CN107667170A - 细胞 - Google Patents
细胞 Download PDFInfo
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- CN107667170A CN107667170A CN201680030192.8A CN201680030192A CN107667170A CN 107667170 A CN107667170 A CN 107667170A CN 201680030192 A CN201680030192 A CN 201680030192A CN 107667170 A CN107667170 A CN 107667170A
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Abstract
本发明涉及细胞，其包含嵌合抗原受体(CAR)和信号传导修饰蛋白，所述信号传导修饰蛋白选自以下之一：(i)截短的蛋白质，其包含来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，但缺少激酶结构域；(ii)截短的蛋白质，其包含来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域，但缺少磷酸酶结构域；(iii)融合蛋白质，其包含(a)来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)异源结构域。
Description
发明领域
本发明涉及实现信号传导通路的融合蛋白质和截短的蛋白质，所述通路在操纵或调节免疫细胞激活之后得以传播。
发明背景
用自体T细胞的过继性免疫疗法涉及从患者中分离T细胞，然后进行它们的离体刺激，修饰和/或扩增以产生显示抗肿瘤特异性的T细胞群体。一旦重新输注到患者中，这些细胞能够识别肿瘤表达的抗原并介导肿瘤排斥。
这种方法已经在不同设置中的大量的试验中显示出具有成为强力的，有效的和长期的癌症治疗的潜力。例如，可以通过离体扩增的EBV特异性T细胞有效治疗EBV驱动的肿瘤，如实体器官移植后的淋巴组织增生性疾病。
非病毒性恶性肿瘤的类似疗法涉及肿瘤浸润性淋巴细胞(TILs)，其分离自切除的肿瘤片段且然后经受使用自体肿瘤样品的刺激和扩增。然后将显示肿瘤反应性的扩增的T细胞培养物重新输注到患者中。
并非用重复暴露至抗原来选择和改善T细胞特异性，可以通过基因修饰和导入肿瘤特异性T细胞受体(TCR)或嵌合抗原受体(CAR)来赋予T细胞期望的抗肿瘤特异性。离体扩增这些细胞以生产足够数量的细胞来实现患者内有意义的临床反应。
但是，上面详述的方法有局限性。例如由于信号传导不足、缺少IL2或分化，过继性转染的T细胞可以表现出有限的体内存留和扩增。作为进一步的例子，过继性转染的T细胞可能会屈服于肿瘤微环境内的抑制性刺激。例如，它们可能会变得耗竭，由于过度激活而经历激活诱导的细胞死亡，或者可能导致靶向肿瘤外效应(on-target off-tumoureffects)。
激活治疗性抗肿瘤免疫的另一种有前景的方法是阻断免疫检查点。免疫检查点是指免疫系统的各种抑制途径，其对于维持自身耐受性和调节外周组织中生理性免疫应答的持续时间和幅度是重要的。
已知肿瘤利用某些免疫检查点途径作为免疫抗性，特别是针对肿瘤抗原特异性的T细胞免疫抗性的主要机制。许多免疫检查点由配体-受体相互作用启动，这意味着它们可被抗体阻断或被重组形式的配体或受体调节。细胞毒性T淋巴细胞相关抗原4(CTLA4)抗体是获得美国食品和药物管理局(FDA)批准的首个该类别的免疫治疗剂。最近，已经开发了另外的免疫检查点蛋白质的阻断剂，例如程序性细胞死亡蛋白1(PD1)，并显示出增强抗肿瘤免疫。
使用免疫检查点抑制剂的一个问题是由众多配体：受体相互作用触发众多抑制途径。使用抗体或重组形式的配体/受体将仅阻断一种此类的抑制性途径，留下肿瘤可以使用其他分子来补偿特定的免疫检查点阻断的可能性。
发明概述
本发明人已经开发了用于调节和/或操纵免疫细胞(例如T细胞和自然杀伤(NK)细胞)中的信号传导途径的系统。
通过蛋白质的可逆的翻译后修饰来起始和控制细胞内信号传导途径。本发明人已经确定了可以通过包含来自直接T细胞信号传导蛋白(immediate T-cell signaltransduction proteins)的SH2结构域的融合蛋白质或截短的蛋白质来调节和/或操纵T细胞中激活和抑制性信号传导。换而言之，可以通过包含来自能够结合磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)或磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)的蛋白质的SH2结构域的融合蛋白质或截短的蛋白质来激活或抑制T细胞中的信号传导通路。
因此，在第一方面，本发明提供了细胞，其包含嵌合抗原受体(CAR)和信号传导修饰蛋白，所述信号传导修饰蛋白选自以下之一：
(i)截短的蛋白质，其包含SH2结构域，但缺少激酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质；
(ii)截短的蛋白质，其包含SH2结构域，但缺少磷酸酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质；
(iii)融合蛋白质，其包含(a)含来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)异源结构域。
信号传导修饰蛋白可以是截短的蛋白质，其包含ZAP70 SH2结构域但缺少ZAP70激酶结构域。
信号传导修饰蛋白可以是截短的蛋白质，其包含PTPN6 SH2但缺少PTPN6磷酸酶结构域。
信号传导修饰蛋白可以是截短的蛋白质，其包含SHP-2 SH2结构域但缺少SHP-2磷酸酶结构域。
