを含む、がんに罹患した患者を治療する方法であって、患者から得られた血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上であると決定されている方法である。ここにまた提供されるものは、がんに罹患した患者が、PD-1軸結合アンタゴニストを含む治療に応答する可能性があるかどうかを決定するための方法である。例えば、PD-1軸結合アンタゴニストは、PD-1結合アンタゴニスト、PD-L1結合アンタゴニスト及びPD-L2結合アンタゴニストを含む。PD-1(プログラム死1)は、当該技術分野では「プログラム細胞死1」、「PDCD1」、「CD279」及び「SLEB2」とまた呼ばれる。例示的なヒトPD-1は、UniProtKB/Swiss-Prot受託番号Q15116に示されている。PD-L1(プログラム死リガンド1)はまた当該技術分野では「プログラム細胞死1リガンド1」、「PDCD1LG1」、「CD274」、「B7-H」、及び「PDL1」と呼ばれる。例示的なヒトPD-L1は、UniProtKB/Swiss-Prot受託番号Q9NZQ7.1に示されている。PD-L2(プログラム死リガンド2)はまた当該技術分野では、「プログラム細胞死1リガンド2」、「PDCD1LG2」、「CD273」、「B7-DC」、「Btdc」、及び「PDL2」と呼ばれる。例示的なヒトPD-L2は、UniProtKB/Swiss-Prot受託番号Q9BQ51に示されている。幾つかの実施態様では、PD-1、PD-L1、及びPD-L2は、ヒトPD-1、PD-L1及びPD-L2である。
幾つかの実施態様では、抗PD-1抗体はMDX-1106である。「MDX-1106」の別名には、MDX-1106-04、ONO-4538、BMS-936558、又はニボルマブが含まれる。幾つかの実施態様では、抗PD-1抗体はニボルマブ(CAS登録番号:946414-94-4)である。また更なる実施態様では、配列番号:1の重鎖可変領域アミノ酸配列を含む重鎖可変領域及び/又は配列番号:2の軽鎖可変領域アミノ酸配列を含む軽鎖可変領域を含む、単離された抗PD-1抗体が提供される。また更なる実施態様では、重鎖及び/又は軽鎖配列を含む単離された抗PD-1抗体が提供され、ここで、
(a)重鎖配列は、重鎖配列:
QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(配列番号:1)
に対して少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%又は100%の配列同一性を有し、かつ
(b)軽鎖配列は、軽鎖配列:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号:2)
に対して少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%又は100%の配列同一性を有する。
幾つかの実施態様では、製剤中の抗体は、重鎖及び/又は軽鎖配列中に少なくとも一つのトリプトファン(例えば、少なくとも二つ、少なくとも三つ、又は少なくとも四つ)を含む。幾つかの実施態様では、アミノ酸トリプトファンは、抗体のHVR領域、フレームワーク領域及び/又は定常領域中にある。幾つかの実施態様では、抗体は、HVR領域に二つ又は三つのトリプトファン残基を含む。幾つかの実施態様では、製剤中の抗体は抗PD-L1抗体である。PDL1、B7-H1、B7-4、CD274、及びB7-Hとしても知られるPD-L1(プログラム死リガンド1)は、膜貫通タンパク質であり、PD-1とのその相互作用はT細胞活性化及びサイトカイン産生を阻害する。幾つかの実施態様では、ここに記載の抗PD-L1抗体はヒトPD-L1に結合する。ここに記載の方法で使用することができる抗PD-L1抗体の例は、その全体が出典明示によりここに援用されるPCT特許出願の国際公開第2010/077634A1号及び米国特許第8217149号に記載されている。
(a)重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA(配列番号:3)
に対して少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%又は100%の配列同一性を有し、かつ
(b)軽鎖配列は、軽鎖配列:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号:4)
に対して少なくとも85%、少なくとも90%、少なくとも91%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%又は100%の配列同一性を有する。
(a)HVR-H1配列はGFTFSX1SWIH(配列番号:5)であり;
(b)HVR-H2配列はAWIX2PYGGSX3YYADSVKG(配列番号:6)であり;
(c)HVR-H3配列はRHWPGGFDY(配列番号:7)であり;
更にここで、X1はD又はGであり;X2はS又はLであり;X3はT又はSである。特定の一態様では、X1はDであり;X2はSであり、X3はTである。
HC-FR1がEVQLVESGGGLVQPGGSLRLSCAAS(配列番号:8)である。
HC-FR2がWVRQAPGKGLEWV(配列番号:9)である。
HC-FR3がRFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(配列番号:10)である。
HC-FR4がWGQGTLVTVSA(配列番号:11)である。
(a)HVR-L1配列はRASQX4X5X6TX7X8A(配列番号:12)であり;
(b)HVR-L2配列はSASX9LX10S,(配列番号:13)であり;
(c)HVR-L3配列はQQX11X12X13X14PX15T(配列番号:14)であり;
ここで、X4はD又はVであり;X5はV又はIであり;X6はS又はNであり;X7はA又はFであり;X8はV又はLであり;X9はF又はTであり;X10はY又はAであり;X11はY、G、F、又はSであり;X12はL、Y、F又はWであり;X13はY、N、A、T、G、F又はIであり;X14はH、V、P、T又はIであり;X15はA、W、R、P又はTである。また更なる態様では、X4はDであり;X5はVであり;X6はSであり;X7はAであり;X8はVであり;X9はFであり;X10はYであり;X11はYであり;X12はLであり;X13はYであり;X14はHであり;X15はAである。
