JP6949030B2 - Pd−1軸結合アンタゴニスト及び抗cea/抗cd3二重特異性抗体を用いたcea陽性がんの治療方法 - Google Patents
Pd−1軸結合アンタゴニスト及び抗cea/抗cd3二重特異性抗体を用いたcea陽性がんの治療方法 Download PDFInfo
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Description
(i)配列番号44のHVR−H1配列、配列番号45のHVR−H2配列、及び配列番号46のHVR−H3配列を含む重鎖可変領域(VHCD3);並びに配列番号47のHVR−L1配列、配列番号48のHVR−L2配列、及び配列番号49のHVR−L3配列を含む軽鎖可変領域(VLCD3)を含み、第1の抗原結合部分が、Fab軽鎖の可変領域又は定常領域、特に特に定常領域と、Fab重鎖の可変領域又は定常領域、特に定常領域とが交換されているクロスオーバーFab分子である、CD3に結合する第1の抗原結合ドメイン;
(ii)配列番号38のHVR−H1配列、配列番号39のHVR−H2配列、及び配列番号40のHVR−H3配列を含む重鎖可変領域(VHCEA);並びに配列番号41のHVR−L1配列、配列番号42のHVR−L2配列、及び配列番号43のHVR−L3配列を含む軽鎖可変領域(VLCEA)を含み、第2及び第3の抗原結合部分の各々がFab分子、特に従来のFab分子である、CEAに結合する第2及び第3の抗原結合ドメイン;
(iii)安定に会合できる第1及び第2のサブユニットからなるFcドメイン
を含み、
第2の抗原結合部分がFab重鎖のC末端において第1の抗原結合ドメインのFab重鎖のN末端に融合しており、第1の抗原結合ドメインがFab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合しており、第3の抗原結合ドメインがFab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合している。
本発明を詳細に説明する前に、本発明は特定の組成物又は生物系に限定されるものではなく、当然多種多様でありうることを理解すべきである。また、本明細書で用いる用語は、特定の実施態様を説明することのみを目的としており、限定することを目的としていないことを理解されたい。
本明細書では、有効量のPD−1軸結合アンタゴニスト及び抗CEA/抗CD3二重特異性抗体を個体に対して投与することを含む、個体におけるがんを治療するため又はその進行を遅延させるための方法が提供される。また、本明細書では、有効量のPD−1軸結合アンタゴニスト及び抗CEA/抗CD3二重特異性抗体を、がんを有する個体に対して投与することを含む、同個体における免疫機能を増強する方法が提供される。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、当技術分野では「プログラム細胞死1」、PDCD1、CD279及びSLEB2とも呼ばれる。PD−L1(プログラム死リガンド1)は、当技術分野では、「プログラム細胞死1リガンド1」、PDCD1LG1、CD274、B7−H、及びPDL1とも呼ばれる。例示的ヒトPD−L1は、UniProtKB/Swiss−Prot Accession No.Q9NZQ7.1に示されている。PD−L2(プログラム死リガンド2)は、当技術分野では、「プログラム細胞死1リガンド2」、PDCD1LG2、CD273、B7−DC、Btdc、及びPDL2とも呼ばれる。例示的ヒトPD−L2は、UniProtKB/Swiss−Prot Accession No.Q9BQ51に示されている。いくつかの実施様態では、PD−1、PD−L1、及びPD−L2は、ヒトPD−1、PD−L1及びPD−L2である。
いくつかの実施様態では、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。いくつかの実施様態では、抗PD−1抗体はニボルマブ(CAS Registry Number:946414(−94−4)である。さらなる実施態様では、配列番号1由来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由来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。さらなる実施態様では、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:
(a)この重鎖配列は、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、
(b)この軽鎖配列は、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。
国際公開第2010/077634号及び米国特許第8217149号に記載される抗PD−L1抗体は、本明細書に記載される方法、使用、組成物及びキットに使用することができる。いくつかの実施様態では、抗PD−L1抗体は、配列番号3の重鎖可変領域配列及び/又は配列番号4の軽鎖可変領域配列を含む。さらなる実施態様では、重鎖及び/又は軽鎖配列を含む単離された抗PD−L1抗体が提供され:
(a)この重鎖配列は、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、
(b)この軽鎖配列は、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;
さらにここで: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。さらなる態様では、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)である。
LC−FR2がWYQQKPGKAPKLLIY(配列番号16)である。
LC−FR3がGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC(配列番号17)である。
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、さらに:
(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、
(b)軽鎖はHVR−L1、HVR−L2及びHVR−L3を含み、さらに:
(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、
(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。別の態様において、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、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配列をさらに含むか、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配列をさらに含む。
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)この重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS(配列番号25)
に対して少なくとも85%の配列同一性を有する、及び/又は
