CN115052887A - 基于lilrb1的嵌合抗原受体 - Google Patents
基于lilrb1的嵌合抗原受体 Download PDFInfo
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Abstract
提供了具有LILRB1的铰链、跨膜区和/或胞内结构域的嵌合抗原受体或其功能片段或变体。本文还提供了包含所述基于LILRB1的受体的细胞，及其制造和使用方法。
Description
相关申请的交叉引用
本申请要求于2019年12月11日提交的美国临时申请62/946,888和2020年8月30日提交的美国临时申请63/085,969的优先权，将其中的每一个的披露内容通过引用以其整体并入本文。
通过引用序列表并入
本申请含有序列表，所述序列表已经以ASCII格式经由EFS-WEB提交并且通过引用以其整体特此并入。2020年12月11日创建的所述ASCII副本被命名为A2BI-015-01WO_SeqList.txt，并且大小为228KB。
背景技术
嵌合抗原受体(CAR)T细胞疗法和T细胞受体(TCR)疗法被证明对于各种疾病，特别是血液恶性肿瘤以及其他癌症是有效治疗方法。CAR NK细胞也可以具有临床应用。常规CAR向工程化免疫细胞(例如T细胞或NK细胞)提供刺激信号。在CAR-T细胞中，这导致针对由CAR的抗原结合结构域鉴定的靶细胞的杀伤活性。已经开发出抑制性CAR(iCAR)作为控制细胞活性或将激活剂CAR的活性限制于特定细胞类型的手段。Fedorov等人Sci.Transl.Med.5(215):215ra172(2013)。抑制性CAR通常具有通过跨膜区和任选地铰链区与抗原结合结构域(例如，单链可变片段，scFv)融合的抑制性信号传导分子(诸如PD-1或CTLA-4)的胞内结构域。
在本领域中已经描述了许多替代性iCAR架构。然而，仍然存在对于具有优越性能的新颖替代性抑制性受体和特定抑制性受体架构的鉴定，以及其相关组合物和使用方法的未满足的需要。
发明内容
在一方面，本公开文本提供了具有LILRB1的铰链、跨膜区和/或胞内结构域的嵌合抗原受体或其功能片段或变体。所述嵌合抗原受体可以包含单一多肽或多于一个多肽。所述受体可以包含以下中的一种或多种或全部：(a)LILRB1铰链结构域或其功能片段或变体；(b)LILRB1跨膜结构域或其功能变体；以及(c)LILRB1胞内结构域或其功能变体，诸如LILRB1胞内结构域和/或包含在LILRB1的多肽序列中找到的至少一个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域。在一些实施方案中，所述受体包含至少两个在LILRB1的多肽序列中找到的ITIM。LILRB1的ITIM是NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。所述受体可以包含这些ITIM中的一个、两个、三个、四个、五个、六个或更多个，呈任何组合，包括相同ITIM的多个拷贝。
在本公开文本的受体的一些实施方案中，所述胞内结构域包含两个ITIM NLYAAV(SEQ ID NO:8)和VTYAEV(SEQ ID NO:9)。在一些实施方案中，所述胞内结构域包含与SEQID NO:12至少95％相同的序列。在一些实施方案中，所述胞内结构域包含两个ITIM VTYAEV(SEQ ID NO:9)和VTYAQL(SEQ ID NO:10)。在一些实施方案中，所述胞内结构域包含与SEQID NO:13至少95％相同的序列。在一些实施方案中，所述胞内结构域包含两个ITIM VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。在一些实施方案中，所述胞内结构域包含与SEQID NO:14至少95％相同的序列。在一些实施方案中，所述多肽包含含有至少三个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ IDNO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。在一些实施方案中，所述胞内结构域包含ITIM NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)和VTYAQL(SEQID NO:10)。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:15至少95％相同的序列。在一些实施方案中，所述胞内结构域包含ITIM VTYAEV(SEQ IDNO:9)、VTYAQL(SEQ IDNO:10)和SIYATL(SEQ ID NO:11)。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:16至少95％相同的序列。在一些实施方案中，所述胞内结构域包含ITIM NLYAAV(SEQ IDNO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:17至少95％相同的序列。在一些实施方案中，所述胞内结构域包含与LILRB1胞内结构域(SEQ ID NO:7)至少95％相同的序列。在一些实施方案中，所述胞内结构域包含SEQ ID NO:12-17的序列。
在本公开文本的受体的一些实施方案中，所述多肽包含LILRB1跨膜结构域或其功能变体。在一些实施方案中，所述LILRB1跨膜结构域或其功能变体包含与SEQ IDNO:5至少95％相同的序列。在一些实施方案中，所述LILRB1跨膜结构域包含SEQ ID NO:5。
在本公开文本的受体的一些实施方案中，所述多肽包含LILRB1铰链结构域或其功能片段或变体。在一些实施方案中，所述LILRB1铰链结构域或其功能片段或变体包含与SEQID NO:4、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82、SEQID NO:83、SEQ ID NO:84或SEQ ID NO:93至少95％相同的序列。在一些实施方案中，所述LILRB1铰链结构域包含与SEQ ID NO:4、SEQ ID NO:18、SEQID NO:19、SEQ ID NO:80、SEQID NO:81、SEQ ID NO:82、SEQ ID NO:83、SEQ ID NO:84或SEQ ID NO:93相同的序列。在一些实施方案中，所述LILRB1铰链结构域或其功能片段或变体包含与SEQ ID NO:4、SEQ IDNO:18、SEQ ID NO:19、SEQ ID NO:80、SEQID NO:81、SEQ ID NO:82、SEQ ID NO:83或SEQ IDNO:84至少95％相同的序列。在一些实施方案中，所述LILRB1铰链结构域包含与SEQ ID NO:4、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82、SEQ ID NO:83或SEQ ID NO:84相同的序列。
在本公开文本的受体的一些实施方案中，所述多肽包含：(a)LILRB1铰链结构域或其功能片段或变体，以及(b)所述LILRB1跨膜结构域或其功能变体。在一些实施方案中，所述多肽包含与SEQ ID NO:20至少95％相同的序列。
在本公开文本的受体的一些实施方案中，所述多肽包含：(a)LILRB1跨膜结构域或其功能变体，以及(b)LILRB1胞内结构域和/或包含至少两个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ IDNO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。在一些实施方案中，所述多肽包含与SEQ ID NO:21至少95％相同的序列。在一些实施方案中，所述多肽包含SEQ ID NO:21的序列。
在本公开文本的受体的一些实施方案中，所述多肽包含：(a)LILRB1铰链结构域或其功能片段或变体；(b)LILRB1跨膜结构域或其功能变体；以及(c)LILRB1胞内结构域和/或包含至少两个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ IDNO:10)和SIYATL(SEQ IDNO:11)。
在本公开文本的受体的一些实施方案中，所述多肽包含与SEQ ID NO:2或SEQIDNO:3至少95％相同的序列。在一些实施方案中，所述多肽包含与SEQ ID NO:20至少99％相同的序列。在一些实施方案中，所述多肽包含与SEQ ID NO:21至少99％相同的序列。在一些实施方案中，所述多肽包含与SEQ ID NO:2或SEQ ID NO:3至少99％相同的序列。在一些实施方案中，所述多肽包含与SEQ ID NO:20相同的序列。在一些实施方案中，所述多肽包含与SEQ ID NO:21相同的序列。在一些实施方案中，所述多肽包含与SEQ IDNO:2或SEQ ID NO:3相同的序列。
在本公开文本的受体的一些实施方案中，所述多肽包含抗原结合结构域。在一些实施方案中，所述抗原结合结构域是除了所述LILRB1胞外配体结合蛋白以外的抗原结合结构域。在一些实施方案中，所述多肽包含两个或更多个抗原结合结构域。在一些实施方案中，所述抗原结合结构域包含单链可变片段(scFv)。在一些实施方案中，所述受体包含第二多肽。在一些实施方案中，所述第一多肽包含抗体的第一链，并且所述第二多肽包含所述抗体的第二链。在一些实施方案中，所述受体包含抗体的Fab片段。在一些实施方案中，(a)第一多肽包含抗体的重链的抗原结合片段，并且(b)第二多肽包含抗体的轻链的抗原结合片段。在一些实施方案中，(a)第一多肽包含抗体的轻链的抗原结合片段，并且(b)第二多肽包含抗体的重链的抗原结合片段。在一些实施方案中，第一多肽包含T细胞受体(TCR)的第一链，并且第二多肽包含所述TCR的第二链。在一些实施方案中，所述受体包含T细胞受体(TCR)的胞外片段。在一些实施方案中，(a)第一多肽包含TCR的α链的抗原结合片段，并且(b)第二多肽包含TCR的β链的抗原结合片段。在一些实施方案中，(a)第一多肽包含TCR的β链的抗原结合片段，并且(b)第二多肽包含TCR的α链的抗原结合片段。在一些实施方案中，所述受体包含单链TCR。在一些实施方案中，所述scFv包含SEQ ID NO:22-33中的任一个的互补决定区(CDR)。在一些实施方案中，所述scFv包含与SEQ ID NO:35-46或125中的任一个至少95％相同的序列。在一些实施方案中，所述scFv包含与SEQ ID NO:35、39、46或125中的任一个至少95％相同的序列。在一些实施方案中，所述scFv包含与SEQ ID NO:35-46或125中的任一个相同的序列。在一些实施方案中，所述scFv包含与SEQ ID NO:35、39、46或125中的任一个相同的序列。在一些实施方案中，所述抗体的重链包含SEQ ID NO:25-27或31-33中的任一个的重链CDR，并且其中所述抗体的轻链包含SEQ ID NO:22-24或28-30中的任一个的轻链CDR。在一些实施方案中，所述抗体的重链包含与SEQ ID NO:35-46或125中的任一个的重链部分至少95％相同的序列，并且其中所述抗体的轻链包含与SEQ ID NO:35-46或125中的任一个的轻链部分至少95％相同的序列。在一些实施方案中，所述抗体的重链包含与SEQ ID NO:35-46或125中的任一个的重链部分相同的序列，并且其中所述抗体的轻链包含与SEQ ID NO:35-46或125中的任一个的轻链部分相同的序列。在一些实施方案中，所述抗体的重链包含与SEQ ID NO:35、39、46或125中的任一个的重链部分相同的序列，并且其中所述抗体的轻链包含与SEQ ID NO:35、39、46或125中的任一个的轻链部分相同的序列。
在本公开文本的受体的一些实施方案中，所述受体包含与SEQ ID NO:47-71、77-79、89-92、120或122中的任一个至少95％相同的氨基酸序列。在一些实施方案中，所述受体包含SEQ ID NO:47-71、77-79、89-92、120或122的氨基酸序列。
在本公开文本的受体的一些实施方案中，所述受体是抑制性受体。
本公开文本提供了一种多核苷酸，其包含编码本公开文本的受体或多肽的核酸序列。
本公开文本提供了一种载体，其包含本公开文本的多核苷酸。在一些实施方案中，所述载体进一步包含编码可操作地连接至所述多核苷酸的启动子的序列。
本公开文本提供了一种免疫细胞，其包含本公开文本的受体、多核苷酸、多肽或受体。在一些实施方案中，当所述细胞与抗原或在其表面上表达所述抗原的细胞接触时，免疫细胞激活降低。在一些实施方案中，免疫细胞激活包括表达可操作地连接至NFAT启动子的基因。在一些实施方案中，所述免疫细胞是T细胞。在一些实施方案中，进一步包含激活剂受体。在一些实施方案中，所述激活剂受体是嵌合抗原受体或T细胞受体。
本公开文本提供了制造免疫细胞的方法，其包括将本公开文本的多核苷酸或载体引入所述免疫细胞中。在一些实施方案中，所述免疫细胞表达所述受体。在一些实施方案中，所述细胞是免疫细胞。在一些实施方案中，所述免疫细胞是T细胞。在一些实施方案中，当所述细胞与对所述嵌合抗原受体特异性的抗原或在其表面上表达所述抗原的细胞接触时，免疫细胞激活降低。在一些实施方案中，免疫细胞激活包括表达可操作地连接至NFAT启动子的基因。
本公开文本提供了治疗患有疾病或障碍的受试者的方法，其包括向所述受试者施用多个本公开文本的免疫细胞。在一些实施方案中，所述疾病或障碍是癌症。
本公开文本提供了一种试剂盒，其包含本公开文本的受体、多肽、多核苷酸、载体或免疫细胞。
本公开文本提供了一种包含嵌合抗原受体的免疫细胞，所述嵌合抗原受体包含多肽，其中所述多肽序列与SEQ ID NO:21共享至少95％同一性或至少100％同一性。
在本公开文本的免疫细胞的一些实施方案中，所述多肽序列与SEQ ID NO:3共享至少95％同一性或至少100％同一性。在一些实施方案中，所述多肽序列与SEQ ID NO:2共享至少95％同一性或至少100％同一性。在一些实施方案中，所述嵌合抗原受体包含抗原结合结构域，所述抗原结合结构域包含分别根据SEQ ID NO:22-27的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3序列。在一些实施方案中，所述嵌合抗原受体包含抗原结合结构域，所述抗原结合结构域包含分别根据SEQ ID NO:28-33的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3序列。在一些实施方案中，所述多肽序列与SEQ ID NO:122共享至少95％同一性或至少100％同一性。在一些实施方案中，所述多肽序列与SEQ ID NO:35、39、46或125中的任一个与SEQ ID NO:2的组合共享至少95％同一性或至少100％同一性。
在一些实施方案中，所述免疫细胞是T细胞。在一些实施方案中，所述T细胞包含特异性结合至肿瘤细胞上表达的靶标的嵌合抗原受体或T细胞受体。在一些实施方案中，所述T细胞包含特异性结合至靶标的嵌合抗原受体或T细胞受体，所述靶标选自黄化受体、ανββ整合素、BCMA、B7-H3、B7-H6、CAIX、CD19、CD20、CD22、CD30、CD33、CD37、CD44、CD44v6、CD44v7/8、CD70、CD123、CD138、CD171、CEA、DLL4、EGP-2、EGP-40、CSPG4、EGFR、包括ErbB2(HER2)在内的EGFR家族、EGFRvIII、EPCAM、EphA2、EpCAM、FAP、FBP、胎儿乙酰胆碱受体、Fzd7、GD2、GD3、磷脂酰肌醇蛋白聚糖-3(GPC3)、h5T4、IL-11R、IL13R-a2、KDR、κ轻链、λ轻链、LeY、LI CAM、MAGE-A1、间皮素、MHC呈递肽、MUC1、MUC16、NCAM、NKG2D配体、Notchl、Notch2/3、NY-ESO-1、PRAME、PSCA、PSMA、存活蛋白、TAG-72、TEM、TERT、VEGFR2和ROR1。
本公开文本提供了治疗和/或预防有需要的受试者的癌症的方法，其包括向所述受试者施用本公开文本的免疫细胞。在一些实施方案中，所述方法包括治疗和/或预防有需要的受试者的癌症，其包括向所述受试者施用本公开文本的免疫细胞。
本文提供的说明性CAR包括但不限于基于抗体的CAR，诸如单链可变片段(scFv)CAR、Fab CAR或其他；以及基于T细胞受体(TCR)的CAR。
在其他方面，本公开文本提供了编码此类受体的多核苷酸；用于递送此类多核苷酸的载体；以及具有此类多核苷酸和受体的免疫细胞。
在进一步的方面，本公开文本提供了将编码此类受体的多核苷酸或载体引入细胞的方法。有利地，当细胞与抗原或在其表面上表达所述抗原的细胞接触时，免疫细胞激活降低。
本发明的又其他方面和实施方案在以下具体实施方式中提供。
附图说明
图1示出了在具有配体结合结构域(LBD)、铰链、跨膜(TM)和胞内信号传导结构域(ICD)的实施方案中的结构域布置的说明性图解。
图2A-2B示出了在具有配体结合结构域(LBD)、铰链、跨膜(TM)和胞内信号传导结构域(ICD)的实施方案中的结构域布置的说明性图解。当配体结合结构域包含两个肽时，例如来自T细胞受体的异二聚体LDB，每个肽可以与铰链、TM和胞内结构域融合(图2A)。可替代地，配体结合结构域的仅一个肽可以融合至铰链、TM和胞内结构域(图2B)。
图3示出了具有激活剂基于scFv的嵌合抗原受体(CAR)[101和102]或激活剂T细胞受体[103和104]和基于抑制性scFv的CAR[101和103]或抑制性基于TCR的CAR[102和104]的免疫细胞的四个说明性实施方案。
图4示出了在50μM NY-ESO-1肽的存在下，对于所指示的构建体，在不同浓度的MAGE-A3激活型肽1(MP1，微升，μM)下，基于NFAT的报告物测定的发光(相对发光单位，RLU)的图。
图5示出了在各种浓度(μM)的NY-ESO-1肽的存在下，对于所指示的构建体，在不同浓度的MAGE-A3肽1(MP1，nM)下，基于NFAT的报告物测定的发光(RLU)的图。
图6示出了在各种浓度(μM)的NY-ESO-1肽的存在下，对于所指示的构建体，在不同浓度的MAGE-A3肽1(MP1，nM)下，基于NFAT的报告物测定的发光(RLU)的图。
图7示出了在50μM NY-ESO-1肽的存在下，对于所指示的构建体，在不同浓度的MAGE-A3肽1(MP1，nM)下，基于NFAT的报告物测定的发光(RLU)的图。
图8示出了在50μM NY-ESO-1肽的存在下，对于所指示的构建体，在不同浓度的MAGE-A3肽1(MP1，nM)下，基于NFAT的报告物测定的发光(RLU)的图。
图9示出了在5μM NY-ESO-1肽的存在下，对于所指示的构建体，在不同浓度的MAGE-A3肽1(MP1，nM)下，基于NFAT的报告物测定的发光(RLU)的图。
图10示出了在50μM NY-ESO-1肽的存在下，对于所指示的构建体，在不同浓度的MAGE-A3肽1(MP1，nM)下，基于NFAT的报告物测定的发光(RLU)的图。
图11示出了在50μM NY-ESO-1肽的存在下，对于所指示的构建体，在不同浓度的MAGE-A3肽1(MP1，nM)下，基于NFAT的报告物测定的发光(RLU)的图。
图12A是示出了LIR-1铰链对HLA-A*02scFv抑制性受体阻断KRAS TCR对Jurkat细胞的激活的能力的影响的绘制图。H：铰链，T：跨膜结构域，ICD：胞内结构域，s：短。图12B中更详细地描述了LIR-1构建体。具有较短LIR-1铰链的人源化PA2.1和人源化BB7.2与原始的较长铰链类似地阻断。
图12B是示出了表达底部表中所示的KRAS TCR激活剂和HLA-A*02scFvLIR-1抑制性受体的Jurkat细胞的EC50位移(+/-HLA-A*02靶细胞)的绘制图和表。
图13A是示出了LIR-1铰链对HLA-A*02抑制性受体阻断KRAS TCR对Jurkat细胞的激活的能力的影响的绘制图。H：铰链，TM：跨膜结构域，ICD：胞内结构域，s：短；tr：截短的。图13B中更详细地描述了LIR-1构建体。在T2-Jurkat测定中，具有稍长铰链的小鼠PA2.1与原始LIR-1铰链类似地发挥功能。
图13B是示出了表达底部表中所示的KRAS TCR激活剂和HLA-A*02scFvLIR-1抑制性受体的Jurkat细胞的EC50位移(+/-HLA-A*02靶细胞)的绘制图和一对表，其中铰链长度示于左侧表中。
图14A是示出了评价阻断剂构建体的T2-Jurkat实验的示意图的图解。
图14B是绘制图解图、表和，其示出了各种NY-ESO-1scFv LBD阻断剂模块(PD-1、CTLA-4、LIR-1)对MAGE-A3 CAR激活剂(MP1-LBD 1-CAR)的EC50的影响，通过加载有固定(50μM)NY-ESO-1阻断剂肽浓度的细胞的MAGE肽滴定测量。在图14B-14F的每一个中，在与加载激活剂和阻断剂肽的T2细胞共培养6小时后，测定用单独的激活剂CAR或与每种阻断剂受体组合转染的Jurkat细胞的NFAT-萤光素酶信号。基线(仅Jurkat)随不同的单独激活剂构建体而变化，并且对于CAR可能尤其高；在大多数情况下，阻断剂受体在缺乏其配体时的表达抑制基线。激活剂肽浓度范围为0μM，然后10-6μM至102μM，并且发光测量值范围为0RLU至80000RLU。
图14C是绘制图解图、表和，其示出了当加载有固定(50μM)肽浓度的对应阻断剂肽(如图14B中所示)时，具有各种scFv LBD(ESO、MP1 LBD 1、MP1 LBD 2、HPV E6 LBD 1、HPVE6 LBD 2、HPV E7)的LIR-1阻断剂受体对MAGE-A3 CAR激活剂(MP1-CAR)的EC50的影响。RLU＝相对光单位；误差棒指示±SD(n＝2)。激活剂肽浓度范围为0μM，然后10-3μM至102μM，并且发光测量值范围为0RLU至100000RLU。
图14D是绘制图解图、表和，其示出了当加载有50uM NY-ESO-1阻断剂肽时，具有NY-ESO-1scFv LBD的LIR-1阻断剂受体对不同MAGE-A3 CAR激活剂(MP1-LBD1-CAR或MP2-CAR)的EC50的影响。激活剂肽浓度范围为0μM，然后10-4μM至102μM，并且发光测量值范围为0RLU至80000RLU。
图14E是绘制图解图、表和，其示出了当加载有50uM NY-ESO-1阻断剂肽时，具有NY-ESO-1scFv LBD的LIR-1阻断剂受体对不同TCR激活剂(MP1-TCR、MP2-TCR、HPV E6-TCR)的EC50的影响。激活剂肽浓度范围为0μM，然后10-4μM至102μM，并且归一化发光测量值范围为0RLU至150RLU。
图14F是绘制图解图、表和，其示出了当加载有50uM NY-ESO-1阻断剂肽时，具有NY-ESO-1TCR LBD的LIR-1阻断剂受体对MAGE-A3 CAR和TCR激活剂(MP1-LBD1-CAR、MP1-TCR)的EC50的影响。RLU＝相对光单位；误差棒指示±SD(n＝2)。激活剂肽浓度范围为0μM，然后10-7μM至101μM，并且归一化发光测量值范围为0RLU至150RLU。
图15是示出了阻断剂肽加载(NY-ESO-1、MAGE-A3、HPV E6和HPV E7各自50μM)对激活型MAGE-A3 CAR的影响的绘制图。MP2-CAR[0μM]，EC50＝44nM；MP2-CAR[50μM HPVp2]，EC50＝495nM。RLU＝相对光单位；误差棒指示±SD(n＝2)。
图16A是一系列绘制图，其示出了在与加载激活剂和阻断剂肽的T2细胞共培养6h后用单独的激活剂MAGE-A3 CAR或与各种量的NY-ESO-1scFv LBD阻断剂组合(在左侧示出激活剂受体组分与阻断剂受体组分的DNA比率为A:B，即激活剂受体:阻断剂受体)转染的Jurkat细胞的NFAT-萤光素酶信号。向T2细胞加载滴定量的激活剂MAGE-A3肽和固定量的阻断剂NY-ESO-1肽浓度。激活剂和/或阻断剂肽浓度范围为0μM，然后10-6μM至102μM，并且发光测量值范围为0RLU至200000RLU。
图16B是一系列绘制图，其示出用单独的激活剂MAGE-A3 CAR或与各种量的NY-ESO-1scFv LBD阻断剂组合转染的Jurkat细胞的NFAT-萤光素酶信号。向T2细胞加载滴定量的阻断剂NY-ESO-1肽和高于Emax浓度(约0.1mM)的固定量的激活剂MAGE-A3肽浓度。激活剂和/或阻断剂肽浓度范围为10-5μM至102μM，并且发光测量值范围为0RLU至200000RLU。
图16C是一系列绘制图和两个表，其示出了用单独的激活剂MAGE-A3 CAR或与各种量的NY-ESO-1scFv LBD阻断剂组合转染的Jurkat细胞的NFAT-萤光素酶信号。将来自图16B的x值阻断剂NY-ESO-1肽浓度相对于用于每条曲线的恒定激活剂MAGE肽浓度进行归一化，并且绘制在x轴上。对于每条曲线指示出50％阻断所需的阻断剂肽与激活剂肽的比率(IC50)。对于所有DNA比率，所需的B:A肽比率小于1，表明对于这对激活剂CAR和阻断剂，靶细胞上需要类似的(或更少的)阻断剂pMHC抗原来阻断激活剂pMHC抗原。激活剂和/或阻断剂肽浓度范围为10-10μM至104μM，并且发光测量值范围为0RLU至200000RLU。
图16D是表和绘制图，其示出了用pMHC阻断剂以类似于激活pMHC CAR所需的那些的阻断剂pMHC抗原密度阻断CD19-CAR激活剂是可能的。在与表达内源性水平的CD19抗原的加载阻断剂肽的T2细胞共培养6h后，用单独的激活剂CD19 CAR或与各种量的NY-ESO-1阻断剂组合(示出了DNA比率)转染的Jurkat细胞的NFAT-萤光素酶信号。IC50由抑制曲线估计范围为0.1-1.0mM，对应于约1,500-3,500pMHC/细胞。RLU＝相对光单位；误差棒指示±SD(n＝2)。
图17A是绘制图，其示出了当加载有各种浓度的NY-ESO-1阻断剂肽时，NY-ESO-1-LIR-1阻断剂对激活MAGE-A3 CAR(MP1-CAR)的EC50的影响。EC50位移随着阻断剂肽(NY-ESO-1)浓度的增加而变大。常规地看到在阴性对照HPV肽(结合HLA-A*02而不结合NY-ESO-1阻断剂scFv)的存在下的位移，并且认为是由对照肽对T2HLA-A*02分子上的结合位点的竞争引起的，减少了激活剂靶标的数目。激活剂浓度范围为0μM，然后10-4μM至102μM，并且发光测量值范围为0RLU至140000RLU。
图17B是绘制图，其示出了当加载有10μM NY-ESO-1阻断剂肽时，不含ICD或含有突变ICD与NY-ESO-1scFv LBD的经修饰的LIR-1阻断剂受体对MAGE-A3 CAR激活剂(MP2-CAR)的EC50的影响。激活剂浓度范围为0μM，然后10-4μM至102μM，并且发光测量值范围为0RLU至140000RLU。
图17C-17E是一系列绘制图，其示出了当刺激或未刺激阻断剂时，各种NY-ESO-1scFv LBD阻断剂受体(CTLA-4(图17C)、PD-1(图17D)和LIR-1(图17E))对MAGE-A3 CAR激活剂(MP1-LBD 1-CAR)的EC50的影响。在与加载肽的T2细胞共培养6h后，用单独的激活剂CAR或与每种阻断剂组合转染的Jurkat细胞的NFAT-萤光素酶信号。向T2细胞加载滴定量的激活型MAGE肽，并且在加载和不加载额外恒定量(50μM)的NY-ESO-1阻断剂肽的情况下进行测试。RLU＝相对光单位；误差棒指示±SD(n＝2)。激活剂浓度范围为0μM，然后10-6μM至102μM，并且发光测量值范围为0RLU至100000RLU。
图18A是图解和一对绘制图，其示出了用HPV E7-CAR或HPV E7-CAR&A2-LIR-1转染的Jurkat细胞与展示各种比率的激活剂(HPV E7)和阻断剂(NY-ESO-1)抗原的珠共培养表明顺式阻断而非反式阻断。
图18B是绘制图，其示出了HLA-A*02-LIR-1阻断剂受体在各种激活剂与阻断剂比率下阻断CD19-CAR激活剂。比率范围为0至10，并且发光(RLU)范围为0至70000。
图18C是绘制图，其示出了滴定的HLA-A*02(A2)LIR-1阻断剂受体的表面表达。
图18D是绘制图，其示出了针对HLA-A*02的scFv当与激活剂CAR融合时也可以充当激活剂。表达内源性HLA-A*02的T2细胞充当靶标。RLU＝相对光单位；误差棒指示±SD(n＝2)。
图19A是以下绘制图，其示出了当加载有NY-ESO-1阻断剂肽时，具有NY-ESO-1scFvLBD的LIR-1阻断剂受体对不同TCR激活剂(MP1-TCR、MP2-TCR、HPVE6-TCR)的EC50的影响。对于图14E，将每组相对于显示仅激活剂的反应的曲线的Emax归一化。激活剂浓度范围为0μM，然后10-4μM至102μM，并且发光测量值范围为0RLU至140000RLU。
图19B是绘制图，其示出了具有NY-ESO-1TCR LBD的LIR-1阻断剂受体对MAGE-A3CAR和TCR激活剂(MP1-LBD 1-CAR、MP1-TCR)的EC50的影响。将每组相对于显示仅激活剂的反应的曲线的Emax归一化。RLU＝相对光单位；误差棒指示±SD(n＝2)。激活剂浓度范围为0μM，然后10-7μM至101μM，并且发光测量值范围为0RLU至140000RLU。
图20A是绘制图，其示出了在原代T细胞杀伤测定中用HPV E7-TCR激活剂和ESO-LIR-1阻断剂转导的原代T细胞(供体1)的EC50位移约25倍(HPV E7 TCR，EC50＝0.044nM；HPV E7 TCR+ESO-LIR-1，EC50＝1.1nM)。使用加载肽的MCF7靶细胞在3:1E:T下进行测定。萤光素酶测量值代表在48小时的活靶细胞。
图20B是绘制图，其示出了使用加载NY-ESO-1肽的T2靶细胞，HLA-A*02-LIR-1在Jurkat细胞中在各种激活剂:阻断剂DNA比率下阻断NY-ESO-1CAR激活剂。RLU＝相对光单位；误差棒指示±SD(n＝2)。
图21A是一系列图像和绘制图，其示出了在体外细胞毒性测定中用CD19 CAR激活剂和HLA-A*02阻断剂转导的原代T细胞(供体1)区分“肿瘤”细胞与“正常”细胞，并且在混合靶细胞测定中在3:1E:T下表明了对“肿瘤”细胞的选择性杀伤。示出的图像在72小时捕获。示出了未转导的T细胞、CD19-CAR T细胞和CD19-CAR T+A2-LIR-1。测量在0小时与150小时之间进行，并且归一化荧光蛋白强度(GFP或RFP)范围为0至10。
图21B是一系列绘制图，其示出了在Incucyte成像测定中原代T细胞(供体1)在各种肿瘤细胞与“正常”细胞比率下在3:1E:T比率下类似地选择性杀伤肿瘤细胞。RLU值相对于在缺乏原代T细胞的情况下生长的靶细胞混合物进行归一化。示出了未转导的T细胞、CD19-CAR T细胞和CD19-CAR T+A2-LIR-1。测量在0小时与150小时之间进行，并且归一化荧光蛋白强度(GFP或RFP)范围为：在顶行从左到右，0至3×107、0至2×107、0至1.6×107、0至7×106、0至2×106；底行，从左到右：0至7×105、0至2×105、0至4×105、0至6×105、0至7×105。
图21C是一系列绘制图，其示出了在定量靶细胞裂解和IFNγ分泌中原代T细胞(供体1)在各种肿瘤细胞与“正常”细胞比率下在3:1E:T比率下类似地选择性杀伤肿瘤细胞。示出了未转导的T细胞、CD19-CAR T细胞和CD19-CAR T+A2-LIR-1。
图22A是一对绘制图，其示出了与表达MSLN或MSLN&HLA-A*02的K562细胞共培养的用MSLN LBD1-CAR或MSLN LBD1-CAR&A2-LIR-1转染的Jurkat细胞显示在HLA-A*02的存在下仅A2-LIR-1阻断剂阻断由高密度抗原引起的激活。
图22B是一对绘制图，其示出了在HLA-A*02的存在下，MLSN LBD1-CAR T细胞对内源性MSLN+HeLa细胞的杀伤被A2-LIR-1阻断剂阻断。
图22C是一对绘制图，其示出了MLSN LBD2-CAR T细胞杀伤内源性MSLN+HeLa细胞。A2-LIR-1阻断剂对T细胞杀伤的作用部分地由激活剂LBD控制。
图23是绘制图，其示出了LIR-1阻断剂受体在不存在阻断剂抗原的情况下对激活剂的杀伤功效几乎没有影响。在不存在NY-ESO-1阻断剂抗原的情况下，用HPV E7-TCR激活剂和ESO-LIR-1阻断剂转导的原代T细胞(供体1)展示出与仅用HPV E7-TCR激活剂转导的原代T细胞类似的杀伤功效。萤光素酶测量值代表活靶细胞。RLU＝相对光单位；误差棒指示±SD(n＝2)。
图24A是一对绘制图，其示出了A2-LIR-1阻断A2+Raji细胞中的Jurkat激活而不阻断WT Raji细胞。直方图示出了Raji WT“肿瘤”细胞和Raji A2+“正常”细胞具有相同的CD19表面表达，而HLA-A*02仅在Raji A2“正常”细胞中表达。
图24B是绘制，其示出了A2-LIR-1阻断A2+Raji细胞中的Jurkat激活而不阻断WTRaji细胞。将用CD19或CD19+A2-LIR-1转染的Jurkat细胞与WT(A2-)Raji细胞或A2+Raji细胞以各种细胞比率共培养。RLU＝相对光单位；误差棒指示±SD(n＝2)。
图25A-25B各自是一系列图像，其示出了被LIR-1抑制性受体的阻断的可逆性。用CD19 CAR激活剂和HLA-A*02阻断剂转导的原代T细胞(供体2)在体外细胞毒性测定中在3:1E:T下在3轮抗原暴露(AB-A-AB和A-AB-A)后显示可逆的阻断(图25A)和激活(图25B)。用三种HLA-A*02阴性供体再现了原代T细胞的细胞毒性测定。示出的图像在72小时捕获。
图25C-25D各自是一对绘制图，其示出了响应于重复暴露于多轮正常细胞和靶细胞，3:1E:T(来自供体2的T细胞)的靶细胞裂解(图25C)和IFNγ(图25D)的定量。所示的条件是未转导的T细胞、CD19-CAR T细胞和CD19-CAR T+A2-LIR-1。误差棒指示±SEM(n＝2)。*p<0.05，**p<0.01，***p<0.001，****p<0.0001，使用双因素方差分析，然后Tukey多重比较检验来确定。在此实验中，IFNγ反应随时间而减弱，而细胞毒性保持稳健。
图26A-26B各自是一对绘制图，其示出了在与单独的供体(供体3)共培养时细胞毒性T细胞的杀伤和IFNγ的分泌。细胞毒性CD19 CAR激活剂和HLA-A*02阻断剂转导的T细胞在多轮抗原暴露后在细胞毒性测定和IFNγ中在9:1E:T下显示出可逆的阻断。我们注意到，此供体的T细胞存活率和活性在培养中随时间推移而减弱。所示的条件是未转导的T细胞、CD19-CAR T细胞和CD19-CAR T+A2-LIR-1。细胞毒性(图26A)和IFNγ(图26B)结果对应于图25C-25D。误差棒指示±SEM(n＝2)。*p<0.05、**p<0.01、***p<0.001、****p<0.0001，使用双因素方差分析，然后Tukey多重比较检验来确定。
图27A是绘制图，其示出了用CD19 CAR激活剂和HLA-A*02阻断剂转导的原代T细胞在10天内在CD3/28刺激下表明约20倍扩增。
图27B是图解，其示出了实验，所述实验显示在异种移植物模型中，表达LIR-1阻断剂受体的CAR-T细胞选择性地杀伤肿瘤。对HLA-A*02NSG小鼠皮下施用“肿瘤细胞”(A2阴性Raji细胞)或“正常细胞”(A2阳性Raji细胞)，并且当Raji异种移植物平均为约70mm3时，将原代T细胞(人，HLA-A*02阴性供体4)注射到尾静脉。
图27C-27E各自是一对绘制图，其示出了卡尺测量的读数(图27C)、通过流式细胞术得到的外周血中人T细胞计数(图27D)、和存活率(图27E)。误差棒指示SEM(n＝7)。*p<0.05，**p<0.01，***p<0.001，****p<0.0001，使用双因素方差分析，然后Tukey多重比较检验来确定。
图28A是一系列绘制图，其示出了为小鼠尾静脉注射而制备的富集和扩增后的原代T细胞的流式细胞术分析。从T细胞注射前10天(-10)开始至T细胞注射后40天(40)，测量自T细胞注射起的天数的肿瘤体积。肿瘤体积范围为0至2500mm3。
图28B是一系列绘制图，其示出了对每组中的单独小鼠绘制的通过卡尺得到的肿瘤测量值。
图28C是一系列绘制图，其示出了小鼠血液中的huCD3+T细胞与肿瘤生长的相关性。huCD3+T细胞与T细胞注射后10天和17天的肿瘤体积比较的图形。
图28D是一对绘制图，其示出了通过流式细胞术得到的外周血中huCD4+T细胞和huCD8+T细胞计数。空心环，用“正常”细胞移植的小鼠；实心环，用肿瘤细胞移植的小鼠。将具有少于100个细胞的样品从分析中排除。误差棒指示±SEM(在所有组中n＝7，不同的是在用CD19-CAR+A2-LIR-1T细胞处理的CD19+/A2-Raji组中，n＝6)。
图29A是一系列图像，其示出了肿瘤中T细胞浸润的组织学分析。示出了在研究结束时收集、切片并针对huCD3染色的肿瘤样品的代表性图像。
图29B是示出了使用ImageJ定量T细胞浸润的绘制图。与未转导的细胞相比，对于CD19+/A2-肿瘤中具有CD19-CAR或CD19-CAR+A2-LIR-1的T细胞，T细胞浸润显著更高。然而，在CD19+/A2+肿瘤中，CD19-CAR+A2-LIR-1T细胞与未转导的细胞相比没有显著差异。在CD19+/A2-肿瘤与CD19+/A2+肿瘤之间CD19-CAR+A2-LIR-1T细胞的浸润也有显著下降。定性地，与仅CD19-CAR的T细胞相比，CD19-CAR+A2-LIR-1T细胞在CD19+/A2+肿瘤中较不普遍；然而，这种差异在统计学上不显著。类似地定量盐水样品以显示背景染色水平。使用普通的单因素方差分析数据组，而使用未配对t检验分析“肿瘤”和“正常”之间的个体对。ns＝不显著，*p<0.05，**p<0.01。
具体实施方式
本公开文本描述了具有来自白细胞免疫球蛋白样受体亚家族B成员1(LILRB1，有时称为LIR1或LIR-1)的一个或多个结构域的受体。本文考虑了许多受体、工程化细胞及其用途。诸位发明人已经发现，包含抗原结合结构域和一个或多个LILRB1结构域(包括LILRB1胞内结构域)的嵌合受体即使在激活性嵌合抗原受体(CAR)或T细胞受体(TCR)的存在下也可以抑制免疫细胞信号传导。
如本文所用的术语“嵌合抗原受体”或“CAR”可以指例如人工T细胞受体、嵌合T细胞受体或嵌合免疫受体，并且包括将人工特异性移植到特定免疫效应细胞诸如辅助T细胞(CD4+)、细胞毒性T细胞(CD8+)或NK细胞上的工程化受体。CAR可以用于将单克隆抗体的特异性赋予T细胞，从而允许产生大量特异性T细胞，例如用于过继细胞疗法。在具体的实施方案中，CAR指导细胞对肿瘤相关抗原的特异性。在一些实施方案中，CAR包含胞内信号传导结构域、跨膜结构域和包含抗原结合区的胞外结构域。在一些实施方案中，CAR包含融合至跨膜结构域和一个或多个胞内信号传导结构域的源自单克隆抗体的单链可变片段(scFv)或scFab的融合体。所述融合体还可以包含铰链。可以使用重-轻(H-L)scFv和轻-重(L-H)scFv中的任一种。CAR设计的特异性可以源自受体的配体(例如，肽)。根据胞内结构域的类型，CAR可以是激活性受体或抑制性受体。在一些实施方案中，例如当CAR是激活性受体时，CAR包含用于额外的共刺激信号传导的结构域，诸如CD3、FcR、CD27、CD28、CD137、DAP10和/或0X40。在一些实施方案中，可以与CAR共表达分子，包括共刺激分子、用于成像(例如，用于正电子发射断层扫描)的报告基因、在添加前药后有条件地消除T细胞的基因产物、归巢受体、细胞因子和细胞因子受体。如本文所用，归因于嵌合抗原受体的特征可以理解为是指受体本身或包含所述受体的宿主细胞。
如本文所用，“TCR”(有时也称为“TCR复合物”或“TCR/CD3复合物”)是指包含TCRα链、TCRβ链以及不变CD3链(ζ、γ、δ和ε)中的一条或多条(有时称为亚基)的蛋白质复合物。TCRα链和TCRβ链可以是二硫键连接的，以充当异二聚体以与肽-MHC复合物结合。一旦TCRα/β异二聚体接合肽-MHC，则诱导TCR复合物中相关的不变CD3亚基的构象变化，这导致它们的磷酸化和与下游蛋白的缔合，从而转导初级刺激信号。在示例性TCR复合物中，TCRα多肽和TCRβ多肽形成异二聚体，CD3ε和CD3δ形成异二聚体，CD3ε和CD3γ形成异二聚体，并且两个CD3ζ形成同二聚体。
术语“刺激”是指通过刺激结构域或刺激分子(例如，TCR/CD3复合物)与其同源配体结合从而介导信号转导事件(诸如但不限于经由TCR/CD3复合物的信号转导)而诱导的初级反应。刺激可以介导某些分子的改变的表达和/或细胞骨架结构的重组等。
术语“刺激分子”或“刺激结构域”是指当由T细胞天然表达时提供一个或多个初级胞质信号传导序列的分子或其部分，所述初级胞质信号传导序列针对T细胞信号传导途径的至少某个方面以刺激方式调节TCR复合物的激活。野生型TCR复合物的TCRα链和/或TCRβ链不含刺激结构域，并且需要与CD3亚基诸如CD3ζ缔合以起始信号传导。在一个方面，所述初级刺激信号通过例如TCR/CD3复合物与结合至肽的主要组织相容性复合物(MHC)的结合而起始，并且其导致介导T细胞反应，包括但不限于增殖、激活、分化等。如本文所述的一个或多个刺激结构域可以融合至TCR复合物的任何一个或多个亚基的胞内部分，所述亚基包括TCRα、TCRβ、CD3δ、CD3γ和CD3ε。
如本文所用，“能够提供刺激信号的结构域”是指可以直接或间接地提供刺激信号的任何结构域，所述刺激信号增强或增加由TCR复合物介导的信号传导的有效性，以增强T细胞信号传导的至少某一方面。能够提供刺激信号的结构域可以直接提供这种信号，例如能够提供刺激信号的结构域是初级刺激结构域或共刺激结构域。可替代地或此外，能够提供刺激信号的结构域可以间接起作用。例如，所述结构域可以是将刺激蛋白质募集至TCR的支架，或提供通过下游靶标起作用以提供刺激信号的酶活性，诸如激酶活性。
如本文所用，“能够提供抑制性信号的结构域”是指可以直接或间接地提供抑制性信号的任何结构域，所述抑制性信号抑制或降低由TCR复合物介导的信号传导的有效性。能够提供抑制性信号的结构域可以完全或部分地减少或阻断T细胞信号传导或功能的至少某一方面。能够提供抑制性信号的结构域可以直接提供这种信号，例如能够提供抑制性信号的结构域提供初级抑制性信号。可替代地或此外，能够提供刺激信号的结构域可以间接起作用。例如，所述结构域可以将额外的抑制性蛋白质募集至TCR，或者可以提供通过下游靶标起作用以提供抑制性信号的酶活性。
范围：贯穿本公开文本，本发明的各方面可以以范围形式呈现。应当理解，范围格式的描述仅仅是为了方便和简洁，并且不应被解释为对本发明的范围的僵硬限制。因此，应当认为范围的描述具体地公开了所有可能的子范围以及所述范围内的单独数值。例如，对范围(诸如从1至6)的描述应该被认为已经具体地公开了子范围(诸如从1至3、从1至4、从1至5、从2至4、从2至6、从3至6等)以及该范围内的单独数字，例如1、2、2.7、3、4、5、5.3和6。作为另一个例子，诸如95％-99％同一性的范围包括具有95％、96％、97％、98％或99％同一性的某物，并且包括子范围，诸如96％-99％、96％-98％、96％-97％、97％-99％、97％-98％和98％-99％同一性。无论范围的宽度如何，这都适用。
通常，“序列同一性”或“序列同源性”是指两个多核苷酸或多肽序列各自的核苷酸与核苷酸或氨基酸与氨基酸的精确对应性。典型地，用于确定序列同一性的技术包括确定多核苷酸的核苷酸序列和/或确定由其编码的氨基酸序列，并将这些序列与第二核苷酸或氨基酸序列进行比较。两个或更多个序列(多核苷酸或氨基酸)可以通过确定它们的“同一性百分比”来比较。两个序列(核酸或氨基酸序列)的同一性百分比是两个比对序列之间的精确匹配数除以较短序列的长度并且乘以100。同一性百分比也可以例如通过使用可从国立卫生研究获得的高级BLAST计算机程序(包括2.2.9版)比较序列信息来确定。BLAST程序是基于Karlin和Altschul，Proc.Natl.Acad.Sci.USA 87:2264-2268(1990)的比对方法并且如Altschul等人,J.Mol.Biol.215:403-410(1990)；Karlin和Altschul,Proc.Natl.Acad.Sci.USA 90:5873-5877(1993)；以及Altschul等人,Nucleic AcidsRes.25:3389-3402(1997)中所讨论。简短地讲，BLAST程序将同一性定义为相同比对符号(通常为核苷酸或氨基酸)的数目除以两个序列中较短序列中的符号的总数。所述程序可以用于确定在被比较的蛋白质的全长上的同一性百分比。提供默认参数以优化例如blastp程序中用短查询序列的搜索。希望的序列同一性程度的范围是大约80％至100％以及其间的整数值。典型地，披露的序列与要求保护的序列之间的同一性百分比为至少80％、至少85％、至少90％、至少95％或至少98％。
如本文所用，“子序列”是指形成本文所述序列的一部分的一定长度的连续氨基酸或核苷酸。当与全长序列比对时，子序列可以与全长序列的一部分相同，或与其比对的全长序列的部分小于100％相同(例如，与全长序列的50％90％相同，等等)。
术语“外源的”在本文中用以指源自生物体外部的任何分子，包括核酸、蛋白质或肽、小分子化合物等。相反，术语“内源的”是指源自生物内部(即，由生物体天然产生的)的任何分子。
当多核苷酸被放置成与另一个多核苷酸具有功能关系时，所述多核苷酸可操作地连接至所述其他多核苷酸。例如，如果启动子或增强子影响序列的转录，则它可操作地连接至编码序列。当编码肽和另一个肽的多核苷酸是可操作地连接的时，所述肽“可操作地连接”至所述另一个肽，优选它们在同一开放阅读框中。
“启动子”是打开或关闭基因所需的DNA序列。启动子位于转录起始位点的紧邻上游和/或与转录起始位点重叠，并且长度通常是在约一百个至数百个之间的碱基对。
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白细胞免疫球蛋白样受体亚家族B成员1(LILRB1)
本公开文本描述了具有来自白细胞免疫球蛋白样受体亚家族B成员1(LILRB1或LIR1)的一个或多个结构域的受体。本文考虑了许多受体、工程化细胞及其用途。
