JP2020535843A - 新規抗hla−a2抗体、およびその使用 - Google Patents
新規抗hla−a2抗体、およびその使用 Download PDFInfo
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- JP2020535843A JP2020535843A JP2020537814A JP2020537814A JP2020535843A JP 2020535843 A JP2020535843 A JP 2020535843A JP 2020537814 A JP2020537814 A JP 2020537814A JP 2020537814 A JP2020537814 A JP 2020537814A JP 2020535843 A JP2020535843 A JP 2020535843A
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Abstract
Description
−重鎖の可変領域は、以下のCDR:
VH−CDR1:SYHIQ(配列番号1)またはGYTFTSY(配列番号4)、
VH−CDR2:WIYPGDGSTQYNEKFKG(配列番号2)またはYPGDGS(配列番号5)、
VH−CDR3:EGTYYAMDY(配列番号3)、
または、配列番号1〜5と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDR
のうちの少なくとも1つを含み、かつ/または
−軽鎖の可変領域は、以下のCDR:
VL−CDR1:RSSQSIVHSNGNTYLE(配列番号6)、
VL−CDR2:KVSNRFS(配列番号7)、
VL−CDR3:FQGSHVPRT(配列番号8)、
または、配列番号6〜8と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDR
のうちの少なくとも1つを含む、
ヒト化抗HLA−A2抗体に関する。
−重鎖の可変領域は、以下のCDR:SYHIQ(配列番号1)、WIYPGDGSTQYNEKFKG(配列番号2)およびEGTYYAMDY(配列番号3)、もしくはGYTFTSY(配列番号4)、YPGDGS(配列番号5)およびEGTYYAMDY(配列番号3)、または配列番号1〜5と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDR、を含み、
−軽鎖の可変領域は、以下のCDR:RSSQSIVHSNGNTYLE(配列番号6)、KVSNRFS(配列番号7)およびFQGSHVPRT(配列番号8)、または配列番号6〜8と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDR、を含む。
−上記のヒト化抗HLA−A2抗体を含む細胞外ドメイン、
−膜貫通ドメイン、および
−細胞内シグナル伝達ドメインを含む細胞質ドメイン。
本発明において、以下の用語は以下の意味を有する。
−重鎖CDR1(HCDR1):SYHIQ(配列番号62);
−重鎖CDR2(HCDR2):WIYPGDGSTQYNEKFKG(配列番号63);
−重鎖CDR3(HCDR3):EGTYYAMDY(配列番号64);
−軽鎖CDR1(LCDR1):RSSQSIVHSNGNTYLE(配列番号65)
−軽鎖CDR2(LCDR2):KVSNRFS(配列番号66);
−軽鎖CDR3(LCDR3):FQGSHVPRT(配列番号67)。
;および/または「超可変ループ」からのそれらの残基(例えば、Chothia番号付けシステム(Chothia and Lesk,J.Mol.Acids Res.27:209−212(1999年)、Ruiz,M.ら、Nucl.Acids Res.28:219−221(2000年))に従って番号付けされた場合、VL中の残基24〜34(L1)、50〜56(L2)および89〜97(L3)、およびVH中の26〜32(H1)、52〜56(H2)、95〜15 101(H3)を含む。任意により、抗体は、AHo(Honneger,A.and Plunkthun,A.J.Mol.Biol.309:657−670(2001年))に従って番号付けされた場合、次のポイント、VL中の28、36(L1)、63、74〜75(L2)および123(L3)、およびVH中の28、36(H1)、63、74〜75(H2)および123(H3)の1つ以上で、対称的な挿入を有する。
抗HLA−A2抗体またはBB7.2抗体を含むCAR、またはBB7.2抗体のVHおよびVL(mA2 CAR)を発現する0.25.106T細胞を、FlowPRA Single Antigen Antibodyビーズパネル(FL1HD01、FL1HD02、FL1HD03、FL1HD04、FL1HD06およびFL1HD08、One Lambda)および固定可能な生存率色素(FVD、ThermoFisher、65−0865−14、eBioscience)と室温で30分間インキュベートする。試料を洗浄し、0.5%ホルムアルデヒドで固定し、フローサイトメトリーで分析する。試料あたり200個の陰性対照ビーズを得る。ビーズのみを陰性対照として使用した。分析のために、死細胞を、最初に固定可能な生存率色素を使用して排除する。死細胞およびダブレットを排除した後、単一の抗原ビーズをゲーティングする。次に、HLAあたりのビーズの数を、それぞれのPE強度ピークによって決定する。データを、各HLAピークにおいて対象となるビーズ数を200で乗算し、試料中の陰性ビーズ数で除算することによって正規化する。各HLAピークについて、対照(非CAR発現細胞)と比較したCAR Tregの相対的結合率を、対照試料中のビーズ数からCAR−Treg中のビーズ数を引き、CAR非発現対照内のビーズの平均数を除算し、100倍することによって求める。