(b)この軽鎖配列は、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。
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。別の態様では、重鎖可変領域は、(HC−FR1)−(HVR−H1)−(HC−FR2)−(HVR−H2)−(HC−FR3)−(HVR−H3)−(HC−FR4)のようにHVR間に並置された一又は複数のフレームワーク配列を含み、軽鎖可変領域は、(LC−FR1)−(HVR−L1)−(LC−FR2)−(HVR−L2)−(LC−FR3)−(HVR−L3)−(LC−FR4)のようにHVR間に並置された一又は複数のフレームワーク配列を含む。また別の態様では、フレームワーク配列は、ヒトコンセンサスフレームワーク配列に由来する。さらなる態様では、重鎖フレームワーク配列はKabatサブグループI、II、又はIIIの配列に由来する。さらなる態様では、重鎖フレームワーク配列はVHサブグループIIIコンセンサスフレームワークである。さらなる態様では、重鎖フレームワーク配列の一又は複数は、配列番号8、9、10及びWGQGTLVTVSS(配列番号27)と規定される。
さらなる態様では、軽鎖フレームワーク配列は、KabatカッパI、II、II又はIVのサブグループ配列に由来する。さらなる態様では、軽鎖フレームワーク配列はVLカッパIコンセンサスフレームワークである。さらなる態様では、軽鎖フレームワーク配列の一又は複数は、配列番号15、16、17及び18と規定される。
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)
である。
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)
である。
(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配列をさらに含む、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配列をさらに含む。
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)この重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS(配列番号25)
に対して少なくとも85%の配列同一性を有するか、又は
(b)この軽鎖配列は、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)この重鎖配列は、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)この軽鎖配列は、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)この重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号32)
に対して少なくとも85%の配列同一性を有する、及び/又は
(b)この軽鎖配列は、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。
さらなる実施態様では、重鎖及び軽鎖配列を含む、単離された抗PD−L1抗体が提供され:
(a)この重鎖配列は、重鎖配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号56)
に対して少なくとも85%の配列同一性を有する、及び/又は
(b)この軽鎖配列は、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。
本明細書では、有効量のPD−1軸結合アンタゴニスト及び抗CEA/抗CD3二重特異性抗体を個体に対して投与することを含む、個体におけるがんを治療するため又はその進行を遅延させるための方法が提供される。また、本明細書では、有効量のPD−1軸結合アンタゴニスト及び抗CEA/抗CD3二重特異性抗体を、がんを有する個体に対して投与することを含む、同個体における免疫機能を増強する方法が提供される。
アミノ酸配列:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWMGWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCARWDFAYYVEAMDYWGQGTTVTVSS(配列番号34)
を含む重鎖可変領域(VHCEA)、及び/又は
アミノ酸配列:
DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPGKAPKLLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYYTYPLFTFGQGTKLEIK(配列番号35)
を含む軽鎖可変領域(VLCEA)
を含む。
(i)配列番号44のHVR−H1配列、配列番号45のHVR−H2配列、及び配列番号46のHVR−H3配列を含む重鎖可変領域(VHCD3);並びに配列番号47のHVR−L1配列、配列番号48のHVR−L2配列、及び配列番号49のHVR−L3配列を含む軽鎖可変領域(VLCD3)を含み、第1の抗原結合部分が、Fab軽鎖の可変領域又は定常領域、特に定常領域と、Fab重鎖の可変領域又は定常領域、特に定常領域とが交換されているクロスオーバーFab分子である、CD3に結合する第1の抗原結合ドメイン;
(ii)配列番号38のHVR−H1配列、配列番号39のHVR−H2配列、及び配列番号40のHVR−H3配列を含む重鎖可変領域(VHCEA);並びに配列番号41のHVR−L1配列、配列番号42のHVR−L2配列、及び配列番号43のHVR−L3配列を含む軽鎖可変領域(VLCEA)を含み、第2及び第3の抗原結合部分の各々がFab分子、特に従来のFab分子である、CEAに結合する第2及び第3の抗原結合ドメイン;
(iii)安定に会合できる第1及び第2のサブユニットから構成されるFcドメイン
を含み、
第2の抗原結合部分がFab重鎖のC末端において第1の抗原結合ドメインのFab重鎖のN末端に融合しており、第1の抗原結合ドメインがFab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合しており、第3の抗原結合ドメインがFab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合している。
本発明において使用される抗CEA/抗CD3二重特異性抗体は、抗体分子の重鎖ドメインを含む一対のポリペプチド鎖からなるFcドメインを含みうる。例えば、免疫グロブリンG(IgG)分子のFcドメインはダイマーであり、その各サブユニットはCH2及びCH3 IgG重鎖定常ドメインを含む。Fcドメインの二つのサブユニットは、互いに安定に会合することができる。
本発明において使用される抗CEA/抗CD3二重特異性抗体は、Fcドメインの二つのサブユニットの一方又は他方に融合した異なる成分(例えば抗原結合ドメイン)を含むことができ、したがってFcドメインの二つのサブユニットは、通常二つの非同一なポリペプチド鎖に含まれている。これらポリペプチドの組み換え同時発現とそれに続く二量体化は、二つのポリペプチドの複数の可能な組合わせをもたらす。したがって、組み換え生成においてこのような抗体の収率及び純度を高めるために、抗体のFcドメインに、所望のポリペプチドの会合を促す修飾を含めることが有利であろう。