LC-FR1がDIQMTQSPSSLSASVGDRVTITC(配列番号:15)であり
LC-FR2がWYQQKPGKAPKLLIY(配列番号:16)であり、
LC-FR3がGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(配列番号:17)であり、
LC-FR4がFGQGTKVEIKR(配列番号:18)である。
(a)重鎖はHVR-H1、HVR-H2及びHVR-H3を含み、更に、
(i)HVR-H1配列はGFTFSX1SWIH;(配列番号:5)であり、
(ii)HVR-H2配列はAWIX2PYGGSX3YYADSVKG(配列番号:6)であり、
(iii)HVR-H3配列はRHWPGGFDY(配列番号:7)であり、かつ
(b)軽鎖はHVR-L1、HVR-L2及びHVR-L3を含み、更に、
(i)HVR-L1配列はRASQX4X5X6TX7X8A(配列番号:12)であり、
(ii)HVR-L2配列はSASX9LX10S(配列番号13)であり、及び
(iii)HVR-L3配列はQQX11X12X13X14PX15T(配列番号:14)であり、
ここで、X1はD又はGであり;X2はS又はLであり;X3はT又はSであり;X4はD又はVであり;X5はV又はIであり;X6はS又はNであり;X7はA又はFであり;X8はV又はLであり;X9はF又はTであり;X10はY又はAであり;X11はY、G、F、又はSであり;X12はL、Y、F又はWであり;X13はY、N、A、T、G、F又はIであり;X14はH、V、P、T又はIであり;X15はA、W、R、P又はTである。特定の態様では、X1はDであり;X2はSであり、X3はTである。別の態様では、X4はDであり;X5はVであり;X6はSであり;X7はAであり;X8はVであり;X9はFであり;X10はYであり;X11はYであり;X12はLであり;X13はYであり;X14はHであり;X15はAである。また別の態様では、X1はDであり;X2はSであり、X3はTであり、X4はDであり;X5はVであり;X6はSであり;X7はAであり;X8はVであり;X9はFであり;X10はYであり;X11はYであり;X12はLであり;X13はYであり;X14はHであり、及びX15はAである。
(a)重鎖は、GFTFSDSWIH(配列番号:19)、AWISPYGGSTYYADSVKG(配列番号:20)及びRHWPGGFDY(配列番号:21)に対してそれぞれ少なくとも85%の配列同一性を有するHVR-H1、HVR-H2及びHVR-H3配列を更に含むか、又は
(b)軽鎖は、RASQDVSTAVA(配列番号:22)、SASFLYS(配列番号:23)及びQQYLYHPAT(配列番号:24)に対してそれぞれ少なくとも85%の配列同一性を有するHVR-L1、HVR-L2及びHVR-L3配列を更に含む。
特定の態様では、配列同一性は、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%又は100%である。
(a)重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS(配列番号:25)
に対して少なくとも85%の配列同一性を有し、及び/又は
(b)軽鎖配列は、軽鎖配列:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号:4)
に対して少なくとも85%の配列同一性を有する。
HC-FR1 EVQLVESGGGLVQPGGSLRLSCAASGFTFS(配列番号:29)
HC-FR2 WVRQAPGKGLEWVA(配列番号:30)
HC-FR3 RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR(配列番号:10)
HC-FR4 WGQGTLVTVSS(配列番号:27)。
LC-FR1 DIQMTQSPSSLSASVGDRVTITC(配列番号:15)
LC-FR2 WYQQKPGKAPKLLIY(配列番号:16)
LC-FR3 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(配列番号:17)
LC-FR4 FGQGTKVEIK(配列番号:28)。
(c)重鎖は、GFTFSDSWIH(配列番号:19)、AWISPYGGSTYYADSVKG(配列番号:20)及びRHWPGGFDY(配列番号:21)に対してそれぞれ少なくとも85%の配列同一性を有するHVR-H1、HVR-H2及びHVR-H3配列を更に含み、及び/又は
(d)軽鎖は、RASQDVSTAVA(配列番号:22)、SASFLYS(配列番号:23)及びQQYLYHPAT(配列番号:24)に対してそれぞれ少なくとも85%の配列同一性を有するHVR-L1、HVR-L2及びHVR-L3配列を更に含む。
特定の態様では、配列同一性は、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%又は100%である。
(a)重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK(配列番号:26)
に対して少なくとも85%の配列同一性を有するか、又は
(b)軽鎖配列は、軽鎖配列:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(配列番号:4)
に対して少なくとも85%の配列同一性を有する。
(a)重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号:32)
に対して少なくとも85%の配列同一性を有し、及び/又は
(b)軽鎖配列は、軽鎖配列:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号:33)
に対して少なくとも85%の配列同一性を有する。
ここに記載される抗体は、抗体を作製するための当該技術分野で利用可能な技術を使用して調製され、その例示的な方法を、次のセクションでより詳細に説明する。