抗HLA−A2抗体またはBB7.2抗体またはBB7.2抗体のVHおよびVLまたは細胞表面上の切り詰め型NGFR形質導入マーカー(NGFR)(例えば、本明細書に記載のキメラ抗原受容体の一部として)を発現する0.25.106T細胞を、FlowPRA Single Antigen Antibodyビーズパネル(FL1HD、One Lambda)および固定可能な生存率色素(FVD、65−0865−14、eBioscience)とインキュベートし、0.5%ホルムアルデヒドで固定し、フローサイトメトリーで分析する。分析のために、死細胞を、最初に固定可能な生存率色素を使用して排除する。死細胞およびダブレットを排除した後、単一ビーズをゲーティングする。次に、HLAあたりのビーズの数を、それぞれのPE強度によって決定する。データを、試料中の陰性ビーズ数をTreg−NGFR試料中の陰性ビーズ数で除算し、Treg−NGFR試料中の陰性ビーズ数を乗算することにより正規化する。相対的結合率は、特定のHLAのNGFR試料中のビーズ数から、そのHLAの試料中の正規化されたビーズ数を引いた数を、NGFR試料中のビーズ数で除算し、100倍したものである。
VH−CDR1:SYHIQ(配列番号1)、
VH−CDR2:WIYPGDGSTQYNEKFKG(配列番号2)、
VH−CDR3:EGTYYAMDY(配列番号3)
のうちの少なくとも1つを含む。
CDRの番号付けおよび定義は、Kabatの定義による。
VH−CDR1:GYTFTSY(配列番号4)、
VH−CDR2:YPGDGS(配列番号5)、
VH−CDR3:EGTYYAMDY(配列番号3)のうちの少なくとも1つを含む。
CDRの番号付けおよび定義は、Chothiaの定義による。
VL−CDR1:RSSQSIVHSNGNTYLE(配列番号6)、
VL−CDR2:KVSNRFS(配列番号7)、
VL−CDR3:FQGSHVPRT(配列番号8)のうちの少なくとも1つを含む。
CDRの番号付けおよび定義は、KabatまたはChothiaの定義による。
−その重鎖中に、3つのCDR、配列番号1、配列番号2および配列番号3;ならびに
−その軽鎖中に、3つのCDR、配列番号6、配列番号7および配列番号8。
−その重鎖中に、3つのCDR、配列番号4、配列番号5および配列番号3;ならびに
−その軽鎖中に、3つのCDR、配列番号6、配列番号7および配列番号8。
(配列番号9)
QVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSS
(配列番号10)
DX1VMTQX2PX3X4LX5VX6X7GX8X9X10X11ISCRSSQSIVHSNGNTYLEWYX12QKPGQX13PRLLIYKVSNRFSGX14PDRFSGSGSGTDFTLX15ISRX16EX17EDX18X19VYYCFQGSHVPRTFGGGTKLEIKR
ここで、X1は、VまたはIであり、X2は、TまたはSであり、X3は、LまたはSまたはAであり、X4は、SまたはTであり、X5は、PまたはSであり、X6は、TまたはSであり、X7は、LまたはPであり、X8は、EまたはDであり、X9は、PまたはRであり、X10は、AまたはVであり、X11は、SまたはTであり、X12は、LまたはQであり、X13は、SまたはAであり、X14は、VまたはIであり、X15は、KまたはTであり、X16は、VまたはLであり、X17は、AまたはPであり、X18は、LまたはFであり、X19は、GまたはAである。
(配列番号11)
DVVMTQTPLSLPVTLGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPRTFGGGTKLEIKR
(配列番号12)
DVVMTQSPSSLSVTLGDRVSISCRSSQSIVHSNGNTYLEWYQQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEPEDLGVYYCFQGSHVPRTFGGGTKLEIKR
(配列番号13)
DIVMTQSPATLSVSPGERATISCRSSQSIVHSNGNTYLEWYQQKPGQAPRLLIYKVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPRTFGGGTKLEIKR
(配列番号86)