Fcドメインは、二重特異性抗体などの抗体に対し、標的組織中への良好な蓄積に貢献する長い血清半減期、及び望ましい組織−血液分布比を含む望ましい薬物動態特性を付与する。しかしながら、同時に、Fcドメインは、好ましい抗原保有細胞ではなく、Fc受容体を発現する細胞への抗体の望ましくないターゲティングの原因となることがある。さらには、Fc受容体シグナル伝達経路の同時活性化はサイトカイン放出の原因となりえ、サイトカイン放出は、抗体が有しうる他の免疫賦活特性及び抗体の長い半減期と組み合わさって、サイトカイン受容体の過剰な活性化を招き、全身投与されると重い副作用性をを引き起こしうる。
本明細書に記載される抗体は、抗体を生成するための当技術分野で利用可能な技術を使用して調製され、その典型的な方法は、以下のセクションでより詳細に説明される。
任意選択的に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、抗体を生成するためのイムノゲンとして使用することができる。受容体などの膜貫通分子のために、これらの断片(例えば、受容体の細胞外ドメイン)をイムノゲンとして使用することができる。代替的に、膜貫通分子を発現する細胞をイムノゲンとして使用することができる。このような細胞は、自然源(例えば、がん細胞株)に由来するものとすることができるか、又は膜貫通分子を発現するように組み換え技術によって形質転換された細胞でもよい。抗体の調製に有用な他の抗原及びその形態は、当業者には自明である。
ポリクローナル抗体は、好ましくは、関連する抗原及び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生成される。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、二機能性剤又は誘導体化剤、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ト)、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(RとR1は異なるアルキル基)にコンジュゲートすることが有益である。
本発明に有用な抗体は、所望の活性(複数可)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することができる。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種々の方法が、当技術分野で既知である。さらなる方法について、例えば、Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., ヒトPress, Totowa, NJ, 2001)に概説があり、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)に記載がある。
特定の実施態様において、本明細書で提供される抗体はキメラ抗体である。特定のキメラ抗体は、例えば、米国特許第4816567号、及びMorrisonら, Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)に記載されている。一例において、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。さらなる例において、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、又は組み換え技術によって生成される。特定の状況下では、全抗体よりも抗体断片を用い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。特定の抗体断片の総説については、Hudson et al. (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ついて結合特異性を有し、これらエピトープは通常異なる抗原に由来している。こ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(即ち二重特異性抗体、BsAb)、この表現を本明細書で使用する場合、さらなる特異性を有する三重特異性抗体のような抗体も包含される。二重特異性抗体は、完全長抗体又は抗体断片(例えばF(ab’)2二重特性抗体)として調製されうる。
b A.A. Zamyatnin, Prog. Biophys. Mol. Biol. 24:107-123, 1972からの値。
c C. Chothia, J. Mol. Biol. 105:1-14, 1975からの値。到達可能表面積は、この参照文献の図6〜20に定義されている。
単一ドメイン抗体は、抗体の重鎖可変ドメインのすべて若しくは一部、又は軽鎖可変ドメインのすべて若しくは一部を含む単一ポリペプチド鎖である。特定の実施態様では、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すべて又は一部からなる。
いくつかの実施態様では、本明細書に記載される抗体のアミノ酸配列修飾を考慮する。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こともある。抗体のアミノ酸配列変異体は、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。このような修飾は、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保有する限りにおいて、欠失、挿入、及び置換のいず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てよい。アミノ酸改変は、配列ができるときに対象の抗体のアミノ酸配列に導入されうる。
特定の実施態様では、一又は複数のアミノ酸置換を有する抗体変異体が提供される。置換突然変異の目的の部位は、HVR及びFRを含む。保存的置換は、「好ましい置換」と題して表1に示す。より実質的な変更は、「例示的置換」と題して表1に示し、アミノ酸側鎖のクラスを参照して下記にさらに説明する。アミノ酸置換は、目的の抗体に導入することができ、その産物は、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若しくは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
特定の実施態様において、本明細書で提供される抗体は、抗体がグリコシル化される程度を上昇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創出又は削除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。
特定の実施態様において、一又は複数のアミノ酸修飾を、本明細書で提供される抗体のFc領域に導入し、それによりFc領域変異体を生成することができる。Fc領域変異体は、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。