信号传导修饰蛋白可以是融合蛋白质，其包含(i)SH2结构域；和(ii)磷酸酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质。
融合蛋白质例如可以包含ZAP70 SH2结构域、PTPN6或SHP-2磷酸酶结构域。
信号传导修饰蛋白可以是融合蛋白质，其包含(i)SH2结构域；和(ii)激酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质。
融合蛋白质可以包含来自PTPN6或SHP-2的SH2结构域。
融合蛋白质可以包含Zap70激酶结构域。
融合蛋白质可以包含AKT或JAK激酶结构域。
信号传导修饰蛋白可以是融合蛋白质，其包含(i)来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)异源信号传导结构域。
融合蛋白质可以包括来自ZAP70、PTPN6或SHP-2的SH2结构域。
异源信号传导结构域可以来自通常不被含有ITAM或ITIM的受体激活的信号传导分子。
异源信号传导结构域可以是共刺激性结构域。在该方面，融合蛋白质可以包含CD28、OX40或41BB共刺激性结构域
异源信号传导结构域可以是抑制性结构域。在该方面，抑制性结构域可以是或包含CD148或CD45的胞内域(endodomain)。或者，异源信号传导结构域是或包含ICOS、CD27、BTLA、CD30、GITR或HVEM的胞内域。
信号传导修饰蛋白可以是融合蛋白质，其包含(i)SH2结构域；和(ii)含有ITAM的结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质。
融合蛋白质包含ZAP70 SH2结构域。
含有ITAM的结构域是或包含CD3-Zeta的胞内域。
信号传导修饰蛋白可以是融合蛋白质，其包含(i)SH2结构域；和(ii)含有ITIM的结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质。
融合蛋白质可以包含来自PTPN6或SHP-2的SH2结构域。
含有ITIM的结构域可以是或包含来自PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3的胞内域。
信号传导修饰蛋白可以是融合蛋白质，其包含(i)来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)蛋白酶结构域。
融合蛋白质包含来自ZAP70、PTPN6或SHP-2的SH2结构域。
蛋白酶结构域是或包含烟草蚀刻病毒蛋白酶(TeV)。
细胞还可以包含具有蛋白酶切割位点的膜栓系转录因子(membrane-tetheredtranscription factor)。蛋白酶切割位点处的切割释放转录因子而导致靶基因的表达增加。
靶基因编码细胞因子，例如选自下组的细胞因子：IL-2、IL-7、IL-15和IL-12。
在该实施方案中，嵌合抗原受体(CAR)可以是包含细胞内蛋白酶切割位点的靶CAR。
靶CAR可以包含激活性或共刺激性胞内域，并且在蛋白酶切割位点处的切割从靶CAR除去胞内域。
或者，靶CAR可以包含抑制性胞内域，并且在蛋白酶切割位点处的切割从所述靶CAR除去所述抑制性胞内域。抑制性胞内域可以包含CD148或CD45胞内域。
本发明的细胞可以包含两种CAR：包含含有ITAM的胞内域的激活性(activating)CAR；和如上定义的靶CAR。
或者，本发明的细胞可以包含两种CAR：包含含有ITIM的胞内域的抑制性CAR；和如上定义的靶CAR。
在第二方面，本发明提供了核酸构建体，其包含：
编码嵌合抗原受体的第一核酸序列；和
编码如本发明第一方面中相关定义的截短的蛋白质或融合蛋白质的第二核酸序列。
核酸构建体还可以包括编码如上定义的膜栓系转录因子的第三核酸序列。
核酸构建体还可以包含编码如上定义的靶CAR的第三核酸序列。
核酸构建体还可以包含编码如上定义的激活性CAR或抑制性CAR的第四核酸序列。
在第三方面，载体，其包含根据本发明第二方面的核酸构建体或如上定义的第一和第二，以及任选地第三和/或第四核酸序列。
还提供了载体组，其包含如上定义的第一和第二，以及任选地第三和/或第四核酸序列。
载体或载体组可以是逆转录病毒或慢病毒载体。
在第四方面，提供了药物组合物，其包含多个根据本发明第一方面的细胞。
在第五方面，提供了根据本发明第四方面的药物组合物，其用于治疗和/或预防疾病。
在第六方面，提供了治疗和/或预防疾病的方法，其包括向受试者施用根据本发明第四方面的药物组合物的步骤。
方法还可以包括以下步骤：
(i)从受试者分离含有细胞的样品；
(ii)用根据本发明第二方面的核酸构建体，根据本发明第三方面的载体或载体组转导或转染所述细胞；并且
(iii)向受试者施用来自(ii)的细胞。
在第七方面，提供了根据本发明第四方面的药物组合物在制备用于治疗和/或预防疾病的药物中的用途。
所述疾病可以是癌症。
在第八方面，提供了制备根据本发明第一方面的细胞的方法，其包括向所述细胞导入：根据本发明第二方面的核酸构建体，根据本发明第三方面的载体或载体组。
细胞可以来自从受试者分离的样品。
在第一进一步的方面中，本发明还提供了融合蛋白质，其包含：(i)ZAP70或PTPN6SH2结构域；和(ii)异源结构域。
融合蛋白质可以包含ZAP70 SH2结构域和含有ITAM的结构域。所述含有ITAM的结构域可以是或包含CD3-Zeta的胞内域。
融合蛋白质可以包含PTPN6 SH2结构域和含有ITIM的结构域。所述含有ITIM的结构域可以是或包含来自PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3的胞内域。
融合蛋白质可以包含PTPN6 SH2结构域并与ZAP70激酶结构域融合。
融合蛋白质可以包含ZAP70 SH2结构域并与PTPN6激酶结构域融合。