白细胞免疫球蛋白样受体亚家族B成员1(LILRB1)(也称为白细胞免疫球蛋白样受体B1，以及ILT2、LIR1、MIR7、PIRB、CD85J、ILT-2LIR-1、MIR-7和PIR-B)是白细胞免疫球蛋白样受体(LIR)家族的成员。LILRB1蛋白属于亚家族B类LIR受体。这些受体含有二至四个胞外免疫球蛋白结构域、一个跨膜结构域和二至四个胞质免疫受体酪氨酸抑制性基序(ITIM)。LILRB1受体在免疫细胞上表达，其中它结合至抗原呈递细胞上的MHC I类分子并且转导抑制免疫应答的刺激的负信号。认为LILRB1调节炎症反应以及细胞毒性并且在限制性自身反应性中起作用。存在编码LILRB1的不同同种型的多种转录物变体，所有这些变体都被考虑在本公开文本的范围内。
在具有LILRB1的一个或多个结构域的受体的一些实施方案中，LILRB1的一个或多个结构域包含与SEQ ID NO:1的序列或子序列至少80％、至少90％、至少95％、至少96％、至少97％、至少98％、至少99％相同或相同的氨基酸序列。在一些实施方案中，LILRB1的一个或多个结构域包含与SEQ ID NO:1的序列或子序列相同的氨基酸序列。在一些实施方案中，LILRB1的一个或多个结构域由与SEQ ID NO:1的序列或子序列至少80％、至少90％、至少95％、至少96％、至少97％、至少98％、至少99％相同或相同的氨基酸序列组成。在一些实施方案中，LILRB1的一个或多个结构域由与SEQ ID NO:1的序列或子序列相同的氨基酸序列组成。
在具有LILRB1的一个或多个结构域的受体的一些实施方案中，LILRB1的一个或多个结构域由与SEQ ID NO:34的序列或子序列至少80％、至少90％、至少95％、至少96％、至少97％、至少98％、至少99％相同或相同的多核苷酸序列编码。
在具有LILRB1的一个或多个结构域的受体的一些实施方案中，LILRB1的一个或多个结构域由与SEQ ID NO:34的序列或子序列相同的多核苷酸序列编码。
受体
在各种实施方案中，提供了一种包含多肽的嵌合抗原受体，其中所述多肽包含以下中的一个或多个：LILRB1铰链结构域或其功能片段或变体；LILRB1跨膜结构域或其功能变体；和LILRB1胞内结构域或包含至少一个或至少两个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
胞内结构域
本公开文本提供了嵌合抗原受体，所述嵌合抗原受体包含多肽。在一些实施方案中，所述多肽包含胞内结构域。在一些实施方案中，所述胞内结构域是LILRB1胞内结构域或其功能变体。
如本文所用，“胞内结构域”是指蛋白质诸如受体的胞质或胞内结构域，其与细胞内部相互作用并且执行胞质功能。如本文所用，“胞质功能”是指在细胞的胞浆中执行的蛋白质或蛋白质复合物的功能。例如，胞内信号转导级联是胞质功能。
如本文所用，“免疫受体酪氨酸抑制性基序”或“ITIM”是指具有S/I/V/LxYxxI/V/L(SEQ ID NO:124)等共有序列的氨基酸保守序列，其存在于免疫系统的许多抑制性受体的胞质尾中。在具有ITIM的抑制性受体与它们的配体相互作用之后，ITIM基序被磷酸化，允许抑制性受体募集其他酶，诸如磷酸酪氨酸磷酸酶SHP-1和SHP-2，或称为SHIP的肌醇磷酸酶。
在一些实施方案中，所述多肽包含胞内结构域，所述胞内结构域包含至少一个免疫受体酪氨酸抑制性基序(ITIM)、至少两个ITIM、至少3个ITIM、至少4个ITIM、至少5个ITIM或至少6个ITIM。在一些实施方案中，所述胞内结构域具有1、2、3、4、5或6个ITIM。
在一些实施方案中，所述多肽包含含有至少一个ITIM的胞内结构域，所述ITIM选自由以下组成的ITIM组：NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ IDNO:10)和SIYATL(SEQ ID NO:11)。
在进一步特定的实施方案中，所述多肽包含含有至少两个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
在一些实施方案中，所述胞内结构域包含两个ITIM NLYAAV(SEQ ID NO:8)和VTYAEV(SEQ ID NO:9)。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:12至少95％相同的序列。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:12相同的序列或基本上由其组成。
在一些实施方案中，所述胞内结构域包含两个ITIM VTYAEV(SEQ ID NO:9)和VTYAQL(SEQ ID NO:10)。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:13至少95％相同的序列。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:13相同的序列或基本上由其组成。
在一些实施方案中，所述胞内结构域包含两个ITIM VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:14至少95％相同的序列。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:14相同的序列或基本上由其组成。
在一些实施方案中，所述胞内结构域包含ITIM NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)和VTYAQL(SEQ ID NO:10)。在一些实施方案中，所述胞内结构域包含与SEQID NO:15至少95％相同的序列。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:15相同的序列或基本上由其组成。
在一些实施方案中，所述胞内结构域包含ITIM VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。在一些实施方案中，所述胞内结构域包含与SEQID NO:16至少95％相同的序列。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:16相同的序列或基本上由其组成。
在一些实施方案中，所述胞内结构域包含ITIM NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。在实施方案中，所述胞内结构域包含与SEQ ID NO:17至少95％相同的序列。在一些实施方案中，所述胞内结构域包含与SEQ ID NO:17相同的序列或基本上由其组成。
在一些实施方案中，所述胞内结构域包含与LILRB1胞内结构域(SEQ ID NO:7)至少95％相同的序列。在一些实施方案中，所述胞内结构域包含与LILRB1胞内结构域(SEQ IDNO:7)相同的序列或基本上由其组成。
本公开文本的LILRB1胞内结构域或其功能变体可以具有至少1个、至少2个、至少4个、至少4个、至少5个、至少6个、至少7个或至少8个ITIM。在一些实施方案中，LILRB1胞内结构域或其功能变体具有2、3、4、5或6个ITIM。
在特定的实施方案中，所述多肽包含含有二个、三个、四个、五个或六个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQID NO:11)。
在特定的实施方案中，所述多肽包含含有至少三个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ IDNO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
在特定的实施方案中，所述多肽包含含有三个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
在特定的实施方案中，所述多肽包含含有四个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
在特定的实施方案中，所述多肽包含含有五个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
在特定的实施方案中，所述多肽包含含有六个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
在特定的实施方案中，所述多肽包含含有至少七个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ IDNO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
在一些实施方案中，所述胞内结构域包含TCRα胞内结构域。在一些实施方案中，所述胞内结构域包含TCRα胞内结构域和LILRB1胞内结构域，如本文所述。在一些实施方案中，TCRα胞内结构域包含Ser-Ser。在一些实施方案中，TCRα胞内结构域由TCCAGC序列编码。
在一些实施方案中，所述胞内结构域包含TCRβ胞内结构域。在一些实施方案中，所述胞内结构域包含TCRβ胞内结构域和LILRB1胞内结构域，如本文所述。在一些实施方案中，所述TCRβ胞内结构域包含与MAMVKRKDSR(SEQ ID NO:94)具有至少80％同一性、至少90％同一性或相同的氨基酸序列。在一些实施方案中，所述TCRβ胞内结构域包含MAMVKRKDSR(SEQID NO:94)或基本上由其组成。在一些实施方案中，所述TCRβ胞内结构域由以下序列编码：ATGGCCATGGTCAAGAGAAAGGATTCCAGA(SEQ ID NO:95)。
跨膜结构域
本公开文本提供了嵌合抗原受体，所述受体包含多肽。在一些实施方案中，所述多肽包含跨膜结构域。在一些实施方案中，所述跨膜结构域是LILRB1跨膜结构域或其功能变体。
如本文所用，“跨膜结构域”是指跨越细胞膜的蛋白质的结构域。跨膜结构域典型地主要由非极性氨基酸组成，并且可以穿过脂质双层一次或数次。跨膜结构域通常包含α螺旋，其构型使内部氢键最大化。
分离自或源自任何来源的跨膜结构域被设想为在本公开文本的融合蛋白的范围内。
在特定的实施方案中，所述多肽包含LILRB1跨膜结构域或其功能变体。
在一些实施方案中，所述LILRB1跨膜结构域或其功能性变体包含与SEQ IDNO:5至少95％相同、至少96％相同、至少97％相同、至少98％相同或至少99％相同的序列。在一些实施方案中，所述LILRB1跨膜结构域或其功能变体包含与SEQ ID NO:5至少95％相同的序列。在一些实施方案中，所述LILRB1跨膜结构域包含与SEQ ID NO:5相同的序列。在实施方案中，所述LILRB1跨膜结构域基本上由与SEQ ID NO:5相同的序列组成。
在本公开文本的嵌合抗原受体的一些实施方案中，所述跨膜结构域不是LILRB1跨膜结构域。在一些实施方案中，所述跨膜结构域是与融合蛋白的其他结构域之一相关的结构域，或者分离自或源自与融合蛋白的其他结构域之一相同的蛋白质。
所述跨膜结构域可以来源于天然来源或重组来源。在来源是天然的情况下，所述结构域可以源自任何膜结合蛋白或跨膜蛋白。示例性跨膜结构域可以包括以下的至少一个或多个跨膜区：例如，TCR的α、β或ζ链，CD3δ、CD3ε或CD3γ，CD28，CD3ε，CD45，CD4，CD5，CD8，CD9，CD16，CD22，CD33，CD37，CD64，CD80，CD86，CD134，CD137，CD154。
在一些实施方案中，所述跨膜包含TCRα跨膜结构域。在一些实施方案中，所述TCRα跨膜结构域包含与序列VIGFRILLLKVAGFNLLMTLRLW(SEQ ID NO:96)具有至少85％同一性、至少90％同一性、至少95％同一性、至少96％同一性、至少97％同一性、至少98％同一性、至少99％同一性或相同的氨基酸序列。在一些实施方案中，所述TCRα跨膜结构域包含VIGFRILLLKVAGFNLLMTLRLW(SEQ ID NO:96)或基本上由其组成。在一些实施方案中，所述TCRα跨膜结构域由以下序列编码：GTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGG(SEQ ID NO:97)。
在一些实施方案中，所述跨膜包含TCRβ跨膜结构域。在一些实施方案中，所述TCRβ跨膜结构域包含与序列TILYEILLGKATLYAVLVSALVL(SEQ ID NO:98)具有至少85％同一性、至少90％同一性、至少95％同一性、至少96％同一性、至少97％同一性、至少98％同一性、至少99％同一性或相同的氨基酸序列。在一些实施方案中，所述TCRβ跨膜结构域包含TILYEILLGKATLYAVLVSALVL(SEQ ID NO:98)或基本上由其组成。在一些实施方案中，所述TCRβ跨膜结构域由以下序列编码：ACCATCCTCTATGAGATCTTGCTAGGGAAGGCCACCTTGTATGCCGTGCTGGTCAGTGCCCTCGTGCTG(SEQ ID NO:99)。
在一些实施方案中，所述TCRα和/或TCRβ跨膜结构域包含减弱或消除TCR与TCRCD3亚基的相互作用的一个或多个突变。在一些实施方案中，所述TCRα跨膜结构域包含R253L突变。在一些实施方案中，所述TCRβ跨膜结构域包含K288L突变。
在一些实施方案中，所述跨膜结构域是CD28跨膜结构域。在一些实施方案中，所述CD28跨膜结构域包含与序列FWVLVVVGGVLACYSLLVTVAFIIFWV(SEQ ID NO:100)具有至少80％同一性、至少90％同一性、至少95％同一性、至少99％同一性或相同的氨基酸序列。在一些实施方案中，所述CD28跨膜结构域包含FWVLVVVGGVLACYSLLVTVAFIIFWV(SEQ ID NO:100)或由基本上其组成。在一些实施方案中，所述CD28跨膜结构域与以下序列具有至少80％同一性、至少90％同一性、至少95％同一性、至少99％同一性或相同的核苷酸序列编码：
TTCTGGGTGCTGGTCGTTGTGGGCGGCGTGCTGGCCTGCTACAGCCTGCTGGTGACAGTGGCCTTCATCATCTTTTGGGTG(SEQ ID NO:101)。
在一些实施方案中，所述跨膜结构域可以经由铰链(例如，来自人蛋白质的铰链)附接至胞外区嵌合抗原受体，例如抗原结合结构域或配体结合结构域。例如，在一些实施方案中，所述铰链可以是人免疫球蛋白(Ig)铰链，例如，IgG4铰链、CD8a铰链或LILRB1铰链。
铰链结构域
本公开文本提供了嵌合抗原受体，所述受体包含多肽。在一些实施方案中，所述多肽包含铰链结构域。在一些实施方案中，所述铰链结构域是LILRB1铰链结构域或其功能变体。
LILRB1蛋白具有四个免疫球蛋白(Ig)样结构域，称为D1、D2、D3和D4。在一些实施方案中，所述LILRB1铰链结构域包含LILRB1 D3D4结构域或其功能性变体。在一些实施方案中，所述LILRB1 D3D4结构域包含与SEQ ID NO:18至少95％、至少96％、至少97％、至少98％、至少99％或相同的序列。在一些实施方案中，所述LILRB1 D3D4结构域包含SEQ IDNO:18或基本由其组成。
在一些实施方案中，所述多肽包含LILRB1铰链结构域或其功能片段或变体。在实施方案中，所述LILRB1铰链结构域或其功能片段或变体包含与SEQ ID NO:4、SEQID NO:18或SEQ ID NO:19至少95％、至少96％、至少97％、至少98％、至少99％相同或相同的序列。在实施方案中，所述LILRB1铰链结构域或其功能片段或变体包含与SEQ IDNO:4、SEQ ID NO:18或SEQ ID NO:19至少95％相同的序列。
在一些实施方案中，所述LILRB1铰链结构域包含与SEQ ID NO:4、SEQ ID NO:18或SEQ ID NO:19相同的序列。
在一些实施方案中，所述LILRB1铰链结构域基本上由与SEQ ID NO:4、SEQ IDNO:18或SEQ ID NO:19相同的序列组成。
在本公开文本的嵌合抗原受体的一些实施方案中，所述多肽包含不是分离自或源自LILRB1的铰链。
在一些实施方案中，所述铰链分离自或源自CD8α或CD28。在一些实施方案中，所述CD8α铰链包含与序列TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO:102)具有至少80％同一性、至少90％同一性、至少95％同一性、至少99％同一性或相同的氨基酸序列。在一些实施方案中，所述CD8α铰链包含TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO:102)。在一些实施方案中，所述CD8α铰链基本上由TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO:102)组成。在一些实施方案中，所述CD8α铰链由与以下序列具有至少80％同一性、至少90％同一性、至少95％同一性、至少99％同一性或相同的核苷酸序列编码：accacgacgccagcgccgcgaccaccaacaccggcgcccaccatcgcgtcgcagcccctgtccctgcgcccagaggcgtgccggccagcggcggggggcgcagtgcacacgagggggctggacttcgcctgtgat(SEQ ID NO:103)。
在一些实施方案中，所述CD28铰链包含与序列CTIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP(SEQ ID NO:104)具有至少80％同一性、至少90％同一性、至少95％同一性、至少99％同一性或相同的氨基酸序列。在一些实施方案中，所述CD28铰链包含CTIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP(SEQ ID NO:104)或基本上由其组成。在一些实施方案中，所述CD28铰链由与以下序列具有至少80％同一性、至少90％同一性、至少95％同一性、至少99％同一性或相同的核苷酸序列编码：tgtaccattgaagttatgtatcctcctccttacctagacaatgagaagagcaatggaaccattatccatgtgaaagggaaacacctttgtccaagtcccctatttcccggaccttctaagccc(SEQ ID NO:105)。
LILRB1结构域的组合
在一些实施方案中，本公开文本的嵌合抗原受体包含含有多于一个LILRB1结构域或其功能等同物的多肽。例如，在一些实施方案中，所述多肽包含LILRB1跨膜结构域和胞内结构域，或LILRB1铰链结构域、跨膜结构域和胞内结构域。
在特定的实施方案中，所述多肽包含LILRB1铰链结构域或其功能片段或变体，和LILRB1跨膜结构域或其功能变体。在一些实施方案中，所述多肽包含与SEQ ID NO:20至少95％相同、至少96％相同、至少97％相同、至少98％相同、至少99％相同或相同的序列。在一些实施方案中，所述多肽包含与SEQ ID NO:20至少95％相同的序列。在一些实施方案中，所述多肽包含与SEQ ID NO:20相同的序列。
在另外的实施方案中，所述多肽包含：LILRB1跨膜结构域或其功能变体，和LILRB1胞内结构域和/或包含至少一个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中所述ITIM选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。在一些实施方案中，所述多肽包含LILRB1跨膜结构域或其功能变体，和LILRB1胞内结构域和/或包含至少两个ITIM的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ IDNO:11)。
在一些实施方案中，所述多肽包含LILRB1跨膜结构域和胞内结构域。在一些实施方案中，所述多肽包含与SEQ ID NO:21至少95％相同、至少96％相同、至少97％相同、至少98％相同、至少99％相同或相同的序列。在一些实施方案中，所述多肽包含与SEQID NO:21至少95％相同的序列。在一些实施方案中，所述多肽包含与SEQ ID NO:21相同的序列。
在优选的实施方案中，所述多肽包含：LILRB1铰链结构域或其功能片段或变体；LILRB1跨膜结构域或其功能变体；和LILRB1胞内结构域和/或包含至少两个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自LYAAV(SEQ IDNO:8)、VTYAE(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
在一些实施方案中，所述多肽包含与SEQ ID NO:2或SEQ ID NO:3至少95％相同、或与SEQ ID NO:2或SEQ ID NO:3至少99％相同、或与SEQ ID NO:2或SEQ ID NO:3相同的序列。
在一些实施方案中，所述多肽包含与SEQ ID NO:20至少99％相同、或与SEQ IDNO:20至少99％相同、或与SEQ ID NO:20相同的序列。
在一些实施方案中，所述多肽包含与SEQ ID NO:21至少99％相同、或与SEQ IDNO:21至少99％相同、或与SEQ ID NO:21相同的序列。
胞外结构域
本公开文本提供了包含多肽的嵌合抗原受体。在一些实施方案中，所述多肽包含配体结合结构域，诸如抗原结合结构域。合适的抗原结合结构域包括但不限于来自抗体的抗原结合结构域、抗体片段、scFv、源自T细胞受体的抗原结合结构域等。本领域已知的抗原结合结构域的所有形式都被设想为在本公开文本的范围内。
如本文所用，“胞外结构域”是指蛋白质的胞外部分。例如，TCRα链和TCRβ链各自包含胞外结构域，所述胞外结构域包含参与肽-MHC识别的恒定区和可变区。“胞外结构域”也可以包含融合结构域，例如在能够结合至且靶向特定抗原的额外结构域与TCR亚基的内源性胞外结构域之间的融合体的融合结构域。
如本文所用，术语“抗体”是指源自免疫球蛋白分子的蛋白质或多肽序列，其与抗原特异性地结合。抗体可以是多克隆或单克隆来源的完整免疫球蛋白或其片段，并且可以源自天然来源或重组来源。
术语“抗体片段”或“抗体结合结构域”是指抗体或其重组变体的至少一部分，所述至少一部分含有抗原结合结构域(即，完整抗体的抗原决定可变区)，所述抗原结合结构域足以赋予抗体片段对靶标(诸如抗原及其定义的表位)的识别和特异性结合。抗体片段的例子包括但不限于Fab、Fab'、F(ab')2和Fv片段、单链(sc)Fv(“scFv”)抗体片段、线性抗体、单结构域抗体(缩写为“sdAb”)(VL或VH)、骆驼VHH结构域、以及由抗体片段形成的多特异性抗体。
术语“scFv”是指包含含有轻链可变区的至少一个抗体片段和含有重链可变区的至少一个抗体片段的融合蛋白，其中所述轻链可变区和重链可变区经由短柔性多肽接头连续地连接，并且能够表示为单个多肽链，并且其中scFv保留衍生其的完整抗体的特异性。
关于抗体的“重链可变区”或“VH”(或者，在单结构域抗体，例如纳米抗体的情况下，为“VHH”)是指重链的片段，其含有插入称为框架区的侧翼延伸段之间的三个CDR，这些框架区通常比CDR更高度保守，并形成支持CDR的支架。
除非具体说明，否则如本文所用，scFv可以具有例如关于多肽的N末端和C末端的任何顺序的VL和VH可变区，所述scFv可以包含VL-接头-VH或可以包含VH-接头-VL。
术语“抗体轻链”是指抗体分子中以其天然存在的构象存在于抗体分子中的两种类型的多肽链中的较小者。卡帕(“κ”)轻链和拉姆达(“λ”)轻链是指两种主要的抗体轻链同种型。
术语“重组抗体”是指使用重组DNA技术产生的抗体，例如像由噬菌体或酵母表达系统表达的抗体。所述术语还应该解释为意指通过合成编码抗体的DNA分子并且所述DNA分子表达抗体蛋白或合成指明所述抗体的氨基酸序列而产生的抗体，其中所述DNA或氨基酸序列是使用本领域可获得的和熟知的重组DNA或氨基酸序列技术获得的。
在一些实施方案中，例如其中受体包含第一多肽和第二多肽的那些实施方案中，所述抗原结合结构域分离自或源自T细胞受体(TCR)胞外结构域或抗体。
在优选的实施方案中，所述多肽包含抗原结合结构域，例如，除了LILRB1抗原结合蛋白以外的抗原结合结构域。具有单一抗原结合结构域的受体的说明性实施方案描绘在图1中。本公开文本考虑的嵌合抗原受体具有两个、三个、四个或更多个抗原结合结构域。所述抗原结合结构域可以提供在嵌合抗原受体的相同或不同链上。在实施方案中，所述嵌合抗原受体是DARIC，如例如Leung等人JCI Insight.2019年6月6日；4(11):e124430；WO2015017214A1；和WO 2017156484A1中所述。
在一些实施方案中，所述受体是抑制性嵌合抗原受体(iCAR)。适用于本文的实施方案公开内容的各种方法和组合物包括在US 2018/0044399A1；WO 2018148454A1；和WO2017087723A1中提供的那些，出于所有目的将这些文献中的每一个并入本文。
在一些实施方案中，所述抗原结合结构域包含单链可变片段(scFv)。
在一些实施方案中，所述受体包含第二多肽。本公开文本提供了具有两个多肽的受体，每个多肽具有配体结合结构域的一部分(例如，异二聚LDB的同源物，诸如基于TCRα/β或Fab的LBD)并且每个多肽具有胞内结构域，如图2A中所描绘的。本公开文本进一步提供了具有两个多肽的受体，每个多肽具有配体结合结构域的一部分(例如，异二聚LDB的同源物，诸如基于TCRα/β或Fab的LBD)，并且配体结合结构域的一部分融合至铰链或跨膜结构域，而配体结合结构域的另一部分不具有胞内结构域，如图2B中所描绘的。进一步的变化包括受体，其中每个多肽具有铰链结构域，并且其中每个多肽具有铰链和跨膜结构域。在一些实施方案中，所述铰链结构域不存在。在其他实施方案中，所述铰链结构域是近膜端胞外区(MPER)，诸如LILRB1 D3D4结构域。在本文公开的任何实施方案中，所述结构域可以彼此相邻地融合，在它们之间具有接头。
在一些实施方案中，所述第一多肽包含抗体的第一链，并且所述第二多肽包含所述抗体的第二链。
在一些实施方案中，所述受体包含抗体的Fab片段。在实施方案中，抗体的重链的抗原结合片段，并且第二多肽包含抗体的轻链的抗原结合片段。在实施方案中，第一多肽包含抗体的轻链的抗原结合片段，并且第二多肽包含抗体的重链的抗原结合片段。
在一些实施方案中，第一多肽包含T细胞受体(TCR)的第一链，并且第二多肽包含所述TCR的第二链。在实施方案中，所述受体包含T细胞受体(TCR)的胞外片段。在实施方案中，第一多肽包含TCR的α链的抗原结合片段，并且第二多肽包含TCR的β链的抗原结合片段。在一些实施方案中，第一多肽包含TCR的β链的抗原结合片段，并且第二多肽包含TCR的α链的抗原结合片段。
在一些实施方案中，所述受体包含单链TCR，诸如而不限于WO 2017091905A1中披露的那些。
说明性抗原结合结构域
本领域已知的或本文公开的各种单一可变结构域适用于实施方案中。此类scFv包括(例如但不限于)以不依赖肽的方式结合HLA-A*02的以下小鼠和人源化scFv抗体(互补决定区加下划线)：
C-001765
MMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPRTSGGGTKLEIKGGGGSGGGGSGGGGSGGQVQLQQSGPELVKPGASVRISCKASGYTFTSYHIHWVKQRPGQGLEWIGWIYPGNVNTEYNEKFKGKATLTADKSSSTAYMHLSSLTSEDSAVYFCAREEITYAMDYWGQGTSVTVSSYG(SEQ ID NO:35)；或
DVLMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPRTSGGGTKLEIKGGGGSGGGGSGGGGSGGQVQLQQSGPELVKPGASVRISCKASGYTFTSYHIHWVKQRPGQGLEWIGWIYPGNVNTEYNEKFKGKATLTADKSSSTAYMHLSSLTSEDSAVYFCAREEITYAMDYWGQGTSVTVSS(SEQ ID NO:125，对应的多核苷酸序列如SEQ ID NO:127所提供)
C-002159
QLVQSGAEVKKPGSSVKVSCKASGYTFTSYHIHWVRQAPGQGLEWMGWIYPGNVNTEYNEKFKGKATITADKSTSTAYMELSSLRSEDTAVYYCAREEITYAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGEIVLTQSPGTLSLSPGERATLSCRSSQSIVHSNGNTYLEWYQQKPGQAPRLLIYKVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPRTFGGGTKVEIK(SEQ ID NO:36)
C-002160
QLVQSGAEVKKPGSSVKVSCKASGYTFTSYHIHWVRQAPGQGLEWMGWIYPGNVNTEYNEKFKGKATITADKSTSTAYMELSSLRSEDTAVYYCAREEITYAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPRTFGGGTKVEIK(SEQ ID NO:37)
C-002161
QLVESGGGLVKPGGSLRLSCAASGYTFTSYHIHWVRQAPGKGLEWVGWIYPGNVNTEYNEKFKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCAREEITYAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRSSQSIVHSNGNTYLEWYQQKPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGSHVPRTFGGGTKVEIK(SEQ ID NO:38)
C-002162
QLVQSGAEVKKPGSSVKVSCKASGYTFTSYHIHWVRQAPGQGLEWIGWIYPGNVNTEYNEKFKGKATITADESTNTAYMELSSLRSEDTAVYYCAREEITYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSTLSASVGDRVTITCRSSQSIVHSNGNTYLEWYQQKPGKAPKLLIYKVSNRFSGVPARFSGSGSGTEFTLTISSLQPDDFATYYCFQGSHVPRTFGQGTKVEVK(SEQ ID NO:39)
C-002163
QLVQSGAEVKKPGSSVKVSCKASGYTFTSYHMHWVRQAPGQGLEWIGYIYPGNVNTEYNEKFKGKATLTADKSTNTAYMELSSLRSEDTAVYFCAREEITYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDVQMTQSPSTLSASVGDRVTITCSSSQSIVHSNGNTYMEWYQQKPGKAPKLLIYKVSNRFSGVPDRFSGSGSGTEFTLTISSLQPDDFATYYCHQGSHVPRTFGQGTKVEVK(SEQ ID NO:40)
C-002164
QVQLQQSGPELVKPGASVKMSCKASGYTFTSYHIQWVKQRPGQGLEWIGWIYPGDGSTQYNEKFKGKTTLTADKSSSTAYMLLSSLTSEDSAIYFCAREGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGDVLMTQTPLSLPVSLGDQVSISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPRTFGGGTKLEIK(SEQ ID NO:41)
C-002165
QLQLQESGPGLVKPSETLSLTCTVSGYTFTSYHIQWIRQPPGKGLEWIGWIYPGDGSTQYNEKFKGRATISVDTSKNQFSLNLDSVSAADTAIYYCAREGTYYAMDYWGKGSTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRSSQSIVHSNGNTYLEWYQQKPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCFQGSHVPRTFGPGTKVDIK(SEQ ID NO:42)
C-002166
EVQLVQSGAELKKPGSSVKVSCKASGYTFTSYHIQWVKQAPGQGLEWIGWIYPGDGSTQYNEKFKGKATLTVDKSTNTAYMELSSLRSEDTAVYYCAREGTYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSTLSASVGDRVTITCRSSQSIVHSNGNTYLEWYQQKPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTLTISSLQPDDFATYYCFQGSHVPRTFGQGTKVEVK(SEQ ID NO:43)
C-002167
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYHIQWVRQAPGQGLEWMGWIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAREGTYYAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGEIVLTQSPGTLSLSPGERATLSCRSSQSIVHSNGNTYLEWYQQKPGQAPRLLIYKVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCFQGSHVPRTFGGGTKVEIK(SEQ ID NO:44)
C-002168
QVTLKQSGAEVKKPGSSVKVSCTASGYTFTSYHVSWVRQAPGQGLEWLGRIYPGDGSTQYNEKFKGKVTITADKSMDTSFMELTSLTSEDTAVYYCAREGTYYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGEIVLTQSPGTLSLSPGERATLSCRSSQSIVHSNGNTYLAWYQQKPGQAPRLLISKVSNRFSGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQGSHVPRTFGGGTKVEIK(SEQ ID NO:45)
C-002169
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYHMHWVRQAPGQRLEWMGWIYPGDGSTQYNEKFKGKVTITRDTSASTAYMELSSLRSEDTAVYYCAREGTYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLDWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGSHVPRTFGGGTKVEIK(SEQ ID NO:46)
在一些实施方案中，所述scFv包含SEQ ID NO:22-33中的任一个的互补决定区(CDR)。在一些实施方案中，所述scFv包含与SEQ ID NO:22-33中的任一个至少95％相同的序列。在一些实施方案中，所述scFv包含与SEQ ID NO:22-33中的任一个相同的序列。在一些实施方案中，所述抗体的重链包含SEQ ID NO:25-27或31-33中的任一个的重链CDR，并且所述抗体的轻链包含SEQ ID NO:22-24或28-30中的任一个的轻链CDR。在一些实施方案中，所述抗体的重链包含与SEQ ID NO:35-46或125中的任一个的重链部分至少95％相同的序列，并且其中所述抗体的轻链包含与SEQ ID NO:35-46或125中的任一个的轻链部分至少95％相同的序列。在一些实施方案中，所述重链包含所有的SEQ ID NO:25-27，并且所述轻链包含所有的SEQ ID NO:22-24。在一些实施方案中，所述重链包含所有的SEQ ID NO:31-33，并且所述轻链包含所有的SEQ ID NO:28-30。
在一些实施方案中，所述抗体的重链包含与SEQ ID NO:35-46或125中的任一个的重链部分相同的序列，并且其中所述抗体的轻链包含与SEQ ID NO:35-46或125中的任一个的轻链部分相同的序列。
在一些实施方案中，所述ScFv包含与SEQ ID NO:35-46或125中的任一个至少95％相同、至少96％相同、至少97％相同、至少98％相同、至少99％相同或相同的序列。B-和T-淋巴细胞衰减因子(BTLA)结构域
在一些实施方案中，所述多肽包含B-和T-淋巴细胞衰减因子(BTLA)铰链结构域、跨膜结构域、胞内结构域或其功能变体、衍生物或组合。
在一些实施方案中，所述多肽包含BTLA胞内结构域。在一些实施方案中，所述BTLA胞内结构域包含以下序列
RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDNDPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEAPTEYASICVRS(SEQ ID NO:87)。在一些实施方案中，所述BTLA胞内结构域包含SEQ ID NO:87或与其具有至少95％同一性的序列。在一些实施方案中，所述BTLA胞内结构域基本上由SEQ ID NO:87组成。
在一些实施方案中，所述BTLA跨膜结构域和胞内结构域包含与以下序列至少95％相同的序列：LLPLGGLPLLITTCFCLFCCLRRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDNDPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEAPTEYASICVRS(SEQ IDNO:88)。在一些实施方案中，所述BTLA跨膜结构域和胞内结构域包含序列SEQ ID NO:88或基本上由其组成。
信号肽
在一些实施方案中，所述多肽包含信号肽。例如，所述多肽包含VK1信号肽。在一些实施方案中，所述信号肽是N末端信号肽。在一些实施方案中，所述信号肽包含与序列MDMRVPAQLLGLLLLWLRGARC(SEQ ID NO:128)至少95％相同的序列。在一些实施方案中，所述信号肽包含序列MDMRVPAQLLGLLLLWLRGARC(SEQ ID NO:128)。在一些实施方案中，所述信号肽由与以下序列至少95％相同的序列或与其相同的序列编码：ATGGACATGAGGGTCCCCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGGTGCCAGATGT(SEQ ID NO:129)。
抗原
本领域技术人员将理解，任何大分子(包括几乎所有的蛋白质或肽)都可以用作针对本文所述的基于LILRB1的受体的抗原。此外，抗原可以源自重组或基因组DNA。本领域技术人员将理解，包含编码引发免疫应答的蛋白质的核苷酸序列或部分核苷酸序列的任何DNA因此编码作为本文所用的术语的“抗原”。此外，本领域技术人员将理解，抗原不需要仅由基因的全长核苷酸序列编码。此外，技术人员将理解抗原根本不需要由“基因”编码。显而易见的是，抗原可以合成产生，或者可以源自生物样品，或者可以是除多肽之外的大分子。这种生物样品可以包括但不限于组织样品、肿瘤样品、细胞或具有其他生物组分的流体。
在一些实施方案中，所述抗原结合结构域特异性结合至靶标，所述靶标选自黄化受体(etiolate receptor)、ανββ整合素、TNF受体超家族成员17(BCMA)、CD276分子(B7-H3)、自然杀伤细胞毒性受体3配体1(B7-H6)、碳酸酐酶9(CAIX)、CD19分子(CD19)、跨膜4-结构域A1(CD20)、CD22分子(CD22)、TNF受体超家族成员8(CD30)、CD33分子(CD33)、CD37分子(CD37)、CD44分子(CD44)、CD44v6、CD44v7/8、CD70分子(CD70)、白细胞介素3受体亚基α(CD123)、多配体蛋白聚糖1(CD138)、L1细胞粘附分子(CD171)、CEA细胞粘附分子(CEA)、δ样典型Notch配体4(DLL4)、上皮细胞粘附分子(EGP-2)、上皮细胞粘附分子(EGP-40)、硫酸软骨素蛋白聚糖4(CSPG4)、表皮生长因子受体(EGFR)、EGFR家族(包括ErbB2(HER2))、EGFRvIII、上皮细胞粘附分子(EPCAM)、EPH受体A2(EphA2)、EpCAM、成纤维细胞激活蛋白α(FAP)、叶酸受体α(FBP)、胎儿乙酰胆碱受体、卷曲类受体7(Fzd7)、二神经节苷脂GD2(GD2)、神经节苷脂GD3(GD3)、磷脂酰肌醇蛋白聚糖-3(GPC3)、滋养层糖蛋白(h5T4)、白细胞介素11受体亚基α(IL-11R)、白细胞介素13受体亚基α2(IL13R-a2)、激酶插入结构域受体(KDR)、κ轻链、λ轻链、LeY、L1细胞粘附分子(L1 CAM)、MAGE-A1、间皮素、MHC呈递肽、细胞表面相关粘蛋白1(MUC1)、细胞表面相关粘蛋白16(MUC16)、神经细胞粘附分子1(NCAM)、杀伤细胞凝集素样受体K1(NKG2D)配体、Notch1、Notch2/3、NY-ESO-1、PRAME核受体转录调节因子(PRAME)、前列腺干细胞抗原(PSCA)、叶酸水解酶1(PSMA)、存活蛋白、TAG-72、TEM、端粒酶逆转录酶(TERT)、激酶插入结构域受体(VEGFR2)和受体酪氨酸激酶样孤儿受体1(ROR1)。
在一些实施方案中，所述抗原结合结构域特异性结合至靶标，所述靶标选自CD33、CD38、人白细胞抗原(HLA)、器官特异性抗原、血脑屏障特异性抗原、上皮-间充质转化(EMT)抗原、E-钙粘蛋白、细胞角蛋白、阿片样物质结合蛋白/细胞粘附分子(OPCML)、HYLA2、结直肠癌缺失型(DCC)、支架/基质附着区结合蛋白1(SMAR1)、细胞表面碳水化合物和粘蛋白型O-聚糖。
在一些实施方案中，本文所述的基于LILRB1的受体的胞外结构域包含对在受试者的细胞中通过杂合性丢失而丢失的抗原特异性的抗原结合结构域。
如本文所用，“杂合性丢失(LOH)”是指在癌症中以高频率发生的遗传变化，其中两个等位基因之一缺失，留下单个单等位(半合子)基因座。
在一些实施方案中，所述基于LILRB1的受体包含对次要组织相容性抗原(MiHA)特异性的抗原结合结构域。MiHA是源自含有等位基因之间的非同义差异并由常见HLA等位基因展示的蛋白质的肽。非同义差异可以由编码MiHA的基因的编码序列中的SNP、缺失、移码突变或插入引起。示例性MiHA可以具有约9-12个氨基酸的长度，并且可以结合至MHC I类和MHC II类蛋白。TCR与展示MiHA的MHC复合物的结合可以激活T细胞。MiHA的遗传和免疫学特性是本领域普通技术人员已知的，并且具体的MiHa描述于PCT/US2020/045228中，其内容通过引用并入本文。
在一些实施方案中，所述基于LILRB1的受体包含对通过Y染色体丢失而在受试者的癌细胞中丢失的抗原特异性的抗原结合结构域。
在一些实施方案中，所述基于LILRB1的受体包含对HLA I类等位基因特异性的抗原结合结构域。主要组织相容性复合物(MHC)I类是将抗原展示给免疫系统的细胞从而触发免疫应答的蛋白质复合物。与MHC I类对应的人白细胞抗原(HLA)是HLA-A、HLA-B和HLA-C。HLA-E在本领域中被认为是非经典的MHC I类分子。在一些实施方案中，所述基于LILR1受体的抗原包含HLA I类等位基因。在一些实施方案中，HLA I类的等位基因通过杂合性丢失(LOH)在靶细胞诸如癌细胞中丢失。
HLA-A是一组由HLA-A基因座编码的主要组织相容性复合物(MHC)的人白细胞抗原(HLA)。HLA-A是三种主要类型的人MHC I类细胞表面受体之一。所述受体是包含重α链和较小β链的异二聚体。所述α链由HLA-A的变体编码，而β链(β2-微球蛋白)是不变的。存在几千种HLA-A变体，所有这些变体都落入本公开文本的范围内。
在一些实施方案中，所述基于LILRB1的受体包含对HLA-B等位基因特异性的抗原结合结构域。HLA-B基因具有许多可能的改变(等位基因)。HLA-B基因的几百种形式(等位基因)是已知的，其中的每一个被给予特定的数字(诸如HLA-B27)。
在一些实施方案中，所述基于LILRB1的受体包含对HLA-C等位基因特异性的抗原结合结构域。HLA-C属于HLA I类重链旁系同源物。这种I类分子是由重链和轻链(β-2微球蛋白)组成的异二聚体。
在一些实施方案中，所述HLA I类等位基因具有广泛或普遍存在的RNA表达。
在一些实施方案中，所述HLA I类等位基因具有已知的或通常高的次要等位基因频率。
在一些实施方案中，所述HLA I类等位基因不需要肽-MHC抗原，例如当所述HLA I类等位基因被泛HLA配体结合结构域识别时。
在一些实施方案中，所述基于LILRB1的受体包含对HLA-A等位基因特异性的抗原结合结构域。在一些实施方案中，所述HLA-A等位基因包含HLA-A*02。结合并识别HLA-A*02的本领域已知的或本文公开的各种单一可变结构域适用于实施方案，并且在本文中描述。
在一些实施方案中，所述抗原结合结构域特异性地结合至HLA-A*02抗原。在一些实施方案中，所述抗原结合结构域以不依赖肽的方式特异性地结合至HLA-A*02抗原。
多核苷酸和载体
在其他方面，本公开文本提供了包含编码本公开文本受体的核酸序列的多核苷酸。在一些实施方案中，所述多核苷酸编码以下中的一个或多个：LILRB1铰链结构域、LILRB1跨膜结构域和LILRB1胞内结构域或其功能衍生物或片段。