本発明に用いられる抗体は、当技術分野で知られ、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さらに改変されうる。特定の実施態様では、抗体の誘導体化に適切な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これらの混合物を含む。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。抗体に付着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付着する場合、それらは同じ分子でも異なる分子でもよい。一般的に、誘導体化に使用されるポリマーの数及び/又は種類は、改善されるべき抗体の特定の特性又は機能、その抗体誘導体が限定条件の下での治療に使用されるかどうかを含めた(但し、これらに限定されない)考慮事項に基づいて決定することができる。
抗体は、組み換え法を使用して生成することもできる。抗抗原抗体の組み換え生産の場合、抗体をコードする核酸が単離され、さらなるクローニング(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、従来の手順を用いて (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、次のうちの一又は複数を通常含むがそれらに限定されない: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。
抗体は、直接的に組み換え手法によって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若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及びプロセシングされる(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及び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ルイベロミセス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る。哺乳動物の細胞発現では、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。
発現ベクター及びクローニングベクターの両方は、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において、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、複製の開始点又は自己複製配列を含む。このような配列は、種々の細菌、酵母及びウイルスについてよく知られている。プラスミドpBR322からの複製の開始点は、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、種々のウイルスの開始点(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、複製開始点の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る)。
発現ベクター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、メトトレキセート、又はテトラサイクリンに耐性を付与する、(b)栄養要求性欠陥を補う、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。
発現ベクター及びクローニングベクターは、一般に、宿主生物体によって認識され、抗体をコードする核酸に動作可能に連結された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、抗体をコードするDNAに動作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現在知られている(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を含む。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)も参照されたい。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’位に位置している。
真核生物の宿主細胞(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も含む。このような配列は、真核生物又はウィルスのDNA又はcDNAの5’、及び時には3’の非翻訳領域から一般に取得できる。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、ウシ増殖ホルモンポリアデニル化領域である。国際公開第94/11026号及びそこに開示される発現ベクターを参照のこと。
本明細書のベクター中におけるDNAのクローニング又は発現に適切な宿主細胞は、原核細胞、酵母、又は上記の高等真核細胞である。この目的のために適切な原核生物には、グラム陰性又はグラム陽性生物体といった真正細菌、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、エルビニア菌属、クレブシエラ菌、プロテウス、サルモネラ菌、例えばネズミチフス菌、セラシア属、例えばセラチア菌、及び赤痢菌、並びに枯草菌及びバチルスリケニフォルミスといった桿菌(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、例えば緑膿菌、及びストレプトマイシンが含まれる。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)といった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種々の培地において培養されうる。市販の培地、例えばHamのF10(シグマ)、最小必須培地((MEM),(シグマ)、RPMI−1640(シグマ)及びダルベッコの改良イーグル培地((DMEM),シグマ)が宿主細胞の培養に適している。加えて、Ham et al., Meth. Enz. 58:44 (1979), Barnes et al., 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号に記載の培地のいずれもが、宿主細胞の培地として使用できる。これら培地のいずれにも、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)、バッファー(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。他のあらゆる必要な補充物も、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で先に用いられたものであり、当業者には明らかであろう。