融合蛋白质可以包含(i)ZAP70或PTPN6 SH2结构域；和(ii)异源信号传导结构域。
异源信号传导结构域可以来自通常不被含有ITAM的受体激活的信号传导分子。异源信号传导结构域可以是或来自CD28、41BB或OX40的胞内域。异源信号传导结构域可以是或来自ICOS、CD27、BTLA、CD30、GITR或HVEM的胞内域。
融合蛋白质可以包含：(i)ZAP70或PTPN6 SH2结构域；和(ii)激酶结构域。
激酶结构域可以是或包含AKT或JAK激酶结构域。
融合蛋白质可以包含：(i)ZAP70或PTPN6 SH2结构域；和(ii)蛋白酶结构域。
蛋白酶结构域可以是或包含烟草蚀刻病毒蛋白酶(TeV)。
在第二进一步的方面中，本发明提供了截短的蛋白质，其包含ZAP70SH2结构域但缺少ZAP70激酶结构域。
在第三进一步的方面中，本发明提供了截短的蛋白质，其包含PTPN6SH2结构域但缺少PTPN6激酶结构域。
本发明还提供了信号传导系统，其包含：
(i)受体，其包含抗原结合域，跨膜域和包含CD3 zeta胞内域的细胞内信号传导结构域；和
(ii)根据本发明的第一进一步的方面中的包含ZAP70 SH2结构域的融合蛋白质；或根据本发明的第二进一步的方面中的截短的蛋白质；
其中抗原与抗原结合域的结合导致CD3 zeta胞内域与融合/截短的蛋白质之间的结合。
本发明还提供了信号传导系统，其包含：
(i)受体，其包含抗原结合域，跨膜域和包含PTPN6结合结构域的细胞内信号传导结构域；和
(ii)根据本发明的第一进一步的方面中的包含PTPN6 SH2结构域的融合蛋白质；或根据本发明的第三进一步的方面中的截短的蛋白质；
其中抗原与抗原结合域的结合导致PTPN6结合结构域与融合/截短的蛋白质之间的结合。
受体可以是T细胞受体(TCR)或嵌合抗原受体(CAR)。
在第四进一步的方面中，本发明提供了编码根据第一进一步的方面中的融合蛋白质或根据第二或第三进一步的方面中的截短的蛋白质的核酸。
在第五进一步的方面中，本发明提供了核酸构建体，其包含编码融合蛋白质的核酸序列，所述融合蛋白质包含(1)ZAP70或PTPN6 SH2结构域；和(ii)蛋白酶结构域(如TeV结构域)和编码膜栓系转录因子的核酸序列，所述膜栓系转录因子包含：
(i)膜栓系物(membrane tether)；
(ii)蛋白酶识别位点；和
(iii)转录因子。
在第六进一步的方面中，本发明提供了核酸构建体，其包含：
(a)编码根据本发明的第一进一步的方面中的包含PTPN6 SH2结构域的融合蛋白质的核酸序列，或编码根据本发明的第三进一步的方面中的截短的蛋白质的核酸序列；和
(b)编码包含含有ITIM的胞内域的受体的核酸分子。
在第七进一步的方面中，本发明提供了核酸构建体，其包含编码融合蛋白质的核酸序列和编码包含蛋白酶切割位点的受体的核酸序列，该融合蛋白质包含(i)ZAP70或PTPN6 SH2结构域；和(ii)蛋白酶结构域(如TeV结构域)。
在第八进一步的方面中，本发明提供了核酸构建体，其包含：
(a)编码融合蛋白质的核酸序列，该融合蛋白质包含(i)PTPN6 SH2结构域；和(ii)蛋白酶结构域(如TeV结构域)。
(b)编码包含蛋白酶切割位点的受体的核酸序列；和
(c)编码包含含有ITIM的胞内域的受体的核酸序列。
受体可以是T细胞受体(TCR)或嵌合抗原受体(CAR)。
适当地，在根据本发明的第八进一步的方面中的核酸构建体中，核酸序列(b)可以是T细胞受体(TCR)或嵌合抗原受体(CAR)，其包含：
(i)在跨膜域和激活性胞内域之间的蛋白酶切割位点；或
(ii)经由蛋白酶切割位点融合至抑制性胞内域的激活性胞内域。
在第九进一步的方面中，本发明提供了载体，其包含根据本发明第四进一步的方面中的核酸或根据本发明第五至第九进一步的方面中的核酸构建体。
载体可以是逆转录病毒载体或慢病毒载体。
在第十进一步的方面中，本发明提供了细胞，其包含根据本发明第一进一步的方面中的融合蛋白质或根据本发明第二或第三进一步的方面中的截短的蛋白质。
在第十一进一步的方面，本发明提供了细胞，其包含(a)根据本发明第一进一步的方面中的包含PTPN6 SH2结构域的融合蛋白质；或根据本发明第三进一步的方面中的截短的蛋白质；和(b)包含含有ITIM的胞内域的受体。
细胞可以是免疫细胞，如T细胞或自然杀伤(NK)细胞。
在第十二进一步的方面，本发明提供了包含融合蛋白质的细胞，该融合蛋白质包含(i)ZAP70或PTPN6 SH2结构域；和(ii)蛋白酶结构域(如TeV结构域)和包含蛋白酶切割位点的受体。
在第十三进一步的方面，本发明提供了细胞，其包含：
(a)融合蛋白质，其包含(i)PTPN6 SH2结构域；和(ii)蛋白酶结构域(如TeV结构域)
(b)包含蛋白酶切割位点的受体；和
(c)包含含有ITIM的胞内域的受体。
受体可以是T细胞受体(TCR)或嵌合抗原受体(CAR)。
受体(b)可以是T细胞受体(TCR)或嵌合抗原受体(CAR)，其包含：
(i)在跨膜域和激活性胞内域之间的蛋白酶切割位点；或
(ii)经由蛋白酶切割位点融合至抑制性胞内域的激活性胞内域。
在第十四进一步的方面，本发明提供了细胞，其包含根据本发明第四进一步的方面中的核酸或根据本发明第五至第九进一步的方面中任一项的核酸构建体。
在第十五进一步的方面中，本发明提供了药物组合物，其包含多个根据本发明第十至第十四进一步的方面中任一项的细胞。
在第十六进一步的方面中，本发明提供了根据本发明第十五进一步的方面中的药物组合物，其用于治疗和/或预防疾病。
在第十七进一步的方面中，本发明涉及治疗和/或预防疾病的方法，其包括向受试者施用根据第十五进一步的方面中的药物组合物的步骤。
所述方法可以包括以下步骤：
(i)从受试者分离含有T细胞或NK细胞的样品；
(ii)用根据本发明第四至第九进一步的方面中任一项的核酸或根据本发明第十进一步的方面中的载体转导或转染所述T细胞或NK细胞；并且
(iii)向受试者施用来自(ii)的T细胞或NK细胞。
