【技术实现步骤摘要】
【国外来华专利技术】抗自相残杀的修饰的免疫细胞及其使用方法
[0001]相关申请的交叉引用
[0002]本申请要求2020年9月25日提交的美国临时申请号63/083,540的优先权,所述申请的全部内容特此通过引用整体并入。
[0003]序列表
[0004]本申请含有序列表,所述序列表已经以ASCII格式以电子方式提交,并且特此通过引用整体并入。所述ASCII副本创建于2021年9月24日,名称为180802
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045001PCT_SL.txt,并且大小为2,266,391字节。
技术介绍
[0005]自体和同种异体免疫疗法是肿瘤治疗方法,其中将表达嵌合抗原受体的免疫细胞施用至受试者。为了生成表达嵌合抗原受体(CAR)的免疫细胞,首先从受试者(自体)或者从分离自接受治疗的受试者的供体(同种异体)收集免疫细胞,并且进行遗传修饰以表达嵌合抗原受体。所得细胞(例如,CAR T细胞)在其细胞表面上表达嵌合抗原受体,并且在施用于受试者后,嵌合抗原受体结合肿瘤细胞表达的标志物。这种与肿瘤标志物的相互作用激活CAR
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T细胞,然后CAR
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T细胞杀死肿瘤细胞。但为了使自体或同种异体细胞疗法有效且高效,必须克服或避免相当数量的条件和细胞反应。靶抗原在肿瘤细胞和健康免疫细胞上的共同表达可能会提供额外的挑战,诸如T细胞自相残杀。编辑参与此过程的基因可以增强CAR
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T细胞的功能并且产生对自相残杀的抗性,但目前用于进行此类编辑的方法有可能在CAR
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T细胞中诱导大 ...
【技术保护点】
【技术特征摘要】
【国外来华专利技术】1.一种嵌合抗原受体(CAR),其包含抗CD2结合结构域;和CD2信号传导结构域和/或CD28信号传导结构域。2.如权利要求1所述的CAR,其还包含跨膜结构域和一个或多个额外的信号传导结构域。3.如权利要求2所述的CAR,其中所述跨膜结构域是CD8α跨膜结构域。4.如权利要求2或3所述的CAR,其中所述一个或多个额外的信号传导结构域选自CD3ζ信号传导结构域、CD28信号传导结构域和CD137(4
‑
1BB)信号传导结构域。5.如权利要求4所述的CAR,其中所述一个或多个额外的信号传导结构域是CD3ζ信号传导结构域。6.一种嵌合抗原受体(CAR),其包含抗CD2结合结构域;CD8α跨膜结构域;CD2信号传导结构域和/或CD28信号传导结构域;和CD3ζ信号传导结构域。7.如权利要求5所述的CAR,其中所述CAR包含所述CD28信号传导结构域和/或CD137(4
‑
1BB)信号传导结构域。8.如权利要求1
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7中任一项所述的CAR,其还包含前导肽序列。9.如权利要求8所述的CAR,其中所述前导肽序列与以下氨基酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性:METDTLLLWVLLLWVPGSTG。10.如权利要求1
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9中任一项所述的CAR,其中所述CD2信号传导结构域与CD2细胞质结构域具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性。11.如权利要求10所述的CAR,其中所述CD2细胞质结构域与人CD2细胞质结构域的残基235
‑
351具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性。12.如权利要求1
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11中任一项所述的CAR,其中所述CD2信号传导结构域与以下氨基酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性:TKRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAENSLSPSSN(SEQ ID NO:370)。13.如权利要求3
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12中任一项所述的CAR,其中所述CD8α跨膜结构域与以下氨基酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性:SDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYC(SEQ ID NO:371)。14.如权利要求4
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13中任一项所述的CAR,其中所述CD3ζ信号传导结构域与以下氨基酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性:RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:372)。15.如权利要求1
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14中任一项所述的CAR,其中所述CD28信号传导结构域与以下氨基酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性:RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO:373)。
16.如权利要求4
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15中任一项所述的CAR,其中所述CD137(4
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1BB)信号传导结构域与以下氨基酸序列之一具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性:KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO:374);或RFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO:375)。17.如权利要求1
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16中任一项所述的CAR,其中所述抗CD2结合结构域包含与以下氨基酸序列之一具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性的scFv轻链序列:DVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLLQRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELK(SEQ ID NO:376);EVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQRPKQQLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSS(SEQ ID NO:377);DVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIK(SEQ ID NO:378);QVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSS(SEQ ID NO:379);DVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIK(SEQ ID NO:378);或QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGRTEYIVVAEGFDYWGQGTLVTVSS(SEQ ID NO:380)。18.如权利要求1
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17中任一项所述的CAR,其中所述抗CD2结合结构域包含与以下氨基酸序列之一具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性的scFv重链序列:EVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQRPKQQLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSS(SEQ ID NO:377);DVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLLQRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELK(SEQ ID NO:376);QVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSS(SEQ ID NO:379);DVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIK(SEQ ID NO:378);QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGRTEYIVVAEGFDYWGQGTLVTVSS(SEQ ID NO:380);和DVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIK(SEQ ID NO:378)。19.如权利要求1
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18中任一项所述的CAR,其还包含接头。20.如权利要求19所述的CAR,其中所述接头将所述scFv轻链序列连接至所述抗CD2结合结构域的所述scFv重链序列。21.如权利要求19或20所述的CAR,其中所述接头包含序列(GGGGS)
n
(SEQ ID NO:247),
其中n是1至10的整数。22.如权利要求19
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21中任一项所述的CAR,其中所述接头包含序列(GGGGS)3(SEQ ID NO:381)。23.如权利要求1