組み換え技術を用いる場合、本発明の抗体は、細胞内、細胞周辺腔内で生成されるか、又は培地中に直接分泌されうる。抗体が細胞内に生成される場合、最初の工程として、宿主細胞か又は溶解断片のいずれかである微粒子状破片は、例えば遠心分離又は限外濾過により除去されうる。Carter et al., Bio/Technology 10: 163-167 (1992)は、大腸菌の細胞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、細胞ペーストは、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。細胞破片は、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、一般的に、そのような発現系からの上清はまず、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、タンパク質分解を阻害するための前述の工程のいずれかに含めることができ、抗生物質を、偶発的夾雑物の増殖を防ぐために含めることができる。
上述のように生成される抗体に一又は複数の「生物活性」アッセイを実行し、治療的見地から有利な特性を持つ抗体を選択すること、又は抗体の生物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、意図された抗原に結合する能力について試験される。例えば、当技術分野で既知の方法(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。
本明細書においてはさらに、PD−1軸結合アンタゴニスト及び/又は本明細書に記載の抗体(例えば抗PD−L1抗体、又はCEAとCD3に結合する二重特異性抗体)並びに薬学的に許容される担体を含む薬学的組成物及び製剤が提供される。
本明細書では、有効量のPD−1軸結合アンタゴニスト及び抗CEA/抗CD3二重特異性抗体を個体に対して投与することを含む、個体におけるがんを治療するため又はその進行を遅延させるための方法が提供される。いく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。いくつかの実施態様では、応答は部分寛解である。いくつかの実施様態では、応答は完全寛解である。いく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、持続性の部分寛解又は完全寛解)をもたらす。本明細書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、本明細書では、有効量のPD−1軸結合アンタゴニスト(例えば、MPDL3280A)及び抗CEA/抗CD3二重特異性抗体(例えばCEA TCB)を、がんを有する個体に対して投与することを含む、同個体における免疫機能を増強する方法が提供される。
本明細書においては、個体のがんを治療するため又はその進行を遅らせるための方法が提供され、この方法は、個体に対し、ヒトPD−1軸結合アンタゴニスト(例えば、抗PD−L1抗体、例えば、MPDL3280A)及び抗CEA/抗CD3二重特異性抗体(例えば、CEA TCB)を別の抗がん剤又はがん治療法と組み合わせて投与することを含む。
本発明の別の実施態様では、PD−1軸結合アンタゴニスト及び/又は抗CEA/抗CD3二重特異性抗体を含む製造品又はキットが提供される。いくつかの実施態様では、製造品又はキットは、個体のがんを治療するため若しくはその進行を遅らせるため又はがんを有する固体の免疫機能を増強するために、抗CEA/抗CD3二重特異性抗体と組み合わせてPD−1軸結合アンタゴニストを使用するための指示を含む添付文書をさらに含む。本明細書に記載されるPD−1軸結合アンタゴニスト及び/又は抗CEA/抗CD3二重特異性抗体は、製造品又はキットに含めることができる。
CEA TCBは、腫瘍細胞上のがん胎児性抗原(CEA)及びT細胞上のCD3を標的とする新規のT細胞二重特異性抗体である。CEA TCBは現在、進行性及び/又は転移性CEA発現腫瘍を有する患者の第I相試験における単剤として研究されている。
非臨床のin vivoでの薬物学試験を、免疫不全NOGマウスにおいてヒト結腸癌異種移植腫瘍モデル(LS174T−fluc2)を用いて実施した。以下の二つの異なる実験設定を用いた。1)腫瘍細胞を、異なるE:T比でヒトPBMCと(皮下[SC])共移植した。2)腫瘍細胞のSC注射に続き、腫瘍が形成された後(蝕知腫瘤に達した後)PBMCを腹腔内(IP)に移した。
エフェクター:標的比(E:T)5:1でのLS174T−fluc2細胞とヒトPBMCとの共移植時に得られたCEA TCBのin vivoでの有効性の結果を図3に示す。
さらに、CEA TCBのin vivoでの有効性を、腫瘍細胞をSC注入した後腫瘍が蝕知腫瘤に達したらPBMCをIP移入する異種移植モデルにおいて評価した。CEA TCB(2.5mg/kg、隔週でIV)は、有意な腫瘍縮小(腫瘍重量の減少、図5)と、腫瘍へのT細胞浸潤の増大(フローサイトメトリー分析(図6)及び組織学(図示しない))とをもたらし、T細胞は活性化表現型を有していた(CD25及びCD69活性化マーカーの上方制御を示すフローサイトメトリー 分析によって示される。図示しない)。これは、少数のT細胞しか腫瘍に浸潤せず、休止表現型を示すビヒクル(PBS)及びMCSP TCB(非標的化コントロール)と対照的である。
CEA TCBの腫瘍活性を、皮下にCEA発現MKN45がん細胞株を有するヒト化マウスモデルにおいてin vivoで評価した。
抗ヒトPD−L1遮断抗体と組み合わせたCEA TCBの抗腫瘍効果を、胃癌腫瘍細胞株(MKN45)を有する完全ヒト化マウスにおいて評価した。
YW243.55.S70 PD−L1 muIgG1 DAPG HC(配列番号36):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSAAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDAPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFGAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK
YW243.55.S70 PD−L1 muIgG1 LC(配列番号37):
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
細胞表面上にヒトCEAを発現するように社内で改変した結腸直腸癌腫瘍細胞株MC38(MC38−huCEA)を有する完全免疫適格マウスにおいて、抗PD−L1遮断抗体と組み合わせたCEA TCBの抗腫瘍効果も評価した。
上述のデータは、CEA TCBとアテゾリズマブがそれらの抗がん特性において相乗的に作用すること、及びそれら組み合わせが集合的に、がん患者に意義のある臨床効果を提供することを実証する。
2016年11月15日の時点で、30名の患者が以下の用量コホートレベルで治療されていた:
5mgのCEA TCB QW+1200のアテゾリズマブQ3W:4名の患者
10mgのCEA TCB QW+1200のアテゾリズマブQ3W:4名の患者
20mgのCEA TCB QW+1200のアテゾリズマブQ3W:4名の患者
40mgのCEA TCB QW+1200のアテゾリズマブQ3W:6名の患者
80mgのCEA TCB QW+1200のアテゾリズマブQ3W:5名の患者
160mgのCEA TCB QW+1200のアテゾリズマブQ3W:7名の患者
Claims (40)
- 抗がん胎児性抗原(CEA)/抗CD3二重特異性抗体を含む、第2の組成物と組み合わせて個体におけるCEA陽性がんを治療するため又はその進行を遅延させるための組成物であって、
第2の組成物がヒトプログラム死−リガンド1(PD−L1)結合アンタゴニストを含み、組成物及び第2の組成物が、逐次的に又は同時に個体に対し投与され、