在第十八进一步的方面中，本发明涉及根据本发明第十五进一步的方面中的药物组合物在制备用于治疗和/或预防疾病的药物中的用途。
疾病可以是癌症。
在第十九进一步的方面中，本发明提供了试剂盒，其包含根据本发明第四进一步的方面中的核酸或根据本发明第五至第八进一步的方面中任一项的核酸构建体或根据本发明第九进一步的方面的载体。
在第二十进一步的方面中，本发明涉及试剂盒，其包含根据本发明第十至第十四进一步的方面中任一项的细胞。
在第二十一进一步的方面中，本发明涉及制备根据本发明第十至第十四进一步的方面中任一项的的细胞的方法，其包括向所述细胞导入：根据本发明第四至第八进一步的方面中任一项的核酸序列或根据本发明第九进一步的方面的载体。
细胞可以来自从受试者分离的样品。
本发明的更进一步的方面总结在以下段落中：
A1.截短的蛋白质，其包含来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，但缺少激酶结构域。
A2.根据段落A1的截短的蛋白质，其包含ZAP70 SH2结构域但缺少ZAP70激酶结构域。
B1.截短的蛋白质，其包含来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域，但缺少磷酸酶结构域
B2.根据段落B1的截短的蛋白质，其包含PTPN6 SH2结构域但缺少PTPN6磷酸酶结构域。
B3.根据段落B1的截短的蛋白质，其包含SHP-2 SH2结构域但缺少SHP-2磷酸酶结构域。
C1.融合蛋白质，其包含(i)来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域；和(ii)磷酸酶结构域。
C2.根据段落C1的融合蛋白质，其包含ZAP70 SH2结构域。
C3.根据段落C1或C2的融合蛋白质，其包含PTPN6或SHP-2磷酸酶结构域。
D1.融合蛋白质，其包含(i)来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)激酶结构域。
D2.根据段落D1的融合蛋白质，其包含来自PTPN6或SHP-2的SH2结构域。
D3.根据段落D1或D2的融合蛋白质，其包含Zap70激酶结构域。
D4.根据段落D1或D2的融合蛋白质，其包含AKT或JAK激酶结构域。
E1.融合蛋白质，其包含(i)来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)异源信号传导结构域。
E2.根据段落E1的融合蛋白质，其包含来自ZAP70、PTPN6或SHP-2的SH2结构域。
E3.根据段落E1或E2的融合蛋白质，其中所述异源信号传导结构域来自通常不被含有ITAM或ITIM的受体激活的信号传导分子。
E4.根据段落E1、E2或E3的融合蛋白质，其中所述异源信号传导结构域是共刺激性结构域。
E5.根据段落E4的融合蛋白质，其包含CD28、OX40或41BB共刺激性结构域
E6.根据段落E1、E2或E3的融合蛋白质，其中所述共刺激性结构域是抑制性结构域。
E7.根据段落E6的融合蛋白质，其中所述抑制性结构域包含CD148或CD45的胞内域。
E8.根据段落E6的融合蛋白质，其中所述异源信号传导结构域是或包含ICOS、CD27、BTLA、CD30、GITR或HVEM的胞内域。
F1.融合蛋白质，其包含(i)来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域；和(ii)含有ITAM的结构域。
F2.根据段落F1的融合蛋白质，其包含ZAP70 SH2结构域。
F3.根据段落F1或F2的融合蛋白质，其中所述含有ITAM的结构域是或包含CD3-Zeta的胞内域。
G1.融合蛋白质，其包含(i)来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)含有ITIM的结构域。
G2.根据段落G1的融合蛋白质，其包含来自PTPN6或SHP-2的SH2结构域。
G3.根据段落G1或G2的融合蛋白质，其中所述含有ITIM的结构域是或包含来自PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3的胞内域。
H1.融合蛋白质，其包含(i)来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)蛋白酶结构域。
H2.根据段落H1的融合蛋白质，其包含来自ZAP70、PTPN6或SHP-2的SH2结构域。
H3.根据段落H1或H2的融合蛋白质，其中所述蛋白酶结构域是或包含烟草蚀刻病毒蛋白酶(TeV)。
I1.核酸序列，其编码根据段落A或B中任一项的截短的蛋白质，或根据段落C、D、E、F、G或H中任一项的融合蛋白质。
J1.核酸构建体，其包含根据段落I的核酸序列和编码嵌合抗原受体的核酸序列。
J2.核酸构建体，其包含根据段落I的核酸序列和编码具有蛋白酶切割位点的膜栓系转录因子的核酸序列。
J3.核酸构建体，其包含根据段落I的核酸序列和编码包含细胞内蛋白酶切割位点的靶CAR的核酸序列。
K1.载体，其包含根据段落I的核酸序列或根据段落J的核酸构建体。
L1.细胞，其包含根据段落A或B中任一项的截短的蛋白质，或根据段落C、D、E、F、G或H中任一项的融合蛋白质。
M1.细胞，其包含根据段落H中任一项的融合蛋白质和具有蛋白酶切割位点的膜栓系转录因子。
M2.根据段落M1的细胞，其中在蛋白酶切割位点处的切割释放转录因子而导致靶基因的表达增加。
M3.根据段落M2的细胞，其中所述靶基因编码细胞因子。
M4.根据段落M3的细胞，其中所述细胞因子选自下组：IL-2、IL-7、IL-15和IL-12。
M5.细胞，其包含根据段落H中任一项的融合蛋白质和包含细胞内蛋白酶切割位点的靶受体(CAR)。