在一些实施方案中，所述多核苷酸包含编码与SEQ ID NO:1-7或12-21中的任一个至少95％相同的多肽的核酸序列。在一些实施方案中，所述多核苷酸包含编码与SEQ IDNO:47-71、77-79、89-92、120或122中的任一个至少95％相同的多肽的核酸序列。在一些实施方案中，所述多核苷酸包含编码与SEQ ID NO:35-46或125中的任一个的重链部分或轻链部分至少95％相同的多肽的核酸序列。在一些实施方案中，所述多核苷酸包含编码与SEQID NO:35、39、46或125中的任一个的重链部分或轻链部分至少95％相同的多肽的核酸序列。在一些实施方案中，所述多核苷酸包含编码与SEQ ID NO:35、39、46或125中的任一个的重链部分或轻链部分相同的多肽的核酸序列。在另一个方面，本公开文本提供了包含编码本公开文本受体的多核苷酸的载体。
在一些实施方案中，所述多核苷酸包含与SEQ ID NO:121或123至少95％相同的序列。在一些实施方案中，所述多核苷酸包含SEQ ID NO:121或123。
在一些实施方案中，所述多核苷酸包含LILRB1铰链、跨膜和胞内结构域的序列。在一些实施方案中，所述多核苷酸包含与SEQ ID NO:126至少95％相同的序列。在一些实施方案中，所述多核苷酸包含序列SEQ ID NO:126。
源自逆转录病毒(诸如慢病毒)的载体是实现长期基因转移的合适工具，因为它们允许转基因的长期稳定整合及其在后代细胞中的传播。慢病毒载体比源自癌逆转录病毒(诸如鼠白血病病毒)的载体具有额外的优势，因为它们可以转导非增殖细胞(诸如肝细胞)。它们还具有低免疫原性的额外优势。
编码受体的天然或合成核酸的表达典型地通过将编码受体或其部分的核酸可操作地连接至启动子并且将构建体掺入表达载体中来实现。所述载体可以适用于复制和整合真核细胞。典型的克隆载体含有转录和翻译终止子、起始序列和可用于调节所希望的核酸序列的表达的启动子。
可以将编码受体的多核苷酸克隆到多种类型的载体中。例如，可以将所述多核苷酸克隆到载体中，所述载体包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。特别感兴趣的载体包括表达载体、复制载体、探针生成载体和测序载体。
此外，所述表达载体可以以病毒载体的形式提供给细胞，诸如免疫细胞。病毒载体技术是本领域中是熟知的，并且描述于例如Sambrook等人(2001,Molecular Cloning:ALaboratory Manual,Cold Spring Harbor Laboratory,纽约)和其他病毒学和分子生物学手册中。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。通常，合适的载体含有在至少一种生物体中有功能的复制起点、启动子序列、方便的限制性内切核酸酶位点和一个或多个选择性标记物(例如，WO 01/96584；WO01/29058；和美国专利号6,326,193)。
已经开发出多种基于病毒的系统用于将基因转移至哺乳动物细胞中。例如，逆转录病毒为基因递送系统提供了便利的平台。可以使用本领域已知的技术将所选择的基因插入载体中并且包装在逆转录病毒颗粒中。然后可以分离重组病毒，并且在体内或离体递送至受试者的细胞。多种逆转录病毒系统是本领域已知的。在一些实施方案中，使用腺病毒载体。多种腺病毒载体是本领域已知的。在一个实施方案中，使用慢病毒载体。
在一些实施方案中，所述载体包含启动子。载体还可以包含额外的调节元件。额外的调节元件(例如，增强子)调节转录起始的频率。典型地，这些位于起始位点上游30-110个碱基对(bp)的区域中，但是最近已经显示许多启动子也含有起始位点下游的功能元件。启动子元件之间的间距通常是灵活的，因此当元件相对于彼此反转或移动时，启动子功能得以保留。在胸苷激酶(tk)启动子中，在活性开始下降之前，启动子元件之间的间距可以增加至相距50bp。取决于启动子，似乎单独的元件可以协同或独立地发挥作用以激活转录。
合适的启动子的一个例子是即刻早期巨细胞病毒(CMV)启动子序列。此启动子序列是能够驱动与其可操作地连接的任何多核苷酸序列的高水平表达的强组成型启动子序列。合适的启动子的另一个例子是延伸生长因子-1α(EF-1α)。然而，也可以使用其他组成型启动子序列，包括但不限于猿猴病毒40(SV40)早期启动子、小鼠乳腺瘤病毒(MMTV)、人类免疫缺陷病毒(HIV)长末端重复序列(LTR)启动子、MoMuLV启动子、禽白血病病毒启动子、爱泼斯坦-巴尔病毒即刻早期启动子、劳斯肉瘤病毒启动子以及人类基因启动子(诸如但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子)。此外，本发明不应局限于使用组成型启动子。诱导型启动子也被考虑是本发明的一部分。诱导型启动子的使用提供了分子开关，所述分子开关能够在希望这样的表达时开启其可操作地连接的多核苷酸序列的表达，或者在不希望表达时关闭表达。诱导型启动子的例子包括但不限于金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
为了评估受体的表达，待引入细胞中的表达载体还可以含有选择性标记物基因或报告基因或两者，以促进从试图通过病毒载体转染或感染的细胞群体中鉴定和选择表达细胞。在其他方面，所述选择性标记物可以被携带在一片单独的DNA上并且用于共转染程序中。选择性标记物和报告基因两者都可以侧接适当的调节序列以使得能够在宿主细胞中表达。有用的选择性标记物包括例如抗生素抗性基因，诸如neo等。
将基因引入细胞中并且使其在细胞中表达的方法是本领域已知的。在表达载体的背景下，可以通过本领域的任何方法将载体容易地引入宿主细胞，例如哺乳动物、细菌、酵母或昆虫细胞中。例如，所述表达载体可以通过物理、化学或生物学手段转移到宿主细胞中。
用于将多核苷酸引入宿主细胞中的物理方法包括磷酸钙沉淀、脂质转染、粒子轰击、显微注射、电穿孔等。用于产生包含载体和/或外源核酸的细胞的方法是本领域熟知的。参见例如Sambrook等人(2001,Molecular Cloning:A Laboratory Manual,Cold SpringHarbor Laboratory,纽约)。一种将多核苷酸引入宿主细胞中的方法是磷酸钙转染。
用于将目的多核苷酸引入宿主细胞中的生物学方法包括使用DNA和RNA载体。病毒载体，并且尤其是逆转录病毒载体，已成为将基因插入哺乳动物例如人细胞中的最广泛使用的方法。其他病毒载体可以衍生自慢病毒、痘病毒、单纯疱疹病毒I、腺病毒和腺相关病毒等。参见，例如，美国专利号5,350,674和5,585,362。
用于将多核苷酸引入宿主细胞中的化学手段包括胶体分散系统，诸如大分子复合物、纳米胶囊、微球、珠和基于脂质的系统(包括水包油乳剂、胶束、混合胶束和脂质体)。用作体外和体内递送媒介物的示例性胶体系统是脂质体(例如，人造膜囊)。
不管使用何种方法将外源核酸引入宿主细胞中或以其他方式将细胞暴露于本发明的抑制剂，为了证实重组DNA序列在宿主细胞中的存在，可以进行多种测定。此类测定包括例如本领域技术人员熟知的“分子生物学”测定，诸如DNA印迹法和RNA印迹法、RT-PCR和PCR；“生物化学”测定，诸如检测特定肽的存在或不存在，例如通过免疫学手段(ELISA和蛋白质印迹法)或通过本文所述的测定以鉴定落入本发明范围内的药剂。
工程化细胞
在另一个方面，本公开文本提供了包含编码本公开文本受体和/或表达本公开文本受体的核酸序列或载体的免疫细胞。
在实施方案中，当细胞与本公开文本的基于LILRB1的受体的抗原或在其表面上表达所述抗原的细胞接触时，免疫细胞激活降低。在实施方案中，免疫细胞激活包括表达可操作地连接至NFAT启动子的基因。免疫细胞激活和/或激活抑制可以通过本领域已知的各种其他方法测量。在一些实施方案中，所述免疫细胞包含额外的外源受体，例如激活剂受体，诸如嵌合抗原受体(CAR)或TCR。
在实施方案中，所述免疫细胞是T细胞。
如本文所用，术语“免疫细胞”是指参与先天性或适应性(获得性)免疫系统的细胞。示例性的先天性免疫细胞包括吞噬细胞，诸如中性粒细胞、单核细胞和巨噬细胞，自然杀伤(NK)细胞，多形核白细胞，诸如中性粒细胞、嗜酸性粒细胞和嗜碱性粒细胞，以及单核细胞，诸如单核细胞、巨噬细胞和肥大细胞。在获得性免疫中起作用的免疫细胞包括淋巴细胞，诸如T细胞和B细胞。
如本文所用，“T细胞”是指源自在胸腺中发育的骨髓前体的一种淋巴细胞类型。有几种不同类型的在迁移至胸腺时发育的T细胞，包括辅助CD4+T细胞、细胞毒性CD8+T细胞、记忆T细胞、调节CD4+T细胞和干记忆T细胞。本领域普通技术人员可以基于标记物的表达来区分不同类型的T细胞。区分T细胞类型的方法对于本领域普通技术人员是显而易见的。
制造工程化细胞的方法
在另一个方面，本公开文本提供了方法，所述方法包括任选地使用本公开文本的载体将本公开文本的多核苷酸引入细胞中。在实施方案中，所得细胞表达由多核苷酸编码的基于LILRB1的受体。在实施方案中，所述细胞是免疫细胞。在实施方案中，所述免疫细胞是T细胞。
用本公开文本的载体转化免疫细胞(诸如T细胞)群体的方法对于本领域普通技术人员是显而易见的。例如，根据制造商的说明书，使用CD3+T细胞阴性分离试剂盒(Miltenyi)可以从PBMC中分离出CD3+T细胞。可以在补充有5％人A/B血清和1％Pen/strep的X-Vivo 15培养基中在CD3/28Dynabeads(1:1细胞与珠的比率)和300单位/mL IL-2(Miltenyi)的存在下以1x 10^6个细胞/mL的密度培养T细胞。2天后，可以使用本领域已知的方法用病毒载体诸如慢病毒载体转导T细胞。在一些实施方案中，以5的感染复数(MOI)转导病毒载体。然后在富集前，可以在IL-2或其他细胞因子(诸如IL-7/15/21组合)中额外培养细胞5天。分离和培养其他免疫细胞诸如B细胞或其他T细胞群体的方法对于本领域普通技术人员是显而易见的。尽管这种方法概述了一种潜在的途径，但是应当注意，这些方法正在快速发展。例如，生长5天后可以实现外周血单核细胞的优异病毒转导，以产生>99％的CD3+高度转导的细胞群体。
激活和培养包含本公开文本的受体、多核苷酸或载体的T细胞群体的方法对于本领域普通技术人员是显而易见的。
无论在遗传修饰之前还是遗传修饰之后，T细胞可以通常使用如例如美国专利号6,352,694；6,534,055；6,905,680；6,692,964；5,858,358；6,887,466；6,905,681；7,144,575；7,067,318；7,172,869；7,232,566；7,175,843；5,883,223；6,905,874；6,797,514；6,867,041；10040846；以及美国专利申请号2006/0121005中所述的方法激活和扩增。
在一些实施方案中，本公开文本的T细胞在体外扩增和激活。通常，本公开文本的T细胞通过与表面接触来体外扩增，所述表面附着有刺激CD3/TCR复合物相关信号的药剂和刺激T细胞表面上的共刺激分子的配体。特别地，可以如本文所述，诸如通过与抗CD3抗体接触来刺激T细胞群体。对于T细胞表面上的辅助分子的共刺激，使用结合所述辅助分子的配体。例如，可以使T细胞群体与抗CD3抗体和抗CD28抗体在适合于刺激T细胞增殖的条件下接触。为了刺激CD4+T细胞或CD8+T细胞的增殖，可以使用抗CD3抗体和抗CD28抗体。抗CD28抗体的例子包括9.3、B-T3、XR-CD28(Diaclone，Besan(Berg等人,Transplant Proc.30(8):3975-3977,1998；Haanen等人,J.Exp.Med.190(9):13191328,1999；Garland等人,J.Immunol Meth.227(1-2):53-63,1999)。
在一些实施方案中，可以通过不同方案提供对于T细胞的初级刺激信号和共刺激信号。例如，提供每种信号的药剂可以在溶液中或偶联至表面。在偶联至表面时，所述药剂可以偶联至同一表面(即，呈“顺式”构造)或分开的表面(即，呈“反式”构造)。可替代地，一种药剂可以偶联至表面，而另一种药剂在溶液中。在一些实施方案中，提供共刺激信号的药剂结合至细胞表面，并且提供初级激活信号的药剂在溶液中或偶联至表面。在某些实施方案中，两种药剂可以都在溶液中。在另一实施方案中，所述药剂可以呈可溶形式，然后与表面交联，所述表面如表达Fc受体的细胞或将与所述药剂结合的抗体或其他结合剂。就此而言，关于本发明中考虑用于激活和扩增T细胞的人工抗原呈递细胞(aAPC)，参见例如美国专利申请公开号20040101519和20060034810。
在一些实施方案中，两种药剂固定在珠上，固定在同一珠上(即“顺式”)或者固定至分开的珠上(即“反式”)。例如，提供初级激活信号的药剂是抗CD3抗体或其抗原结合片段，并且提供共刺激信号的药剂是抗CD28抗体或其抗原结合片段；并且两种药剂以相等的分子量共同固定到同一珠上。在一个实施方案中，使用1:1比率的结合至用于CD4+T细胞扩增和T细胞生长的珠的每种抗体。在一些实施方案中，结合至珠的CD3:CD28抗体的比率范围为100:1至1:100以及其间的所有整数值。在本发明的一个方面，与抗CD3抗体相比，更多的抗CD28抗体结合至颗粒，即CD3:CD28的比率小于1。在本发明的某些实施方案中，结合至珠的抗CD28抗体与抗CD3抗体的比率大于2:1。
可以使用1:500至500:1以及其间的所有整数值的颗粒与细胞的比率来刺激T细胞或其他靶细胞。如本领域普通技术人员可以容易地了解的，颗粒与细胞的比率可以取决于相对于靶细胞的颗粒大小。例如，小尺寸的珠仅能结合少许细胞，而较大的珠可以结合许多细胞。在某些实施方案中，细胞与颗粒的比率范围为1:100至100:1以及其间的所有整数值，并且在另外的实施方案中，所述比率包括1:9至9:1以及其间的所有整数值，也可以用于刺激T细胞。在一些实施方案中，使用1:1比率的细胞与珠。本领域技术人员将了解，多种其他比率可以适用于本发明。特别地，比率将根据颗粒大小以及细胞大小和类型而变化。
在另外的实施方案中，将细胞诸如T细胞与药剂包被的珠组合，随后分离所述珠与所述细胞，并且然后培养细胞。在一个替代性实施方案中，在培养前，不分离药剂包被的珠与细胞，而是将它们一起培养。在另一实施方案中，首先通过施加力诸如磁力来浓缩珠和细胞，导致细胞表面标记物的连接增加，从而诱导细胞刺激。
例如，细胞表面蛋白可以通过允许抗CD3和抗CD28所附着的顺磁珠接触T细胞来连接。在一个实施方案中，将细胞(例如，CD4+T细胞)和珠(例如，DYNABEADS CD3/CD28 T顺磁珠，比率为1:1)在缓冲液中组合。同样，本领域普通技术人员可以容易地了解，可以使用任何细胞浓度。在某些实施方案中，可能希望显著减小其中将颗粒与细胞混合在一起的体积(即，增加细胞浓度)，以确保细胞与颗粒的最大接触。例如，在一个实施方案中，使用约20亿个细胞/ml的浓度。在另一实施方案中，使用大于1亿个细胞/ml。在另一实施方案中，使用1000万、1500万、2000万、2500万、3000万、3500万、4000万、4500万或5000万个细胞/ml的细胞浓度。在又一个实施方案中，使用7500万、8000万、8500万、9000万、9500万或1亿个细胞/ml的细胞浓度。在另外的实施方案中，可以使用1.25或1.5亿个细胞/ml的浓度。在一些实施方案中，使用以1x106个细胞/mL的密度培养的细胞。
在一些实施方案中，可以将混合物培养几小时(约3小时)至约14天或其间的任何小时整数值。在另一实施方案中，将珠和T细胞一起培养2-3天。适合用于T细胞培养的条件包括适当的培养基(例如，极限必需培养基或RPMI培养基1640或X-vivo 15(Lonza))，其可以含有增殖和活力所需的因子，包括血清(例如，胎牛血清或人血清)、白细胞介素-2(IL-2)、胰岛素、IFN-γ、IL-4、IL-7、GM-CSF、IL-10、IL-12、IL-15、TGFβ和TNF-α或熟练技术人员已知的用于细胞生长的任何其他添加剂。用于细胞生长的其他添加剂包括但不限于表面活性剂、人血浆蛋白粉(plasmanate)和还原剂(诸如N-乙酰基-半胱氨酸和2-巯基乙醇)。培养基可以包括RPMI 1640、AIM-V、DMEM、MEM、α-MEM、F-12、X-Vivo 15和X-Vivo 20、Optimizer，其添加有氨基酸、丙酮酸钠和维生素，无血清或补充有适当量的血清(或血浆)或一组限定的激素和/或足够用于T细胞生长和扩增的量的一种或多种细胞因子。在一些实施方案中，培养基包含补充有5％人A/B血清、1％青霉素/链霉素(pen/strep)和300单位/ml IL-2(Miltenyi)的X-VIVO-15培养基。
将T细胞维持在支持生长所需的条件下，例如，适当温度(例如，37℃)和气氛(例如，空气加5％CO2)。
在一些实施方案中，包含本公开文本的受体的T细胞是自体的。在扩增和遗传修饰之前，从受试者获得T细胞来源。免疫细胞诸如T细胞可以获自多种来源，包括外周血单核细胞、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、胸腔积液、脾组织和肿瘤。在本发明的某些实施方案中，可以使用任何数目的在本领域中可获得的T细胞系。在本发明的某些实施方案中，可以使用熟练技术人员已知的任何数目的技术(诸如FicollTM分离)从收集自受试者的血液单位获得T细胞。
在一些实施方案中，来自个体的循环血液的细胞是通过单采术获得的。单采术产物典型地含有淋巴细胞，包括T细胞、单核细胞、粒细胞、B细胞、其他有核白细胞、红细胞和血小板。在一些实施方案中，可以洗涤通过单采术收集的细胞以去除血浆级分并且将细胞置于适当的缓冲液或培养基中用于后续处理步骤。在一些实施方案中，用磷酸盐缓冲盐水(PBS)洗涤细胞。在替代性实施方案中，洗涤溶液缺少钙，并且可能缺少镁，或者可能缺少许多(如果不是全部)二价阳离子。如本领域普通技术人员应容易地了解的，洗涤步骤可以通过本领域技术人员已知的方法来完成，诸如通过根据制造商的说明书使用半自动化“流通式”离心机(例如，Cobe 2991细胞处理器、Baxter CytoMate或Haemonetics Cell Saver 5)来完成。洗涤后，可以将细胞重悬于多种生物相容的缓冲液中，例如像无Ca2+、无Mg2+的PBS、PlasmaLyte A或者具有或没有缓冲液的其他盐水溶液。可替代地，可以去除单采术样品的不希望组分，并且将细胞直接重悬于培养基中。
在一些实施方案中，通过裂解红细胞并且耗尽单核细胞，例如通过经由PERCOLLTM梯度离心或通过逆流离心淘析法，从外周血淋巴细胞中分离免疫细胞诸如T细胞。可以通过阳性或阴性选择技术进一步分离免疫细胞的特定亚群，诸如T细胞、B细胞或CD4+T细胞。例如，在一个实施方案中，通过与抗CD4缀合的珠一起孵育持续足以进行所希望的T细胞的阳性选择的时间段来分离T细胞。
通过阴性选择富集免疫细胞群体诸如T细胞群体可以用针对阴性选择的细胞独有的表面标记物的抗体的组合来完成。一种方法是经由使用针对阴性选择的细胞上存在的细胞表面标记物的单克隆抗体混合物(cocktail)的阴性磁性免疫粘附或流式细胞术进行细胞分选和/或选择。例如，为了通过阴性选择富集CD4+细胞，单克隆抗体混合物典型地包括针对CD 14、CD20、CD 11b、CD 16、HLA-DR和CD8的抗体。
对于通过阳性或阴性选择分离所希望的免疫细胞群体，可以改变细胞和表面(例如颗粒，诸如珠)的浓度。在某些实施方案中，可能希望显著减小将珠与细胞混合在一起的体积(即，增加细胞浓度)，以确保细胞与珠的最大接触。
在一些实施方案中，可以在2℃-10℃下或在室温下将细胞在旋转器上以变化的速度孵育变化的时间长度。
用于刺激的T细胞或从中分离免疫细胞诸如T细胞的PBMC也可以在洗涤步骤后冷冻。不希望受限于理论，冷冻和后续解冻步骤通过去除细胞群体中的粒细胞和在一定程度上去除单核细胞来提供更均匀的产物。在去除血浆和血小板的洗涤步骤之后，可以将细胞悬浮于冷冻溶液中。尽管许多冷冻溶液和参数是本领域中已知的并且将可用于该情况下，一种方法涉及使用含有20％DMSO和8％人血清白蛋白的PBS；或含有以下的培养基：10％葡聚糖40和5％右旋糖，20％人血清白蛋白和7.5％DMSO，或31.25％Plasmalyte-A、31.25％右旋糖5％、0.45％NaCl、10％葡聚糖40和5％右旋糖，20％人血清白蛋白和7.5％DMSO；或含有例如Hespan和PlasmaLyte A的其他合适的细胞冷冻培养基，然后将细胞以1°/分钟的速率冷冻至-80℃，并且储存在液氮储存罐的气相中。可以使用其他受控冷冻方法，以及在-20℃下或在液氮中立即不受控冷冻。
测定信号传导
在一些实施方案中，当免疫细胞与对应于本公开文本的基于LILRB1的受体的抗原或在其表面上表达所述抗原的细胞接触时，免疫细胞激活降低。在一些实施方案中，免疫细胞激活包括表达可操作地连接至NFAT启动子的基因。激活的T细胞的核因子(NFAT)是显示出在免疫应答中重要的转录因子家族。NFAT转录因子家族由五个成员NFATc1、NFATc2、NFATc3、NFATc4和NFAT5组成。NFAT在调节炎症中起作用。
如本文所用，NFAT启动子是当NFAT在细胞中表达时受调节(即，激活或抑制)的启动子。NFAT靶启动子描述于Badran,B.M.等人(2002)J.Biological Chemistry第277卷:47136-47148中，并且含有NFAT共有序列诸如GGAAA。
评估受体激活对基因表达的影响的方法是本领域已知的，并且包括使用报告基因，其表达可以被定量。使用报告基因鉴定潜在转染或转导的细胞，并且评价调节序列的功能性。通常，报告基因是这样的基因，其在受体生物体或组织中不存在或不表达，并且编码表达表现为一些可容易地检测的特性(例如，酶活性)的多肽。在已经将DNA引入受体细胞中之后，在合适的时间测定报告基因的表达。合适的报告基因可以包括编码以下的基因：萤光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌型碱性磷酸酶或绿色荧光蛋白基因(例如，Ui-Tei等人2000FEBS Letters 479:79-82)。合适的表达系统是熟知的并且可以使用已知技术来制备或商购获得。通常，具有最小5'侧翼区的显示出报告基因的最高水平表达的构建体被鉴定为启动子。此类启动子区可以与报告基因连接，并且用于评价药剂调节启动子驱动的转录的能力。在示例性实施方案中，使用可操作地连接至报告基因的NFAT启动子来评价本公开文本的受体对NFAT信号传导的表达。
药物组合物
本公开文本提供了药物组合物，其包含含有本公开文本的基于LILRB1的受体的免疫细胞、药学上可接受的稀释剂、载体或赋形剂。
此类组合物可以包含缓冲液，诸如中性缓冲盐水、磷酸盐缓冲盐水等；碳水化合物，诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇；蛋白质；多肽或氨基酸，诸如甘氨酸；抗氧化剂；螯合剂，诸如EDTA或谷胱甘肽；以及防腐剂。
治疗疾病的方法
本文提供了治疗有需要的受试者的方法，其包括向所述受试者施用治疗有效量的组合物，所述组合物包含多个免疫细胞，所述免疫细胞包含本文所述的基于LILRB1的受体。在一些实施方案中，所述免疫细胞进一步包含激活剂受体，诸如激活剂CAR或TCR。
治疗受试者的额外方法以及与抑制性受体组合的激活剂受体组合描述于PCT/US2020/045228中，将其内容通过引用以其整体并入本文。
在一些实施方案中，有需要的受试者患有癌症。在一些实施方案中，所述治疗受试者的方法包括向所述受试者施用包含本公开文本的LILRB1受体的多个免疫细胞。在一些实施方案中，所述多个免疫细胞进一步包含激活剂受体，诸如CAR或TCR。在一些实施方案中，所述CAR或TCR包含对肿瘤抗原特异性的抗原结合结构域。对癌症抗原特异性的激活剂受体可以包含从本领域已知的任何抗体或抗原结合结构域分离或衍生的抗原结合结构域，所述抗体或抗原结合结构域包括但不限于乌瑞鲁单抗(urelumab)、乌托鲁单抗(utomilumab)、奥来鲁单抗(oleclumab)、那普妥莫单抗(naptumomab)、阿伐苏单抗(ascrinvacumab)、替他珠单抗(tacatuzumab)、奈伐苏单抗(nesvacumab)、伐努赛珠单抗(vanucizumab)、贝利木单抗(belimumab)、他巴鲁单抗(tabalumab)、替利组单抗(tibulizumab)、贝兰妥单抗(belantamab)、伊戈伏单抗、奥戈伏单抗(oregovomab)、索非妥珠单抗(sofituzumab)、莫格利珠单抗(mogamulizumab)、塔妥珠单抗(talacotuzumab)、他利昔珠单抗(tavolimab)、珀伽利珠单抗(vonlerolizumab)、伊匹单抗、度妥昔珠单抗(duvortuxizumab)、博纳吐单抗、考妥昔单抗(coltuximab)、地宁妥珠单抗(denintuzumab)、伊奈利珠单抗(inebilizumab)、朗妥昔单抗(loncastuximab)、帕他莫单抗(taplitumomab)、替伊莫单抗、奥比妥珠单抗(obinutuzumab)、奥卡妥珠单抗(ocaratuzumab)、奥瑞珠单抗(ocrelizumab)、奥法木单抗、利妥昔单抗(rituximab)、托西莫单抗、维妥珠单抗(veltuzumab)、沙马组单抗(samalizumab)、贝妥莫单抗(bectumomab)、依帕珠单抗、奥英妥珠单抗(inotuzumab)、莫塞妥莫单抗(moxetumomab)、匹那妥珠单抗(pinatuzumab)、戈利木单抗(gomiliximab)、鲁米利昔单抗(lumiliximab)、卡普赛珠单抗(camidanlumab)、巴司利昔单抗、伊诺莫单抗、达克利珠单抗、伐立鲁单抗(varlilumab)、依诺妥珠单抗(enoblituzumab)、奥博妥单抗(omburtamab)、本妥昔单抗、伊妥木单抗(iratumumab)、吉妥珠单抗、林妥珠单抗(lintuzumab)、伐达妥昔单抗(vadastuximab)、利洛托单抗(lilotomab)、奥乐妥珠单抗(otlertuzumab)、tetulomab、达雷木单抗、艾萨妥昔单抗(isatuximab)、比伐妥珠单抗(bivatuzumab)、阿比妥珠单抗(abituzumab)、英妥木单抗(intetumumab)、洛沃妥珠单抗(lorvotuzumab)、艾托利珠单抗(itolizumab)、古妥珠单抗(cusatuzumab)、沃瑟妥珠单抗(vorsetuzumab)、米拉妥珠单抗(milatuzumab)、泊洛妥珠单抗(polatuzumab)、iladatuzumab、加利昔单抗(galixima)、阿妥莫单抗(altumomab)、阿西莫单抗、拉贝珠单抗(labetuzumab)、赛必妥单抗(cibisatamab)、佐妥昔单抗(zolbetuximab)、拉妥珠单抗(lacnotuzumab)、卡比利珠单抗(cabiralizumab)、艾马珠单抗(emactuzumab)、净利尤单抗(gimsilumab)、仑兹鲁单抗(lenzilumab)、奥替利单抗(otilimab)、玛弗利木单抗(mavrilimumab)、曲美木单抗、乌洛鲁单抗(ulocuplumab)、tepoditamab、洛伐妥珠单抗(rovalpituzumab)、登赛珠单抗(demcizumab)、曲齐妥单抗(drozitumab)、帕萨妥珠单抗(parsatuzumab)、西妥昔单抗(cetuximab)、迪妥昔珠单抗(depatuxizumab)、伏妥昔单抗(futuximab)、伊马曲单抗(imgatuzumab)、拉妥昔单抗(laprituximab)、马妥珠单抗(matuzumab)、耐昔妥珠单抗(necitumumab)、尼妥珠单抗、帕尼单抗、扎鲁木单抗(zalutumumab)、莫妥昔单抗(modotuximab)、埃万妥单抗(amivantamab)、托木妥昔单抗(tomuzotuximab)、罗妥昔珠单抗(losatuxizumab)、阿德木单抗(adecatumumab)、西他妥珠单抗(citatuzumab)、依决洛单抗、奥珀妥珠单抗(oportuzumab)、索利托单抗(solitomab)、西莫白介素单抗(tucotuzumab)、卡妥索单抗、伊波妥组单抗(ifabotuzumab)、度戈妥珠单抗(duligotuzumab)、依更妥单抗(elgemtumab)、鲁妥珠单抗(lumretuzumab)、帕曲妥单抗(patritumab)、瑟瑞妥单抗(seribantumab)、泽妥珠单抗(zenocutuzumab)、阿普卢妥单抗(aprutumab)、贝马里妥珠单抗(bemarituzumab)、万替妥单抗(vantictumab)、地努妥昔单抗(dinutuximab)、依美昔单抗(ecromeximab)、米妥莫单抗(mitumomab)、考曲妥珠单抗(codrituzumab)、格巴妥木单抗(glembatumumab)、扎妥昔单抗(zatuximab)、厄妥索单抗(ertumaxomab)、玛格妥昔单抗(margetuximab)、替米妥珠单抗(timigutuzumab)、甘妥单抗(gancotamab)、帕妥珠单抗、曲妥珠单抗、非拉妥组单抗(ficlatuzumab)、利妥木单抗(rilotumumab)、特立妥珠单抗(telisotuzumab)、依玛妥珠单抗(emibetuzumab)、西妥木单抗、dalotuzumab、芬妥木单抗(figitumumab)、加尼妥单抗(ganitumab)、罗妥木单抗(robatumumab)、替妥木单抗(teprotumumab)、伏妥珠单抗(flotetuzumab)、贝迈奇单抗(bermekimab)、瑟妥珠单抗(cergutuzumab)、伏洛昔单抗(volociximab)、埃达珠单抗(etaracizumab)、瑞拉利单抗(relatlimab)、卡芦单抗(carlumab)、阿麦妥单抗(amatuximab)、克利妥珠单抗(clivatuzumab)、伽妥珠单抗(gatipotuzumab)、pemtumomab、莫坎妥珠单抗(cantuzumab)、pankomab、雷妥莫单抗(racotumomab)、布隆妥珠单抗(brontictuzumab)、他瑞妥单抗(tarextumabm)、维森苏单抗(vesencumab)、卡瑞利珠单抗(camrelizumab)、西利单抗(cetrelimab)、纳武单抗、派姆单抗、匹地利珠单抗、塞米普利单抗(cemiplimab)、斯巴达珠单抗(spartalizumab)、阿特利珠单抗、阿维鲁单抗、德瓦鲁单抗、西妥珠单抗、替妥莫单抗(tenatumomab)、夫苏木单抗(fresolimumab)、布洛赛珠单抗(brolucizumab)、贝伐单抗、雷珠单抗(ranibizumab)、伐利苏单抗(varisacumab)、法瑞西单抗(faricimab)、艾芦库单抗(icrucumab)、阿拉赛珠单抗(alacizumab)和雷莫芦单抗(ramucirumab)。
在一些实施方案中，本公开文本的基于LILRB1的受体包含对通过杂合性丢失而在癌细胞中丢失的抗原特异性的抗原结合结构域。在一些实施方案中，所述抗原是次要组织相容性抗原(MiHA)。在一些实施方案中，所述抗原是HLA I类等位基因。在一些实施方案中，所述HLA I类等位基因包含HLA-A、HLA-B或HLA-C。在一些实施方案中，所述HLA I类等位基因包含HLA-E。在一些实施方案中，所述HLA I类等位基因是HLA-A*02等位基因。在一些实施方案中，由于Y染色体的丢失，所述抗原不在靶细胞中表达。在一些实施方案中，对基于LILRB1的受体特异性的抗原是HLA-A*02抗原。
在一些实施方案中，有需要的受试者患有癌症。癌症是异常细胞不受控制地分裂并且扩散到附近组织的疾病。在一些实施方案中，所述癌症包括液体肿瘤或实体肿瘤。示例性液体肿瘤包括白血病和淋巴瘤。作为液体肿瘤的另外癌症可以是例如在血液、骨髓和淋巴结中出现的那些，并且可以包括例如白血病、髓细胞性白血病、淋巴细胞白血病、淋巴瘤、霍奇金淋巴瘤、黑色素瘤和多发性骨髓瘤。白血病包括例如急性成淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性髓细胞性白血病(CML)和毛细胞白血病。示例性实体瘤包括肉瘤和癌。癌症实际上可以出现在体内的器官中，所述器官包括血液、骨髓、肺、乳腺、结肠、骨、中枢神经系统、胰腺、前列腺和卵巢。作为实体瘤的另外癌症包括例如前列腺癌，睾丸癌，乳腺癌，脑癌，胰腺癌，结肠癌，甲状腺癌，胃癌，肺癌，卵巢癌，卡波西肉瘤，皮肤癌，鳞状细胞皮肤癌，肾癌，头颈癌，喉癌，在鼻、口、喉的湿润粘膜内壁上形成的鳞状癌，膀胱癌，骨肉瘤，宫颈癌，子宫内膜癌，食道癌，肝癌，和肾癌。在一些实施方案中，通过本文所述的方法治疗的病症是以下细胞的转移：黑色素瘤细胞、前列腺癌细胞、睾丸癌细胞、乳腺癌细胞、脑癌细胞、胰腺癌细胞、结肠癌细胞、甲状腺癌细胞、胃癌细胞、肺癌细胞、卵巢癌细胞、卡波西肉瘤细胞、皮肤癌细胞、肾癌细胞、头颈癌细胞、喉癌细胞、鳞癌细胞、膀胱癌细胞、骨肉瘤细胞、宫颈癌细胞、子宫内膜癌细胞、食道癌细胞、肝癌细胞或肾癌细胞。
其中多个癌细胞表达第一激活剂配体而不表达第二抑制剂配体的任何癌症被设想为在本公开文本的范围内。例如，可以使用本文所述的方法治疗的CEA阳性癌症包括结直肠癌、胰腺癌、食道癌、胃癌、肺腺癌、头颈癌、弥漫性大B细胞癌或急性髓性白血病癌症。
治疗癌症可以导致肿瘤大小的减小。肿瘤大小的减小也可以被称为“肿瘤消退”。优选地，治疗后，肿瘤大小相对于其治疗前的大小减小5％或更多；更优选地，肿瘤大小减小10％或更多；更优选地，减小20％或更多；更优选地，减小30％或更多；更优选地，减小40％或更多；甚至更优选地，减小50％或更多；并且最优选地，减小大于75％或更多。肿瘤的大小可以通过任何可再现的测量手段来测量。肿瘤的大小可以测量为肿瘤的直径。
治疗癌症可以导致肿瘤体积的减小。优选地，治疗后，肿瘤体积相对于其治疗前的大小减小5％或更多；更优选地，肿瘤体积减小10％或更多；更优选地，减小20％或更多；更优选地，减小30％或更多；更优选地，减小40％或更多；甚至更优选地，减小50％或更多；并且最优选地，减小大于75％或更多。肿瘤体积可以通过任何可再现的测量手段来测量。
治疗癌症导致肿瘤数目的减少。优选地，治疗后，肿瘤数目相对于治疗前的数目减少5％或更多；更优选地，肿瘤数目减少10％或更多；更优选地，减少20％或更多；更优选地，减少30％或更多；更优选地，减少40％或更多；甚至更优选地，减少50％或更多；并且最优选地，减少大于75％。肿瘤数目可以通过任何可再现的测量手段来测量。肿瘤数目可以通过计数肉眼可见的或在指定的放大倍数下的肿瘤来测量。优选地，指定的放大倍数是2x、3x、4x、5x、10x或50x。
治疗癌症可以导致远离原发性肿瘤部位的其他组织或器官中的转移病灶的数目减少。优选地，治疗后，转移病灶的数目相对于治疗前的数目减少5％或更多；更优选地，转移病灶的数目减少10％或更多；更优选地，减少20％或更多；更优选地，减少30％或更多；更优选地，减少40％或更多；甚至更优选地，减少50％或更多；并且最优选地，减少大于75％。转移病灶的数目可以通过任何可再现的测量手段来测量。转移病灶的数目可以通过计数肉眼可见的或在指定的放大倍数下可见的转移病灶来测量。优选地，指定的放大倍数是2x、3x、4x、5x、10x或50x。
与仅接受载体的群体相比，治疗癌症可以导致受治疗的受试者群体的平均存活时间增加。优选地，平均存活时间增加大于30天；更优选地，大于60天；更优选地，大于90天；并且最优选地，大于120天。群体的平均存活时间的增加可以通过任何可再现的手段测量。群体的平均存活时间的增加可以例如通过计算用活性化合物开始治疗后群体的平均存活时间长度来测量。群体的平均存活时间的增加也可以例如通过计算用活性化合物完成第一轮治疗后群体的平均存活时间长度来测量。
与未治疗的受试者群体相比，治疗癌症可以导致受治疗的受试者群体的平均存活时间增加。优选地，平均存活时间增加大于30天；更优选地，大于60天；更优选地，大于90天；并且最优选地，大于120天。群体的平均存活时间的增加可以通过任何可再现的手段测量。群体的平均存活时间的增加可以例如通过计算用活性化合物开始治疗后群体的平均存活时间长度来测量。群体的平均存活时间的增加也可以例如通过计算用活性化合物完成第一轮治疗后群体的平均存活时间长度来测量。
与接受使用不是本发明的化合物或其药学上可接受的盐、前药、代谢物、类似物或衍生物的药物的单一疗法的群体相比，治疗癌症可以导致受治疗的受试者群体的平均存活时间增加。优选地，平均存活时间增加大于30天；更优选地，大于60天；更优选地，大于90天；并且最优选地，大于120天。群体的平均存活时间的增加可以通过任何可再现的手段测量。群体的平均存活时间的增加可以例如通过计算用活性化合物开始治疗后群体的平均存活时间长度来测量。群体的平均存活时间的增加也可以例如通过计算用活性化合物完成第一轮治疗后群体的平均存活时间长度来测量。
与仅接受载体的群体相比，治疗癌症可以导致受治疗的受试者群体的死亡率降低。与未治疗的群体相比，治疗癌症可以导致受治疗的受试者群体的死亡率降低。与接受使用不是本发明的化合物或其1a药学上可接受的盐、前药、代谢物、类似物或衍生物的药物的单一疗法的群体相比，治疗癌症可以导致受治疗的受试者群体的死亡率降低。优选地，死亡率降低大于2％；更优选地，大于5％；更优选地，大于10％；并且最优选地，大于25％。受治疗的受试者群体的死亡率降低可以通过任何可再现的手段测量。群体的死亡率的降低可以例如通过计算用活性化合物开始治疗后群体的疾病相关死亡的平均数目/单位时间来测量。群体的死亡率的降低也可以例如通过计算用活性化合物完成第一轮治疗后群体的疾病相关死亡的平均数目/单位时间来测量。
治疗癌症可以导致肿瘤生长速率的降低。优选地，治疗后，肿瘤生长速率相对于治疗前的数值降低至少5％；更优选地，肿瘤生长速率降低至少10％；更优选地，降低至少20％；更优选地，降低至少30％；更优选地，降低至少40％；更优选地，降低至少50％；甚至更优选地，降低至少50％；并且最优选地，降低至少75％。肿瘤生长速率可以通过任何可再现的测量手段来测量。肿瘤生长速率可以根据肿瘤直径的变化/单位时间来测量。
治疗癌症可以导致肿瘤再生长的减少。优选地，治疗后，肿瘤再生长小于5％；更优选地，肿瘤再生长小于10％；更优选地，小于20％；更优选地，小于30％；更优选地，小于40％；更优选地，小于50％；甚至更优选地，小于50％；并且最优选地，小于75％。肿瘤再生长可以通过任何可再现的测量手段来测量。肿瘤再生长例如通过测量在治疗后的先前肿瘤缩小后肿瘤直径的增加来测量。肿瘤再生长的减少由治疗停止后肿瘤不能再复发来指示。
治疗或预防细胞增殖障碍可以导致细胞增殖速率的降低。优选地，治疗后，细胞增殖速率降低至少5％；更优选地，至少10％；更优选地，至少20％；更优选地，至少30％；更优选地，至少40％；更优选地，至少50％；甚至更优选地，至少50％；并且最优选地，至少75％。细胞增殖速率可以通过任何可再现的测量手段来测量。细胞增殖速率例如通过测量组织样品中的分裂细胞的数目/单位时间来测量。
治疗或预防细胞增殖障碍可以导致增殖细胞比例的降低。优选地，治疗后，增殖细胞的比例降低至少5％；更优选地，至少10％；更优选地，至少20％；更优选地，至少30％；更优选地，至少40％；更优选地，至少50％；甚至更优选地，至少50％；并且最优选地，至少75％。增殖细胞的比例可以通过任何可再现的测量手段来测量。优选地，增殖细胞的比例例如通过相对于未分裂细胞的数目定量组织样品中分裂细胞的数目来测量。增殖细胞的比例可以等同于有丝分裂指数。
治疗或预防细胞增殖障碍可以导致细胞增殖的区域或区的大小减小。优选地，治疗后，细胞增殖的区域或区的大小相对于治疗前的大小减小至少5％；更优选地，减小至少10％；更优选地，减小至少20％；更优选地，减小至少30％；更优选地，减小至少40％；更优选地，减小至少50％；甚至更优选地，减小至少50％；并且最优选地，减小至少75％。细胞增殖的区域或区的大小可以通过任何可再现的测量手段来测量。细胞增殖的区域或区的大小可以测量为细胞增殖的区域或区的直径或宽度。
治疗或预防细胞增殖障碍可以导致具有异常外观或形态的细胞的数目或比例的减少。优选地，治疗后，具有异常形态的细胞的数目相对于治疗前的大小减少至少5％；更优选地，减少至少10％；更优选地，减少至少20％；更优选地，减少至少30％；更优选地，减少至少40％；更优选地，减少至少50％；甚至更优选地，减少至少50％；并且最优选地，减少至少75％。异常细胞外观或形态可以通过任何可再现的测量手段来测量。异常细胞形态可以通过显微镜检查，例如使用倒置组织培养显微镜来测量。异常细胞形态可以采取核多形的形式。
试剂盒和制品
本公开文本提供了包含编码本文所述受体的多核苷酸和载体的试剂盒和制品。在一些实施方案中，所述试剂盒包括制品，诸如小瓶、注射器和使用说明书。
在一些实施方案中，所述试剂盒包含多核苷酸或载体，所述多核苷酸或载体包含编码一种或多种本公开文本的嵌合抗原受体的序列。例如，所述多核苷酸或载体包含一个或多个如本文所述的LILRB1结构域的序列。
在一些实施方案中，所述试剂盒包含多个免疫细胞，所述免疫细胞包含如本文所述的嵌合抗原受体。在一些实施方案中，所述多个免疫细胞包含多个T细胞。
说明性嵌合抗原受体的元件的多肽序列
说明性嵌合抗原受体的多肽序列
本说明书阐述了许多示例性构型、方法、参数等。然而，应认识到，这样的描述并不旨在作为对本公开文本的范围的限制，而是旨在作为示例性实施方案的描述而提供。
实施例
实施例1：基于LILRB1的抑制性scFv-CAR与PD-1、KIR3DL2、KIR3DL3相比较
通过将NY-ESO-1配体结合scFv结构域(C-266)与受体的结构域融合产生NY-ESO-1反应性抑制性构建体，所述受体的结构域包括白细胞免疫球蛋白样受体亚家族B成员1(LILRB1(LILRB1))；杀伤细胞免疫球蛋白样受体3DL2(KIR3DL2)；杀伤细胞免疫球蛋白样受体3DL3(KIR3DL3)；和/或B-和T-淋巴细胞衰减因子BTLA的铰链、跨膜区和/或胞内结构域。使用金门(Golden Gate)克隆将基因片段组合，并且插入慢病毒表达质粒(pLenti1)中所含的eF1ɑ启动子的下游。
作为报告细胞，将编码NFAT萤光素酶报告物的Jurkat细胞维持在补充有10％FBS、1％Pen/Strep和0.4mg/mL G418/遗传霉素的RPMI培养基中。将T2细胞(ATCC CLR-1992)维持在IMDM培养基+20％FBS和1％Pen/Strep中。对于每种待评价的构建体，根据制造商的方案，使用以下设置：3脉冲，1500V，10msec，经由100μL格式Neon电穿孔系统(Thermo Fisher)转染Jurkat细胞。
用3μg激活型CAR构建体(C-563)或TCR构建体(CT-139)和3μg失活型CAR构建体或空载体(pLenti0)/100万个细胞进行共转染，并且将其回收于补充有20％热灭活的FBS和0.1％Pen/Strep的RPMI培养基中。
通过Genscript合成肽(MAGE-A3(FLWGPRALV)(SEQ ID NO:106)和经修饰的NY-ESO-1(SLLMWITQV)(SEQ ID NO:107))。将激活型肽MAGE-A3从50μM开始连续稀释5倍。将失活型肽NY-ESO-1稀释至50μM、5μM、0.5μM或0.05μM，并且将这些恒定量添加到MAGE-A3连续稀释液中并且随后加载到15μL补充有1％BSA和0.1％Pen/Strep的RPMI中的10,000个T2细胞上，并且在
384孔低凸缘白色平底聚苯乙烯TC处理的微板中孵育。第二天，将10,000个Jurkat细胞重悬于15uL补充有10％热灭活FBS和0.1％Pen/Strep的RPMI中，添加到加载肽的T2细胞中，并且共培养6小时。使用一步萤光素酶测定系统(BPS Bioscience)来评价Jurkat发光。以一式两份的技术重复进行测定。
LILRB1与PD-1、KIR3DL2、KIR3DL3相比较
图4示出了对表1中提供的构建体的测试。数据显示scFv-LILRB1以反式抑制CAR激活。因为具有LILRB1结构域的构建体表明在较高浓度的MAGE-A3激活剂肽下抑制信号传导，所以数据表明具有来自LILRB1的铰链、跨膜结构域和胞内结构域的CAR优于用来自PD-1、KIR3DL2或KIR3DL3的相同结构域产生的CAR。
表1
由基于LILRB1的CAR引起的抑制需要由其配体结合结构域进行的抗原识别
图5示出了对来自表1的所选构建体进行的测试。数据显示LILRB1以剂量依赖方式以反式抑制信号传导。在抑制性肽NY-ESO-1的浓度递增时，对激活型肽MAGE-A3的反应向下移动。这表明基于LILRB1的CAR的抑制性作用依赖于抗原的接合，配体结合结构域是对所述抗原特异性的。
LILRB1 CAR通过T细胞受体(TCR)抑制信号传导
图6示出了对来自表1的所选构建体，特别是对激活型肽MAGE-A3特异性的TCR，而不是在先前实验中使用的CAR进行的测试。基于LILRB1的抑制性CAR以剂量依赖方式抑制TCR介导的信号传导。
当存在四种天然ITIM中的两种时，LIRLB1 CAR抑制得到保持
图7示出了对在LILRB1的ITIM基序中具有失活型突变的LILRB1胞内结构域进行的测试。使用酪氨酸突变为苯丙氨酸(Y→F)来失活由表2中的星号指示的ITIM。
表2
所有四种ITIM的失活产生非功能性抑制性CAR(C2182)。四种ITIM中仅两种的失活在测试的浓度下保留了CAR的抑制剂功能(C1760和C1762)。所有四种ITIM的失活(C1759)表明ITIM是抑制性功能所必需的。当所有四种ITIM都突变时，分子丧失抑制性功能。当四种ITIM中只有两种突变时，保留了抑制活性。
图8示出了对与天然LILRB1胞内结构域的那些不同的LILRB1 ITIM组合进行的测试。如表3中所示，具有总共四个或六个拷贝的LILRB1的第三ITIM和第四ITIM的CAR实现了与天然LILRB1胞内结构域相当的抑制活性。当使用第三ITIM和第四ITIM各自仅一个拷贝时(C2179)，或当每种ITIM使用两个拷贝时(C2180)，或当使用多个拷贝时(C2302或C2180)，也观察到抑制活性。
表3
实施例2：LILRB1铰链和跨膜结构域增强基于BTLA的抑制性CAR的抑制活性
基于BTLA的CAR和基于LILRB1/BTLA的CAR经由NFAT抑制信号传导
B-和T-淋巴细胞衰减因子(BTLA)，也称为CD272(分化簇272)，与B7同源性B7H4相互作用。与CTLA-4和PD-1不同，BTLA还是肿瘤坏死因子(受体)超家族成员14(TNFRSF14)的配体。通过BTLA的抑制性信号传导响应于B7H4或TNFRSF14的结合而发生。