(a)抗CEA/抗CD3二重特異性抗体が、
(i)配列番号44のHVR−H1配列、配列番号45のHVR−H2配列、及び配列番号46のHVR−H3配列を含む重鎖可変領域(V H CD3)、並びに配列番号47のHVR−L1配列、配列番号48のHVR−L2配列、及び配列番号49のHVR−L3配列を含む軽鎖可変領域(V L CD3)を含むFab分子である、CD3に結合する第1の抗原結合ドメイン;(ii)それぞれ、配列番号38のHVR−H1配列、配列番号39のHVR−H2配列、及び配列番号40のHVR−H3配列を含む重鎖可変領域(V H CEA)、並びに配列番号41のHVR−L1配列、配列番号42のHVR−L2配列、及び配列番号43のHVR−L3配列を含む軽鎖可変領域(V L CEA)を含むFab分子である、CEAに結合する第2及び第3の抗原結合ドメイン;及び(iii)安定に会合できる第1及び第2のサブユニットからなるFcドメイン
を含み、ここで、第2の抗原結合ドメインが、Fab重鎖のC末端において第1の抗原結合ドメインのFab重鎖のN末端に融合し、第1の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合し、かつ第3の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合し;かつ
(b)PD−L1結合アンタゴニストが、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、並びに配列番号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、を含む抗体である、
組成物。 - ヒトPD−L1結合アンタゴニストを含む、第2の組成物と組み合わせて個体におけるCEA陽性がんを治療するため又はその進行を遅延させるための組成物であって、
第2の組成物が抗CEA/抗CD3二重特異性抗体を含み、組成物及び第2の組成物が、逐次的に又は同時に個体に対し投与され、
(a)抗CEA/抗CD3二重特異性抗体が、
(i)配列番号44のHVR−H1配列、配列番号45のHVR−H2配列、及び配列番号46のHVR−H3配列を含む重鎖可変領域(V H CD3)、並びに配列番号47のHVR−L1配列、配列番号48のHVR−L2配列、及び配列番号49のHVR−L3配列を含む軽鎖可変領域(V L CD3)を含むFab分子である、CD3に結合する第1の抗原結合ドメイン;(ii)それぞれ、配列番号38のHVR−H1配列、配列番号39のHVR−H2配列、及び配列番号40のHVR−H3配列を含む重鎖可変領域(V H CEA)、並びに配列番号41のHVR−L1配列、配列番号42のHVR−L2配列、及び配列番号43のHVR−L3配列を含む軽鎖可変領域(V L CEA)を含むFab分子である、CEAに結合する第2及び第3の抗原結合ドメイン;及び(iii)安定に会合できる第1及び第2のサブユニットからなるFcドメイン
を含み、ここで、第2の抗原結合ドメインが、Fab重鎖のC末端において第1の抗原結合ドメインのFab重鎖のN末端に融合し、第1の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合し、かつ第3の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合し;かつ
(b)PD−L1結合アンタゴニストが、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、並びに配列番号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、を含む抗体である、
組成物。 - 抗CEA/抗CD3二重特異性抗体を含む、個体におけるCEA陽性がんを治療するため又はその進行を遅延させるための組成物であって、
ヒトPD−L1結合アンタゴニストを含む第2の組成物と組み合わせて、逐次的又は同時に投与され、
(a)抗CEA/抗CD3二重特異性抗体が、
(i)配列番号44のHVR−H1配列、配列番号45のHVR−H2配列、及び配列番号46のHVR−H3配列を含む重鎖可変領域(V H CD3)、並びに配列番号47のHVR−L1配列、配列番号48のHVR−L2配列、及び配列番号49のHVR−L3配列を含む軽鎖可変領域(V L CD3)を含むFab分子である、CD3に結合する第1の抗原結合ドメイン;(ii)それぞれ、配列番号38のHVR−H1配列、配列番号39のHVR−H2配列、及び配列番号40のHVR−H3配列を含む重鎖可変領域(V H CEA)、並びに配列番号41のHVR−L1配列、配列番号42のHVR−L2配列、及び配列番号43のHVR−L3配列を含む軽鎖可変領域(V L CEA)を含むFab分子である、CEAに結合する第2及び第3の抗原結合ドメイン;及び(iii)安定に会合できる第1及び第2のサブユニットからなるFcドメイン
を含み、ここで、第2の抗原結合ドメインが、Fab重鎖のC末端において第1の抗原結合ドメインのFab重鎖のN末端に融合し、第1の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合し、かつ第3の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合し;かつ
(b)PD−L1結合アンタゴニストが、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、並びに配列番号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、を含む抗体である、
組成物。 - ヒトPD−L1結合アンタゴニストを含む、個体におけるCEA陽性がんを治療するため又はその進行を遅延させるための組成物であって、
抗CEA/抗CD3二重特異性抗体を含む第2の組成物と組み合わせて、逐次的又は同時に投与され、
(a)抗CEA/抗CD3二重特異性抗体が、
(i)配列番号44のHVR−H1配列、配列番号45のHVR−H2配列、及び配列番号46のHVR−H3配列を含む重鎖可変領域(V H CD3)、並びに配列番号47のHVR−L1配列、配列番号48のHVR−L2配列、及び配列番号49のHVR−L3配列を含む軽鎖可変領域(V L CD3)を含むFab分子である、CD3に結合する第1の抗原結合ドメイン;(ii)それぞれ、配列番号38のHVR−H1配列、配列番号39のHVR−H2配列、及び配列番号40のHVR−H3配列を含む重鎖可変領域(V H CEA)、並びに配列番号41のHVR−L1配列、配列番号42のHVR−L2配列、及び配列番号43のHVR−L3配列を含む軽鎖可変領域(V L CEA)を含むFab分子である、CEAに結合する第2及び第3の抗原結合ドメイン;及び(iii)安定に会合できる第1及び第2のサブユニットからなるFcドメイン
を含み、ここで、第2の抗原結合ドメインが、Fab重鎖のC末端において第1の抗原結合ドメインのFab重鎖のN末端に融合し、第1の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合し、かつ第3の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合し;かつ