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22中任一项所述的CAR,其中所述抗CD2结合结构域包含与以下氨基酸序列之一具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性的抗CD2 scFv:DVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLLQRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELKGGGGSGGGGSGGGGSEVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQRPKQQLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSS(SEQ ID NO:382);EVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQRPKQQLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLLQRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELK(SEQ ID NO:383);DVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSS(SEQ ID NO:384);QVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIK(SEQ ID NO:385);DVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGRTEYIVVAEGFDYWGQGTLVTVSS(SEQ ID NO:386);或QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGRTEYIVVAEGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIK(SEQ ID NO:387)。24.一种嵌合抗原受体(CAR),其中所述CAR与以下氨基酸序列中的任一者的氨基酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%的同一性:METDTLLLWVLLLWVPGSTGDVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLLQRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELKGGGGSGGGGSGGGGSEVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQRPKQQLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSSSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCTKRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAENSLSPSSNRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEI
GMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:754);METDTLLLWVLLLWVPGSTGEVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQRPKQQLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLLQRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELKSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCTKRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAENSLSPSSNRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:755);METDTLLLWVLLLWVPGSTGDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSSSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCTKRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAENSLSPSSNRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:756);METDTLLLWVLLLWVPGSTGQVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCTKRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAENSLSPSSNRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:757);METDTLLLWVLLLWVPGSTGDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGRTEYIVVAEGFDYWGQGTLVTVSSSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCTKRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAENSLSPSSNRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:758);METDTLLLWVLLLWVPGSTGQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGRTEYIVVAEGFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCTKRKKQRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQAPSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAEN
SLSPSSNRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:759);METDTLLLWVLLLWVPGSTGDVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLLQRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELKGGGGSGGGGSGGGGSEVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQRPKQQLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSSSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:761);METDTLLLWVLLLWVPGSTGEVQLQQSGPELQRPGASVKLSCKASGYIFTEYYMYWVKQRPKQQLELVGRIDPEDGSIDYVEKFKKKATLTADTSSNTAYMQLSSLTSEDTATYFCARGKFNYRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDVVLTQTPPTLLATIGQSVSISCRSSQSLLHSSGNTYLNWLLQRTGQSPQPLIYLVSKLESGVPNRFSGSGSGTDFTLKISGVEAEDLGVYYCMQFTHYPYTFGAGTKLELKSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:762);METDTLLLWVLLLWVPGSTGDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSSSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:763);METDTLLLWVLLLWVPGSTGQVQLVQSGAEVKKPGASVKVSCKASGYTFTEYYMYWVRQAPGQGLELMGRIDPEDGSIDYVEKFKKKVTLTADTSSSTAYMELSSLTSDDTAVYYCARGKFNYRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRv(SEQ ID NO:764);METDTLLLWVLLLWVPGSTGDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGRTEYIVVAEGFDYWGQGTLVTVSSSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:765);和METDTLLLWVLLLWVPGSTGQVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGRINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGRTEYIVVAEGFDYWGQGTLVTVSSGGGGS
GGGGSGGGGSDVVMTQSPPSLLVTLGQPASISCRSSQSLLHSSGNTYLNWLLQRPGQSPQPLIYLVSKLESGVPDRFSGSGSGTDFTLKISGVEAEDVGVYYCMQFTHYPYTFGQGTKLEIKSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:766)。25.一种修饰的免疫细胞,其包含:如权利要求1
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24中任一项所述的嵌合抗原受体;和所述修饰的免疫细胞的基因组中的使所述修饰的免疫细胞的内源CD2基因失活的一个或多个突变。26.如权利要求25所述的修饰的免疫细胞,其还包含至少一个额外的基因序列或其调控元件中的一个或多个突变。27.如权利要求25或26所述的修饰的免疫细胞,其中所述一个或多个突变是至少一个单一靶标核碱基修饰。28.如权利要求27所述的修饰的免疫细胞,其中所述至少一个单一靶标核碱基修饰由一种或多种碱基编辑器生成。29.如权利要求28所述的修饰的免疫细胞,其中所述一种或多种碱基编辑器是CBE和/或ABE。30.如权利要求27
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29中任一项所述的修饰的免疫细胞,其中与没有所述修饰的对照细胞相比,所述单一靶标核碱基修饰减少或消除表达和/或功能。31.如权利要求30所述的修饰的免疫细胞,其中与没有所述修饰的对照细胞相比,表达和/或功能减少至少50%、至少60%、至少70%、至少80%、至少90%或至少100%。32.如权利要求26
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31中任一项所述的修饰的免疫细胞,其中所述至少一个额外的基因序列包含检查点抑制基因序列、免疫反应调控基因序列和/或免疫原性基因序列。33.如权利要求26
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32中任一项所述的修饰的免疫细胞,其中所述至少一个额外的基因序列包...
【专利技术属性】
技术研发人员:杰森,
申请(专利权)人:比姆医疗股份有限公司,
类型:发明
国别省市:
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