将全长BTLA蛋白克隆到具有胞外scFv结构域的构建体(C2220)，产生用LILRB1的胞外结构域替代BTLA的胞外结构域的构建体(C2219)和用LILRB1的胞外结构域和跨膜结构域替代BTLA的胞外结构域和跨膜结构域的构建体(C2218)，并且进行测试，如表4和图9中所示。LILRB1-BTLA融合体展现出与基于LILRB1的CAR相当的抑制性信号传导。
表4
实施例3：LILRB1铰链和跨膜与CD8或CD28相比较
具有LILRB1铰链和跨膜的基于LILRB1的CAR优于CD8铰链和CD28跨膜区
将基于LILRB1的CAR与具有LILRB1胞内结构域但具有CD8铰链和CD28跨膜区的CAR相比较，如表5和图10中所示。
表5
LILRB1铰链和跨膜区产生的结果令人惊奇地优于具有CD8铰链和CD28跨膜区的构建体。Emin降低。整体动态范围增加。抑制效力增加。
表6：实施例1-3中所示的结果的归纳。
| 抑制剂构建体 | 激活剂构建体 | uM抑制剂肽 | E<sub>min</sub>[RLU] | EC<sub>50</sub>[nM] | E<sub>max</sub>[RLU] |
| - | C563 | 50 | 30,000 | 10 | 100,000 |
| - | CT139 | 50 | 0 | 20 | 100,000 |
| C1761 | C563 | 50 | 1,000 | >10,000 | NA |
| C1761 | CT139 | 50 | 400 | >1,000 | NA |
| C1759 | C563 | 50 | 20,000 | 200 | 100,000 |
| C1760 | C563 | 50 | 5,000 | 60 | 100,000 |
| C1762 | C563 | 50 | 5,000 | 600 | 90,000 |
| C2184 | C563 | 50 | 1,000 | >1,000 | NA |
| C2183 | C563 | 50 | 4,000 | >1,000 | NA |
| C2182 | C563 | 50 | 30,000 | 30 | 90,000 |
| C2302 | C563 | 50 | 0 | >10,000 | NA |
| C2181 | C563 | 50 | 0 | >10,000 | NA |
| C2180 | C563 | 50 | 0 | >10,000 | NA |
| C2179 | C563 | 50 | 0 | >10,000 | NA |
| C2218 | C563 | 50 | 1,000 | >1,000 | NA |
| C2219 | C563 | 50 | 2,000 | >1,000 | NA |
| C2220 | C563 | 50 | 3,000 | >1,000 | NA |
| C2153 | C563 | 50 | 20,000 | 2,000 | 60,000 |
| C2107 | CT139 | 5 | 0 | 100 | 100,000 |
| C2106 | CT139 | 5 | 0 | 40 | 100,000 |
实施例4：基于TCR的抑制性嵌合抗原受体
构建体设计和克隆
使用高亲和性抗HLA-A*02:01/NY-ESO-1 1G4α95:LY T细胞受体(TCR)变体产生NY-ESO-1-反应性抑制性构建体。TCRα的TM中的带电荷的残基(R253和K258)和TCRβ的TM中的带电荷的残基(K288)突变为亮氨酸。然后，将LILRB1 ITIM(残基484-650)附加到突变的TCRα或TCRβ上。内部产生抗HLA-A*02:01/MAGE-A3单链可变片段(scFv)。本研究中使用的抗HLA-A2*02:01/MAGE-A3嵌合抗原受体(CAR)含有抗HLA-A*02:01/MAGE-A3 scFv，CD8铰链，CD28 TM，以及CD28、41BB和CD3ζ胞内结构域(ICD)。使用Q5聚合酶(New England Biolabs)扩增所有片段(包括5'和3'BsmBI位点)，并且在37℃下用DpnI(Thermo Scientific)消化60min。使用Nucleospin凝胶和PCR净化试剂盒(Macherey-Nagel)纯化产生的PCR片段。在含有BsmBI(Thermo Scientific)、T4 DNA连接酶(Thermo Scientific)、10mM ATP和1xFastDigest缓冲液(Thermo Scientific)的反应中进行质粒的金门组装。
Jurkat NFAT激活测定
使用Neon转染系统(Thermo Fisher)，用编码TCR和/或scFv-融合构建体的质粒共转染含有在激活剂T细胞核因子(NFAT)转录因子(BPS Bioscience)控制下的萤火虫萤光素酶基因的Jurkat T淋巴细胞。将电穿孔的细胞在RPMI培养基中孵育，所述RPMI培养基补充有在56℃下热灭活60min的20％胎牛血清(FBS)(HIA-FBS)和0.1％青霉素-链霉素(P/S)(Gibco)。向TAP缺陷的T2淋巴母细胞(ATCC RL-1992)加载不同量的单独的经修饰的NY-ESO-1肽(SLLMWITQV)(SEQ ID NO:107)、单独的经MAGE-A3肽(FLWGPRALV)(SEQ ID NO:106)或除了在补充有1％BSA和0.1％P/S(Gibco)的RPMI中的50μM NY-ESO-1肽之外，还有不同量的MAGE-A3肽。合成测定中使用的肽，通过质谱法(Genscript)评估纯度>95％。转染后18小时，将Jurkat以0.8x 106个细胞/mL重悬于补充有10％HIA-FBS和1％P/S的RPMI中。在384孔板中，将12000个Jurkat与12000个加载肽的T2/孔在37℃、5％CO2下共培养6小时。通过添加15uL的一步萤光素酶测定试剂(BPS Bioscience)测量NFAT介导的萤光素酶产生。20分钟后，使用酶标仪(Tecan)检测发光。
使用LILRB1胞内结构域的基于TCR的抑制性CAR
如表7和图11中所示，仅具有TCR的胞外结构域或还具有TCR的跨膜区(具有突变成极性残基的突变)的基于TCR的CAR的共表达产生功能性抑制性CAR。
表7
基于TCR的CAR以反式抑制抗HLA-A*02:01MAGE-A3 CAR。将Jurkat-NFAT萤光素酶报告细胞如下转染：(1)用单独的抗HLA-A*02:01/MAGE-A3 CAR(C563)转染，(2)用MAGE-A3CAR(C563)和TCRα(R253L/K258L)-LILRB1融合体和TCRβ(K288L)-LILRB1 ICD融合体TCR抑制性融合构建体(C2156+C2157)共转染，或(3)用MAGE-A3 CAR和TCRαECD/TCRβECD-LIRT1(TM+ICD)融合体(C2057+C2058)TCR抑制性融合构建体共转染。通过将转染的Jurkat细胞与加载有50μM NY-ESO-1肽与不同量的MAGE-A3肽的组合的T2细胞共培养，测量两种抑制性变体对NFAT激活的作用。数据归纳于表8中。
表8：TCR抑制性融合构建体对MAGE-A3 CAR的反式作用
截短的TCRα或TCRβ胞外结构域(ECD)-与LILRB1 TM-ICD的融合体抑制CAR激活。当TCR跨膜突变消除了TCR-CD3亚基相互作用时，TCRα或TCRβ胞外结构域(ECD)-与TCR TM-LILRB1 ICD的融合体也充当抑制剂CAR。实验表明TCRα链和TCRβ链可以通过干扰由CD3亚基进行的刺激因子募集而用于产生抑制性嵌合抗原受体。
实施例5：用于实施例6-14的方法
细胞培养
编码NFAT萤光素酶报告物的Jurkat细胞从BPS Bioscience获得。本研究中使用的所有其他细胞系都从ATCC获得。在培养中，将Jurkat细胞维持在补充有10％FBS、1％Pen/Strep和0.4mg/mL G418/遗传霉素的RPMI培养基中。按照ATCC的提示，维持T2、MCF7、Raji、K562和HeLa细胞。通过用HLA-A*02慢病毒(定制慢病毒，Alstem)以5的MOI转导Raji细胞来制备“正常”Raji细胞。使用FACSMelody细胞分选仪(BD)分选HLA-A*02阳性Raji细胞。
质粒构建
通过将NY-ESO-1scFv LBD融合至受体的结构域来产生NY-ESO-1-反应性抑制性构建体，所述受体的结构域包括白细胞免疫球蛋白样受体亚家族B成员1(LILRB1(LIR-1))；程序性细胞死亡蛋白1(PDCD1(PD-1))；或细胞毒性T-淋巴细胞蛋白4(CTLA4(CTLA-4))的铰链、跨膜区和/或胞内结构域。所有激活型CAR构建体均含有与CD8α铰链，CD28 TM，以及CD28、4-1BB和CD3ζICD融合的scFv。CD19激活型CAR scFv来源于FMC63小鼠杂交瘤。MSLN激活型CAR scFv来源于如所述的人M5(LBD1)和人源化SS1(LBD2)。使用金门克隆将基因片段组合，并且插入慢病毒表达质粒中所含的人EF1ɑ启动子的下游。
Jurkat细胞转染
根据制造商的方案，使用以下设置：3脉冲，1500V，10msec，经由100uL格式Neon电穿孔系统(Thermo Fisher Scientific)瞬时转染Jurkat细胞。用1-3ug的激活剂CAR或TCR构建体和1-3ug的scFv或TCRα/TCRβLIR-1阻断剂构建体或空载体/1e6个细胞进行共转染，并且将其回收于补充有20％热灭活FBS和0.1％Pen/Strep的RPMI培养基中。为了证实阻断剂表面表达，在转染后18-24小时，将Jurkat细胞用10ug/mL链霉亲和素-PE-HLA-A*02-pMHC四聚体在4℃下在含有1％BSA的PBS中染色60分钟，并且通过流式细胞术(BD FACScantoII)表征。
Jurkat-NFAT-萤光素酶激活研究
肽MAGE-A3(MP1；FLWGPRALV；SEQ ID NO:106)、MAGE-A3(MP2；MPKVAELVHFL；SEQ IDNO:108)、HPV E6(TIHDIILECV；SEQ ID NO:109)、HPV E7(YMLDLQPET；SEQ ID NO:110)和经修饰的NY-ESO-1ESO(ESO；SLLMWITQV；SEQ ID NO:107)是由Genscript合成的。将激活型肽从50uM开始连续稀释。将阻断剂肽NY-ESO-1稀释至50uM(除非另有说明)，将其添加到激活型肽连续稀释液中并且随后加载到在15uL的补充有1％BSA和0.1％Pen/Strep的RPMI中的1e4个T2细胞上，并且在
384孔低凸缘白色平底聚苯乙烯TC处理的微板中孵育。第二天，将1e4个Jurkat细胞重悬于15uL补充有10％热灭活FBS和0.1％Pen/Strep的RPMI中，添加到加载肽的T2细胞中，并且共培养6小时。使用一步萤光素酶测定系统(BPSBioscience)来评价Jurkat发光。对于涉及高密度靶标的测定，类似地转染Jurkat细胞，并且将其与表达靶抗原的肿瘤细胞一起以各种Jurkat细胞:肿瘤细胞比率共培养。以一式两份的技术重复进行测定。
原代T细胞转导、扩增和富集
Leukopak购自
收集方案和供体知情同意书由机构审查委员会(IRB)批准，并严格监督。还遵循HIPAA依从性和批准的方案。将冷冻的PBMC在37℃水浴中解冻，并且在含有1％人血清的LymphoONE(Takara)中以1e6个细胞/mL培养，并且使用1:100的补充有IL-15(10ng/mL)和IL-21(10ng/mL)的T细胞Transact(Miltenyi)激活。24小时后，以MOI＝5将慢病毒添加到PBMC。对于每种慢病毒，以MOI＝5同时共转导激活剂受体和阻断剂受体。将PBMC额外培养2-3天，以允许细胞在TransAct刺激下扩增。扩增后，根据制造商的说明书，使用抗PE微珠(Miltenyi)通过阳性选择针对阻断剂阳性T细胞对激活剂和阻断剂转导的原代T细胞进行富集。简短地讲，将原代T细胞与10ug/mL链霉亲和素-PE-HLA-A*02-pMHC四聚体在MACS缓冲液(在PBS中的0.5％BSA+2mM EDTA)中在4℃下一起孵育60分钟。将细胞在MACS缓冲液中洗涤3次，并且使其通过LS柱(Miltenyi)以从未转导的细胞和仅激活剂的细胞中分离出阻断剂阳性细胞(仅阻断剂细胞和激活剂+阻断剂细胞的混合物)。
原代T细胞体外细胞毒性研究
对于用pMHC靶标进行的细胞毒性研究，将富集的原代T细胞与2e3个加载有滴定的如上所述的靶肽的表达海肾萤光素酶(Biosettia)的MCF7细胞以3:1的效应物:靶标比率一起孵育48小时。使用海肾萤光素酶报告物测定系统(Promega)定量表达萤光素酶的活MCF7细胞。对于用非pMHC靶标进行的细胞毒性研究，将富集的原代T细胞与2e3个WT Raji细胞(“肿瘤”细胞)或HLA-A*02转导的Raji细胞(“正常”细胞)以3:1的效应物:靶标比率一起孵育长达6天。使用IncuCyte活细胞成像仪，将稳定表达GFP和海肾萤光素酶(Biosettia)的WT“肿瘤”Raji细胞或稳定表达RFP和萤火虫萤光素酶(Biosettia)的HLA-A*02转导的“正常”Raji细胞与未标记的原代T细胞一起成像。使用IncuCyte成像软件定量活Raji细胞随时间的荧光强度。对于可逆性研究，类似地将富集的原代T细胞与“正常”或“肿瘤”Raji细胞共培养3天并且成像。3天后，使用CD19阴性选择从剩余的Raji细胞中分离出T细胞，并且用如所述的新鲜“正常”或“肿瘤”Raji细胞再接种。在单独的孔中，在72小时时使用双重萤光素酶报告物测定系统(Promega)定量表达萤光素酶的活Raji细胞。对于评估IFNγ分泌的研究，使用BD人IFNγflex试剂盒遵循制造商的精确说明书，测试共培养48小时后收集的上清液中的IFNγ。
小鼠异种移植研究
将冷冻的PBMC在37℃水浴中解冻，并且在激活前在无血清的TexMACS培养基(Miltenyi)中静置过夜。使用T细胞TransAct(Miltenyi)和补充有IL-15(20ng/mL)和IL-21(20ng/mL)的TexMACS培养基以1.5e6个细胞/mL激活PBMC。24小时后，将慢病毒以5的MOI添加到PBMC中。将PBMC额外培养8-9天，以允许细胞在TransAct刺激下扩增。扩增后，在体内注射前，使用针对链霉亲和素-PE-HLA-A*02-pMHC的抗PE微珠(Miltenyi)在A2-LIR-1上富集T细胞额外2天-5天。还通过流式细胞术(BD FACScanto II)通过对于激活剂用CD19-Fc(1:100；R&D Systems)和山羊抗人IgG-FITC(1:200；Invitrogen)和对于阻断剂用10ug/mL的链霉亲和素-APC-HLA-A*02-pMHC依序染色，验证富集的T细胞的CD19 scFv激活剂和HLA-A*02LIR-1阻断剂的表达。
由Explora BioLabs在机构动物护理和使用委员会(Institutional Animal Careand Use Committee，IACUC)批准的方案下进行体内实验。5-6周龄雌性NOD.Cg-PrkdcscidIl2rgtm1Wjl Tg(HLA-A/H2-D/B2M)1Dvs/SzJ(NSG-HLA-A2/HHD)小鼠购自Jackson Labs。在研究开始前，使动物适应居住环境至少3天。对动物在右胁腹皮下注射100uL体积的2e6个WTRaji细胞或HLA-A*02转导的Raji细胞。当肿瘤达到平均70mm3(V＝L x W x W/2)时，将动物随机分成5组(n＝7)，并且经由尾静脉施用2e6个或1e7个T细胞。注射T细胞后，每周进行3次肿瘤测量，并且在10天和17天后收集血液用于流式分析。由于失败的尾静脉注射，从研究中排除来自接受1e7个CD19-CAR+A2-LIR-1T细胞的WT Raji组的一只动物，随后通过流式细胞术证实血液中不存在人T细胞。在每个时间点，RBC溶解后通过流式细胞术(BD FACScantoII)定量血液中的人T细胞。将细胞用抗小鼠CD45-FITC(克隆30-F11)、抗人CD3-PE(克隆SK7)、抗人CD4-APC(克隆OKT4)和抗人CD8-PerCP-Cy5.5(克隆RPA-T8)染色。所有抗体均从Biolenging获得并且以1:100的稀释度使用。使用DAPI(Invitrogen)以从分析中排除死细胞。对于组织学分析，将肿瘤样品固定、切片并且对于huCD3(克隆EP449E)进行染色。使用ImageJ软件进行图像定量。
统计分析
使用GraphPad Prism软件进行统计分析。除非另有说明，否则所有肽和细胞滴定研究都显示为平均值±标准差(SD)，而使用原代T细胞的体外和体内研究显示为平均值±平均值的标准误差(SEM)。使用四参数非线性回归分析拟合肽和细胞滴定曲线。EC50值直接从曲线计算。除非另有说明，否则所有其他数据组都使用普通双因素方差分析，随后使用Tukey多重比较检验进行分析。
实施例6：测定LIR-1铰链对阻断活性的影响
使用上述Jurkat NFat萤光素酶测定，测定不同LIR-1铰链对HLA-A*02scFv LIR-1抑制性受体阻断由表达KRAS TCR激活剂的Jurkat细胞引起的杀伤的能力的影响。如前所述在Jurkat细胞中测定具有较短LIR-1铰链的人源化PA2.1 scFv LIR-1受体和人源化BB7.2scFv LIR-1，并且结果示出于图12A-12B中。用具有各种LIR-1衍生的铰链的KRAS TCR激活剂受体和/或HLA-A*02scFv LIR-1抑制性受体(人源化PA2.1或人源化BB7.2)转染Jurkat细胞，并且将其与T2靶细胞共培养，所述T2靶细胞是HLA:A11阳性的或HA:A11和HLA:A02阳性的。具有较短铰链和较长铰链的抑制性受体表现相似(图12A-12B)。在T2-Jurkat测定中，还测定具有小鼠PA2.1 scFv和稍长铰链的抑制性受体与较短LIR-1铰链在功能上类似(图13A-13B)。铰链序列在图12B和图13B中以黑色示出，图13B中序列中的灰色SS代表抗原结合结构域与铰链之间的接头，并且灰色VIGIL代表LIR-1跨膜结构域的起点。抑制性受体的铰链、跨膜结构域和胞内结构域都来源于LIR-1。图12A-12B和图13A-13B示出了LIR-1铰链长度可以变化，而不会不利地影响LIR-1抑制性受体。当将编码LIR-1抑制性受体的核酸序列包装在慢病毒载体中以进行递送时，较短的铰链可以提供优势。
表9.构建体的序列
实施例7：LIR-1、CTLA-4和PD-1抑制性受体的比较
通过将NY-ESO-1scFv LBD融合至受体的结构域来产生NY-ESO-1-反应性抑制性构建体，所述受体的结构域包括白细胞免疫球蛋白样受体亚家族B成员1(LILRB1(LIR-1))；程序性细胞死亡蛋白1(PDCD1(PD-1))；或细胞毒性T-淋巴细胞蛋白4(CTLA4(CTLA-4))的铰链、跨膜区和/或胞内结构域。MAGE-A3激活型CAR构建体含有与CD8α铰链，CD28 TM，以及CD28、4-1BB和CD3ζ胞内结构域(ICD)融合的scFv。使用金门克隆将基因片段组合，并且插入慢病毒表达质粒中所含的人EF1ɑ启动子的下游。
最初，使用对于激活剂受体和阻断剂受体两者的肽-MHC(pMHC)靶标，因为pMHC允许方便地定量系统的药理学(图14A)。具体而言，使用结合HLA-A*02-NY-ESO-1(SLLMWITQC/V)的单链可变片段(scFv)作为抑制剂受体配体结合结构域(LBD)，并且将针对HLA-A*02-MAGE-A3(FLWGPRALV)pMHC(Gallo，未公开的)的第二scFv作为激活剂受体第三代CAR的一部分。使用NFAT激活后表达萤光素酶的Jurkat效应细胞读出激活剂敏感性，EC50值报告反应所需的半最大激活剂肽浓度。PD-1和CTLA-4胞内结构域(ICD)两者均介导Jurkat细胞中的激活的EC50的位移小于约10x，通过滴定作为刺激物加载在T2细胞上的肽来测量(图14B)。
筛选多种潜在的抑制剂(阻断剂)受体构建体，并且发现所构建的LIR-1阻断剂具有比PD-1和CTLA-4更强的阻断特性。这种阻断剂受体包括LIR-1(LILRB1)受体的胞内结构域、跨膜(TM)结构域和铰链结构域，数种LIR家族分子中的一种由人基因组编码。融合至NY-ESO-1LBD的LIR-1阻断剂(下文称作LIR-1)介导>5,000x的EC50位移(图14B，图17A-17D)。不相关的HLA-A*02结合肽的对照滴定提供了加载在T2细胞上的肽对可用HLA分子的竞争所引起的位移的估计，对总位移的贡献典型地小于约10x(图15)。对于此处报告的EC50位移值，典型地与仅有激活剂的构建体的EC50进行比较。此外，对于给定的一对激活剂受体/阻断剂受体，对于抑制的滴定的中点是大致恒定的并且取决于激活型肽与阻断型肽的比率，据推测与靶标-抗原比率直接相关(图16A-16D)。在这些实验中的大多数中研究的靶标浓度估计范围为约1,000-10,000个拷贝/细胞。
实施例8：具有多个scFv配体结合结构域的LIR-1抑制性受体
用对其他pMHC靶标特异性的多种抗原结合结构域测试LIR-1抑制性受体的活性。对于四种不同的pMHC靶标，接枝到LIR-1上的总共六个不同的scFv介导EC50的显著位移，范围为10x至1,000x(图14C)。关于其与激活剂受体的相互作用，LIR-1受体也是稳健的；其阻断行为适用于多种靶标和scFv(图14D)。阻断是配体依赖性的(图17A)，尽管许多LIR-1构建体在与特异性激活剂受体配对时产生较低的基础/强直(tonic)信号传导。EC50位移依赖于融合ICD的存在，因为完全缺乏ICD或在ICD的关键元件中含有突变的LIR-1构建体没有影响(图17B)。然而，配体非依赖性阻断剂活性对不存在配体的激活EC50几乎没有影响(图16A-16D)。LIR-1抑制性受体是模块化的、适应性的、配体门控的系统，其功能跨多个靶标和抗原结合结构域。
实施例9：融合至TCRα和TCRβ的LIR-1抑制性结构域
当LIR-1抑制性受体与TCRα及TCRβ亚单位融合时或当与TCR激活剂受体组合时，测试LIR-1抑制性受体。TCR针对3种不同的pMHC靶标，2种来自MAGE-A3，并且一种来自HPV(参见方法，见上文)。在每种情况下，LIR-1使激活EC50以大量位移，估计范围>1,000x(图14E；图19A)。此外，NY-ESO-1TCR LBD在与LIR-1融合时也产生显著的EC50位移(图14F；图19B)。实际上，MAGE-A3(FLWGPRALV)CAR或TCR与NY-ESO-1(SLLMWITQV)scFv或TCR的所有组合都展示出大位移。因此，LIR-1抑制性受体展现出涵盖CAR和TCR两者的调节性。
实施例10：LIR-1抑制性受体对以相对于激活剂受体靶抗原顺式存在的靶抗原具有反应
测定当激活剂靶标和抑制剂靶标以顺式存在时LIR-1阻断剂受体抑制由激活剂受体引起的激活的能力。在第一测定中，使用由大致为细胞大小(d约2.8um)的加载靶标的珠组成的简化刺激物。表达激活剂受体和阻断剂受体的Jurkat细胞仅被含有A(激活剂)靶标的珠激活，而不被具有双重A/B(激活剂/阻断剂)靶标的珠激活(图18A)。有趣的是，效应细胞被A+珠和B+珠的混合物激活，即使当A+珠仅占总量的20％时。这表明表达激活剂受体和阻断剂受体的细胞：(i)当靶标以顺式存在于同一表面上时，被阻断剂受体阻断激活；以及(ii)被过量B+珠中的单独A+珠激活。
实施例11：LIR-1抑制性受体和细胞表面抗原
测定LIR-1抑制剂受体阻断响应于非pMHC靶标的激活的能力，所述非pMHC靶标代表可以延伸到100,000个表位/细胞范围的表面抗原。测试以不依赖肽的方式结合B细胞标记物CD19、实体瘤抗原间皮素(MSLN)或HLA-A*02的scFv。在这些情况下，靶抗原浓度不受控制，与外源肽和pMHC一样。相反，在瞬时转染测定中使用不同的DNA浓度改变激活剂表达与阻断剂表达的比率。尽管测定灵敏度阻止了对EC50位移的全部范围的研究，但观察到Emax的位移超过10x。这些实验表明，LIR-1受体在双重受体系统中的特性对于高密度靶标通常是相同的(图18B；图16-16D；图21A)，并且阻断剂受体阻断A受体的激活至由其在效应细胞上的相对表面水平所反映的程度(图18C)。LIR-1受体在这种高抗原密度环境中也以模块化方式发挥作用。针对HLA-A*02的scFv当融合到激活剂受体或阻断剂受体时分别充当激活剂(图18D)或阻断剂。LIR-1受体足够灵活以适应低靶标密度和高靶标密度，原则上允许优化pMHC靶标以及非pMHC表面抗原。
实施例12：原代T细胞中的LIR-1抑制性受体
测定LIR-1受体阻断原代T细胞激活的能力。首先使用pMHC靶标。在经由物理选择富集转导的T细胞后，使用工程化以表达萤光素酶的靶细胞作为活细胞的读数，测定表达激活物受体和阻断剂受体的工程化T细胞。以HPV TCR作为激活剂，与LIR-1融合的NY-ESO-1scFv使加载肽的MCF7肿瘤细胞中的细胞计数相对于肽浓度曲线位移约25x(图20A；图23)。因此，在Jurkat细胞激活测定中表明的LIR-1受体的行为扩展到原代T细胞功能，包括细胞毒性。
为了建立概念验证，显示HLA-A*02LIR-1构建体在Jurkat细胞与T2靶细胞中在pMHC依赖性激活剂的存在下充当阻断剂(图20B)。对于激活剂，将CD19 scFv用作CAR。显示这种激活剂/阻断剂对与先前在Jurkat细胞中测试的其他对一样强稳健地一起发挥功能(图18B)。使用差异表达LIR-1受体配体的T模型肿瘤细胞，CD19阳性、HLA-A*02阴性的Raji细胞。为了对于对应的正常细胞进行建模，使用稳定表达HLA-A*02基因的相同细胞系(图24A)。如果靶细胞仅表达CD19，则细胞系激活Jurkat细胞，但如果它们表达CD19和HLA-A*02两者，则不激活Jurkat细胞；即HLA-A*02阻断剂受体以配体依赖性方式阻断由CD19-CAR引起的激活(图24B)。
CD19/HLA-A*02受体对也在原代T细胞中起作用(图21)。工程化T细胞在不存在HLA-A*02表达的情况下杀伤表达CD19的Raji细胞。表达CD19和HLA-A*02两者的Raji细胞被阻断免于细胞毒性。重要的是，携带所述受体对的原代T细胞在混合培养物中将CD19+“肿瘤”与CD19+/HLA-A*02+“正常”细胞区分开。这些发现反映了来自上述珠实验的结果，但是在更复杂的细胞环境中，其中效应细胞的细胞毒性集中在“肿瘤”靶标上，即使当被“正常”细胞包围时。鉴于没有对任一种受体进行针对最大选择性的有意优化，选择性的程度是令人印象深刻的。用第二抗原MSLN证实了这种行为(图22B)。
实施例13：LIR-1抑制性受体的抑制的可逆性
测试LIR-1抑制性受体可逆地发挥功能的能力；即从阻断状态到激活状态并且再回到阻断状态的循环。测试表达LIR-1受体和激活剂受体的效应T细胞，以观察它们是否能够可逆且反复地发挥功能。将效应细胞与Raji细胞共培养，以模拟肿瘤(CD19+)或正常(CD19+/HLA-A*02+)细胞相遇。在每一轮暴露于靶细胞之后，从培养物中除去Raji细胞并且引入新的靶细胞群体。在每轮结束时测量细胞毒性和γ-干扰素(IFNγ。在阻断-杀伤-阻断和杀伤-阻断-杀伤两种排列中，T细胞按照这种类型的细胞治疗剂的需要而发挥功能(图25A-25D)。它们可逆地从阻断状态循环至细胞毒性，然后循环回来，这取决于它们所暴露的靶细胞。这个结果表明，表达激活剂受体和LIR-1抑制性受体的T细胞不会被固定在一种状态(阻断或激活)，而是可以随着其整合来自正常细胞和肿瘤细胞的信号而来回转换。另外，这些实验在来自多个供体的原代T细胞中重复(图21A-21D；图25A-25D；图26A-26B)，尽管这些原代T细胞具有复杂性、不均一性以及供体与供体之间的变异性，表明LIR-1抑制性受体的稳健功能。
实施例14：在小鼠模型中，表达激活剂受体和LIR-1阻断剂受体的人T细胞选择性地靶向癌细胞
测定在原代T细胞中工程化的CD19/HLA-A*02激活剂/阻断剂对允许使用标准CD3/CD28刺激在体外将T细胞扩增至大量的能力(图27A；图28A)。因此，表达激活剂受体和LIR-1受体c的T细胞可以扩大到足够用于动物实验和最终用于患者的数目。
体外测试CD19/HLA-A*02激活剂/阻断剂组合以表明对CD19+肿瘤细胞的选择性杀伤，而在小鼠异种移植癌模型中不波及CD19+/HLA-A*02+细胞(图27B)。将与上述相同的两种Raji细胞系(一种是CD19+和另一种是CD19+/HLA-A*02+)注射到免疫受损(NGS-HLA-A2.1)小鼠的胁腹。以两个剂量：2e6个T细胞(未显示)或1e7个T细胞注射用测试构建体工程化的T细胞。分析随时间推移肿瘤的生长以及植入的T细胞的持久性。在小鼠中仅CD19+肿瘤细胞被杀伤，并且肿瘤对照用转移的T细胞数目跟踪，促进了宿主小鼠的存活率(图27C-27E；图28B-28C)。设计用于对正常细胞进行建模的CD19+/HLA-A*02+细胞未受影响。携带工程化细胞的小鼠的血液中人CD4+/CD8+细胞比率用其对照对应物跟踪；即，在“肿瘤”移植的小鼠中，CD4+细胞>CD8+细胞，如在CD19 CAR阳性对照小鼠中；以及，在“正常”移植的小鼠中，CD4+细胞<CD8+细胞，类似于带有未转导的T细胞的小鼠(图28D)。此外，肿瘤中的huCD3+细胞(图29A-29B)与肿瘤体积逆相关，并且表达这两种受体的工程化T细胞表现类似于“正常”移植物(低浸润)中的未转导的T细胞，且类似于“肿瘤”移植物(高浸润)中的CD19 CAR。最后，小鼠在典型的临床观察中表现正常(表10)。总之，这些结果表明在被设计为模拟患者中将遇到的不同的正常细胞类型和肿瘤细胞类型的简化情况下，LIR-1抑制性受体可以在体内发挥功能以抑制激活剂受体。
表10.体内实验期间小鼠的临床观察
在研究第0天注射肿瘤细胞和“正常”细胞，并且在研究第10天开始治疗。每周3次针对健康不良、压力和疼痛进行临床观察(CO)。根据IACUC指南，如果肿瘤达到>2000mm3，则对小鼠实施安乐死。代码：N＝正常；19A＝异常肿瘤[N＝坏死，O＝开放]，EUT＝致死。严重程度代码：0＝不存在，1＝中度，2＝重度。
序列表
<110> A2生物治疗公司
<120> 基于LILRB1的嵌合抗原受体
<130> A2BI-015/04WO 331656-2036
<150> US 62/946,888
<151> 2019-12-11
<150> US 63/085,969
<151> 2020-08-30
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Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val
50 55 60
Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu
65 70 75 80
Leu Leu Phe Leu Ile Leu
85
<210> 21
<211> 190
<212> PRT
<213> 智人 (Homo sapiens)
<400> 21
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
1 5 10 15
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp
20 25 30
Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val
35 40 45
Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala
50 55 60
Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln
65 70 75 80
Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp
85 90 95
Pro Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg
100 105 110
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
115 120 125
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
130 135 140
Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu
145 150 155 160
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
165 170 175
Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
180 185 190
<210> 22
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR
<400> 22
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 23
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR
<400> 23
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg
1 5 10
<210> 24
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR
<400> 24
Phe Gln Gly Ser His Val Pro Arg Thr
1 5
<210> 25
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR
<400> 25
Ala Ser Gly Tyr Thr Phe Thr Ser Tyr His Ile His
1 5 10
<210> 26
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR
<400> 26
Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly Lys
<210> 27
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR
<400> 27
Glu Glu Ile Thr Tyr Ala Met Asp Tyr
1 5
<210> 28
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR
<400> 28
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Asp
1 5 10 15
<210> 29
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR
<400> 29
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg
1 5 10
<210> 30
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 轻链CDR
<400> 30
Met Gln Gly Ser His Val Pro Arg Thr
1 5
<210> 31
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR
<400> 31
Ser Gly Tyr Thr Phe Thr Ser Tyr His Met His
1 5 10
<210> 32
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR
<400> 32
Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 33
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 重链CDR
<400> 33
Glu Gly Thr Tyr Tyr Ala Met Asp Tyr
1 5
<210> 34
<211> 3229
<212> DNA
<213> 智人 (Homo sapiens)
<400> 34
aaatgagttt taaaaaggct tgtccaggaa gcacatatgg gagctggtca ctctgcattt 60
tgggccctcc tggaggtgtt tagaccttcc gagagagaaa ctgagacaca tgagagggaa 120
gaaatgactc agtggtgaga ccctgtggag tcccacccac aaccagcaca ctgtgaccca 180
ctgcacaaac ctctagccca cagctcactt cctcctttaa gaagagaaga gaaaagagga 240
gaggagagga ggaacagaaa agaaaagaaa agaaaaagtg ggaaacaaat aatctaagaa 300
tgaggagaaa gcaagaagag tgaccccctt gtgggcactc cattggtttt atggcgcctc 360
tactttctgg agtttgtgta aaacaaaaat attatggtct ttgtgcacat ttacatcaag 420
ctcagcctgg gcggcacagc cagatgcgag atgcgtctct gctgatctga gtctgcctgc 480
agcatggacc tgggtcttcc ctgaagcatc tccagggctg gagggacgac tgccatgcac 540
cgagggctca tccatccaca gagcagggca gtgggaggag acgccatgac ccccatcctc 600
acggtcctga tctgtctcgg gctgagtctg ggcccccgga cccacgtgca ggcagggcac 660
ctccccaagc ccaccctctg ggctgaacca ggctctgtga tcacccaggg gagtcctgtg 720
accctcaggt gtcagggggg ccaggagacc caggagtacc gtctatatag agaaaagaaa 780
acagcaccct ggattacacg gatcccacag gagcttgtga agaagggcca gttccccatc 840
ccatccatca cctgggaaca cacagggcgg tatcgctgtt actatggtag cgacactgca 900
ggccgctcag agagcagtga ccccctggag ctggtggtga caggagccta catcaaaccc 960
accctctcag cccagcccag ccccgtggtg aactcaggag ggaatgtaac cctccagtgt 1020
gactcacagg tggcatttga tggcttcatt ctgtgtaagg aaggagaaga tgaacaccca 1080
caatgcctga actcccagcc ccatgcccgt gggtcgtccc gcgccatctt ctccgtgggc 1140
cccgtgagcc cgagtcgcag gtggtggtac aggtgctatg cttatgactc gaactctccc 1200
tatgagtggt ctctacccag tgatctcctg gagctcctgg tcctaggtgt ttctaagaag 1260
ccatcactct cagtgcagcc aggtcctatc gtggcccctg aggagaccct gactctgcag 1320
tgtggctctg atgctggcta caacagattt gttctgtata aggacgggga acgtgacttc 1380
cttcagctcg ctggcgcaca gccccaggct gggctctccc aggccaactt caccctgggc 1440
cctgtgagcc gctcctacgg gggccagtac agatgctacg gtgcacacaa cctctcctcc 1500
gagtggtcgg cccccagcga ccccctggac atcctgatcg caggacagtt ctatgacaga 1560
gtctccctct cggtgcagcc gggccccacg gtggcctcag gagagaacgt gaccctgctg 1620
tgtcagtcac agggatggat gcaaactttc cttctgacca aggagggggc agctgatgac 1680
ccatggcgtc taagatcaac gtaccaatct caaaaatacc aggctgaatt ccccatgggt 1740
cctgtgacct cagcccatgc ggggacctac aggtgctacg gctcacagag ctccaaaccc 1800
tacctgctga ctcaccccag tgaccccctg gagctcgtgg tctcaggacc gtctgggggc 1860
cccagctccc cgacaacagg ccccacctcc acatctggcc ctgaggacca gcccctcacc 1920
cccaccgggt cggatcccca gagtggtctg ggaaggcacc tgggggttgt gatcggcatc 1980
ttggtggccg tcatcctact gctcctcctc ctcctcctcc tcttcctcat cctccgacat 2040
cgacgtcagg gcaaacactg gacatcgacc cagagaaagg ctgatttcca acatcctgca 2100
ggggctgtgg ggccagagcc cacagacaga ggcctgcagt ggaggtccag cccagctgcc 2160
gatgcccagg aagaaaacct ctatgctgcc gtgaagcaca cacagcctga ggatggggtg 2220
gagatggaca ctcggagccc acacgatgaa gacccccagg cagtgacgta tgccgaggtg 2280
aaacactcca gacctaggag agaaatggcc tctcctcctt ccccactgtc tggggaattc 2340
ctggacacaa aggacagaca ggcggaagag gacaggcaga tggacactga ggctgctgca 2400
tctgaagccc cccaggatgt gacctacgcc cagctgcaca gcttgaccct cagacgggag 2460
gcaactgagc ctcctccatc ccaggaaggg ccctctccag ctgtgcccag catctacgcc 2520
actctggcca tccactagcc caggggggga cgcagacccc acactccatg gagtctggaa 2580
tgcatgggag ctgccccccc agtggacacc attggacccc acccagcctg gatctacccc 2640
aggagactct gggaactttt aggggtcact caattctgca gtataaataa ctaatgtctc 2700
tacaattttg aaataaagca acagacttct caataatcaa tgaagtagct gagaaaacta 2760
agtcagaaag tgcattaaac tgaatcacaa tgtaaatatt acacatcaag cgatgaaact 2820
ggaaaactac aagccacgaa tgaatgaatt aggaaagaaa aaaagtagga aatgaatgat 2880
cttggctttc ctataagaaa tttagggcag ggcacggtgg ctcacgcctg taattccagc 2940
actttgggag gccgaggcgg gcagatcacg agttcaggag atcgagacca tcttggccaa 3000
catggtgaaa ccctgtctct cctaaaaata caaaaattag ctggatgtgg tggcagtgcc 3060
tgtaatccca gctatttggg aggctgaggc aggagaatcg cttgaaccag ggagtcagag 3120
gtttcagtga gccaagatcg caccactgct ctccagcctg gcgacagagg gagactccat 3180
ctcaaattaa aaaaaaaaaa aaaaaagaaa gaaaaaaaaa aaaaaaaaa 3229
<210> 35
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> C-001765 scFv抗体构建体
<400> 35
Met Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln
1 5 10 15
Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly
20 25 30
Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys
35 40 45
Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg
65 70 75 80
Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly Ser His
85 90 95
Val Pro Arg Thr Ser Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln
115 120 125
Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser
130 135 140
Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr His
145 150 155 160
Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
165 170 175
Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys
180 185 190
Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met
195 200 205
His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala
210 215 220
Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
225 230 235 240
Val Thr Val Ser Ser Tyr Gly
245
<210> 36
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> C-002159 scFv抗体构建体
<400> 36
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val
1 5 10 15
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr His Ile
20 25 30
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp
35 40 45
Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys Gly
50 55 60
Lys Ala Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu
65 70 75 80
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gln
145 150 155 160
Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg
180 185 190
Phe Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
210 215 220
Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Glu Ile Lys
245
<210> 37
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> C-002160 scFv抗体构建体
<400> 37
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val
1 5 10 15
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr His Ile
20 25 30
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp
35 40 45
Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys Gly
50 55 60
Lys Ala Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu
65 70 75 80
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu
130 135 140
Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln
145 150 155 160
Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln
165 170 175
Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg
180 185 190
Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr
210 215 220
Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Glu Ile Lys
245
<210> 38
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> C-002161 scFv抗体构建体
<400> 38
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu
1 5 10 15
Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr His Ile
20 25 30
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Trp
35 40 45
Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
130 135 140
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln
145 150 155 160
Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg
180 185 190
Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Glu Ile Lys
245
<210> 39
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> C-002162 scFv抗体构建体
<400> 39
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val
1 5 10 15
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr His Ile
20 25 30
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Trp
35 40 45
Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys Gly
50 55 60
Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr Met Glu
65 70 75 80
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu
130 135 140
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln
145 150 155 160
Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg
180 185 190
Phe Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln Gly Thr
225 230 235 240
Lys Val Glu Val Lys
245
<210> 40
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> C-002163 scFv抗体构建体
<400> 40
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val
1 5 10 15
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr His Met
20 25 30
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr
35 40 45
Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys Gly
50 55 60
Lys Ala Thr Leu Thr Ala Asp Lys Ser Thr Asn Thr Ala Tyr Met Glu
65 70 75 80
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg
85 90 95
Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Asp Val Gln Met Thr Gln Ser Pro Ser Thr Leu
130 135 140
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ser Ser Gln
145 150 155 160
Ser Ile Val His Ser Asn Gly Asn Thr Tyr Met Glu Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg
180 185 190
Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys His Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln Gly Thr
225 230 235 240
Lys Val Glu Val Lys
245
<210> 41
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> C-002164 scFv抗体构建体
<400> 41
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Ile Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Leu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys
85 90 95
Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Asp Val Leu Met Thr Gln Thr Pro Leu
130 135 140
Ser Leu Pro Val Ser Leu Gly Asp Gln Val Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly
210 215 220
Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys
245
<210> 42
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> C-002165 scFv抗体构建体
<400> 42
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Ile Gln Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Asn Leu Asp Ser Val Ser Ala Ala Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Lys Gly Ser
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala
210 215 220
Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Pro
225 230 235 240
Gly Thr Lys Val Asp Ile Lys
245
<210> 43
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> C-002166 scFv抗体构建体
<400> 43
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Ile Gln Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Val Lys
245
<210> 44
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> C-002167 scFv抗体构建体
<400> 44
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
130 135 140
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
210 215 220
Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 45
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> C-002168 scFv抗体构建体
<400> 45
Gln Val Thr Leu Lys Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Thr Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Val Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Leu
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Met Asp Thr Ser Phe
65 70 75 80
Met Glu Leu Thr Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Leu Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
130 135 140
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Ser Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
210 215 220
Val Tyr Tyr Cys Gln Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 46
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> C-002169 scFv抗体构建体
<400> 46
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Asp Ile Val Met Thr Gln Thr Pro Leu
130 135 140
Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Asp Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Met Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 47
<211> 511
<212> PRT
<213> 人工序列
<220>
<223> C563嵌合抗原受体构建体
<400> 47
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Asp
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Val Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Pro Phe Gly Asp Trp Trp Tyr Phe Asp Leu Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser
130 135 140
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln
180 185 190
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Ser Tyr Ser Phe Val Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
245 250 255
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
260 265 270
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
275 280 285
Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
290 295 300
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg
305 310 315 320
Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro
325 330 335
Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe
340 345 350
Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
355 360 365
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
370 375 380
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
385 390 395 400
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln
405 410 415
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
420 425 430
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
435 440 445
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
450 455 460
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
465 470 475 480
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
485 490 495
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 48
<211> 403
<212> PRT
<213> 人工序列
<220>
<223> C1759嵌合抗原受体构建体
<400> 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Phe Gly Ser Phe Arg Ala Leu Pro Cys Val Trp Ser Asn Ser Ser
245 250 255
Asp Pro Leu Leu Val Ser Val Thr Gly Asn Pro Ser Ser Ser Trp Pro
260 265 270
Ser Pro Thr Glu Pro Ser Ser Lys Ser Gly Ile Cys Arg His Leu His
275 280 285
Val Leu Ile Gly Thr Ser Val Val Ile Phe Leu Phe Ile Leu Leu Leu
290 295 300
Phe Phe Leu Leu Tyr Arg Trp Cys Ser Asn Lys Lys Asn Ala Ala Val
305 310 315 320
Met Asp Gln Glu Pro Ala Gly Asp Arg Thr Val Asn Arg Gln Asp Ser
325 330 335
Asp Glu Gln Asp Pro Gln Glu Val Thr Tyr Ala Gln Leu Asp His Cys
340 345 350
Val Phe Ile Gln Arg Lys Ile Ser Arg Pro Ser Gln Arg Pro Lys Thr
355 360 365
Pro Leu Thr Asp Thr Ser Val Tyr Thr Glu Leu Pro Asn Ala Glu Pro
370 375 380
Arg Ser Lys Val Val Ser Cys Pro Arg Ala Pro Gln Ser Gly Leu Glu
385 390 395 400
Gly Val Phe
<210> 49
<211> 358
<212> PRT
<213> 人工序列
<220>
<223> C1760嵌合抗原受体构建体
<400> 49
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Phe Gly Ser Phe Arg Ala Leu Pro His Ala Trp Ser Asp Pro Ser
245 250 255
Asp Pro Leu Pro Val Ser Val Thr Gly Asn Ser Arg Asn Leu His Val
260 265 270
Leu Ile Gly Thr Ser Val Val Ile Ile Pro Phe Ala Ile Leu Leu Phe
275 280 285
Phe Leu Leu His Arg Trp Cys Ala Asn Lys Lys Asn Ala Val Val Met
290 295 300
Asp Gln Glu Pro Ala Gly Asn Arg Thr Val Asn Arg Glu Asp Ser Asp
305 310 315 320
Glu Gln Asp Pro Gln Glu Val Thr Tyr Ala Gln Leu Asn His Cys Val
325 330 335
Phe Thr Gln Arg Lys Ile Thr Arg Pro Ser Gln Arg Pro Lys Thr Pro
340 345 350
Pro Thr Asp Thr Ser Val
355
<210> 50
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> C1761嵌合抗原受体构建体
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp
325 330 335
Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val
340 345 350
Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala
355 360 365
Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln
370 375 380
Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp
385 390 395 400
Pro Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg
405 410 415
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
420 425 430
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
435 440 445
Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu
450 455 460
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
465 470 475 480
Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
485 490
<210> 51
<211> 385
<212> PRT
<213> 人工序列
<220>
<223> C1762嵌合抗原受体构建体
<400> 51
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser
245 250 255
Pro Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly
260 265 270
Gly Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile
275 280 285
Cys Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln
290 295 300
Pro Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr
305 310 315 320
Gly Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val
325 330 335
Pro Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser
340 345 350
Gly Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro
355 360 365
Arg Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro
370 375 380
Leu
385
<210> 52
<211> 439
<212> PRT
<213> 人工序列
<220>
<223> C2057嵌合抗原受体构建体
<400> 52
Met Glu Thr Leu Leu Gly Leu Leu Ile Leu Trp Leu Gln Leu Gln Trp
1 5 10 15
Val Ser Ser Lys Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val
20 25 30
Pro Glu Gly Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala
35 40 45
Ile Tyr Asn Leu Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr
50 55 60
Ser Leu Leu Leu Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg
65 70 75 80
Leu Asn Ala Ser Leu Asp Lys Ser Ser Gly Arg Ser Thr Leu Tyr Ile
85 90 95
Ala Ala Ser Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg
100 105 110
Pro Leu Tyr Gly Gly Ser Tyr Ile Pro Thr Phe Gly Arg Gly Thr Ser
115 120 125
Leu Ile Val His Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln
130 135 140
Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr
165 170 175
Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser
180 185 190
Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn
195 200 205
Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro
210 215 220
Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Val Ile Gly Ile Leu Val
245 250 255
Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe Leu Ile Leu
260 265 270
Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala
275 280 285
Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg
290 295 300
Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn
305 310 315 320
Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met
325 330 335
Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala
340 345 350
Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser
355 360 365
Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu
370 375 380
Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp
385 390 395 400
Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr
405 410 415
Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile
420 425 430
Tyr Ala Thr Leu Ala Ile His
435
<210> 53
<211> 466
<212> PRT
<213> 人工序列
<220>
<223> C2058嵌合抗原受体构建体
<400> 53
Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg
85 90 95
Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Tyr Val Gly Asn Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu
275 280 285
Leu Leu Leu Leu Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln
290 295 300
Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro
305 310 315 320
Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg
325 330 335
Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val
340 345 350
Lys His Thr Gln Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro
355 360 365
His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser
370 375 380
Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu
385 390 395 400
Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp
405 410 415
Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln
420 425 430
Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser
435 440 445
Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala
450 455 460
Ile His
465
<210> 54
<211> 421
<212> PRT
<213> 人工序列
<220>
<223> C2070嵌合抗原受体构建体
<400> 54
Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg
85 90 95
Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Tyr Val Gly Asn Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Gly Gly Gly Gly Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg
325 330 335
Arg Thr Gly Gln Pro Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe
340 345 350
Ser Val Asp Tyr Gly Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro
355 360 365
Glu Pro Pro Val Pro Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile
370 375 380
Val Phe Pro Ser Gly Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser
385 390 395 400
Ala Asp Gly Pro Arg Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His
405 410 415
Cys Ser Trp Pro Leu
420
<210> 55
<211> 416
<212> PRT
<213> 人工序列
<220>
<223> C2071嵌合抗原受体构建体
<400> 55
Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg
85 90 95
Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Tyr Val Gly Asn Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Gly Gly Gly Gly Ser Asn Lys Lys Asn Ala Ala Val Met Asp Gln
325 330 335
Glu Pro Ala Gly Asp Arg Thr Val Asn Arg Gln Asp Ser Asp Glu Gln
340 345 350
Asp Pro Gln Glu Val Thr Tyr Ala Gln Leu Asp His Cys Val Phe Ile
355 360 365
Gln Arg Lys Ile Ser Arg Pro Ser Gln Arg Pro Lys Thr Pro Leu Thr
370 375 380
Asp Thr Ser Val Tyr Thr Glu Leu Pro Asn Ala Glu Pro Arg Ser Lys
385 390 395 400
Val Val Ser Cys Pro Arg Ala Pro Gln Ser Gly Leu Glu Gly Val Phe
405 410 415
<210> 56
<211> 493
<212> PRT
<213> 人工序列
<220>
<223> C2072嵌合抗原受体构建体
<400> 56
Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg
85 90 95
Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Tyr Val Gly Asn Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Gly Gly Gly Gly Ser Arg His Arg Arg Gln Gly Lys His Trp Thr
325 330 335
Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly
340 345 350
Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala
355 360 365
Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro
370 375 380
Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro
385 390 395 400
Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu
405 410 415
Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys
420 425 430
Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala
435 440 445
Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr
450 455 460
Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser
465 470 475 480
Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
485 490
<210> 57
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> C2106嵌合抗原受体构建体
<400> 57
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
245 250 255
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
260 265 270
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
275 280 285
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
290 295 300
Val Ile Thr Leu Tyr Cys Asn His Asp Arg Glu Lys Lys Pro Arg Gln
305 310 315 320
His Ser Gly Asp His Glu Asn Leu Met Asn Val Pro Ser Asp Lys Glu
325 330 335
Met Phe Ser Arg Ser Val Thr Ser Leu Ala Thr Asp Ala Pro Ala Ser
340 345 350
Ser Glu Gln Asn Gly Ala Leu Thr Asn Gly Asp Ile Leu Ser Glu Asp
355 360 365
Ser Thr Leu Thr Cys Met Gln His Tyr Glu Glu Val Gln Thr Ser Ala
370 375 380
Ser Asp Leu Leu Asp Ser Gln Asp Ser Thr Gly Lys Pro Lys Cys His
385 390 395 400
Gln Ser Arg Glu Leu Pro Arg Ile Pro Pro Glu Ser Ala Val Asp Thr
405 410 415
Met Leu Thr Ala Arg Ser Val Asp Gly Asp Gln Gly Leu Gly Met Glu
420 425 430
Gly Pro Tyr Glu Val Leu Lys Asp Ser Ser Ser Gln Glu Asn Met Val
435 440 445
Glu Asp Cys Leu Tyr Glu Thr Val Lys Glu Ile Lys Glu Val Ala Ala
450 455 460
Ala Ala His Leu Glu Lys Gly His Ser Gly Lys Ala Lys Ser Thr Ser
465 470 475 480
Ala Ser Lys Glu Leu Pro Gly Pro Gln Thr Glu Gly Lys Ala Glu Phe
485 490 495
Ala Glu Tyr Ala Ser Val Asp Arg Asn Lys Lys Cys Arg Gln Ser Val
500 505 510
Asn Val Glu Ser Ile Leu Gly Asn Ser Cys Asp Pro Glu Glu Glu Ala
515 520 525
Pro Pro Pro Val Pro Val Lys Leu Leu Asp Glu Asn Glu Asn Leu Gln
530 535 540
Glu Lys Glu Gly Gly Glu Ala Glu Glu Ser Ala Thr Asp Thr Thr Ser
545 550 555 560
Glu Thr Asn Lys Arg Phe Ser Ser Leu Ser Tyr Lys Ser Arg Glu Glu
565 570 575
Asp Pro Thr Leu Thr Glu Glu Glu Ile Ser Ala Met Tyr Ser Ser Val
580 585 590
Asn Lys Pro Gly Gln Leu Val Asn Lys Ser Gly Gln Ser Leu Thr Val
595 600 605
Pro Glu Ser Thr Tyr Thr Ser Ile Gln Gly Asp Pro Gln Arg Ser Pro
610 615 620
Ser Ser Cys Asn Asp Leu Tyr Ala Thr Val Lys Asp Phe Glu Lys Thr
625 630 635 640
Pro Asn Ser Thr Leu Pro Pro Ala Gly Arg Pro Ser Glu Glu Pro Glu
645 650 655
Pro Asp Tyr Glu Ala Ile Gln Thr Leu Asn Arg Glu Glu Glu Lys Ala
660 665 670
Thr Leu Gly Thr Asn Gly His His Gly Leu Val Pro Lys Glu Asn Asp
675 680 685
Tyr Glu Ser Ile Ser Asp Leu Gln Gln Gly Arg Asp Ile Thr Arg Leu
690 695 700
<210> 58
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> C2107嵌合抗原受体构建体
<400> 58
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
245 250 255
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
260 265 270
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Leu Trp
275 280 285
Gly Ser Leu Ala Ala Val Ala Ile Phe Phe Val Ile Thr Phe Leu Ile
290 295 300
Phe Leu Cys Ser Ser Cys Asp Arg Glu Lys Lys Pro Arg Gln His Ser
305 310 315 320
Gly Asp His Glu Asn Leu Met Asn Val Pro Ser Asp Lys Glu Met Phe
325 330 335
Ser Arg Ser Val Thr Ser Leu Ala Thr Asp Ala Pro Ala Ser Ser Glu