CAGGTCCAGCTAGTACAAAGCGGCCCTGAAGTAAAGAAACCTGGTGCCTCTGTGAAGGTGAGCTGCAAGGCCAGCGGCTACACCTTCACCAGCTACCACATCCAGTGGGTTCGACAGGCCCCTGGACAGGGACTAGAGTGGATCGGCTGGATCTATCCTGGCGACGGCAGCACCCAGTACAACGAGAAGTTCAAGGGCAGAGTTACCATCACCGCCGACAAGAGCACCAGCACAGCCTATATGGAGCTGAGCAGCCTGACCAGCGAGGACACAGCTGTTTACTATTGTGCCAGAGAGGGCACCTACTACGCAATGGATTATTGGGGCCAGGGGACCAGCGTGACCGTTTCTTCT
(配列番号87)
GATGTTGTAATGACCCAGACACCTCTGAGCCTGCCTGTGACCCTGGGAGAACCAGCATCCATCAGCTGTCGGAGCAGCCAGAGCATCGTTCACAGCAACGGCAACACCTACCTGGAATGGTATCTACAGAAGCCCGGACAGAGCCCCAGGCTGCTGATCTACAAGGTGTCCAACCGCTTCAGTGGTGTGCCCGATAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGAAGATCTCCAGAGTGGAAGCCGAGGACCTGGGCGTGTACTACTGCTTCCAAGGCAGCCATGTGCCAAGAACCTTTGGTGGAGGCACAAAGCTGGAAATCAAGCGG
(配列番号88)
GATGTTGTAATGACCCAGAGCCCTAGTAGCCTGTCTGTGACCCTGGGAGATCGAGTATCCATCAGCTGTCGGAGCAGCCAGAGCATCGTTCACAGCAACGGCAACACCTACCTGGAATGGTATCAACAGAAGCCCGGACAGAGCCCCAGGCTGCTGATCTACAAGGTGTCCAACCGCTTCAGTGGTGTGCCCGATAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACGATCTCCAGAGTGGAACCAGAGGACCTGGGCGTGTACTACTGCTTCCAAGGCAGCCATGTGCCAAGAACCTTTGGTGGAGGCACAAAGCTGGAAATCAAGCGG
(配列番号89)
GATATTGTAATGACCCAGAGCCCTGCAACACTGTCTGTGTCCCCTGGAGAACGAGCAACAATCAGCTGTCGGAGCAGCCAGAGCATCGTTCACAGCAACGGCAACACCTACCTGGAATGGTATCAACAGAAGCCCGGACAGGCCCCCAGGCTGCTGATCTACAAGGTGTCCAACCGCTTCAGTGGAATACCCGATAGATTTTCTGGCAGCGGCTCTGGCACCGACTTCACCCTGACGATCTCCAGATTAGAACCAGAGGACTTTGCAGTGTACTACTGCTTCCAAGGCAGCCATGTGCCAAGAACCTTTGGTGGAGGCACAAAGCTGGAAATCAAGCGG
(配列番号69)
QVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDX1VMTQX2PX3X4LX5VX6X7GX8X9X10X11ISCRSSQSIVHSNGNTYLEWYX12QKPGQX13PRLLIYKVSNRFSGX14PDRFSGSGSGTDFTLX15ISRX16EX17EDX18X19VYYCFQGSHVPRTFGGGTKLEIKR
ここで、X1は、VまたはIであり、X2は、TまたはSであり、X3は、LまたはSまたはAであり、X4は、SまたはTであり、X5は、PまたはSであり、X6は、TまたはSであり、X7は、LまたはPであり、X8は、EまたはDであり、X9は、PまたはRであり、X10は、AまたはVであり、X11は、SまたはTであり、X12は、LまたはQであり、X13は、SまたはAであり、X14は、VまたはIであり、X15は、KまたはTであり、X16は、VまたはLであり、X17は、AまたはPであり、X18は、LまたはFであり、X19は、GまたはAである。配列番号69は、N末端からC末端へと、配列番号9、配列番号18および配列番号10からなる。
(配列番号70)
QVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDVVMTQTPLSLPVTLGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPRTFGGGTKLEIKR
(配列番号71)
QVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDVVMTQSPSSLSVTLGDRVSISCRSSQSIVHSNGNTYLEWYQQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEPEDLGVYYCFQGSHVPRTFGGGTKLEIKR
(配列番号72)
QVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIVMTQSPATLSVSPGERATISCRSSQSIVHSNGNTYLEWYQQKPGQAPRLLIYKVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPRTFGGGTKLEIKR
(配列番号74)
SQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDVVMTQSPSSLSVTLGDRVSISCRSSQSIVHSNGNTYLEWYQQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEPEDLGVYYCFQGSHVPRTFGGGTKLEIKR
(配列番号75)
SQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDVVMTQSPSSLSVTLGDRVSISCRSSQSIVHSNGNTYLEWYQQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEPEDLGVYYCFQGSHVPRTFGGGTKLEIKR
(配列番号76)
SQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIVMTQSPATLSVSPGERATISCRSSQSIVHSNGNTYLEWYQQKPGQAPRLLIYKVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPRTFGGGTKLEIKR
試験A:
試験B:
(配列番号26)
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD
(配列番号27)
ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGAT
(配列番号28)
ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM
(配列番号29)
GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATG
(配列番号30)
RWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDH
(配列番号31)
AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCACAGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTCCATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTTGTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACCTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGACCTCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGATGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCAGCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCCCCCAGCCAGCCACATACACCTGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTACGTGACTGACCATT
(配列番号32)
IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP
(配列番号33)
ATTGAAGTTATGTATCCTCCTCCTTACCTAGACAATGAGAAGAGCAATGGAACCATTATCCATGTGAAAGGGAAACACCTTTGTCCAAGTCCCCTATTTCCCGGACCTTCTAAGCCC
(配列番号34)
IYIWAPLAGTCGVLLLSLVITLYC
(配列番号35)
ATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGC
(配列番号36)
FWVLVVVGGVLACYSLLVTVAFIIFWV
(配列番号37)
TTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTG
(配列番号38)
RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号39)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号40)
RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号41)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号42)
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC
(配列番号43)
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC
(配列番号44)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
(配列番号45)
QRRKYRSNKGESPVEPAEPCRYSCPREEEGSTIPIQEDYRKPEPACSP
(配列番号46)
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
(配列番号47)
AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG
(配列番号48)
CAACGAAGGAAATATAGATCAAACAAAGGAGAAAGTCCTGTGGAGCCTGCAGAGCCTTGTCGTTACAGCTGCCCCAGGGAGGAGGAGGGCAGCACCATCCCCATCCAGGAGGATTACCGAAAACCGGAGCCTGCCTGCTCCCCC
(配列番号49)
AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC
−配列番号44の4−1BB細胞内ドメインのアミノ酸配列または配列番号44に対して95〜99%の同一性を有するアミノ酸配列、および/または配列番号45のCD27細胞内ドメインのアミノ酸配列もしくは配列番号45に対して95〜99%の同一性を有するアミノ酸配列、および/または配列番号46のCD28細胞内ドメインのアミノ酸配列もしくは配列番号46に対して95〜99%の同一性を有するアミノ酸配列、ならびに
−配列番号38〜41のCD3ゼータ細胞内ドメインのアミノ酸配列、または配列番号38〜41に対して95〜99%の同一性を有するアミノ酸配列
を含み、
細胞内ドメインに含まれる配列は、同じフレームでかつ単一のポリペプチド鎖として発現される。
−配列番号47の4−1BB細胞内ドメインの核酸配列または配列番号47に対して95〜99%の同一性を有する核酸配列、および/または配列番号48のCD27細胞内ドメインの核酸配列もしくは配列番号48に対して95〜99%の同一性を有する核酸配列、および/または配列番号49のCD28細胞内ドメインの核酸配列もしくは配列番号49に対して95〜99%の同一性を有する核酸配列、ならびに
−配列番号42または配列番号43のCD3−ゼータ細胞内ドメインの核酸配列、または配列番号42または配列番号43に対して95〜99%の同一性を有する核酸配列
を含む。
(配列番号50)
MALPVTALLLPLALLLHAARP
(配列番号51)
NWSHPQFEK
(配列番号52)
SAWSHPQFEK
(配列番号68)
MVSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLTYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTIFFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDGNILGHKLEYNYNSHNVYIMADKQKNGIKVNFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSTQSALSKDPNEKRDHMVLLEFVTAAGITLGMDELYK
(配列番号53)
AAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号54)
AAAIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号55)
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号56)
NWSHPQFEKMHTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELTRRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号57)
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号58)
NWSHPQFEKMHTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELTRRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号77)
SQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDX1VMTQX2PX3X4LX5VX6X7GX8X9X10X11ISCRSSQSIVHSNGNTYLEWYX12QKPGQX13PRLLIYKVSNRFSGX14PDRFSGSGSGTDFTLX15ISRX16EX17EDX18X19VYYCFQGSHVPRTFGGGTKLEIKRRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