場合によっては他の分子にコンジュゲートされる、可溶型抗原又はその断片を、抗体を作製するための免疫原として使用することができる。受容体などの膜貫通分子では、これらの断片(例えば、受容体の細胞外ドメイン)を免疫原として使用することができる。あるいは、膜貫通分子を発現する細胞を免疫原として使用することができる。このような細胞は、天然源(例えば、がん細胞株)に由来するものであり得、又は膜貫通分子を発現するように組換え技術によって形質転換された細胞でありうる。抗体の調製に有用な他の抗原及びその形態は、当業者には明らかであろう。
ポリクローナル抗体は、好ましくは、関連する抗原とアジュバントの複数回にわたる皮下(sc)又は腹腔内(ip)注入により動物内で産生される。関連抗原を、免疫化される種において免疫原性であるタンパク質、例えばキーホールリンペットヘモシアニン、血清アルブミン、ウシサイログロブリン、又はダイズトリプシン阻害因子に、二官能性又は誘導体化剤、例えば、マレイミドベンゾイルスルホスクシンイミドエステル(システイン残基によるコンジュゲーション)、N-ヒドロキシスクシンイミド(リジン残基による)、グルタルアルデヒド、無水コハク酸、SOCl2、又はR1N=C=NR(ここで、RとR1は異なるアルキル基)にコンジュゲートさせることが有用である場合がある。
本発明の抗体は、所望の活性又は活性群を有する抗体のコンビナトリアルライブラリーをスクリーニングすることによって単離されうる。例えば、ファージディスプレイライブラリーを作成して所望の結合特性を有する抗体のそのようなライブラリーをスクリーニングするための様々な方法が、当該技術分野で知られている。更なる方法は、例えば、Hoogenboom等, in Methods in Molecular Biology 178:1-37 (O’Brien等編, Human Press, Totowa, NJ, 2001)に概説があり、更に例えば、McCafferty等, Nature 348:552-554;Clackson等, Nature 352: 624-628 (1991);Marks等, J. Mol. Biol. 222: 581-597 (1992);Marks及びBradbury, in Methods in Molecular Biology 248:161-175 (Lo編, Human Press, Totowa, NJ, 2003);Sidhu等, J. Mol. Biol. 338(2): 299-310 (2004);Lee等, J. Mol. Biol. 340(5): 1073-1093 (2004);Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004);及びLee等, J. Immunol. Methods 284(1-2): 119-132(2004)に記載されている。
所定の実施態様では、ここで提供される抗体はキメラ抗体である。所定のキメラ抗体は、例えば、米国特許第4816567号、及びMorrison等, Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)に記載されている。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、又はサル等の非ヒト霊長類由来の可変領域)とヒト定常領域とを含む。更なる例では、キメラ抗体は、クラス又はサブクラスが親抗体のものから変更されている「クラススイッチ」抗体である。キメラ抗体は、その抗原結合断片を含む。
抗体断片は、酵素消化などの常套的手段によって、又は組換え技術によって作製されうる。所定の状況下では、全抗体よりも抗体断片を使用することに利点がある。より小さいサイズの断片であると、迅速なクリアランスが可能になり、固形腫瘍へのアクセス改善につながりうる。所定の抗体断片の概説については、Hudson等 (2003) Nat. Med. 9:129-134を参照のこと。
多重特異性抗体は、少なくとも二つの異なるエピトープに対して結合特異性を有し、そのエピトープは通常異なる抗原に由来している。そのような分子は通常二つの異なるエピトープにのみ結合するが(すなわち二重特異性抗体、BsAb)、この表現をここで使用する場合、三重特異性抗体のような更なる特異性を有する抗体も包含される。二重特異性抗体は、完全長抗体又は抗体断片(例えばF(ab’)2二重特異性抗体)として調製されうる。
幾つかの実施態様では、本発明の抗体は単一ドメイン抗体である。単一ドメイン抗体は、抗体の重鎖可変ドメインの全てもしくは一部、又は軽鎖可変ドメインの全てもしくは一部を含む単一ポリペプチド鎖である。所定の実施態様では、単一ドメイン抗体はヒト単一ドメイン抗体である(Domantis, Inc., Waltham, Mass.;例えば、米国特許第6248516B1号参照)。一実施態様では、単一ドメイン抗体は、抗体の重鎖可変ドメインの全て又は一部からなる。
幾つかの実施態様では、ここに記載される抗体のアミノ酸配列修飾が考慮される。例えば、抗体の結合親和性及び/又は他の生物学的特性を改善することが望ましい場合がある。抗体のアミノ酸配列バリアントは、抗体をコードするヌクレオチド配列に適切な改変を導入することにより、又はペプチド合成により調製されうる。そのような修飾は、例えば抗体のアミノ酸配列内の残基からの欠失、及び/又はそれへの挿入、及び/又はそれの置換を含む。最終コンストラクトが所望の特性を有する限り、欠失、挿入、及び置換の何れの組み合わせも最終コンストラクトに到達するように行なわれうる。アミノ酸改変は、配列が作製されるときに対象の抗体のアミノ酸配列に導入されうる。
所定の実施態様では、一又は複数のアミノ酸置換を有する抗体バリアントが提供される。置換変異誘発の目的の部位は、HVR及びFRを含む。好ましい置換は、「好ましい置換」と題して表3に示される。より実質的な変化は、「例示的置換」と題して表3に示され、アミノ酸側鎖クラスを参照して以下に更に記載される。アミノ酸置換は、目的の抗体に導入することができ、産物は、所望の活性、例えば、抗原結合の保持/改善、免疫原性の低下、又はADCCもしくはCDCの改善についてスクリーニングされる。
a.疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
b.中性の親水性:Cys、Ser、Thr、Asn、Gln;
c.酸性:Asp、Glu;
d.塩基性:His、Lys、Arg;
e.鎖配向に影響する残基:Gly、Pro;
f.芳香性:Trp、Tyr、Phe。