340 345 350
Gln Asn Gly Ala Leu Thr Asn Gly Asp Ile Leu Ser Glu Asp Ser Thr
355 360 365
Leu Thr Cys Met Gln His Tyr Glu Glu Val Gln Thr Ser Ala Ser Asp
370 375 380
Leu Leu Asp Ser Gln Asp Ser Thr Gly Lys Pro Lys Cys His Gln Ser
385 390 395 400
Arg Glu Leu Pro Arg Ile Pro Pro Glu Ser Ala Val Asp Thr Met Leu
405 410 415
Thr Ala Arg Ser Val Asp Gly Asp Gln Gly Leu Gly Met Glu Gly Pro
420 425 430
Tyr Glu Val Leu Lys Asp Ser Ser Ser Gln Glu Asn Met Val Glu Asp
435 440 445
Cys Leu Tyr Glu Thr Val Lys Glu Ile Lys Glu Val Ala Ala Ala Ala
450 455 460
His Leu Glu Lys Gly His Ser Gly Lys Ala Lys Ser Thr Ser Ala Ser
465 470 475 480
Lys Glu Leu Pro Gly Pro Gln Thr Glu Gly Lys Ala Glu Phe Ala Glu
485 490 495
Tyr Ala Ser Val Asp Arg Asn Lys Lys Cys Arg Gln Ser Val Asn Val
500 505 510
Glu Ser Ile Leu Gly Asn Ser Cys Asp Pro Glu Glu Glu Ala Pro Pro
515 520 525
Pro Val Pro Val Lys Leu Leu Asp Glu Asn Glu Asn Leu Gln Glu Lys
530 535 540
Glu Gly Gly Glu Ala Glu Glu Ser Ala Thr Asp Thr Thr Ser Glu Thr
545 550 555 560
Asn Lys Arg Phe Ser Ser Leu Ser Tyr Lys Ser Arg Glu Glu Asp Pro
565 570 575
Thr Leu Thr Glu Glu Glu Ile Ser Ala Met Tyr Ser Ser Val Asn Lys
580 585 590
Pro Gly Gln Leu Val Asn Lys Ser Gly Gln Ser Leu Thr Val Pro Glu
595 600 605
Ser Thr Tyr Thr Ser Ile Gln Gly Asp Pro Gln Arg Ser Pro Ser Ser
610 615 620
Cys Asn Asp Leu Tyr Ala Thr Val Lys Asp Phe Glu Lys Thr Pro Asn
625 630 635 640
Ser Thr Leu Pro Pro Ala Gly Arg Pro Ser Glu Glu Pro Glu Pro Asp
645 650 655
Tyr Glu Ala Ile Gln Thr Leu Asn Arg Glu Glu Glu Lys Ala Thr Leu
660 665 670
Gly Thr Asn Gly His His Gly Leu Val Pro Lys Glu Asn Asp Tyr Glu
675 680 685
Ser Ile Ser Asp Leu Gln Gln Gly Arg Asp Ile Thr Arg Leu
690 695 700
<210> 59
<211> 481
<212> PRT
<213> 人工序列
<220>
<223> C2153嵌合抗原受体构建体
<400> 59
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
245 250 255
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
260 265 270
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp
275 280 285
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
290 295 300
Thr Val Ala Phe Ile Ile Phe Trp Val Leu Arg His Arg Arg Gln Gly
305 310 315 320
Lys His Trp Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala
325 330 335
Gly Ala Val Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser
340 345 350
Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys
355 360 365
His Thr Gln Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His
370 375 380
Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg
385 390 395 400
Pro Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe
405 410 415
Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr
420 425 430
Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu
435 440 445
His Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln
450 455 460
Glu Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile
465 470 475 480
His
<210> 60
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> C2156嵌合抗原受体构建体
<400> 60
Met Glu Thr Leu Leu Gly Leu Leu Ile Leu Trp Leu Gln Leu Gln Trp
1 5 10 15
Val Ser Ser Lys Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val
20 25 30
Pro Glu Gly Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala
35 40 45
Ile Tyr Asn Leu Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr
50 55 60
Ser Leu Leu Leu Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg
65 70 75 80
Leu Asn Ala Ser Leu Asp Lys Ser Ser Gly Arg Ser Thr Leu Tyr Ile
85 90 95
Ala Ala Ser Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Arg
100 105 110
Pro Leu Tyr Gly Gly Ser Tyr Ile Pro Thr Phe Gly Arg Gly Thr Ser
115 120 125
Leu Ile Val His Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln
130 135 140
Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr
165 170 175
Ile Thr Asp Lys Cys Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser
180 185 190
Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn
195 200 205
Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro
210 215 220
Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Leu Ile Leu
245 250 255
Leu Leu Leu Val Ala Gly Phe Asn Leu Leu Met Thr Leu Leu Leu Trp
260 265 270
Ser Ser Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser
275 280 285
Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro
290 295 300
Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp
305 310 315 320
Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu
325 330 335
Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln
340 345 350
Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met
355 360 365
Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp
370 375 380
Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser
385 390 395 400
Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu
405 410 415
Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro
420 425 430
Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
435 440
<210> 61
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> C2157嵌合抗原受体构建体
<400> 61
Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg
85 90 95
Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Tyr Val Gly Asn Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Leu Ile Leu Leu Gly Leu Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Leu Ile Leu
290 295 300
Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala
305 310 315 320
Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg
325 330 335
Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn
340 345 350
Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met
355 360 365
Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala
370 375 380
Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser
385 390 395 400
Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu
405 410 415
Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp
420 425 430
Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr
435 440 445
Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile
450 455 460
Tyr Ala Thr Leu Ala Ile His
465 470
<210> 62
<211> 484
<212> PRT
<213> 人工序列
<220>
<223> C2158嵌合抗原受体构建体
<400> 62
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Asp
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Val Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Pro Phe Gly Asp Trp Trp Tyr Phe Asp Leu Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser
130 135 140
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln
180 185 190
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Ser Tyr Ser Phe Val Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
245 250 255
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
260 265 270
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
275 280 285
Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser
290 295 300
Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Leu Arg His Arg
305 310 315 320
Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln
325 330 335
His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln
340 345 350
Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala
355 360 365
Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met Asp Thr Arg
370 375 380
Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala Glu Val Lys
385 390 395 400
His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser
405 410 415
Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln
420 425 430
Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr
435 440 445
Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro
450 455 460
Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr
465 470 475 480
Leu Ala Ile His
<210> 63
<211> 414
<212> PRT
<213> 人工序列
<220>
<223> C2179嵌合抗原受体构建体
<400> 63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Arg Pro Arg Arg
325 330 335
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
340 345 350
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
355 360 365
Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu
370 375 380
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
385 390 395 400
Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
405 410
<210> 64
<211> 576
<212> PRT
<213> 人工序列
<220>
<223> C2180嵌合抗原受体构建体
<400> 64
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp
325 330 335
Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val
340 345 350
Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala
355 360 365
Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln
370 375 380
Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp
385 390 395 400
Pro Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg
405 410 415
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
420 425 430
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
435 440 445
Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu
450 455 460
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
465 470 475 480
Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Arg Pro
485 490 495
Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu
500 505 510
Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu
515 520 525
Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His
530 535 540
Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu
545 550 555 560
Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
565 570 575
<210> 65
<211> 496
<212> PRT
<213> 人工序列
<220>
<223> C2181嵌合抗原受体构建体
<400> 65
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Arg Pro Arg Arg
325 330 335
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
340 345 350
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
355 360 365
Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu
370 375 380
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
385 390 395 400
Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Arg Pro
405 410 415
Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu
420 425 430
Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu
435 440 445
Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His
450 455 460
Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu
465 470 475 480
Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
485 490 495
<210> 66
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> C2182嵌合抗原受体构建体
<400> 66
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp
325 330 335
Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val
340 345 350
Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala
355 360 365
Ala Asp Ala Gln Glu Glu Asn Leu Phe Ala Ala Val Lys His Thr Gln
370 375 380
Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp
385 390 395 400
Pro Gln Ala Val Thr Phe Ala Glu Val Lys His Ser Arg Pro Arg Arg
405 410 415
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
420 425 430
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
435 440 445
Ala Ser Glu Ala Pro Gln Asp Val Thr Phe Ala Gln Leu His Ser Leu
450 455 460
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
465 470 475 480
Ser Pro Ala Val Pro Ser Ile Phe Ala Thr Leu Ala Ile His
485 490
<210> 67
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> C2183嵌合抗原受体构建体
<400> 67
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp
325 330 335
Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val
340 345 350
Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala
355 360 365
Ala Asp Ala Gln Glu Glu Asn Leu Phe Ala Ala Val Lys His Thr Gln
370 375 380
Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp
385 390 395 400
Pro Gln Ala Val Thr Phe Ala Glu Val Lys His Ser Arg Pro Arg Arg
405 410 415
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
420 425 430
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
435 440 445
Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu
450 455 460
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
465 470 475 480
Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
485 490
<210> 68
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> C2184嵌合抗原受体构建体
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp
325 330 335
Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val
340 345 350
Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala
355 360 365
Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln
370 375 380
Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp
385 390 395 400
Pro Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg
405 410 415
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
420 425 430
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
435 440 445
Ala Ser Glu Ala Pro Gln Asp Val Thr Phe Ala Gln Leu His Ser Leu
450 455 460
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
465 470 475 480
Ser Pro Ala Val Pro Ser Ile Phe Ala Thr Leu Ala Ile His
485 490
<210> 69
<211> 438
<212> PRT
<213> 人工序列
<220>
<223> C2218嵌合抗原受体构建体
<400> 69
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg Arg His Gln Gly Lys Gln Asn Glu
325 330 335
Leu Ser Asp Thr Ala Gly Arg Glu Ile Asn Leu Val Asp Ala His Leu
340 345 350
Lys Ser Glu Gln Thr Glu Ala Ser Thr Arg Gln Asn Ser Gln Val Leu
355 360 365
Leu Ser Glu Thr Gly Ile Tyr Asp Asn Asp Pro Asp Leu Cys Phe Arg
370 375 380
Met Gln Glu Gly Ser Glu Val Tyr Ser Asn Pro Cys Leu Glu Glu Asn
385 390 395 400
Lys Pro Gly Ile Val Tyr Ala Ser Leu Asn His Ser Val Ile Gly Pro
405 410 415
Asn Ser Arg Leu Ala Arg Asn Val Lys Glu Ala Pro Thr Glu Tyr Ala
420 425 430
Ser Ile Cys Val Arg Ser
435
<210> 70
<211> 437
<212> PRT
<213> 人工序列
<220>
<223> C2219嵌合抗原受体构建体
<400> 70
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Leu Leu Pro Leu Gly Gly Leu Pro Leu Leu Ile Thr Thr Cys Phe
305 310 315 320
Cys Leu Phe Cys Cys Leu Arg Arg His Gln Gly Lys Gln Asn Glu Leu
325 330 335
Ser Asp Thr Ala Gly Arg Glu Ile Asn Leu Val Asp Ala His Leu Lys
340 345 350
Ser Glu Gln Thr Glu Ala Ser Thr Arg Gln Asn Ser Gln Val Leu Leu
355 360 365
Ser Glu Thr Gly Ile Tyr Asp Asn Asp Pro Asp Leu Cys Phe Arg Met
370 375 380
Gln Glu Gly Ser Glu Val Tyr Ser Asn Pro Cys Leu Glu Glu Asn Lys
385 390 395 400
Pro Gly Ile Val Tyr Ala Ser Leu Asn His Ser Val Ile Gly Pro Asn
405 410 415
Ser Arg Leu Ala Arg Asn Val Lys Glu Ala Pro Thr Glu Tyr Ala Ser
420 425 430
Ile Cys Val Arg Ser
435
<210> 71
<211> 397
<212> PRT
<213> 人工序列
<220>
<223> C2220嵌合抗原受体构建体
<400> 71
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Thr Asp Val Lys Ser Ala Ser Glu Arg Pro Ser Lys Asp Glu Met
245 250 255
Ala Ser Arg Pro Trp Leu Leu Tyr Arg Leu Leu Pro Leu Gly Gly Leu
260 265 270
Pro Leu Leu Ile Thr Thr Cys Phe Cys Leu Phe Cys Cys Leu Arg Arg
275 280 285
His Gln Gly Lys Gln Asn Glu Leu Ser Asp Thr Ala Gly Arg Glu Ile
290 295 300
Asn Leu Val Asp Ala His Leu Lys Ser Glu Gln Thr Glu Ala Ser Thr
305 310 315 320
Arg Gln Asn Ser Gln Val Leu Leu Ser Glu Thr Gly Ile Tyr Asp Asn
325 330 335
Asp Pro Asp Leu Cys Phe Arg Met Gln Glu Gly Ser Glu Val Tyr Ser
340 345 350
Asn Pro Cys Leu Glu Glu Asn Lys Pro Gly Ile Val Tyr Ala Ser Leu
355 360 365
Asn His Ser Val Ile Gly Pro Asn Ser Arg Leu Ala Arg Asn Val Lys
370 375 380
Glu Ala Pro Thr Glu Tyr Ala Ser Ile Cys Val Arg Ser
385 390 395
<210> 72
<400> 72
000
<210> 73
<400> 73
000
<210> 74
<400> 74
000
<210> 75
<400> 75
000
<210> 76
<400> 76
000
<210> 77
<211> 578
<212> PRT
<213> 人工序列
<220>
<223> C2302嵌合抗原受体构建体
<400> 77
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Val Tyr Asp Tyr Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Val Ile Tyr Ser
165 170 175
Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
195 200 205
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Ser Tyr Tyr
210 215 220
Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser
225 230 235 240
Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser
245 250 255
Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser
260 265 270
Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu
275 280 285
Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly
290 295 300
Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu
305 310 315 320
Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Arg Pro Arg Arg
325 330 335
Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr
340 345 350
Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala
355 360 365
Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu
370 375 380
Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro
385 390 395 400
Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Arg Pro
405 410 415
Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu
420 425 430
Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu
435 440 445
Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His
450 455 460
Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu
465 470 475 480
Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
485 490 495
Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu
500 505 510
Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp
515 520 525
Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln
530 535 540
Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser
545 550 555 560
Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala
565 570 575
Ile His
<210> 78
<211> 600
<212> PRT
<213> 人工序列
<220>
<223> CT138嵌合抗原受体构建体
<400> 78
Met Gly Pro Val Thr Cys Ser Val Leu Val Leu Leu Leu Met Leu Arg
1 5 10 15
Arg Ser Asn Gly Asp Gly Asp Ser Val Thr Gln Thr Glu Gly Leu Val
20 25 30
Thr Leu Thr Glu Gly Leu Pro Val Met Leu Asn Cys Thr Tyr Gln Thr
35 40 45
Ile Tyr Ser Asn Pro Phe Leu Phe Trp Tyr Val Gln His Leu Asn Glu
50 55 60
Ser Pro Arg Leu Leu Leu Lys Ser Phe Thr Asp Asn Lys Arg Thr Glu
65 70 75 80
His Gln Gly Phe His Ala Thr Leu His Lys Ser Ser Ser Ser Phe His
85 90 95
Leu Gln Lys Ser Ser Ala Gln Leu Ser Asp Ser Ala Leu Tyr Tyr Cys
100 105 110
Ala Phe Asp Thr Asn Thr Tyr Lys Val Ile Phe Gly Lys Gly Thr His
115 120 125
Leu His Val Leu Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln
130 135 140
Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe
165 170 175
Ile Thr Asp Lys Thr Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser
180 185 190
Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp
195 200 205
Ile Phe Lys Glu Thr Asn Thr Thr Tyr Pro Ser Ser Asp Val Pro Cys
210 215 220
Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn
225 230 235 240
Phe Gln Asn Leu Ser Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val
245 250 255
Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala
260 265 270
Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala
275 280 285
Gly Asp Val Glu Glu Asn Pro Gly Pro Met Arg Val Arg Leu Ile Ser
290 295 300
Ala Val Val Leu Cys Ser Leu Gly Thr Gly Leu Val Asp Met Lys Val
305 310 315 320
Thr Gln Met Pro Arg Tyr Leu Ile Lys Arg Met Gly Glu Asn Val Leu
325 330 335
Leu Glu Cys Gly Gln Asp Met Ser His Glu Thr Met Tyr Trp Tyr Arg
340 345 350
Gln Asp Pro Gly Leu Gly Leu Gln Leu Ile Tyr Ile Ser Tyr Asp Val
355 360 365
Asp Ser Asn Ser Glu Gly Asp Ile Pro Lys Gly Tyr Arg Val Ser Arg
370 375 380
Lys Lys Arg Glu His Phe Ser Leu Ile Leu Asp Ser Ala Lys Thr Asn
385 390 395 400
Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Ser Thr Asn Thr Glu Val
405 410 415
Phe Phe Gly Lys Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn
420 425 430
Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile
435 440 445
Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe
450 455 460
Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His
465 470 475 480
Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser
485 490 495
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn
500 505 510
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu
515 520 525
Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile
530 535 540
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser
545 550 555 560
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
565 570 575
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met
580 585 590
Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 79
<211> 605
<212> PRT
<213> 人工序列
<220>
<223> CT139嵌合抗原受体构建体
<400> 79
Met Val Leu Val Thr Ile Leu Leu Leu Ser Ala Phe Phe Ser Leu Arg
1 5 10 15
Gly Asn Ser Ala Gln Ser Val Asp Gln Pro Asp Ala His Val Thr Leu
20 25 30
Ser Glu Gly Ala Ser Leu Glu Leu Arg Cys Ser Tyr Ser Tyr Ser Ala
35 40 45
Ala Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Gly Gln Ser Leu Gln
50 55 60