M6.根据权利要求M5的细胞，其中靶CAR包含激活性或共刺激性胞内域，并且在所述蛋白酶切割位点处的切割从所述靶CAR除去所述胞内域。
M7.根据权利要求M5的细胞，其中靶CAR包含抑制性胞内域，并且在所述蛋白酶切割位点处的切割从所述靶CAR除去所述抑制性胞内域。
M8.根据段落M7的细胞，其中所述抑制性胞内域包含CD148或CD45胞内域。
M9.细胞，其包含根据段落H中任一项的融合蛋白质和两种CAR：包含含有ITAM的胞内域的激活性CAR；和如段落M5至M8中任一项所定义的靶CAR。
M10.细胞，其包含根据段落H中任一项的融合蛋白质和两种CAR：包含含有ITIM的胞内域的抑制性CAR；和如段落M5至M8中任一项所定义的靶CAR。
以上描述的本发明的方面能够例如通过表1中描述的机制而调节和改变T细胞信号传导途径。
表1：信号调节的应用
附图简述
图1(a)-直接T细胞活化途径的图解。T细胞受体的激活导致ITAM的磷酸化。磷酸化的ITAM被ZAP70 SH2结构域识别。识别后，ZAP70被募集到近膜区，并且其激酶结构域随后磷酸化LAT。磷酸化的LAT随后被GRAP、GRB2和PLC-γ的SH2结构域识别。(b)-直接T细胞抑制途径的图解。抑制性免疫受体(如PD1)的激活导致ITIM结构域的磷酸化。这些被PTPN6的SH2结构域识别。识别后，PTPN6被募集到近膜区，并且其磷酸酶结构域随后对ITAM去磷酸化，抑制了免疫激活。
图2-阻断信号系统的图解-a)过表达不包含激酶结构域的截短的ZAP70。结果，它与全长ZAP70竞争ITAM并减少ITAM信号传导。(b)过表达不包含磷酸酶结构域的截短的PTPN6，其与全长PTPN6竞争并减少ITIM信号传导。
图3-串扰信号系统的图解：(a)ZAP70 SH2与PTPN6磷酸酶融合，因此此起到抑制ITAM磷酸化的作用；(b)PTPN6 SH2与ZAP70激酶融合，导致响应抑制信号的矛盾性激活(paradoxical activation)。
图4-放大信号系统的图解：(a)将具有CD3Zeta胞内域的全长ZAP70附接至其氨基末端，从而组装了ITAM的级联。(b)将具有PD1胞内域的全长PTPN6附接至其氨基末端使得组装ITIM级联。
图5-旁路信号系统的图解：(a)ZAP70与CD28胞内域融合；(b)ZAP70与41BB胞内域融合；(c)ZAP70与AKT激酶融合；(d)PTPN6 SH2域与41BB胞内域融合。
图6-说明性转录信号系统的图解：a)ZAP-TeV融合物与膜栓系转录因子共表达，该膜栓系转录因子可以通过切割其TeV识别基序而从膜上释放。显示这与CD19 CAR共表达。因此，在识别目标细胞上的CD19后，T细胞被激活，另外，转录因子变得活化。(b)使用PTPN6-TeV融合物的备选系统。这里，CAR由带有ITIM的胞内域组成。因此，在CAR识别CD19后，转录因子变得活化，但这独立于T细胞激活。
图7-去势信号系统的图解：显示了两种CAR-一种识别CD19并且是激活性的，以及一种识别CD33并且是抑制性的-这些特性仅供说明(a)And Not信号去势；这里，激活后的SH2-Tev融合蛋白质被招募以激活ITIM CAR。这导致ITAM从激活性CAR上切割，所述激活性CAR构建成TeV切割位点连接跨膜域与ITAM结构域。因此，激活性CAR被抑制。(b)AND信号去势：这里激活后的SH2-Tev融合蛋白质被招募到ITIM CAR。这导致磷酸酶结构域从激活性CAR释放，所述激活性CAR构建成磷酸酶经由TeV切割结构域与其羧基末端连接。这导致释放组成型抑制，允许CAR在关联抗原(cognate antigen)的存在下激活。
图8-构建了不同的SH2结构域与AKT激酶结构域的几种融合物：ZAP-AKT、GRAP-AKT、GRB-AKT和PLC-γ。
图9-(a)用不同SH2/AKT融合物转导的T细胞的磷酸化-AKT染色，其用有丝分裂抗体OKT3激活或不激活。(b)用ZAP-AKT融合物、改善的ZAP-AKT融合物(其中ZAP和AKT经由柔性接头连接)，和对照ZAP-AKT(其中R190K取代除去了ZAP结合至ITAM的能力)转导的T细胞的磷酸化-AKT染色。用OKT3刺激T细胞或不用OKT3刺激T细胞。facs图覆盖于未转导的T细胞之上。
图10-(a)用增加量的OKT3激活的T细胞的磷酸化-AKT印记。(b)未刺激的，用仅OKT3刺激的或用OKT3和IL-2两者刺激的ZAP-AKT或对照T细胞的显微镜检查。用仅OKT3刺激的ZAP-AKT T细胞与用OKT3和IL-2两者刺激的未转导的T细胞类似。
图11-(a)直接TeV转录开关(switch)的实现。将CD19 CAR的胞内域替换为TeV蛋白酶。还共表达了膜栓系VP16/GAL4转录因子。荧光素酶报告物检测VP16/GAL5的活性。(b)用ZAP-TeV实现。标准CD19 CAR与ZAP-TeV的融合物以及膜栓系转录因子共表达。
图12-暴露于CD19阴性(左)或CD19阳性(右)靶物后，基于ZAP-TeV的转录开关和表达对照的T细胞的活性。通过添加荧光素酶后的光输出来测量活性。按顺序，测试的条件为：(a)aCD19 CAR与ZAP-TeV共表达；(b)aCD19CAR与无活性(R190K)共表达；(c)aCD19 CAR与ZAP-TeV和膜栓系转录因子共表达；(d)与无活性(R190K)ZAP-TEV共表达的aCD19 CAR与膜栓系转录因子共表达；(e)aCD19 CAR/TeV融合物与膜栓系转录因子共表达；(f)组成性活化的GAL4/VP16转录因子。
图13-(a)CAR的一般架构：结合结构域识别抗原；间隔区从细胞表面提升结合结构域；跨膜结构域将蛋白质锚定在膜上并且胞内域传输信号。(b)至(d)：CAR胞内域的不同世代(generation)和排列：(b)初始设计通过FcεR1-γ或CD3ζ胞内域仅传输ITAM信号，而之后的设计顺式传输另外的(c)一种或(d)两种共刺激信号。
图14-本发明的说明性蛋白质序列。