所定の実施態様では、ここで提供される抗体は、抗体がグリコシル化される度合いを上昇させ又は低下させるように改変される。グリコシル化部位の抗体への付加又は欠失は、一又は複数のグリコシル化部位がつくり出され又は除去されるようにアミノ酸配列を改変することにより、簡便に達成することができる。
所定の実施態様では、一又は複数のアミノ酸修飾を、ここで提供される抗体のFc領域に導入し、それによりFc領域バリアントを作製することができる。Fc領域バリアントは、一又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又はIgG4 Fc領域)を含みうる。
本発明の抗体は、当該技術分野で知られ、容易に入手可能な追加の非タンパク質部分を含むように更に改変されうる。所定の実施態様では、抗体の誘導体化に適した部分は水溶性ポリマーである。水溶性ポリマーの非限定的な例には、限定しないが、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共重合体、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-トリオキソラン、エチレン/無水マレイン酸共重合体、ポリアミノ酸(単独重合体又はランダム共重合体)、及びデキストラン又はポリ(n-ビニルピロリドン)ポリエチレングリコール、プロピレングリコール単独重合体、プロピレンオキシド/エチレンオキシド共重合体、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、及び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その水中での安定性のために製造上の利点を有しうる。ポリマーは、任意の分子量であってよく、分枝状でも非分枝状でもよい。抗体に結合するポリマーの数は変化してもよく、一を超えるポリマーが結合する場合、それらは同じ分子でも異なる分子でもよい。一般に、誘導体化に使用されるポリマーの数及び/又は種類は、限定されないが、改善されるべき抗体の特定の特性又は機能、その抗体誘導体が定まった条件下で治療に使用されるかどうかを含む考慮事項に基づいて決定することができる。
抗体は、組換え法を使用して生成することもできる。抗抗原抗体の組換え生産では、抗体をコードする核酸が単離され、更なるクローニング(DNAの増幅)又は発現のために複製可能なベクター中に挿入される。抗体をコードするDNAは、容易に単離され得、常套的な手順を使用して (例えば、抗体の重鎖と軽鎖をコードする遺伝子に特異的に結合することができるオリゴヌクレオチドプローブを使用することによって)配列決定されうる。多くのベクターが利用可能である。ベクターの成分は、限定されないが、次のうちの一又は複数を一般に含む:シグナル配列、複製開始点、一又は複数のマーカー遺伝子、エンハンサーエレメント、プロモーター、及び転写終結配列。
本発明の抗体は、直接的に組換えで生産されるだけではなく、シグナル配列又は成熟タンパク質もしくはポリペプチドのN末端に特異的切断部位を有する他のポリペプチドである異種性ポリペプチドとの融合ペプチドとしても生産されうる。選択される異種シグナル配列は、好ましくは、宿主細胞によって認識され、プロセシング(例えば、シグナルペプチダーゼによって切断)されるものである。天然抗体シグナル配列を認識しプロセシングしない原核生物宿主細胞の場合、シグナル配列は、例えば、アルカリホスファターゼ、ペニシリナーゼ、lpp、又は熱安定性エンテロトキシンIIリーダーの群から選択される原核生物シグナル配列により置換される。酵母分泌の場合、天然シグナル配列は、例えば、酵母インベルターゼリーダー、因子リーダー(サッカロミセス及びクリベロマイセスα因子リーダーを含む)、又は酸ホスファターゼリーダー、カンジダアルビカンスグルコアミラーゼリーダー、又は国際公開第90/13646号に記載のシグナルによって置換されうる。哺乳動物細胞での発現では、哺乳動物シグナル配列並びにウイルス分泌リーダー、例えば単純ヘルペスgDシグナルが利用可能である。
発現及びクローニングベクターは両方とも、一又は複数の選択された宿主細胞においてベクターが複製することを可能にする核酸配列を含む。一般に、クローニングベクター中では、この配列は、宿主の染色体DNAから独立してベクターが複製することを可能にするものであり、複製開始点又は自己複製配列を含む。そのような配列は、様々な細菌、酵母及びウイルスに対してよく知られている。プラスミドpBR322からの複製開始点は、大部分のグラム陰性細菌に適しており、2μ,プラスミド開始点は酵母に適しており、様々なウイルス開始点(SV40、ポリオーマ、アデノウイルス、VSV又はBPV)は哺乳動物細胞中におけるクローニングベクターに有用である。一般に、複製開始点成分は哺乳動物の発現ベクターには不要である(早期プロモーターを含むという理由のみでSV40開始点が通常使用されうる)。
発現及びクローニングべクターは、選択可能マーカーとも呼ばれる選択遺伝子を含みうる。典型的な選択遺伝子は、(a)抗生物質又は他の毒素、例えば、アンピシリン、ネオマイシン、メトトレキサート、又はテトラサイクリンに耐性を付与し、(b)栄養要求性欠陥を補い、又は(c)複合培地から得られない重要な栄養素、例えば、バシリに対する遺伝子コードD-アラニンラセマーゼを供給するタンパク質をコードする。
発現及びクローニングベクターは、一般に、宿主生物によって認識され、抗体をコードする核酸に作用可能に連結されるプロモーターを含む。原核生物宿主との使用に適したプロモーターには、phoAプロモーター、β-ラクタマーゼ及びラクトースプロモーター系、アルカリホスファターゼプロモーター、トリプトファン(trp)プロモーター系、及びtacプロモーターのようなハイブリッドプロモーターが含まれる。しかしながら、他の既知の細菌プロモーターも適している。細菌系に使用されるプロモーターもまた、抗体をコードするDNAに作用可能に連結されたシャイン-ダルガーノ(S.D.)配列を含むであろう。
より高等の真核生物による本発明の抗体をコードしているDNAの転写は、ベクター中にエンハンサー配列を挿入することによってしばしば増強される。哺乳動物遺伝子由来の多くのエンハンサー配列が今は知られている(グロビン、エラスターゼ、アルブミン、α-フェトプロテイン、及びインスリン)。しかしながら、典型的には、真核細胞ウイルスからのエンハンサーが使用されるであろう。例としては、複製起点の後期側のSV40エンハンサー(100~270塩基対)、サイトメガロウィルス初期プロモーターエンハンサー、複製起点の後期側のポリオーマエンハンサー、及びアデノウィルスエンハンサーが含まれる。真核生物プロモーターの活性化の増強要素についてYaniv, Nature 297:17-18 (1982)をまた参照のこと。エンハンサーは、抗体コード配列の5’又は3’位でベクター中にスプライシングされうるが、好ましくはプロモーターから5’部位に位置している。