Phe Leu Leu Lys Tyr Ile Thr Gly Asp Thr Val Val Lys Gly Thr Lys
65 70 75 80
Gly Phe Glu Ala Glu Phe Arg Lys Ser Asn Ser Ser Phe Asn Leu Lys
85 90 95
Lys Ser Pro Ala His Trp Ser Asp Ser Ala Lys Tyr Phe Cys Ala Leu
100 105 110
Glu Gly Pro Asp Thr Gly Asn Tyr Lys Tyr Val Phe Gly Ala Gly Thr
115 120 125
Arg Leu Lys Val Ile Ala His Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Thr Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Ser Val Met Gly Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Ile Gln Thr Leu
290 295 300
Cys Cys Val Ile Phe Tyr Val Leu Ile Ala Asn His Thr Asp Ala Gly
305 310 315 320
Val Thr Gln Thr Pro Arg His Glu Val Ala Glu Lys Gly Gln Thr Ile
325 330 335
Ile Leu Lys Cys Glu Pro Val Ser Gly His Asn Asp Leu Phe Trp Tyr
340 345 350
Arg Gln Thr Lys Ile Gln Gly Leu Glu Leu Leu Ser Tyr Phe Arg Ser
355 360 365
Lys Ser Leu Met Glu Asp Gly Gly Ala Phe Lys Asp Arg Phe Lys Ala
370 375 380
Glu Met Leu Asn Ser Ser Phe Ser Thr Leu Lys Ile Gln Pro Thr Glu
385 390 395 400
Pro Arg Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Phe Gly Thr Ala
405 410 415
Ser Ala Glu Thr Leu Tyr Phe Gly Ser Gly Thr Arg Leu Thr Val Leu
420 425 430
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
435 440 445
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
450 455 460
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
465 470 475 480
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr Lys
485 490 495
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
500 505 510
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
515 520 525
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
530 535 540
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
545 550 555 560
Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu
565 570 575
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
580 585 590
Gly Leu Val Leu Met Ala Met Val Lys Lys Lys Asn Ser
595 600 605
<210> 80
<211> 64
<212> PRT
<213> 智人 (Homo sapiens)
<400> 80
Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp
1 5 10 15
Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro
20 25 30
Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr
35 40 45
Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val
50 55 60
<210> 81
<211> 44
<212> PRT
<213> 智人 (Homo sapiens)
<400> 81
Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro
1 5 10 15
Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser
20 25 30
Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val
35 40
<210> 82
<211> 67
<212> PRT
<213> 人工序列
<220>
<223> 在实验室中制造 - 长铰链1序列
<400> 82
Ala Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Pro Val Pro Ser
1 5 10 15
Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser
20 25 30
Gly Gly Ser Gly Asn Ser Ser Gly Ser Gly Gly Ser Pro Val Pro Ser
35 40 45
Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser
50 55 60
Ala Ser Val
65
<210> 83
<211> 75
<212> PRT
<213> 人工序列
<220>
<223> 在实验室中制造 - 长铰链2序列
<400> 83
Ala Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Pro Val Pro Ser
1 5 10 15
Thr Pro Pro Thr Asn Ser Ser Ser Thr Pro Pro Thr Pro Ser Pro Ser
20 25 30
Pro Val Pro Ser Thr Pro Pro Thr Asn Ser Ser Ser Thr Pro Pro Thr
35 40 45
Pro Ser Pro Ser Pro Val Pro Ser Thr Pro Pro Thr Asn Ser Ser Ser
50 55 60
Thr Pro Pro Thr Pro Ser Pro Ser Ala Ser Val
65 70 75
<210> 84
<211> 85
<212> PRT
<213> 人工序列
<220>
<223> 在实验室中制造 - 2x短铰链序列
<400> 84
Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro
1 5 10 15
Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser
20 25 30
Asp Pro Gln Ser Gly Leu Gly Arg His Val Val Ser Gly Pro Ser Gly
35 40 45
Gly Pro Ser Ser Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu
50 55 60
Asp Gln Pro Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly
65 70 75 80
Arg His Leu Gly Val
85
<210> 85
<400> 85
000
<210> 86
<400> 86
000
<210> 87
<211> 111
<212> PRT
<213> 智人 (Homo sapiens)
<400> 87
Arg Arg His Gln Gly Lys Gln Asn Glu Leu Ser Asp Thr Ala Gly Arg
1 5 10 15
Glu Ile Asn Leu Val Asp Ala His Leu Lys Ser Glu Gln Thr Glu Ala
20 25 30
Ser Thr Arg Gln Asn Ser Gln Val Leu Leu Ser Glu Thr Gly Ile Tyr
35 40 45
Asp Asn Asp Pro Asp Leu Cys Phe Arg Met Gln Glu Gly Ser Glu Val
50 55 60
Tyr Ser Asn Pro Cys Leu Glu Glu Asn Lys Pro Gly Ile Val Tyr Ala
65 70 75 80
Ser Leu Asn His Ser Val Ile Gly Pro Asn Ser Arg Leu Ala Arg Asn
85 90 95
Val Lys Glu Ala Pro Thr Glu Tyr Ala Ser Ile Cys Val Arg Ser
100 105 110
<210> 88
<211> 132
<212> PRT
<213> 智人 (Homo sapiens)
<400> 88
Leu Leu Pro Leu Gly Gly Leu Pro Leu Leu Ile Thr Thr Cys Phe Cys
1 5 10 15
Leu Phe Cys Cys Leu Arg Arg His Gln Gly Lys Gln Asn Glu Leu Ser
20 25 30
Asp Thr Ala Gly Arg Glu Ile Asn Leu Val Asp Ala His Leu Lys Ser
35 40 45
Glu Gln Thr Glu Ala Ser Thr Arg Gln Asn Ser Gln Val Leu Leu Ser
50 55 60
Glu Thr Gly Ile Tyr Asp Asn Asp Pro Asp Leu Cys Phe Arg Met Gln
65 70 75 80
Glu Gly Ser Glu Val Tyr Ser Asn Pro Cys Leu Glu Glu Asn Lys Pro
85 90 95
Gly Ile Val Tyr Ala Ser Leu Asn His Ser Val Ile Gly Pro Asn Ser
100 105 110
Arg Leu Ala Arg Asn Val Lys Glu Ala Pro Thr Glu Tyr Ala Ser Ile
115 120 125
Cys Val Arg Ser
130
<210> 89
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> PA2.1.14 scFv LIR1 HTICD构建体
<400> 89
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Val Lys Tyr Gly Ser Gln Ser Ser Lys Pro Tyr
245 250 255
Leu Leu Thr His Pro Ser Asp Pro Leu Glu Leu Val Val Ser Gly Pro
260 265 270
Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly
275 280 285
Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly
290 295 300
Leu Gly Arg His Leu Gly Val Val Ile Gly Ile Leu Val Ala Val Ile
305 310 315 320
Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe Leu Ile Leu Arg His Arg
325 330 335
Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln
340 345 350
His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln
355 360 365
Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala
370 375 380
Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met Asp Thr Arg
385 390 395 400
Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala Glu Val Lys
405 410 415
His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser
420 425 430
Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln
435 440 445
Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr
450 455 460
Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro
465 470 475 480
Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr
485 490 495
Leu Ala Ile His
500
<210> 90
<211> 480
<212> PRT
<213> 人工序列
<220>
<223> PA2.1.14 scFv LIR1 sHTICD构建体
<400> 90
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Val Lys Val Val Ser Gly Pro Ser Gly Gly Pro
245 250 255
Ser Ser Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln
260 265 270
Pro Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His
275 280 285
Leu Gly Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu
290 295 300
Leu Leu Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys
305 310 315 320
His Trp Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly
325 330 335
Ala Val Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser
340 345 350
Pro Ala Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His
355 360 365
Thr Gln Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp
370 375 380
Glu Asp Pro Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro
385 390 395 400
Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu
405 410 415
Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu
420 425 430
Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His
435 440 445
Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu
450 455 460
Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
465 470 475 480
<210> 91
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> PA2.1.14 (VL:VH) scFv LIR1 HTICD构建体
<400> 91
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly
130 135 140
Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser
145 150 155 160
Tyr His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
165 170 175
Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys
180 185 190
Phe Lys Gly Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala
195 200 205
Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr
245 250 255
Leu Leu Thr His Pro Ser Asp Pro Leu Glu Leu Val Val Ser Gly Pro
260 265 270
Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly
275 280 285
Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly
290 295 300
Leu Gly Arg His Leu Gly Val Val Ile Gly Ile Leu Val Ala Val Ile
305 310 315 320
Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe Leu Ile Leu Arg His Arg
325 330 335
Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln
340 345 350
His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln
355 360 365
Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala
370 375 380
Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met Asp Thr Arg
385 390 395 400
Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala Glu Val Lys
405 410 415
His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser
420 425 430
Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln
435 440 445
Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr
450 455 460
Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro
465 470 475 480
Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr
485 490 495
Leu Ala Ile His
500
<210> 92
<211> 407
<212> PRT
<213> 人工序列
<220>
<223> PA2.1.14 (VL:VH) scFv LIR1 sHTICD构建体
<400> 92
Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala
1 5 10 15
Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln
20 25 30
Gly Thr Lys Val Glu Val Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gln Val Gln Leu Val Gln Ser Gly
50 55 60
Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala
65 70 75 80
Ser Gly Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Arg Gln Ala
85 90 95
Pro Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val
100 105 110
Asn Thr Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Ile Thr Ala
115 120 125
Asp Glu Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser
130 135 140
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Glu Ile Thr Tyr Ala
145 150 155 160
Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Val Val
165 170 175
Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro Thr Ser
180 185 190
Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser Asp Pro
195 200 205
Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly Ile Leu Val
210 215 220
Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe Leu Ile Leu
225 230 235 240
Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala
245 250 255
Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg
260 265 270
Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn
275 280 285
Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met
290 295 300
Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala
305 310 315 320
Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser
325 330 335
Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu
340 345 350
Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp
355 360 365
Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr
370 375 380
Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile
385 390 395 400
Tyr Ala Thr Leu Ala Ile His
405
<210> 93
<211> 32
<212> PRT
<213> 智人 (Homo sapiens)
<400> 93
Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr
1 5 10 15
Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val
20 25 30
<210> 94
<211> 10
<212> PRT
<213> 智人 (Homo sapiens)
<400> 94
Met Ala Met Val Lys Arg Lys Asp Ser Arg
1 5 10
<210> 95
<211> 30
<212> DNA
<213> 智人 (Homo sapiens)
<400> 95
atggccatgg tcaagagaaa ggattccaga 30
<210> 96
<211> 23
<212> PRT
<213> 智人 (Homo sapiens)
<400> 96
Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
1 5 10 15
Leu Met Thr Leu Arg Leu Trp
20
<210> 97
<211> 69
<212> DNA
<213> 智人 (Homo sapiens)
<400> 97
gtgattgggt tccgaatcct cctcctgaaa gtggccgggt ttaatctgct catgacgctg 60
cggctgtgg 69
<210> 98
<211> 23
<212> PRT
<213> 智人 (Homo sapiens)
<400> 98
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
1 5 10 15
Leu Val Ser Ala Leu Val Leu
20
<210> 99
<211> 69
<212> DNA
<213> 智人 (Homo sapiens)
<400> 99
accatcctct atgagatctt gctagggaag gccaccttgt atgccgtgct ggtcagtgcc 60
ctcgtgctg 69
<210> 100
<211> 27
<212> PRT
<213> 智人 (Homo sapiens)
<400> 100
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 101
<211> 81
<212> DNA
<213> 智人 (Homo sapiens)
<400> 101
ttctgggtgc tggtcgttgt gggcggcgtg ctggcctgct acagcctgct ggtgacagtg 60
gccttcatca tcttttgggt g 81
<210> 102
<211> 45
<212> PRT
<213> 智人 (Homo sapiens)
<400> 102
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 103
<211> 135
<212> DNA
<213> 智人 (Homo sapiens)
<400> 103
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 104
<211> 41
<212> PRT
<213> 智人 (Homo sapiens)
<400> 104
Cys Thr Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys
1 5 10 15
Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser
20 25 30
Pro Leu Phe Pro Gly Pro Ser Lys Pro
35 40
<210> 105
<211> 123
<212> DNA
<213> 智人 (Homo sapiens)
<400> 105
tgtaccattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 60
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 120
ccc 123
<210> 106
<211> 9
<212> PRT
<213> 智人 (Homo sapiens)
<400> 106
Phe Leu Trp Gly Pro Arg Ala Leu Val
1 5
<210> 107
<211> 9
<212> PRT
<213> 智人 (Homo sapiens)
<400> 107
Ser Leu Leu Met Trp Ile Thr Gln Val
1 5
<210> 108
<211> 11
<212> PRT
<213> 智人 (Homo sapiens)
<400> 108
Met Pro Lys Val Ala Glu Leu Val His Phe Leu
1 5 10
<210> 109
<211> 10
<212> PRT
<213> 人类乳突病毒
<400> 109
Thr Ile His Asp Ile Ile Leu Glu Cys Val
1 5 10
<210> 110
<211> 9
<212> PRT
<213> 人类乳突病毒
<400> 110
Tyr Met Leu Asp Leu Gln Pro Glu Thr
1 5
<210> 111
<211> 1503
<212> DNA
<213> 人工序列
<220>
<223> 编码PA2.1.14 scFv LIR1 HTICD构建体的多核苷酸
<400> 111
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60
tcctgcaagg cttctggata caccttcact agctatcata tacattgggt gcgccaggcc 120
cccggacaag ggcttgagtg gatcggatgg atctaccctg gcaatgttaa cacagaatat 180
aatgagaagt tcaagggcaa agccaccatt accgcggacg aatccacgaa cacagcctac 240
atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagggaggaa 300
attacctacg ctatggacta ctggggccag ggaaccctgg tcaccgtgtc ctcaggcgga 360
ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgacat tcaaatgacc 420
cagagcccat ccaccctgag cgcatctgta ggtgaccggg tcaccatcac ttgtagatcc 480
agtcagagta ttgtacacag taatgggaac acctatttgg aatggtatca gcagaaacca 540
ggtaaagccc caaaattgct catctacaaa gtctctaaca gatttagtgg tgtaccagcc 600
aggttcagcg gttccggaag tggtactgaa ttcaccctca cgatctcctc tctccagcca 660
gatgatttcg ccacttatta ctgttttcaa ggttcacatg tgccgcgcac attcggtcag 720
ggtactaaag tagaagtcaa atacggctca cagagctcca aaccctacct gctgactcac 780
cccagtgacc ccctggagct cgtggtctca ggaccgtctg ggggccccag ctccccgaca 840
acaggcccca cctccacatc tggccctgag gaccagcccc tcacccccac cgggtcggat 900
ccccagagtg gtctgggaag gcacctgggg gttgtgatcg gcatcttggt ggccgtcatc 960
ctactgctcc tcctcctcct cctcctcttc ctcatcctcc gacatcgacg tcagggcaaa 1020
cactggacat cgacccagag aaaggctgat ttccaacatc ctgcaggggc tgtggggcca 1080
gagcccacag acagaggcct gcagtggagg tccagcccag ctgccgatgc ccaggaagaa 1140
aacctctatg ctgccgtgaa gcacacacag cctgaggatg gggtggagat ggacactcgg 1200
agcccacacg atgaagaccc ccaggcagtg acgtatgccg aggtgaaaca ctccagacct 1260
aggagagaaa tggcctctcc tccttcccca ctgtctgggg aattcctgga cacaaaggac 1320
agacaggcgg aagaggacag gcagatggac actgaggctg ctgcatctga agccccccag 1380
gatgtgacct acgcccagct gcacagcttg accctcagac gggaggcaac tgagcctcct 1440
ccatcccagg aagggccctc tccagctgtg cccagcatct acgccactct ggccatccac 1500
tag 1503
<210> 112
<211> 1443
<212> DNA
<213> 人工序列
<220>
<223> 编码PA2.1.14 scFv LIR1 sHTICD构建体的多核苷酸
<400> 112
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60
tcctgcaagg cttctggata caccttcact agctatcata tacattgggt gcgccaggcc 120
cccggacaag ggcttgagtg gatcggatgg atctaccctg gcaatgttaa cacagaatat 180
aatgagaagt tcaagggcaa agccaccatt accgcggacg aatccacgaa cacagcctac 240
atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagggaggaa 300
attacctacg ctatggacta ctggggccag ggaaccctgg tcaccgtgtc ctcaggcgga 360
ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgacat tcaaatgacc 420
cagagcccat ccaccctgag cgcatctgta ggtgaccggg tcaccatcac ttgtagatcc 480
agtcagagta ttgtacacag taatgggaac acctatttgg aatggtatca gcagaaacca 540
ggtaaagccc caaaattgct catctacaaa gtctctaaca gatttagtgg tgtaccagcc 600
aggttcagcg gttccggaag tggtactgaa ttcaccctca cgatctcctc tctccagcca 660
gatgatttcg ccacttatta ctgttttcaa ggttcacatg tgccgcgcac attcggtcag 720
ggtactaaag tagaagtcaa agtggtctca ggaccgtctg ggggccccag ctccccgaca 780
acaggcccca cctccacatc tggccctgag gaccagcccc tcacccccac cgggtcggat 840
ccccagagtg gtctgggaag gcacctgggg gttgtgatcg gcatcttggt ggccgtcatc 900
ctactgctcc tcctcctcct cctcctcttc ctcatcctcc gacatcgacg tcagggcaaa 960
cactggacat cgacccagag aaaggctgat ttccaacatc ctgcaggggc tgtggggcca 1020
gagcccacag acagaggcct gcagtggagg tccagcccag ctgccgatgc ccaggaagaa 1080
aacctctatg ctgccgtgaa gcacacacag cctgaggatg gggtggagat ggacactcgg 1140
agcccacacg atgaagaccc ccaggcagtg acgtatgccg aggtgaaaca ctccagacct 1200
aggagagaaa tggcctctcc tccttcccca ctgtctgggg aattcctgga cacaaaggac 1260
agacaggcgg aagaggacag gcagatggac actgaggctg ctgcatctga agccccccag 1320
gatgtgacct acgcccagct gcacagcttg accctcagac gggaggcaac tgagcctcct 1380
ccatcccagg aagggccctc tccagctgtg cccagcatct acgccactct ggccatccac 1440
tag 1443
<210> 113
<211> 1503
<212> DNA
<213> 人工序列
<220>
<223> 多核苷酸PA2.1.14 (VL:VH) scFv LIR1 HTICD构建体
<400> 113
gacattcaaa tgacccagag cccatccacc ctgagcgcat ctgtaggtga ccgggtcacc 60
atcacttgta gatccagtca gagtattgta cacagtaatg ggaacaccta tttggaatgg 120
tatcagcaga aaccaggtaa agccccaaaa ttgctcatct acaaagtctc taacagattt 180
agtggtgtac cagccaggtt cagcggttcc ggaagtggta ctgaattcac cctcacgatc 240
tcctctctcc agccagatga tttcgccact tattactgtt ttcaaggttc acatgtgccg 300
cgcacattcg gtcagggtac taaagtagaa gtcaaaggcg gaggtggaag cggaggggga 360
ggatctggcg gcggaggaag cggaggccag gtgcagctgg tgcagtctgg ggctgaggtg 420
aagaagcctg ggtcctcagt gaaggtttcc tgcaaggctt ctggatacac cttcactagc 480
tatcatatac attgggtgcg ccaggccccc ggacaagggc ttgagtggat cggatggatc 540
taccctggca atgttaacac agaatataat gagaagttca agggcaaagc caccattacc 600
gcggacgaat ccacgaacac agcctacatg gagctgagca gcctgagatc tgaagacacg 660
gctgtgtatt actgtgcgag ggaggaaatt acctacgcta tggactactg gggccaggga 720
accctggtca ccgtgtcctc atacggctca cagagctcca aaccctacct gctgactcac 780
cccagtgacc ccctggagct cgtggtctca ggaccgtctg ggggccccag ctccccgaca 840
acaggcccca cctccacatc tggccctgag gaccagcccc tcacccccac cgggtcggat 900
ccccagagtg gtctgggaag gcacctgggg gttgtgatcg gcatcttggt ggccgtcatc 960
ctactgctcc tcctcctcct cctcctcttc ctcatcctcc gacatcgacg tcagggcaaa 1020
cactggacat cgacccagag aaaggctgat ttccaacatc ctgcaggggc tgtggggcca 1080
gagcccacag acagaggcct gcagtggagg tccagcccag ctgccgatgc ccaggaagaa 1140
aacctctatg ctgccgtgaa gcacacacag cctgaggatg gggtggagat ggacactcgg 1200
agcccacacg atgaagaccc ccaggcagtg acgtatgccg aggtgaaaca ctccagacct 1260
aggagagaaa tggcctctcc tccttcccca ctgtctgggg aattcctgga cacaaaggac 1320
agacaggcgg aagaggacag gcagatggac actgaggctg ctgcatctga agccccccag 1380
gatgtgacct acgcccagct gcacagcttg accctcagac gggaggcaac tgagcctcct 1440
ccatcccagg aagggccctc tccagctgtg cccagcatct acgccactct ggccatccac 1500
tag 1503
<210> 114
<211> 1443
<212> DNA
<213> 人工序列
<220>
<223> 编码PA2.1.14 (VL:VH) scFv LIR1 sHTICD构建体的多核苷酸
<400> 114
gacattcaaa tgacccagag cccatccacc ctgagcgcat ctgtaggtga ccgggtcacc 60
atcacttgta gatccagtca gagtattgta cacagtaatg ggaacaccta tttggaatgg 120
tatcagcaga aaccaggtaa agccccaaaa ttgctcatct acaaagtctc taacagattt 180
agtggtgtac cagccaggtt cagcggttcc ggaagtggta ctgaattcac cctcacgatc 240
tcctctctcc agccagatga tttcgccact tattactgtt ttcaaggttc acatgtgccg 300
cgcacattcg gtcagggtac taaagtagaa gtcaaaggcg gaggtggaag cggaggggga 360
ggatctggcg gcggaggaag cggaggccag gtgcagctgg tgcagtctgg ggctgaggtg 420
aagaagcctg ggtcctcagt gaaggtttcc tgcaaggctt ctggatacac cttcactagc 480
tatcatatac attgggtgcg ccaggccccc ggacaagggc ttgagtggat cggatggatc 540
taccctggca atgttaacac agaatataat gagaagttca agggcaaagc caccattacc 600
gcggacgaat ccacgaacac agcctacatg gagctgagca gcctgagatc tgaagacacg 660
gctgtgtatt actgtgcgag ggaggaaatt acctacgcta tggactactg gggccaggga 720