ここで、X1は、VまたはIであり、X2は、TまたはSであり、X3は、LまたはSまたはAであり、X4は、SまたはTであり、X5は、PまたはSであり、X6は、TまたはSであり、X7は、LまたはPであり、X8は、EまたはDであり、X9は、PまたはRであり、X10は、AまたはVであり、X11は、SまたはTであり、X12は、LまたはQであり、X13は、SまたはAであり、X14は、VまたはIであり、X15は、KまたはTであり、X16は、VまたはLであり、X17は、AまたはPであり、X18は、LまたはFであり、X19は、GまたはAである。
(配列番号81)
MALPVTALLLPLALLLHAARPSQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDX1VMTQX2PX3X4LX5VX6X7GX8X9X10X11ISCRSSQSIVHSNGNTYLEWYX12QKPGQX13PRLLIYKVSNRFSGX14PDRFSGSGSGTDFTLX15ISRX16EX17EDX18X19VYYCFQGSHVPRTFGGGTKLEIKRRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号78)
SQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDVVMTQTPLSLPVTLGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPRTFGGGTKLEIKRRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号82)
MALPVTALLLPLALLLHAARPSQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDVVMTQTPLSLPVTLGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPRTFGGGTKLEIKRRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号79)
SQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDVVMTQSPSSLSVTLGDRVSISCRSSQSIVHSNGNTYLEWYQQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEPEDLGVYYCFQGSHVPRTFGGGTKLEIKRRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号83)
MALPVTALLLPLALLLHAARPSQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDVVMTQSPSSLSVTLGDRVSISCRSSQSIVHSNGNTYLEWYQQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEPEDLGVYYCFQGSHVPRTFGGGTKLEIKRRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号80)
SQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIVMTQSPATLSVSPGERATISCRSSQSIVHSNGNTYLEWYQQKPGQAPRLLIYKVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPRTFGGGTKLEIKRRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号84)
MALPVTALLLPLALLLHAARPSQVQLVQSGPEVKKPGASVKVSCKASGYTFTSYHIQWVRQAPGQGLEWIGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLTSEDTAVYYCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIVMTQSPATLSVSPGERATISCRSSQSIVHSNGNTYLEWYQQKPGQAPRLLIYKVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPRTFGGGTKLEIKRRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号59)
MHTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSTRRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(配列番号60)
MHTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSTRRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
(Boisselら、Nucleic Acids Res.2014年2月;42(4):2591−601)。