真核生物宿主細胞(酵母、真菌、昆虫、植物、動物、ヒト、又は他の多細胞生物由来の有核細胞)において使用される発現ベクターは、転写の終結及びmRNAの安定化に必要な配列をまた含む。そのような配列は、真核生物又はウイルスのDNA又はcDNAの5’、及び時には3’の未翻訳領域から一般に入手できる。これら領域は、抗体をコードするmRNAの未翻訳部分にポリアデニル化断片として転写されるヌクレオチドセグメントを含む。一つの有用な転写終結成分は、ウシ成長ホルモンポリアデニル化領域である。国際公開第94/11026号とそこに開示される発現ベクターを参照のこと。
ここでのベクター中でのDNAのクローニング又は発現に適した宿主細胞は、上記の原核細胞、酵母、又は高等真核細胞である。この目的のための適切な原核生物には、グラム陰性又はグラム陽性生物のような真正細菌、例えば、大腸菌類のような腸内細菌科、例えば、大腸菌、エンテロバクター属、エルウィニア属、クレブシエラ属、プロテウス属、サルモネラ属、例えばネズミチフス菌、セラチア属、例えば霊菌、及びシゲラ属、並びに桿菌、例えば枯草菌及びバチルス・リケニフォルミス(例えば、1989年4月12日公開のDD266710に開示されたバチルス・リケニフォルミス41P)、シュードモナス属、例えば緑膿菌、及びストレプトマイセス属が含まれる。一つの好ましい大腸菌クローニング宿主は大腸菌294(ATCC31446)であるが、大腸菌B、大腸菌X1776(ATCC31537)、及び大腸菌W3110(ATCC27325)のような他の菌株も適している。これらの例は限定的なものではなく例示的なものである。
この発明の抗体を産生するために使用される宿主細胞は様々な培地中で培養されうる。市販の培地、例えばHamのF10(Sigma)、最小必須培地((MEM),(Sigma)、RPMI-1640(Sigma)及びダルベッコの改良イーグル培地((DMEM),Sigma)が宿主細胞の培養に適している。加えて、Ham等, Meth. Enz. 58:44 (1979)、Barnes等, Anal. Biochem. 102:255 (1980)、米国特許第4767704号;同第4657866号;同第4927762号;同第4560655号;又は同第5122469号;国際公開第90/03430号;国際公開第87/00195号;又は米国再発行特許第30985号に記載の培地の何れもが、宿主細胞の培地として使用できる。これら培地の何れにも、ホルモン及び/又は他の増殖因子(例えばインスリン、トランスフェリン、又は上皮増殖因子)、塩(例えば塩化ナトリウム、カルシウム、マグネシウム、及びホスフェート)、緩衝液(例えばHEPES)、ヌクレオチド(例えばアデノシン及びチミジン)、抗生物質(例えばGENTAMYCINTM薬)、微量元素(最終濃度がマイクロモル範囲で通常存在する無機化合物として定義される)、及びグルコース又は同等のエネルギー源を必要に応じて補充することができる。任意の他の必要な補充物もまた当業者に既知の適切な濃度で含めることができる。温度、pHなどの培養条件は、発現のために選択された宿主細胞と共に以前に使用されたものであり、当業者には明らかであろう。
組換え技術を使用する場合、抗体は、細胞内、細胞膜周辺腔内で産生されるか、又は培地中に直接分泌されうる。抗体が細胞内に産生される場合、最初の工程として、宿主細胞か又は溶解断片の何れかである微粒子状デブリが、例えば遠心分離又は限外濾過により除去される。Carter等, Bio/Technology 10: 163-167 (1992)は、大腸菌の細胞膜周辺腔に分泌される抗体を単離するための手順を記載する。簡潔には、細胞ペーストが、酢酸ナトリウム(pH3.5)、EDTA、及びフッ化フェニルメチルスルホニル(PMSF)の存在下で約30分間にわたって融解される。細胞デブリは遠心分離により除去されうる。抗体が培地中に分泌される場合、一般に、そのような発現系からの上清が先ず、市販のタンパク質濃縮フィルター、例えばAmicon又はMillipore Pellicon限外濾過ユニットを使用して濃縮される。PMSF等のプロテアーゼ阻害剤を、タンパク分解を阻害する前述の工程の何れかに含めることができ、抗生物質を、不定の夾雑物の増殖を防ぐために含めることができる。
上述のように産生された抗体を一又は複数の「生物学的活性」アッセイに供し、治療的見地から有利な特性を持つ抗体を選択し、又は抗体の生物学的活性を保持する製剤及び条件を選択することができる。抗体は、それが産生された抗原に結合する能力について試験されうる。例えば、当該技術分野で知られている方法(例えばELISA、ウェスタンブロットなど)を使用することができる。
ここにまた提供されるのは、ここに記載のPD-1軸結合アンタゴニスト及び/又は抗体(例えば抗PD-1抗体又は抗PD-L1抗体)と場合によっては薬学的に許容可能な担体とを含有する薬学的組成物及び製剤である。
ここに提供されるものは、有効量のPD-1軸結合アンタゴニストを個体に投与することを含む、個体におけるがん(例えば、メラノーマ)を治療し又はその進行を遅延させるための方法であり、ここで、患者から得られた血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上であると決定されている。幾つかの実施態様では、治療は、治療後の個体に応答をもたらす。幾つかの実施態様では、応答は部分応答である。幾つかの実施態様では、応答は完全寛解である。幾つかの実施態様では、治療は、治療休止後の個体に持続性の応答(例えば、持続性の部分応答又は完全寛解)をもたらす。ここに記載される方法は、免疫原性の増強、例えばがんの治療のための腫瘍免疫原性の増大が望ましい状態の治療に用途を見出しうる。また、ここに提供されるものは、有効量のPD-1軸結合アンタゴニスト(例えば、ニボルマブ(Nivolomab)、ペンブロリズマブ、アテゾリズマブ、又はアベルマブ)を、個体に投与することを含む、メラノーマを有する個体において免疫機能を増強する方法である。当該技術分野で知られているか又はここに記載されているPD-1軸結合アンタゴニストの何れも、本方法において使用することができる。