accctggtca ccgtgtcctc agtggtctca ggaccgtctg ggggccccag ctccccgaca 780
acaggcccca cctccacatc tggccctgag gaccagcccc tcacccccac cgggtcggat 840
ccccagagtg gtctgggaag gcacctgggg gttgtgatcg gcatcttggt ggccgtcatc 900
ctactgctcc tcctcctcct cctcctcttc ctcatcctcc gacatcgacg tcagggcaaa 960
cactggacat cgacccagag aaaggctgat ttccaacatc ctgcaggggc tgtggggcca 1020
gagcccacag acagaggcct gcagtggagg tccagcccag ctgccgatgc ccaggaagaa 1080
aacctctatg ctgccgtgaa gcacacacag cctgaggatg gggtggagat ggacactcgg 1140
agcccacacg atgaagaccc ccaggcagtg acgtatgccg aggtgaaaca ctccagacct 1200
aggagagaaa tggcctctcc tccttcccca ctgtctgggg aattcctgga cacaaaggac 1260
agacaggcgg aagaggacag gcagatggac actgaggctg ctgcatctga agccccccag 1320
gatgtgacct acgcccagct gcacagcttg accctcagac gggaggcaac tgagcctcct 1380
ccatcccagg aagggccctc tccagctgtg cccagcatct acgccactct ggccatccac 1440
tag 1443
<210> 115
<211> 71
<212> PRT
<213> 智人 (Homo sapiens)
<400> 115
Ser Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro
1 5 10 15
Ser Asp Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser
20 25 30
Ser Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro
35 40 45
Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu
50 55 60
Gly Val Val Ile Gly Ile Leu
65 70
<210> 116
<211> 39
<212> PRT
<213> 智人 (Homo sapiens)
<400> 116
Ser Ser Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro
1 5 10 15
Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu
20 25 30
Gly Val Val Ile Gly Ile Leu
35
<210> 117
<211> 74
<212> PRT
<213> 人工序列
<220>
<223> 在实验室中制造 - 铰链序列
<400> 117
Ser Ser Ala Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Pro Val
1 5 10 15
Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser
20 25 30
Pro Ser Gly Gly Ser Gly Asn Ser Ser Gly Ser Gly Gly Ser Pro Val
35 40 45
Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser
50 55 60
Pro Ser Ala Ser Val Val Ile Gly Ile Leu
65 70
<210> 118
<211> 82
<212> PRT
<213> 人工序列
<220>
<223> 在实验室中制造 - 铰链序列
<400> 118
Ser Ser Ala Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Pro Val
1 5 10 15
Pro Ser Thr Pro Pro Thr Asn Ser Ser Ser Thr Pro Pro Thr Pro Ser
20 25 30
Pro Ser Pro Val Pro Ser Thr Pro Pro Thr Asn Ser Ser Ser Thr Pro
35 40 45
Pro Thr Pro Ser Pro Ser Pro Val Pro Ser Thr Pro Pro Thr Asn Ser
50 55 60
Ser Ser Thr Pro Pro Thr Pro Ser Pro Ser Ala Ser Val Val Ile Gly
65 70 75 80
Ile Leu
<210> 119
<211> 92
<212> PRT
<213> 人工序列
<220>
<223> 在实验室中制造 - 铰链序列
<400> 119
Ser Ser Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr
1 5 10 15
Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr
20 25 30
Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Val Val Ser Gly Pro
35 40 45
Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly
50 55 60
Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly
65 70 75 80
Leu Gly Arg His Leu Gly Val Val Ile Gly Ile Leu
85 90
<210> 120
<211> 522
<212> PRT
<213> 人工序列
<220>
<223> 具有信号肽的C1765嵌合抗原受体构建体
<400> 120
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Val Leu Met Thr Gln Thr Pro Leu Ser
20 25 30
Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn
65 70 75 80
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val
100 105 110
Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Ser Gly Gly Gly
115 120 125
Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Pro
145 150 155 160
Glu Leu Val Lys Pro Gly Ala Ser Val Arg Ile Ser Cys Lys Ala Ser
165 170 175
Gly Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Lys Gln Arg Pro
180 185 190
Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn
195 200 205
Thr Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp
210 215 220
Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr Ser Glu
225 230 235 240
Asp Ser Ala Val Tyr Phe Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met
245 250 255
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Tyr Gly Ser
260 265 270
Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu
275 280 285
Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly
290 295 300
Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly
305 310 315 320
Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly
325 330 335
Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe
340 345 350
Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln
355 360 365
Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro
370 375 380
Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln
385 390 395 400
Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly
405 410 415
Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val
420 425 430
Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser
435 440 445
Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln
450 455 460
Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala
465 470 475 480
Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg
485 490 495
Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val
500 505 510
Pro Ser Ile Tyr Ala Thr Leu Ala Ile His
515 520
<210> 121
<211> 1569
<212> DNA
<213> 人工序列
<220>
<223> 编码具有信号肽的C1765嵌合抗原受体构建体的多核苷酸
<400> 121
atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60
agatgtgatg ttttgatgac ccaaactcca ctctccctgc ctgtcagtct tggagatcaa 120
gcctccatct cttgcagatc tagtcagagc attgtacata gtaatggaaa cacctattta 180
gaatggtacc tgcagaaacc aggccagtct ccaaagctcc tgatctacaa agtttccaac 240
cgattttctg gggtcccaga caggttcagt ggcagtggat cagggacaga tttcacactc 300
aagatcagta gagtggaggc tgaggatctg ggagtttatt actgctttca aggttcacat 360
gttcctcgga cgtccggtgg aggcaccaag ctggaaatca aaggcggagg tggaagcgga 420
gggggaggat ctggcggcgg aggaagcgga ggccaggtcc agctgcagca gtctggacct 480
gagctggtga agcctggggc ttcagtgagg atatcctgca aggcttctgg ctacaccttc 540
acaagttacc atatacattg ggtgaagcag aggcctggac agggacttga gtggattgga 600
tggatttatc ctggaaatgt taatactgag tacaatgaga agttcaaggg caaggccaca 660
ctgactgcag acaaatcgtc cagcacagcc tacatgcacc tcagcagcct gacctctgag 720
gactctgcgg tctatttctg tgccagagag gagattacct atgctatgga ctactggggt 780
caaggaacct cagtcaccgt gtcctcatac ggctcacaga gctccaaacc ctacctgctg 840
actcacccca gtgaccccct ggagctcgtg gtctcaggac cgtctggggg ccccagctcc 900
ccgacaacag gccccacctc cacatctggc cctgaggacc agcccctcac ccccaccggg 960
tcggatcccc agagtggtct gggaaggcac ctgggggttg tgatcggcat cttggtggcc 1020
gtcatcctac tgctcctcct cctcctcctc ctcttcctca tcctccgaca tcgacgtcag 1080
ggcaaacact ggacatcgac ccagagaaag gctgatttcc aacatcctgc aggggctgtg 1140
gggccagagc ccacagacag aggcctgcag tggaggtcca gcccagctgc cgatgcccag 1200
gaagaaaacc tctatgctgc cgtgaagcac acacagcctg aggatggggt ggagatggac 1260
actcggagcc cacacgatga agacccccag gcagtgacgt atgccgaggt gaaacactcc 1320
agacctagga gagaaatggc ctctcctcct tccccactgt ctggggaatt cctggacaca 1380
aaggacagac aggcggaaga ggacaggcag atggacactg aggctgctgc atctgaagcc 1440
ccccaggatg tgacctacgc ccagctgcac agcttgaccc tcagacggga ggcaactgag 1500
cctcctccat cccaggaagg gccctctcca gctgtgccca gcatctacgc cactctggcc 1560
atccactag 1569
<210> 122
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> 没有信号肽的C1765嵌合抗原受体构建体
<400> 122
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Arg Thr Ser Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly
130 135 140
Ala Ser Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser
145 150 155 160
Tyr His Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp
165 170 175
Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys
180 185 190
Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala
195 200 205
Tyr Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe
210 215 220
Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Ser Val Thr Val Ser Ser Tyr Gly Ser Gln Ser Ser Lys Pro Tyr
245 250 255
Leu Leu Thr His Pro Ser Asp Pro Leu Glu Leu Val Val Ser Gly Pro
260 265 270
Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly
275 280 285
Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly
290 295 300
Leu Gly Arg His Leu Gly Val Val Ile Gly Ile Leu Val Ala Val Ile
305 310 315 320
Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe Leu Ile Leu Arg His Arg
325 330 335
Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln
340 345 350
His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln
355 360 365
Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala
370 375 380
Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met Asp Thr Arg
385 390 395 400
Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala Glu Val Lys
405 410 415
His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser Pro Leu Ser
420 425 430
Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln
435 440 445
Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr
450 455 460
Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro
465 470 475 480
Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr
485 490 495
Leu Ala Ile His
500
<210> 123
<211> 1503
<212> DNA
<213> 人工序列
<220>
<223> 编码没有信号肽的C1765嵌合抗原受体构建体的多核苷酸
<400> 123
gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agtagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcct 300
cggacgtccg gtggaggcac caagctggaa atcaaaggcg gaggtggaag cggaggggga 360
ggatctggcg gcggaggaag cggaggccag gtccagctgc agcagtctgg acctgagctg 420
gtgaagcctg gggcttcagt gaggatatcc tgcaaggctt ctggctacac cttcacaagt 480
taccatatac attgggtgaa gcagaggcct ggacagggac ttgagtggat tggatggatt 540
tatcctggaa atgttaatac tgagtacaat gagaagttca agggcaaggc cacactgact 600
gcagacaaat cgtccagcac agcctacatg cacctcagca gcctgacctc tgaggactct 660
gcggtctatt tctgtgccag agaggagatt acctatgcta tggactactg gggtcaagga 720
acctcagtca ccgtgtcctc atacggctca cagagctcca aaccctacct gctgactcac 780
cccagtgacc ccctggagct cgtggtctca ggaccgtctg ggggccccag ctccccgaca 840
acaggcccca cctccacatc tggccctgag gaccagcccc tcacccccac cgggtcggat 900
ccccagagtg gtctgggaag gcacctgggg gttgtgatcg gcatcttggt ggccgtcatc 960
ctactgctcc tcctcctcct cctcctcttc ctcatcctcc gacatcgacg tcagggcaaa 1020
cactggacat cgacccagag aaaggctgat ttccaacatc ctgcaggggc tgtggggcca 1080
gagcccacag acagaggcct gcagtggagg tccagcccag ctgccgatgc ccaggaagaa 1140
aacctctatg ctgccgtgaa gcacacacag cctgaggatg gggtggagat ggacactcgg 1200
agcccacacg atgaagaccc ccaggcagtg acgtatgccg aggtgaaaca ctccagacct 1260
aggagagaaa tggcctctcc tccttcccca ctgtctgggg aattcctgga cacaaaggac 1320
agacaggcgg aagaggacag gcagatggac actgaggctg ctgcatctga agccccccag 1380
gatgtgacct acgcccagct gcacagcttg accctcagac gggaggcaac tgagcctcct 1440
ccatcccagg aagggccctc tccagctgtg cccagcatct acgccactct ggccatccac 1500
tag 1503
<210> 124
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 免疫受体酪氨酸抑制性基序
<220>
<221> 尚未归类的特征
<222> (1)..(1)
<223> Xaa = Ser、Ile、Val或Leu
<220>
<221> 尚未归类的特征
<222> (2)..(2)
<223> Xaa = 任何氨基酸
<220>
<221> 尚未归类的特征
<222> (4)..(5)
<223> Xaa = 任何氨基酸
<220>
<221> 尚未归类的特征
<222> (6)..(6)
<223> Xaa = Ile、Val或Leu
<400> 124
Xaa Xaa Tyr Xaa Xaa Xaa
1 5
<210> 125
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> C-001765 scFv抗体构建体
<400> 125
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Arg Thr Ser Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly
130 135 140
Ala Ser Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser
145 150 155 160
Tyr His Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp
165 170 175
Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys
180 185 190
Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala
195 200 205
Tyr Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe
210 215 220
Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Ser Val Thr Val Ser Ser
245
<210> 126
<211> 759
<212> DNA
<213> 智人 (Homo sapiens)
<400> 126
tacggctcac agagctccaa accctacctg ctgactcacc ccagtgaccc cctggagctc 60
gtggtctcag gaccgtctgg gggccccagc tccccgacaa caggccccac ctccacatct 120
ggccctgagg accagcccct cacccccacc gggtcggatc cccagagtgg tctgggaagg 180
cacctggggg ttgtgatcgg catcttggtg gccgtcatcc tactgctcct cctcctcctc 240
ctcctcttcc tcatcctccg acatcgacgt cagggcaaac actggacatc gacccagaga 300
aaggctgatt tccaacatcc tgcaggggct gtggggccag agcccacaga cagaggcctg 360
cagtggaggt ccagcccagc tgccgatgcc caggaagaaa acctctatgc tgccgtgaag 420
cacacacagc ctgaggatgg ggtggagatg gacactcgga gcccacacga tgaagacccc 480
caggcagtga cgtatgccga ggtgaaacac tccagaccta ggagagaaat ggcctctcct 540
ccttccccac tgtctgggga attcctggac acaaaggaca gacaggcgga agaggacagg 600
cagatggaca ctgaggctgc tgcatctgaa gccccccagg atgtgaccta cgcccagctg 660
cacagcttga ccctcagacg ggaggcaact gagcctcctc catcccagga agggccctct 720
ccagctgtgc ccagcatcta cgccactctg gccatccac 759
<210> 127
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> C-001765 scFv抗体构建体多核苷酸
<400> 127
gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agtagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcct 300
cggacgtccg gtggaggcac caagctggaa atcaaaggcg gaggtggaag cggaggggga 360
ggatctggcg gcggaggaag cggaggccag gtccagctgc agcagtctgg acctgagctg 420
gtgaagcctg gggcttcagt gaggatatcc tgcaaggctt ctggctacac cttcacaagt 480
taccatatac attgggtgaa gcagaggcct ggacagggac ttgagtggat tggatggatt 540
tatcctggaa atgttaatac tgagtacaat gagaagttca agggcaaggc cacactgact 600
gcagacaaat cgtccagcac agcctacatg cacctcagca gcctgacctc tgaggactct 660
gcggtctatt tctgtgccag agaggagatt acctatgcta tggactactg gggtcaagga 720
acctcagtca ccgtgtcctc a 741
<210> 128
<211> 22
<212> PRT
<213> 智人 (Homo sapiens)
<400> 128
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys
20
<210> 129
<211> 66
<212> DNA
<213> 智人 (Homo sapiens)
<400> 129
atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60
agatgt 66
Claims (90)
1.一种包含多肽的嵌合抗原受体，其中所述多肽包含以下中的一种或多种：
a)LILRB1铰链结构域或其功能片段或变体；
b)LILRB1跨膜结构域或其功能变体；或
c)LILRB1胞内结构域或包含至少一个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中所述ITIM选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
2.根据权利要求1所述的受体，其中所述多肽包含LILRB1胞内结构域和/或包含至少两个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
3.根据权利要求2所述的受体，其中所述胞内结构域包含两个ITIM NLYAAV(SEQ IDNO:8)和VTYAEV(SEQ ID NO:9)。
4.根据权利要求3所述的受体，其中所述胞内结构域包含与SEQ ID NO:12至少95％相同的序列。
5.根据权利要求2所述的受体，其中所述胞内结构域包含两个ITIM VTYAEV(SEQ IDNO:9)和VTYAQL(SEQ ID NO:10)。
6.根据权利要求5所述的受体，其中所述胞内结构域包含与SEQ ID NO:13至少95％相同的序列。
7.根据权利要求2所述的受体，其中所述胞内结构域包含两个ITIM VTYAQL(SEQ IDNO:10)和SIYATL(SEQ ID NO:11)。
8.根据权利要求5所述的受体，其中所述胞内结构域包含与SEQ ID NO:14至少95％相同的序列。
9.根据权利要求1所述的受体，其中所述多肽包含含有至少三个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
10.根据权利要求2所述的受体，其中所述胞内结构域包含ITIM NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)和VTYAQL(SEQ ID NO:10)。
11.根据权利要求10所述的受体，其中所述胞内结构域包含与SEQ ID NO:15至少95％相同的序列。
12.根据权利要求2所述的受体，其中所述胞内结构域包含ITIM VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
13.根据权利要求12所述的受体，其中所述胞内结构域包含与SEQ ID NO:16至少95％相同的序列。
14.根据权利要求2所述的受体，其中所述胞内结构域包含ITIM NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQ ID NO:10)和SIYATL(SEQ ID NO:11)。
15.根据权利要求14所述的受体，其中所述胞内结构域包含与SEQ ID NO:17至少95％相同的序列。
16.根据权利要求15所述的受体，其中所述胞内结构域包含与LILRB1胞内结构域(SEQID NO:7)至少95％相同的序列。
17.根据权利要求1所述的受体，其中所述胞内结构域包含SEQ ID NO:12-17的序列。
18.根据权利要求1-17中任一项所述的受体，其中所述多肽包含所述LILRB1跨膜结构域或其功能变体。
19.根据权利要求18所述的受体，其中所述LILRB1跨膜结构域或其功能变体包含与SEQID NO:5至少95％相同的序列。
20.根据权利要求19所述的受体，其中所述LILRB1跨膜结构域包含SEQ ID NO:5。
21.根据权利要求1-20中任一项所述的受体，其中所述多肽包含所述LILRB1铰链结构域或其功能片段或变体。
22.根据权利要求21所述的受体，其中所述LILRB1铰链结构域或其功能片段或变体包含与SEQ ID NO:4、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:80、SEQ ID NO:81、SEQ IDNO:82、SEQ ID NO:83、SEQ ID NO:84或SEQ ID NO:93至少95％相同的序列。
23.根据权利要求21所述的受体，其中所述LILRB1铰链结构域包含与SEQ ID NO:4、SEQID NO:18、SEQ ID NO:19、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82、SEQ ID NO:83、SEQID NO:84或SEQ ID NO:93相同的序列。
24.根据权利要求21所述的受体，其中所述LILRB1铰链结构域或其功能片段或变体包含与SEQ ID NO:4、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:80、SEQ ID NO:81、SEQ IDNO:82、SEQ ID NO:83或SEQ ID NO:84至少95％相同的序列。
25.根据权利要求21所述的受体，其中所述LILRB1铰链结构域包含与SEQ ID NO:4、SEQID NO:18、SEQ ID NO:19、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82、SEQ ID NO:83或SEQ ID NO:84相同的序列。
26.根据权利要求1-25中任一项所述的受体，其中所述多肽包含：
a)LILRB1铰链结构域或其功能片段或变体，以及
b)所述LILRB1跨膜结构域或其功能变体。
27.根据权利要求26所述的受体，其中所述多肽包含与SEQ ID NO:20至少95％相同的序列。
28.根据权利要求1-27中任一项所述的受体，其中所述多肽包含：
a)所述LILRB1跨膜结构域或其功能变体，以及
b)LILRB1胞内结构域和/或包含至少两个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQID NO:10)和SIYATL(SEQ ID NO:11)。
29.根据权利要求28所述的受体，其中所述多肽包含与SEQ ID NO:21至少95％相同的序列。
30.根据权利要求28所述的受体，其中所述多肽包含SEQ ID NO:21的序列。
31.根据权利要求1所述的受体，其中所述多肽包含：
a)LILRB1铰链结构域或其功能片段或变体；
b)LILRB1跨膜结构域或其功能变体；以及
c)LILRB1胞内结构域和/或包含至少两个免疫受体酪氨酸抑制性基序(ITIM)的胞内结构域，其中每个ITIM独立地选自NLYAAV(SEQ ID NO:8)、VTYAEV(SEQ ID NO:9)、VTYAQL(SEQID NO:10)和SIYATL(SEQ ID NO:11)。
32.根据权利要求1所述的受体，其中所述多肽包含与SEQ ID NO:2或SEQ ID NO:3至少95％相同的序列。
33.根据权利要求1所述的受体，其中所述多肽包含与SEQ ID NO:20至少99％相同的序列。
34.根据权利要求1所述的受体，其中所述多肽包含与SEQ ID NO:21至少99％相同的序列。
35.根据权利要求1所述的受体，其中所述多肽包含与SEQ ID NO:2或SEQ ID NO:3至少99％相同的序列。
36.根据权利要求1所述的受体，其中所述多肽包含与SEQ ID NO:20相同的序列。
37.根据权利要求1所述的受体，其中所述多肽包含与SEQ ID NO:21相同的序列。
38.根据权利要求1所述的受体，其中所述多肽包含与SEQ ID NO:2或SEQ ID NO:3相同的序列。
39.根据权利要求1所述的受体，其中所述多肽包含抗原结合结构域。
40.根据权利要求39所述的受体，其中所述抗原结合结构域是除了所述LILRB1胞外配体结合蛋白以外的抗原结合结构域。
41.根据权利要求39所述的受体，其中所述多肽包含两个或更多个抗原结合结构域。
42.根据权利要求1-41中任一项所述的受体，其中所述受体是抑制性受体。
43.根据权利要求39所述的受体，其中所述抗原结合结构域包含单链可变片段(scFv)。
44.根据权利要求1所述的受体，其中所述受体包含第二多肽。
45.根据权利要求44所述的受体，其中所述第一多肽包含抗体的第一链，并且所述第二多肽包含所述抗体的第二链。
46.根据权利要求44所述的受体，其中所述受体包含抗体的Fab片段。
47.根据权利要求44所述的受体，其中：
a)所述第一多肽包含所述抗体的重链的抗原结合片段，并且
b)所述第二多肽包含所述抗体的轻链的抗原结合片段。
48.根据权利要求44所述的受体，其中：
a)所述第一多肽包含所述抗体的轻链的抗原结合片段，并且
b)所述第二多肽包含所述抗体的重链的抗原结合片段。
49.根据权利要求44所述的受体，其中所述第一多肽包含T细胞受体(TCR)的第一链，并且所述第二多肽包含所述TCR的第二链。
50.根据权利要求44所述的受体，其中所述受体包含T细胞受体(TCR)的胞外片段。
51.根据权利要求50所述的受体，其中：
a)所述第一多肽包含所述TCR的α链的抗原结合片段，并且
b)所述第二多肽包含所述TCR的β链的抗原结合片段。
52.根据权利要求50所述的受体，其中：
a)所述第一多肽包含所述TCR的β链的抗原结合片段，并且
b)所述第二多肽包含所述TCR的α链的抗原结合片段。
53.根据权利要求1所述的受体，其中所述受体包含单链TCR。
54.根据权利要求43所述的受体，其中所述scFv包含SEQ ID NO:22-33中的任一个的互补决定区(CDR)。
55.根据权利要求43所述的受体，其中所述scFv包含与SEQ ID NO:35-46或125中的任一个至少95％相同的序列。
56.根据权利要求43所述的受体，其中所述scFv包含与SEQ ID NO:35-46或125中的任一个相同的序列。
57.根据权利要求47或权利要求48所述的受体，其中所述抗体的重链包含SEQ ID NO:25-27或31-33中的任一个的重链CDR，并且其中所述抗体的轻链包含SEQ ID NO:22-24或28-30中的任一个的轻链CDR。
58.根据权利要求47或权利要求48所述的受体，其中所述抗体的重链包含与SEQ IDNO:35-46或125中的任一个的重链部分至少95％相同的序列，并且其中所述抗体的轻链包含与SEQ ID NO:35-46或125中的任一个的轻链部分至少95％相同的序列。
59.根据权利要求47或权利要求48所述的受体，其中所述抗体的重链包含与SEQ IDNO:35-46或125中的任一个的重链部分相同的序列，并且其中所述抗体的轻链包含与SEQID NO:35-46或125中的任一个的轻链部分相同的序列。
60.根据权利要求1所述的受体，其中所述受体包含与SEQ ID NO:47-71、77-79、89-92、120或122中的任一个至少95％相同的氨基酸序列。
61.根据权利要求1所述的受体，其中所述受体包含SEQ ID NO:47-71、77-79、89-92、120或122的氨基酸序列。
62.一种多核苷酸，其包含编码根据权利要求1-61中任一项所述的受体的核酸序列。
63.一种载体，其包含根据权利要求62所述的多核苷酸。
64.根据权利要求63所述的载体，其进一步包含编码可操作地连接至所述多核苷酸的启动子的序列。
65.一种免疫细胞，其包含根据权利要求1-61中任一项所述的受体、根据权利要求62所述的多核苷酸或根据权利要求63或64所述的载体。
66.根据权利要求65所述的免疫细胞，其中当所述细胞与抗原或在其表面上表达所述抗原的细胞接触时，免疫细胞激活降低。
67.根据权利要求65或权利要求66所述的免疫细胞，其中免疫细胞激活包括表达可操作地连接至NFAT启动子的基因。
68.根据权利要求65-67中任一项所述的免疫细胞，其中所述免疫细胞是T细胞。
69.根据权利要求65-68中任一项所述的免疫细胞，其进一步包含激活剂受体。
70.根据权利要求69所述的免疫细胞，其中所述激活剂受体是嵌合抗原受体或T细胞受体。
71.一种制造免疫细胞的方法，其包括将根据权利要求62所述的多核苷酸或根据权利要求63或64所述的载体引入所述免疫细胞中。
72.根据权利要求69所述的方法，其中所述免疫细胞表达所述受体。
73.根据权利要求69或权利要求70所述的方法，其中所述细胞是免疫细胞。
74.根据权利要求71所述的方法，其中所述免疫细胞是T细胞。
75.根据权利要求69-72中任一项所述的方法，其中当所述细胞与对所述嵌合抗原受体特异性的抗原或在其表面上表达所述抗原的细胞接触时，免疫细胞激活降低。
76.根据权利要求73所述的方法，其中免疫细胞激活包括表达可操作地连接至NFAT启动子的基因。
77.一种治疗患有疾病或障碍的受试者的方法，其包括向所述受试者施用多个根据权利要求65-70中任一项所述的免疫细胞。
78.根据权利要求77所述的方法，其中所述疾病或障碍是癌症。
79.一种试剂盒，其包含根据权利要求1-61中任一项所述的受体、根据权利要求62所述的多核苷酸、根据权利要求63或64所述的载体或根据权利要求65-68中任一项所述的免疫细胞。
80.一种包含嵌合抗原受体的免疫细胞，所述嵌合抗原受体包含多肽，其中所述多肽序列与SEQ ID NO:21共享至少95％同一性或100％同一性。
81.根据权利要求80所述的免疫细胞，其中所述多肽序列与SEQ ID NO:3共享至少95％同一性或100％同一性。
82.根据权利要求80所述的免疫细胞，其中所述多肽序列与SEQ ID NO:2共享至少95％同一性或100％同一性。
83.根据权利要求81所述的免疫细胞，其中所述嵌合抗原受体包含抗原结合结构域，所述抗原结合结构域包含分别根据SEQ ID NO:22-27的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3序列。
84.根据权利要求81所述的免疫细胞，其中所述嵌合抗原受体包含抗原结合结构域，所述抗原结合结构域包含分别根据SEQ ID NO:28-33的CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3序列。
85.根据权利要求80所述的免疫细胞，其中所述多肽序列与SEQ ID NO:122共享至少95％同一性或100％同一性。
86.根据权利要求80-83中任一项所述的免疫细胞，其中所述免疫细胞是T细胞。
87.根据权利要求84所述的免疫细胞，其中所述T细胞包含特异性结合至肿瘤细胞上表达的靶标的嵌合抗原受体或T细胞受体。
88.根据权利要求87所述的免疫细胞，其中所述T细胞包含特异性结合至靶标的嵌合抗原受体或T细胞受体，所述靶标选自黄化受体、ανββ整合素、BCMA、B7-H3、B7-H6、CAIX、CD19、CD20、CD22、CD30、CD33、CD37、CD44、CD44v6、CD44v7/8、CD70、CD123、CD138、CD171、CEA、DLL4、EGP-2、EGP-40、CSPG4、EGFR、包括ErbB2(HER2)在内的EGFR家族、EGFRvIII、EPCAM、EphA2、EpCAM、FAP、FBP、胎儿乙酰胆碱受体、Fzd7、GD2、GD3、磷脂酰肌醇蛋白聚糖-3(GPC3)、h5T4、IL-11R、IL13R-a2、KDR、κ轻链、λ轻链、LeY、L1 CAM、MAGE-A1、间皮素、MHC呈递肽、MUC1、MUC16、NCAM、NKG2D配体、Notchl、Notch2/3、NY-ESO-1、PRAME、PSCA、PSMA、存活蛋白、TAG-72、TEM、TERT、VEGFR2和ROR1。
89.一种治疗和/或预防有需要的受试者的癌症的方法，其包括向所述受试者施用根据权利要求87所述的免疫细胞。
90.一种治疗和/或预防有需要的受试者的癌症的方法，其包括向所述受试者施用根据权利要求88所述的免疫细胞。
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