(b)PD−L1結合アンタゴニストが、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、並びに配列番号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、を含む抗体である、
組成物。 - PD−L1結合アンタゴニストが、アテゾリズマブである、請求項1〜4のいずれか一項に記載の組成物。
- PD−L1結合アンタゴニストが、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1〜4のいずれか一項に記載の組成物。
- PD−L1結合アンタゴニストが、非グリコシル化部位の変異を含む、請求項1〜6のいずれか一項に記載の組成物。
- 非グリコシル化部位の変異が置換変異である、請求項7に記載の組成物。
- 置換変異がアミノ酸残基N297、L234、L235、及び/又はD265(EU番号付け)におけるものである、請求項8に記載の組成物。
- 置換変異が、N297G、N297A、L234A、L235A、及びD265Aからなる群より選択される、請求項8又は9に記載の組成物。
- 置換変異が、D265A変異及びN297G変異である、請求項8〜10のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体の第1の抗原結合ドメインが、配列番号50のアミノ酸配列を含む重鎖可変領域(VHCD3)及び/又は配列番号51のアミノ酸配列を含む軽鎖可変領域(VLCD3)を含む、請求項1〜11のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体の第2及び第3の抗原結合ドメインが、それぞれ、配列番号34のアミノ酸配列を含む重鎖可変領域(VHCEA)及び/又は配列番号35のアミノ酸配列を含む軽鎖可変領域(VLCEA)を含む、請求項1〜12のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体の第1の抗原結合ドメインが、Fab重鎖とFab軽鎖の可変ドメイン又は定常ドメインが交換されているクロスオーバーFab分子であり、抗CEA/抗CD3二重特異性抗体の第2及び第3の抗原結合ドメインが、それぞれ、従来型のFab分子である、請求項1〜13のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体のFcドメインが、IgGのFcドメインである、請求項1〜14のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体のFcドメインが、IgG 1 のFcドメインである、請求項1〜15のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体のFcドメインが、ヒトFcドメインである、請求項1〜16のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体のFcドメインが、Fcドメインの第1のサブユニットと第2のサブユニットの会合を促す修飾を含む、請求項1〜17のいずれか一項に記載の組成物。
- Fcドメインの第1のサブユニットのCH3ドメインにおいて、アミノ酸残基がそれよりも大きな側鎖体積を有するアミノ酸残基で置き換えられ、それにより、第1のサブユニットのCH3ドメイン内部に、第2のサブユニットのCH3ドメイン内部の空洞内に配置可能な隆起が生成され、Fcドメインの第2のサブユニットのCH3ドメインにおいて、アミノ酸残基がそれよりも小さな側鎖体積を有するアミノ酸残基で置き換えられ、それにより、第2のサブユニットのCH3ドメイン内部に、第1のサブユニットのCH3ドメイン内部の隆起を配置可能な空洞が生成される、請求項18に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体のFcドメインの第1のサブユニットのCH3ドメインにおいて、366位のトレオニン残基がトリプトファン残基で置き換えられ(T366W)、かつ抗CEA/抗CD3二重特異性抗体のFcドメインの第2のサブユニットのCH3ドメインにおいて407位のチロシン残基がバリン残基で置き換えられる(Y407V)、請求項1〜19のいずれか一項に記載の組成物。
- (a)Fcドメインの第2のサブユニットにおいて、追加的に366位のトレオニン残基がセリン残基で置き換えられ(T366S)、かつ368位のロイシン残基がアラニン残基で置き換えられる(L368A)、かつ/又は
(b)Fcドメインの第1のサブユニットにおいて、追加的に354位のセリン残基がシステイン残基で置き換えられ(S354C)又は356位のグルタミン酸残基がシステイン残基で置き換えられ(E356C)、かつFcドメインの第2のサブユニットにおいて、追加的に349位のチロシン残基がシステイン残基で置き換えられる(Y349C)(EU番号付け)、
請求項20に記載の組成物。 - 抗CEA/抗CD3二重特異性抗体のFcドメインの第1のサブユニットが、S354C及びT366Wのアミノ酸置換を含み、かつ抗CEA/抗CD3二重特異性抗体のFcドメインの第2のサブユニットが、Y349C、T366S、L368A、及びY407V(EU番号付け)のアミノ酸置換を含む、
請求項1〜21のいずれか一項に記載の組成物。 - 抗CEA/抗CD3二重特異性抗体のFcドメインが、天然IgG1のFcドメインと比較して、Fc受容体に対する結合親和性の低下及び/又はエフェクター機能の低下を呈する、請求項1〜22のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体のFcドメインが、Fc受容体への結合を低減する及び/又はエフェクター機能を低下させる一又は複数のアミノ酸置換を含む、請求項1〜23のいずれか一項に記載の組成物。
- 前記一又は複数のアミノ酸置換が、L234、L235、及びP329(EU番号付け)の群より選択される一又は複数の位置におけるものである、請求項24に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体のFcドメインの各サブユニットが、アミノ酸置換L234A、L235A及びP329G(EU番号付け)を含む、請求項1〜25のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体が、配列番号52の配列と少なくとも95%同一である配列を含むポリペプチド、配列番号53の配列と少なくとも95%同一である配列を含むポリペプチド、配列番号54の配列と少なくとも95%同一である配列を含むポリペプチド、及び配列番号55の配列と少なくとも95%同一である配列を含むポリペプチドを含む、請求項1〜26のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体が、配列番号52の配列を含むポリペプチド、配列番号53の配列を含むポリペプチド、配列番号54の配列を含むポリペプチド、及び配列番号55の配列を含むポリペプチドを含む、請求項1〜27のいずれか一項に記載の組成物。
- がんが、結腸がん、肺がん、卵巣がん、胃がん、膀胱がん、膵臓がん、子宮内膜がん、乳がん、腎臓がん、食道がん、又は前立腺がんである、請求項1〜28のいずれか一項に記載の組成物。
- ヒトPD−L1結合アンタゴニストが、1200mgの用量で3週毎に投与される、請求項1〜29のいずれか一項に記載の組成物。