本発明の別の実施態様では、PD-1軸結合アンタゴニスト(例えば、抗PD-L1抗体、例えば、MPDL3280A)と、個体から得られた血液試料におけるグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上の個体において、又は個体から得られた血液試料におけるグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上の個体の免疫機能を増強するために、PD-1軸結合アンタゴニストを使用するための説明書を含む添付文書とを含む製造品又はキットが提供される。ここに記載のPD-1軸結合アンタゴニストの何れも製造品又はキットに含めることができる。
mMLRアッセイにおけるCD4+T細胞及び同種DC
PD-1遮断の根底にある機序を解明するために、我々は、CD4+T細胞が同種MHCIIを認識し、検出可能な免疫応答を開始することができる、CD4+T細胞に焦点を合わせたインビトロ機能アッセイを開発した。最小MLR(mMLR)と呼ばれるこのアッセイで我々は、健康なドナーから得た選別されたCD4T細胞を、無関係のドナー由来の単球由来成熟樹状細胞と共培養した。
[統計]**は、一元配置分散分析(GraphPad Prism)で計算したP<0.01に、***はP<0.001に対応する。
PD-1遮断はCD4+T細胞によるIFN-γ分泌及びグランザイムB産生を増加させる
我々は次に実施例1に記載したmMLR培養物に添加した抗PD-1遮断抗体の効果を決定した 。
[サイトカイン細胞内染色及びELISA]mMLR共培養から5日目に、我々は細胞培養上清を回収し、ELISA(R&Dシステムズ、製造者の指示に従う)によるIFN-γレベルの測定に使用し、細胞を、ゴルジプラグ(ブレフェルジンA,BD Bioscience)及びゴルジストップ(モネンシン,BD Bioscience)の存在下で更に5時間の間37℃に放置した。次に細胞を洗浄し、Fix/Perm緩衝液(BD Bioscience)で固定/透過処理する前に、抗ヒトCD4抗体及びLive/Dead固定化色素Aqua(Invitrogen)で表面を染色した。次に、グランザイムB(BD Bioscience)、IFN-γ及びIL-2(両方ともeBioscienceからの抗体)について細胞内染色を実施した。共培養後1日目に抗PD-1遮断抗体(Roche 0376)を添加することにより、5日目までに上清中に放出されるIFN-γの量を増加させることができ(図2)、驚くべきことに、共培養単独とアイソタイプ対照の存在下と比較した場合、CD4+T細胞による有意なグランザイムBの産生を誘導することができた(図3)。
様々な抗PD-1軸遮断抗体に応答した細胞傷害性CD4+T細胞の誘導
抗PD-1抗体0376、MDX-1106(ニボルマブ,Bristol-Myers Squibb)及びMK-3475(ペンブロリズマブ,Merck)を、本質的に実施例2に記載の通りに実施したmMLRアッセイにおいて比較した。試験した全ての抗体は最小MLRアッセイにおいてCD4+T細胞によるIFN-γ分泌の誘導において同等であったが(図4A)、0376は、細胞傷害性グランザイムB+CD4+T細胞の増殖及び/又はその出現の誘導において優れた効果を示した(図4B)。
我々はまた抗PD-L1抗体(表5のPD-L1 mulgG1 DAPG)でPD- 1リガンド、PD-L1を遮断することが、最小MLRアッセイにおいてCD4+T細胞に対して同様な効果を有するかどうかを評価した。全ての抗PD-1抗体(0376、MDX-1106及びMK-3475)及び抗PD-L1抗体が、CD4+T細胞によるIFN-γ分泌を誘導した(図4A、図5A)。抗PD-L1抗体はまた細胞傷害性グランザイムB+CD4+T細胞の出現を誘導した(図4B及び図5B)。
ニボルマブで処置されたメラノーマ患者の末梢血中のCD4+T細胞プロファイル
[メラノーマ患者のPBMCのエクスビボ表現型及び機能特徴付け]解凍後、PBMCを、ゴルジプラグ(ブレフェルジンA,BD Bioscience)及びゴルジストップ(モネンシン,BD Bioscience)の存在下で1ml当たり2×105~106の範囲の濃度でRPMI10%FBSに再懸濁し、37℃で12時間インキュベートした。ついでPBMCを洗浄し、表面を抗CD3(BD Horizon,BD Biosciences)、抗CD8(BD Biosciences)及び抗CD4抗体(BioLegend)で染色し、続いてFOXP3/転写因子緩衝液セット(eBioscience)を用いた透過処理/固定を行った。細胞をFOXP3(eBioscience)、グランザイムB(BD Bioscience)、IFN-γ、IL-2(両方ともeBioscienceから)及びKi67(BD Pharmingen)について細胞内染色し、フローサイトメーター(LSRFortessa,BD Biosciences)で取得した。
細胞傷害性CD4+T細胞は、健康な個体の末梢血中に非常に低い頻度で存在し、それらが抗ウイルス免疫応答において決定的な役割を果たすウイルス感染の間に数が増加することが記載されている(Appay, Clin. Exp. Immunol. 138(1):10-13 (2004))。
前述の発明は、理解を明確にする目的で例示及び実施例によってある程度詳細に説明されてきたが、説明及び実施例は、本発明の範囲を限定するものとして解釈されるべきではない。ここに引用された全ての特許及び科学文献の開示は、その全体が出典明示により明示的に援用される。
Claims (61)
- 個体におけるがんを治療するか又はがんの進行を遅らせるための方法であって、治療有効量のPD-1軸結合アンタゴニストを個体に投与することを含み、個体から得られる血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上であると決定 されている、方法。
- がんに罹患している個体がPD-1軸結合アンタゴニストを含む治療に応答しているかどうかを決定するための方法であって、
個体から得られた試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比を決定することを含み、試料中の1以上のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が、個体がPD-1軸結合アンタゴニストを含む治療に応答していることを示す、方法。 - 試料が血液試料である、請求項1又は2に記載の方法。