ヒト化HLA−A2特異的scFvの生成。HLA−A2特異的scFvの配列は、米国特許出願公開第2013/0078243号(A1)に開示される配列に由来した。ヒト化scFvをコードするコドン最適化遺伝子配列は、供給業者によって提供されるコドン最適化アルゴリズムを使用して、GeneArt,Life Technologies(Regensburg)によって「String」として合成された。ScFvは、N末端で、コザック配列およびCD8シグナル配列と隣接させた。構築物は、BamHIおよびMfeI制限部位にさらに隣接し、これは、自己不活性化レンチウイルスCAR発現プラスミドのCD8ヒンジ領域へのフレーム内クローニングを可能にした。PGKプロモーター駆動のCAR発現プラスミドは、ヒトCD8ヒンジおよびCD8膜貫通ドメインを含み、その後にヒトCD3ζに融合された細胞内ヒト41BB共刺激ドメインが続く。CAR配列に続いて、EGFPレポータータンパク質が、細胞中の遺伝子導入の検出のために自己切断可能な2A部位を介してフレーム内で連結された。
ヒト化HLA−A2特異的CARの構築
1つのヒト化重鎖および3つの異なるヒト化軽鎖を生成し、合計3つの異なるキメラ抗原受容体を、ヒト化重鎖と軽鎖とを組み合わせることによって生成した。
CARの発現および正しい折り畳みを、Jurkat NFATレポーター細胞株を使用して検証した。
より少ない数の祖先対立遺伝子から時間をかけて進化した、HLAの多くの異なる対立遺伝子がある。その結果、数個のアミノ酸のみが異なり得る対立遺伝子ファミリーがあり、単一の抗HLA抗体が、進化的に関連したファミリー内の複数の対立遺伝子を認識し得る。マウスモノクローナル抗体(BB7.2)は、追加のHLA−A対立遺伝子に対し交差反応を有することが公知である(Hilton&Parham、2013年)。具体的には、固相アッセイでテストした場合、BB7.2は、HLA−A2の5個のサブタイプ(*02:01、*02:02、*02:03、*02:05、*02:06)を認識すること、およびHLA−A*69:01と交差反応すること、かつ高濃度でテストした場合、HLA−A*23:01、A*24:02、A*24:03、A*68:01、およびA*68:02(Hilton&Parham、2013年)と交差反応することが判明した。本発明のヒト化抗HLA−A2抗体の交差反応性を評価し、かつBB7.2抗体のVHおよびVLを含む抗体と比較するために、血清中の抗HLA抗体を測定するために設計された、ONEラムダ固相アッセイを採用して、目的のヒト化CARへのHLAコーティングビーズの結合を測定した。指示されたヒト化CARを発現するGFP+TregをFlow Panel Reactive Single Antigenビーズとインキュベートし、単一クラスのビーズへの結合を、前方/側方散布図のビーズゲートでのシグナルの損失として定量化した。データを、試料中の陰性対照ビーズの数に対して正規化し、GFP+−対照Tregによる結合の量に関連して、hCAR発現Tregへの相対的結合量を、GFP試料中の陰性ビーズの数にGFP試料中の陰性ビーズの数を乗算することによって計算した。
Claims (21)
- 抗体BB7.2と比較して、またはBB7.2抗体のVHおよびVLを含む抗体と比較して、A03、A11、A23、A25、A26、A29、A30、A31、A33、A34およびそれらの任意の組み合わせを含む群から選択されるHLA−Aサブタイプに対して低い反応性を有する、ヒト化抗HLA−A2抗体であって、
重鎖の可変領域が、以下のCDR:
VH−CDR1:SYHIQ(配列番号1)またはGYTFTSY(配列番号4)、
VH−CDR2:WIYPGDGSTQYNEKFKG(配列番号2)またはYPGDGS(配列番号5)、
VH−CDR3:EGTYYAMDY(配列番号3)、
または配列番号1〜5と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDR
のうちの少なくとも1つを含む、および/または
軽鎖の可変領域が、以下のCDR:
VL−CDR1:RSSQSIVHSNGNTYLE(配列番号6)、
VL−CDR2:KVSNRFS(配列番号7)、
VL−CDR3:FQGSHVPRT(配列番号8)、
または配列番号6〜8と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDR
のうちの少なくとも1つを含む、
ヒト化抗HLA−A2抗体。 - 前記重鎖の可変領域が、請求項1で定義されるCDRのうちの少なくとも1つを含み、前記軽鎖の可変領域が、請求項1で定義されるCDRのうちの少なくとも1つを含む、請求項1に記載のヒト化抗HLA−A2抗体。
- 前記重鎖の可変領域が、以下のCDR:SYHIQ(配列番号1)、WIYPGDGSTQYNEKFKG(配列番号2)およびEGTYYAMDY(配列番号3);またはGYTFTSY(配列番号4)、YPGDGS(配列番号5)およびEGTYYAMDY(配列番号3)または配列番号1〜5と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDRを含み、
前記軽鎖の可変領域が、以下のCDR:RSSQSIVHSNGNTYLE(配列番号6)、KVSNRFS(配列番号7)およびFQGSHVPRT(配列番号8)または配列番号6〜8と少なくとも60%の同一性を共有するアミノ酸配列を有する任意のCDRを含む、