图15-使用截短的SHP-1(PTPN6)或截短的SHP-2的PD-1信号阻断
将PBMC细胞用以下共转导：PD1和仅CAR(FMC63)；或含有CAR和截短的SHP-1，或CAR和截短的SHP-2的双顺反子构建体。将这些细胞与用CD19，PDL1或两者转导的SupT1细胞共培养48小时，并且通过ELISA测量IFNγ释放。
图16-使用SHP-2 SH2结构域与Zap70激酶的融合物的信号劫持(hijack)
将PBMC细胞与以下共转导：P1和仅CAR(FMC63)；或含有CAR和包含SHP-2 SH2结构域和ZAP70激酶的融合蛋白的双顺反子构建体。将这些细胞与CD19或PDL1转导的SupT1细胞以1：1的比例共同培养24小时。通过ELISA测量IFNγ释放(A)，并通过FACS定量对SupT1细胞的杀伤(B)。
发明详述
蛋白质
本发明提供了包含SH2结构域的截短蛋白。
本发明还提供了融合蛋白，其包含(i)SH2结构域；和(ii)异源结构域。
SH2结构域可以来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质。
结合ITAM的蛋白质的例子是ZAP70。结合ITIM的蛋白质的例子包括PTPN6和SHP-2。
因此，本发明的融合蛋白包含SH2结构域和至少一种不存在于SH2结构域衍生自的野生型蛋白中的另外的结构域。
SRC同源性2(SH2)结构域
细胞内信号传导通路由蛋白质的可逆性翻译后修饰(包括磷酸化，泛素化和乙酰化)来启动和控制。
SH2域是作为衔接子(adaptro)的模块化蛋白结构域，并通过与其各自的蛋白质结合伴侣(通常为细胞表面受体)中的磷酸化肽结合来介导蛋白-蛋白相互作用。SH2结构域通常结合靶蛋白内较长的肽基序环境中的磷酸化的酪氨酸残基，并且SH2结构域代表已知的pTyr识别结构域的最大类别。
尽管SH2结构域缺乏任何固有的催化活性，但它们通常偶联于独立的催化结构域，并因此响应于特定的输入信号，用于将这些催化结构域定位至特定亚细胞位置处或定位至适当底物、活化剂或抑制剂的附近。另外还可以发现SH2结构域与衔接子蛋白结构域连接并因此可以用于形成大的多蛋白复合物。
ZETA链相关蛋白激酶70(ZAP70)
ZAP70是通常在T细胞和自然杀伤细胞表面膜附近表达的蛋白质。它是T细胞受体(TCR)的一部分，并在T细胞信号传导中起着关键的作用。其分子量为70kDa，并由2个N末端SH2结构域和一个C末端激酶结构域组成。它是蛋白酪氨酸激酶家族的成员。
T细胞激活中最早的步骤是通过TCR识别靶细胞上的肽MHC复合物。这一初始事件导致Lck激酶与TCR复合物中CD3-zeta的胞质尾部的紧密关联。然后Lck磷酸化CD3-zeta细胞质尾中的酪氨酸残基，其允许招募ZAP70。ZAP70是含有SH2的激酶，其在TCR接合后在T细胞激活中起关键作用。ZAP70中的串联SH2结构域与磷酸化的CD3结合，导致Lck或其它ZAP70分子反式地将ZAP70磷酸化和活化。然后活化的ZAP70能够磷酸化下游膜蛋白，其中关键的膜蛋白是活化的T细胞接头(LAT)蛋白质。LAT是一种支架蛋白，并且在其多个残基上的磷酸化允许其与数种其它含有SH2结构域的蛋白质相互作用，所述其它含有SH2结构域的蛋白质包括Grb2，PLC-g和Grap，它们其识别LAT中的磷酸化的肽并向下游传递T细胞活化信号，最终导致一系列T细胞应答。该过程总结在图1中。
人ZAP70蛋白具有UniProtKB登录号P43403。该序列的长度为619个氨基酸，如SEQID NO:1所示。
ZAP70氨基酸序列(SEQ
ID
NO:1)
MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA
本发明的融合蛋白可以包含ZAP70 SH2结构域。本发明的截短的蛋白质可以包含ZAP70 SH2结构域或由ZAP70 SH2结构域组成。在这方面，融合或截短的蛋白质可以包含SEQID NO:2所示的序列或由其组成。
ZAP70完整SH2结构域(SEQ
ID
NO:2)
MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHP
ZAP70在序列的N-末端在如SEQ ID No.1所示的序列的残基10-102和163-254处具有两个SH2结构域。本发明的截短的蛋白或融合蛋白因此可以包含SEQ ID No.3和4所示的序列中的一个或两个。
ZAP70 SH2 1(SEQ ID NO:3)
FFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPC
ZAP70 SH2 2(SEQ ID NO:4)
WYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEAC
融合蛋白可以包含具有至少80、85、90、95、98或99％序列同一性的SEQ ID NO:2、3或4的变体，条件是变体序列是具有所需性质的SH2结构域序列。换句话说，变体序列应该能够结合CD3-zeta细胞质尾部中的磷酸化酪氨酸残基，其允许招募ZAP70。