- 抗CEA/抗CD3二重特異性抗体が、5mgから100mgの用量で毎週投与される、請求項1〜30のいずれか一項に記載の組成物。
- 治療周期を含み、個体は、各周期の1日目にヒトPD−L1結合アンタゴニストを1200mgの用量で投与され、かつ、各周期の1、8、及び15日目に抗CEA/抗CD3二重特異性抗体を5mg、10mg、20mg、40mg、80mg又は160mgの用量で投与され、各周期は21日毎に繰り返される、請求項1〜30のいずれか一項に記載の組成物。
- 治療周期を含み、個体は、各周期の1日目にヒトPD−L1結合アンタゴニストを1200mgの用量でされ、かつ、各周期の1、8、及び15日目に抗CEA/抗CD3二重特異性抗体を少なくとも80mgの用量で投与され、各周期は21日毎に繰り返される、請求項1〜30のいずれか一項に記載の組成物。
- 個体が化学療法剤による治療に不応性である、請求項1〜33のいずれか一項に記載の組成物。
- 個体が化学療法剤による治療に不耐性である、請求項1〜33のいずれか一項に記載の組成物。
- 治療が個体に応答をもたらす、請求項1〜35のいずれか一項に記載の組成物。
- PD−L1結合アンタゴニスト及び/又は抗CEA/抗CD3二重特異性抗体が、静脈内に投与される、請求項1〜36のいずれか一項に記載の組成物。
- がんを治療するため又はその進行を遅延させるための化学療法剤を投与することをさらに含む、請求項1〜37のいずれか一項に記載の組成物。
- 個体におけるCEA陽性がんを治療するため又はその進行を遅延させるための医薬の製造におけるヒトPD−L1結合アンタゴニストの使用であって、医薬が、ヒトPD−L1結合アンタゴニストと任意の薬学的に許容される担体とを含み、治療が、抗CEA/抗CD3二重特異性抗体と任意の薬学的に許容される担体とを含む組成物と組み合わせて医薬を投与することを含み、
(a)抗CEA/抗CD3二重特異性抗体が、
(i)配列番号44のHVR−H1配列、配列番号45のHVR−H2配列、及び配列番号46のHVR−H3配列を含む重鎖可変領域(V H CD3)、並びに配列番号47のHVR−L1配列、配列番号48のHVR−L2配列、及び配列番号49のHVR−L3配列を含む軽鎖可変領域(V L CD3)を含むFab分子である、CD3に結合する第1の抗原結合ドメイン;(ii)それぞれ、配列番号38のHVR−H1配列、配列番号39のHVR−H2配列、及び配列番号40のHVR−H3配列を含む重鎖可変領域(V H CEA)、並びに配列番号41のHVR−L1配列、配列番号42のHVR−L2配列、及び配列番号43のHVR−L3配列を含む軽鎖可変領域(V L CEA)を含むFab分子である、CEAに結合する第2及び第3の抗原結合ドメイン;及び(iii)安定に会合できる第1及び第2のサブユニットからなるFcドメイン
を含み、ここで、第2の抗原結合ドメインが、Fab重鎖のC末端において第1の抗原結合ドメインのFab重鎖のN末端に融合し、第1の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合し、かつ第3の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合し;かつ
(b)PD−L1結合アンタゴニストが、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、並びに配列番号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、を含む抗体である、
使用。 - 個体におけるCEA陽性がんを治療するため又はその進行を遅延させるための医薬の製造における抗CEA/抗CD3二重特異性抗体の使用であって、医薬が、抗CEA/抗CD3二重特異性抗体と任意の薬学的に許容される担体とを含み、治療が、ヒトPD−L1結合アンタゴニストと任意の薬学的に許容される担体とを含む組成物と組み合わせて医薬を投与することを含み、
(a)抗CEA/抗CD3二重特異性抗体が、
(i)配列番号44のHVR−H1配列、配列番号45のHVR−H2配列、及び配列番号46のHVR−H3配列を含む重鎖可変領域(V H CD3)、並びに配列番号47のHVR−L1配列、配列番号48のHVR−L2配列、及び配列番号49のHVR−L3配列を含む軽鎖可変領域(V L CD3)を含むFab分子である、CD3に結合する第1の抗原結合ドメイン;(ii)それぞれ、配列番号38のHVR−H1配列、配列番号39のHVR−H2配列、及び配列番号40のHVR−H3配列を含む重鎖可変領域(V H CEA)、並びに配列番号41のHVR−L1配列、配列番号42のHVR−L2配列、及び配列番号43のHVR−L3配列を含む軽鎖可変領域(V L CEA)を含むFab分子である、CEAに結合する第2及び第3の抗原結合ドメイン;及び(iii)安定に会合できる第1及び第2のサブユニットからなるFcドメイン
を含み、ここで、第2の抗原結合ドメインが、Fab重鎖のC末端において第1の抗原結合ドメインのFab重鎖のN末端に融合し、第1の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第1のサブユニットのN末端に融合し、かつ第3の抗原結合ドメインが、Fab重鎖のC末端においてFcドメインの第2のサブユニットのN末端に融合し;かつ
(b)PD−L1結合アンタゴニストが、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、並びに配列番号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、を含む抗体である、
使用。
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MX2018008347A (es) | 2018-12-06 |
US10596257B2 (en) | 2020-03-24 |
CA3006529A1 (en) | 2017-07-13 |
BR112018011029A2 (pt) | 2018-11-21 |
HK1259020A1 (zh) | 2019-11-22 |
AU2017205089A1 (en) | 2018-06-21 |
AU2017205089B2 (en) | 2023-10-05 |
IL259588A (en) | 2018-07-31 |
IL259588B2 (en) | 2023-09-01 |
IL259588B1 (en) | 2023-05-01 |
CN108368179A (zh) | 2018-08-03 |
CN108368179B (zh) | 2022-08-23 |
US20200376119A1 (en) | 2020-12-03 |
KR20180097615A (ko) | 2018-08-31 |
AR107303A1 (es) | 2018-04-18 |
ES2837428T3 (es) | 2021-06-30 |
JP2019502712A (ja) | 2019-01-31 |
EP3400246A1 (en) | 2018-11-14 |
WO2017118675A1 (en) | 2017-07-13 |
US20180000931A1 (en) | 2018-01-04 |
EP3400246B1 (en) | 2020-10-21 |
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