- 試料が全血試料又は末梢血単核細胞試料である、請求項3に記載の方法。
- 個体が、PD-1軸結合アンタゴニストを含む治療を受けているか又は受けたことがある、請求項1から4の何れか一項に記載の方法。
- がんが、膀胱がん、扁平上皮がん、小細胞肺がん(SCLC)、非小細胞肺がん(NSCLC)、肺腺がん、肺扁平上皮がんを含む肺がん、腹膜がん、肝細胞がん、胃腸がんを含む胃(gastric又はstomach)がん、膵臓がん、膠芽腫、子宮頸がん、卵巣がん、肝臓がん(liver cancer)、ヘパトーマ、乳がん、結腸がん、直腸がん、結腸直腸がん、子宮内膜又は子宮がん、唾液腺がん、腎がん、前立腺がん、外陰がん、甲状腺がん、肝がん(hepatic carcinoma)、肛門がん、陰茎がん、メルケル細胞がん、精巣がん、食道がん、胆道腫瘍、頭頸部がん及び血液悪性腫瘍からなる群から選択される、請求項1から5の何れか一項に記載の方法。
- がんがメラノーマである、請求項6に記載の方法。
- がんが尿路上皮膀胱がんである、請求項6に記載の方法。
- 尿路上皮膀胱がんが転移性尿路上皮膀胱がんである、請求項8に記載の方法。
- 尿路上皮膀胱がんが局所進行性尿路上皮膀胱がんである、請求項8に記載の方法。
- 個体におけるがん細胞がPD-L1を発現する、請求項1から10の何れか一項に記載の方法。
- PD-L1発現が免疫組織化学(IHC)アッセイによって決定される、請求項11に記載の方法。
- 個体が、局所進行性又は転移性がんに対して以前に2回以下の細胞傷害性治療レジメンを受けたことがある、請求項1から12の何れか一項に記載の方法。
- 個体が、局所進行性又は転移性がんに対して以前に標的全身治療を受けたことがない、請求項1から13の何れか一項に記載の方法。
- 治療に対する個体の応答が完全寛解である、請求項2に記載の方法。
- 治療に対する個体の応答が部分応答である、請求項2に記載の方法。
- 治療に対する個体の応答が、治療中止後の持続応答である、請求項2に記載の方法。
- グランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が4である、請求項1から17の何れか一項に記載の方法。
- グランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が45である、請求項1から17の何れか一項に記載の方法。
- PD-L1軸結合アンタゴニストが、PD-L1結合アンタゴニスト、PD-1結合アンタゴニスト、及びPD-L2結合アンタゴニストからなる群から選択される、請求項1から19の何れか一項に記載の方法。
- PD-L1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20に記載の方法。
- PD-L1結合アンタゴニストが、PD-L1のそのリガンド結合パートナーの一又は複数への結合を阻害する、請求項21に記載の方法。
- PD-L1結合アンタゴニストが、PD-L1のPD-1への結合を阻害する、請求項21に記載の方法。
- PD-L1結合アンタゴニストが、PD-L1のB7-1への結合を阻害する、請求項21に記載の方法。
- PD-L1結合アンタゴニストが、PD-L1のPD-1とB7-1の両方への結合を阻害する、請求項20に記載の方法。
- PD-L1結合アンタゴニストが抗体である、請求項21から25の何れか一項に記載の方法。
- 抗体が、アテゾリズマブ(MPDL3280A)、YW243.55.S70、MDX-1105、MEDI4736(デュルバルマブ)、及びMSB0010718C(アベルマブ)からなる群から選択される、請求項26に記載の方法。
- 抗体が、配列番号 19のHVR-H1配列、配列番号20のHVR-H2配列、及び配列番号21のHVR-H3配列を含む重鎖と;配列番号22のHVR-L1配列、配列番号23のHVR-L2配列、及び配列番号24のHVR-L3配列を含む軽鎖とを含む、請求項26に記載の方法。
- 抗体が、配列番号25のアミノ酸配列を含む重鎖可変領域と配列番号4のアミノ酸配列を含む軽鎖可変領域とを含む、請求項28に記載の方法。
- PD-L1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20に記載の方法。
- PD-1結合アンタゴニストが、PD-1のそのリガンド結合パートナーの一又は複数への結合を阻害する、請求項30に記載の方法。
- PD-1結合アンタゴニストが、PD-1のPD-L1への結合を阻害する、請求項30に記載の方法。
- PD-1結合アンタゴニストが、PD-1のPD-L2への結合を阻害する、請求項30に記載の方法。
- PD-1結合アンタゴニストが、PD-1のPD-L1とPD-L2の両方への結合を阻害する、請求項30に記載の方法。
- PD-1結合アンタゴニストが抗体である、請求項30から34の何れか一項に記載の方法。
- 抗体が、MDX-1106(ニボルマブ)、MK-3475(ペンブロリズマブ)、MEDI-0680(AMP-514)、PDR001、REGN2810、及びBGB-108からなる群から選択される、請求項35に記載の方法。
- PD-1結合アンタゴニストがFc融合タンパク質である、請求項30から34の何れか一項に記載の方法。
- Fc融合タンパク質がAMP-224である、請求項37に記載の方法。
- 個体に有効量の第二の治療剤を投与することを更に含む、請求項1から38の何れか一項に記載の方法。
- 第二の治療剤が、細胞傷害剤、増殖阻害剤、放射線療法剤、抗血管新生剤、及びそれらの組み合わせからなる群から選択される、請求項39に記載の方法。
- 細胞傷害剤が化学療法剤である、請求項40に記載の方法。
- 化学療法剤がタキサンである、請求項41に記載の方法。
- タキサンが、PD-1軸結合アンタゴニストの前、PD-1軸結合アンタゴニストと同時、又はPD-1軸結合アンタゴニストの後に投与される、請求項42に記載の方法。
- タキサンが、nab-パクリタキセル(ABRAXANE(登録商標))、パクリタキセル、又はドセタキセルである、請求項42又は43に記載の方法。
- 個体が、白金系化学療法剤による治療後に進行している、請求項1から44の何れか一項に記載の方法。
- グランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が、グランザイムBタンパク質を発現するCD4+T細胞の数とFOXP3タンパク質を発現するCD4+T細胞の数を決定することによって決定される、請求項1から45の何れか一項に記載の方法。
- グランザイムBとFOXP3の少なくとも一つのタンパク質発現レベルが、免疫組織化学(IHC)、免疫蛍光法、フローサイトメトリー、及びウエスタンブロットからなる群から選択される方法を使用して決定される、請求項46に記載の方法。
- グランザイムBとFOXP3の少なくとも一つのタンパク質発現レベルが、フローサイトメトリーを使用して決定される、請求項46に記載の方法。
- グランザイムBとFOXP3の少なくとも一つの発現レベルがmRNA発現レベルである、請求項1から45の何れか一項に記載の方法。
- グランザイムBとFOXP3の少なくとも一つのmRNA発現レベルが、定量的ポリメラーゼ連鎖反応(qPCR)、逆転写qPCR(RT-qPCR)、RNAシークエンシング、マイクロアレイ解析、インサイツハイブリダイゼーション、及び遺伝子発現連続解析(SAGE)からなる群から選択される方法を使用して決定される、請求項49に記載の方法。
- がんに罹患している患者の、PD-L1軸結合アンタゴニストを含む治療に対する応答性を予測するための方法であって、
個体から得られた試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比を決定することを含み、1以上のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が、個体がPD-1軸結合アンタゴニストを含む治療に応答する可能性が高いことを示す、方法。 - 個体に少なくとも1用量のPD-L1軸結合アンタゴニストが投与された後に個体から試料が得られる、請求項51に記載の方法。
- がんに罹患している個体に対する治療法を選択するための方法であって、
個体から得られた試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比を決定し、試料中の1以上のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比に基づいて個体に対してPD-L1軸結合アンタゴニストを含む治療法を選択することを含む、方法。 - がんに罹患している個体を治療するのに使用するためのPD-1軸結合アンタゴニストであって、個体から得られた血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上であると決定されている、PD-1軸結合アンタゴニスト。
- がんに罹患している個体の治療における使用のための医薬の製造における有効量のPD-1軸結合アンタゴニストの使用であって、個体から得られた血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上であると決定されている、使用。
- がんに罹患している個体を治療する方法における使用のための有効量のPD-1軸結合アンタゴニストを含有する組成物であって、個体から得られた血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上であると決定されている、組成物。
- PD-1軸結合アンタゴニストを用いてメラノーマを有する個体において免疫機能を増強する方法であって、
有効量のPD-1軸結合アンタゴニストを個体に投与することを含み、個体から得られた血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上であると決定されている、方法。 - 個体から得られた血液試料中のグランザイムB+CD4+T細胞の数が、PD-1軸結合アンタゴニストの投与前と比較して増加している、請求項57に記載の方法。
- 個体から得られた血液試料中のFOXP3+CD4+T細胞の数が、PD-1軸結合アンタゴニストの投与前と比較して減少している、請求項57又は58に記載の方法。
- T細胞消耗が、PD-1軸結合アンタゴニストの投与前と比較して減少している、請求項57から59の何れか一項に記載の方法。
- 治療のための個体を選択し、個体におけるがんを治療するか又はがんの進行を遅らせる方法であって、
a.少なくとも1用量のPD-1軸結合アンタゴニストが投与されている個体から血液試料を得るステップ;
b.個体から得られた血液試料中のグランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比を決定するステップ;
c.グランザイムB+CD4+T細胞とFOXP3+CD4+T細胞との比が1以上である場合、PD-1軸結合アンタゴニストを含む治療のために個体を選択するステップ;及び
d.PD-1軸結合アンタゴニストを個体に投与するステップ
を含む、方法。
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2017
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- 2017-08-07 EP EP17752343.8A patent/EP3497129A1/en active Pending
- 2017-08-07 CN CN201780045938.7A patent/CN109476748B/zh active Active
- 2017-08-07 WO PCT/EP2017/069884 patent/WO2018029124A1/en unknown
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US20190315868A1 (en) | 2019-10-17 |
CN109476748A (zh) | 2019-03-15 |
WO2018029124A1 (en) | 2018-02-15 |
CN109476748B (zh) | 2023-05-23 |
EP3497129A1 (en) | 2019-06-19 |
JP7250674B2 (ja) | 2023-04-03 |
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