請求項1に記載のヒト化抗HLA−A2抗体。 - 前記重鎖可変領域のアミノ酸配列が、配列番号9であるか、または前記配列番号9と少なくとも60%の同一性を共有する任意のアミノ酸配列である、請求項1に記載のヒト化抗HLA−A2抗体。
- 前記軽鎖可変領域のアミノ酸配列が、配列番号10であるか、または前記配列番号10と少なくとも60%の同一性を共有する任意のアミノ酸配列であり、ここで、X1はVまたはIであり、X2はTまたはSであり、X3はLまたはSまたはAであり、X4はSまたはTであり、X5はPまたはSであり、X6はTまたはSであり、X7はLまたはPであり、X8はEまたはDであり、X9はPまたはRであり、X10はAまたはVであり、X11はSまたはTであり、X12はLまたはQであり、X13はSまたはAであり、X14はVまたはIであり、X15はKまたはTであり、X16はVまたはLであり、X17はAまたはPであり、X18はLまたはFであり、X19はGまたはAである、請求項1に記載のヒト化抗HLA−A2抗体。
- 前記軽鎖可変領域のアミノ酸配列が、配列番号11、配列番号12および配列番号13または前記配列番号11〜13と少なくとも60%の同一性を共有する任意のアミノ酸配列を含む群から選択される、請求項1に記載のヒト化抗HLA−A2抗体。
- 前記重鎖可変領域のアミノ酸配列が、配列番号9または前記配列番号9と少なくとも60%の同一性を共有する任意のアミノ酸配列であり、前記軽鎖可変領域のアミノ酸配列が、配列番号10であり、ここで、X1はVまたはIであり、X2はTまたはSであり、X3はLまたはSまたはAであり、X4はSまたはTであり、X5はPまたはSであり、X6はTまたはSであり、X7はLまたはPであり、X8はEまたはDであり、X9はPまたはRであり、X10はAまたはVであり、X11はSまたはTであり、X12はLまたはQであり、X13はSまたはAであり、X14はVまたはIであり、X15はKまたはTであり、X16はVまたはLであり、X17はAまたはPであり、X18はLまたはFであり、およびX19はGまたはAであり、好ましくは、前記軽鎖可変領域のアミノ酸配列は、配列番号11、配列番号12および配列番号13または前記配列番号10〜13と少なくとも60%の同一性を共有する任意のアミノ酸配列を含む群から選択される、請求項1に記載のヒト化抗HLA−A2抗体。
- 前記抗体が、全抗体、一本鎖抗体、二量体一本鎖抗体、Fv、scFv、Fab、F(ab)’2、脱フコシル化抗体、二重特異性抗体、ダイアボディ、トリアボディ、テトラボディ;ユニボディ、ドメイン抗体、およびナノボディからなる群から選択される抗体断片;またはアフィボディ、アルファボディ、アルマジロリピートタンパク質ベースの足場、ノッティン、kunitzドメインペプチド、アフィリン、アフィチン、アドネクチン、アトリマー、エバシン、DARPin、アンチカリン、アビマー、ファイノマー、バーサボディもしくはデュオカリンからなる群から選択される抗体模倣物である、請求項1に記載のヒト化抗HLA−A2抗体。
- 前記抗体が、scFv、好ましくは配列番号70〜72または74〜76の配列を有するscFvである、請求項1に記載のヒト化抗HLA−A2抗体。
- 請求項1に記載のヒト化抗HLA−A2抗体を含む細胞外ドメイン、
膜貫通ドメイン、および
細胞内シグナル伝達ドメインを含む細胞質ドメイン
を含む、キメラ抗原受容体(CAR)。 - 請求項10に記載のCARをコードする、核酸配列。
- 請求項10に記載のCARまたは請求項11に記載の核酸配列を含む免疫細胞であって、好ましくは調節性T細胞である、免疫細胞。
- 請求項12に記載の免疫細胞を含む組成物であって、好ましくは医薬組成物でありかつ医薬的に許容される賦形剤をさらに含む、組成物。
- それを必要とする対象において免疫寛容を誘導するための方法であって、前記対象に請求項12に記載の免疫細胞を投与することを含み、好ましくは前記寛容が、移植臓器または組織に対する寛容である、方法。
- それを必要とする対象における臓器または組織移植拒絶反応または移植片対宿主病(GVHD)を治療するための方法であって、前記対象に請求項12に記載の免疫細胞を投与することを含む、方法。
- 前記対象に少なくとも1つの免疫抑制剤を投与することをさらに含む、請求項14または15に記載の方法。
- それを必要とする対象において免疫寛容を誘導するための請求項12に記載の免疫細胞。
- それを必要とする対象において臓器または組織移植拒絶反応または移植片対宿主病(GVHD)を治療するための請求項12に記載の免疫細胞。
- 前記対象が、免疫抑制剤をさらに受けている、請求項16または17に記載の使用のための免疫細胞。
- それを必要とする対象において免疫寛容を誘導するための、またはそれを必要とする対象において臓器もしくは組織移植拒絶反応もしくは移植片対宿主病(GVHD)を治療するための、少なくとも1つの免疫抑制剤と請求項12に記載の免疫細胞の組み合わせ。
- 請求項12に記載の免疫細胞を第1の部分に含み、少なくとも1つの免疫抑制剤を第2の部分に含む、キット。
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