序列比对方法在本领域中是公知的，并且使用合适的比对程序来完成。％序列同一性指当两个序列最佳对齐时，两序列中相同氨基酸或核苷酸残基的百分比。可使用标准算法诸如BLAST程序(在国家生物技术信息中心基本局部比对搜索工具(Basic LocalAlignment Search Tool at the Natio nal Center for Biotechnology Information))使用默认参数确定核苷酸和蛋白质序列的同源性或同一性，这在http://blast.ncbi.nlm.nih.gov是可公开获得的。用于确定序列同一性或同源性的其它算法包括：LALIGN(http://www.ebi.ac.uk/Tools/psa/lalign/和http://www.ebi.ac.uk/Tools/psa/lalign/nucleotide.html)，AMAS(多比对序列分析(Analysis of Multiply AlignedSequences)，在http://www.compbio.dundee.ac.uk/Software/Amas/amas.html)，FASTA(http://ww w.ebi.ac.uk/Tools/sss/fasta/)，Clustal Omega(http://www.ebi.ac.uk/Tools/msa/c lustalo/),SIM(http://web.expasy.org/sim/),和EMBOSS Needle(http://www.ebi.ac.uk/Tools/psa/emboss_needle/nucleotide.html)。
在某些实施方案中，融合蛋白可以包含ZAP70 SH2结构域和ZAP70激酶结构域。例如，融合蛋白可以包含如SEQ ID NO:1所示的序列或其具有至少80、85、90、95、98或99％序列同一性的变体。
酪氨酸蛋白磷酸酶非受体类型6(PTPN6)
PTPN 6也称为含有Src同源区2结构域的磷酸酶-1(SHP-1)。它是蛋白酪氨酸磷酸酶家族的成员。
PTPN6的N末端区域含有两个串联的SH2结构域，其介导PTPN6与其底物的相互作用。C末端区域含有酪氨酸蛋白磷酸酶结构域。
PTPN6能够与许多抑制性免疫受体或含有ITIM的受体结合并传播信号。此类受体的例子包括但不限于PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1和KIR3DL3。
人PTPN6蛋白具有UniProtKB登录号P29350。该序列的长度为595个氨基酸，如SEQID NO:5所示。
PTPN6氨基酸序列(SEQ ID NO:5)
MVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPYYATRVNAADIENRVLELNKKQESEDTAKAGFWEEFESLQKQEVKNLHQRLEGQRPENKGKNRYKNILPFDHSRVILQGRDSNIPGSDYINANYIKNQLLGPDENAKTYIASQGCLEATVNDFWQMAWQENSRVIVMTTREVEKGRNKCVPYWPEVGMQRAYGPYSVTNCGEHDTTEYKLRTLQVSPLDNGDLIREIWHYQYLSWPDHGVPSEPGGVLSFLDQINQRQESLPHAGPIIVHCSAGIGRTGTIIVIDMLMENISTKGLDCDIDIQKTIQMVRAQRSGMVQTEAQYKFIYVAIAQFIETTKKKLEVLQSQKGQESEYGNITYPPAMKNAHAKASRTSSKHKEDVYENLHTKNKREEKVKKQRSADKEKSKGSLKRK
本发明的融合蛋白可以包含PTPN6 SH2结构域。本发明的截短蛋白可以包含PTPN6SH2结构域或由PTPN6 SH2结构域组成。在这方面，融合或截短的蛋白质可以包含SEQ IDNO:6所示的序列或由其组成。
PTPN6 SH2完整结构域(SEQ
ID
NO:6)
MVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPYY
PTPN6在序列的N-末端在如SEQ ID No.5所示的序列的残基4-100和110-213处具
有两个SH2结构域。本发明的截短的蛋白或融合蛋白因此可以包含SEQ ID No.3和4所示的
序列中的一个或两个。
PTPN6 SH2 1(SEQ ID NO:7)
WFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPL
PTPN6 SH2 2(SEQ ID No. 8)
WYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPY
融合蛋白可以包含具有至少80、85、90、95、98或99％序列同一性的SEQ ID NO:6、7或8的变体，条件是变体序列是具有所需性质的SH2结构域序列。换句话说，变体序列应该能够结合至少一种以下蛋白质胞质尾部中的磷酸化酪氨酸残基：PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3，其允许招募PTPN6。
在某些实施方案中，融合蛋白可以包含PTPN6 SH2结构域和PTPN6磷酸酶结构域。例如，融合蛋白可以包含如SEQ ID NO:5所示的序列或其具有至少80、85、90、95、98或99％序列同一性的变体。
SHP-2
SHP-2(也称为PTPN11,PTP-1D和PTP-2C)是蛋白酪氨酸磷酸酶(PTP)家族的成员。与PTPN6相似，SHP-2在其N端具有由两个串联的SH2域组成的结构域结构，随后是蛋白酪氨酸磷酸酶(PTP)结构域。在无活性状态下，N末端SH2结构域结合PTP结构域并阻断潜在的底物进入活性部位。因此，SHP-2是自抑制的。在与靶磷酸化-酪氨酰残基结合后，N末端SH2结构域从PTP结构域释放，通过减轻自抑制来催化性地激活酶。
人SHP-2具有UniProtKB登录号P35235-1。该序列的长度为597个氨基酸，如SEQ IDNO:9所示。
SHP-2氨基酸序列(SEQ ID NO:9)
MTSRRWFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTGDYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPLNCADPTSERWFHGHLSGKEAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYDVGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPLNTTRINAAEIESRVRELSKLAETTDKVKQGFWEEFETLQQQECKLLYSRKEGQRQENKNKNRYKNILPFDHTRVVLHDGDPNEPVSDYINANIIMPEFETKCNNSKPKKSYIATQGCLQNTVNDFWRMVFQENSRVIVMTTKEVERGKSKCVKYWPDEYALKEYGVMRVRNVKESAAHDYTLRELKLSKVGQALLQGNTERTVWQYHFRTWPDHGVPSDPGGVLDFLEEVHHKQESIVDAGPVVVHCSAGIGRTGTFIVIDILIDIIREKGVDCDIDVPKTIQMVRSQRSGMVQTEAQYRFIYMAVQHYIETLQRRIEEEQKSKRKGHEYTNIKYSLVDQTSGDQSPLPPCTPTPPCAEMREDSARVYENVGLMQQQRSFR
本发明的融合蛋白可以包含SHP-2 SH2结构域。本发明的截短的蛋白可以包含SHP-2 SH2结构域或由SHP-2 SH2结构域组成。在这方面，融合或截短的蛋白质可以包含SHP-2的第一SH2结构域(如包含SEQ ID NO.9的氨基酸6-102)或第二SH2结构域(如包含SHP-2的氨基酸112-216)或由其组成。融合或截短的蛋白质可以包含SEQ ID NO:10、11或12所示的序列或由其组成。
SHP-2第一SH2结构域(SEQ ID NO:10)
WFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTGDYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPL
SHP-2第二SH2结构域(SEQ
ID
No.11)
WFHGHLSGKEAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYDVGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPL
SHP-2两个SH2结构域(SEQ ID No.12)
WFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTGDYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPLNCADPTSERWFHGHLSGKEAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYDVGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPL
融合蛋白可以包含具有至少80、85、90、95、98或99％序列同一性的SEQ ID NO:10,11或12的变体，条件是变体序列是能够结合含有ITIM的结构域的SH2结构域序列。例如变体序列可以能够结合以下蛋白质细胞质尾部中的磷酸化的酪氨酸残基：PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3。
异源结构域
如本文所用，术语“异源结构域”指不存在于以下的任何蛋白结构域：
i)野生型ZAP70(参见SEQ ID NO:1)，其用于包含ZAP70 SH2结构域的融合蛋白；
ii)野生型PTPN6(参见SEQ ID NO:5)，其用于包含PTPN6 SH2结构域的融合蛋白；或
iii)野生型SHP-2(参见SEQ ID No.9)，其用于包含SHP-2 SH2结构域的融合蛋白。
异源结构域可以是或衍生自(如部分)与ZAP70，SHP-2或PTPN6不同的蛋白质。
或者融合蛋白可以包含ZAP70 SH2结构域和来自PTPN6的结构域(如PTPN6激酶结构域)的融合物。同样，融合蛋白可以包含PTPN6 SH2结构域和来自ZAP70的结构域(如ZAP70激酶结构域)的融合物。
放大信号
本发明提供融合蛋白，其包含：来自ITAM结合蛋白的SH2结构域；和含有ITAM的结构域。
本发明还提供融合蛋白，其包含：来自ITIM结合蛋白的SH2结构域；和含有ITIM的结构域。
这些“放大”信号传导分子将放大免疫细胞(如T细胞)内的刺激性或抑制性信号。
如图4所示，此类分子的存在将导致ITAM或ITIM的串接(concatenation)，这导致分别增强激活性或抑制性信号。
在期望增加免疫细胞(例如CAR-T细胞)对抗原的敏感性的情况下，激活性信号的放大是有用的。例如，当靶细胞上的靶抗原以低水平表达时可以是这种情况。
在希望减少或防止T细胞激活的情况下放大抑制性系统。WO2015/075469描述了一组“逻辑门(logic gate)”嵌合抗原受体对，当其由细胞(如T细胞)表达时，能够检测至少两种靶抗原A和B的特定表达模式。本申请中描述的“与非门(AND NOT gate)”包含一对CAR使得仅当抗原A而不是抗原B存在于靶细胞上时，T细胞才会触发。在该与非门中，一个CAR(识别抗原A)具有包含ITAM的激活性胞内域，而另一个CAR(识别抗原B)具有可以包含ITIM的抑制性胞内域。在单独存在抗原A的情况下，未连接(unligated)的抑制性CAR的存在不足以防止T细胞激活，因此发生激活。然而在两种抗原的存在下，形成具有高浓度的激活性和抑制性CAR两者的膜区域。由于两种胞内域是集中的，T细胞激活被阻止或减少。
使用本发明的放大信号分子来放大抑制性信号可以用于与门(“AND gate”)中，以减少或除去在两种抗原存在下发生的任何残留信号传导，即来自通过抑制性CAR不完全地抑制激活性CAR。
含有ITAM的结构域
在一个实施方案中，融合蛋白包含ZAP70 SH2结构域和含有基于免疫受体酪氨酸的激活基序(ITAM)的结构域。
具有含有ITAM的结构域的全长ZAP70的融合物产生放大激活性免疫信号的结构。这里，融合蛋白被招募到磷酸化的ITAM免疫受体胞内域。ZAP70发挥正常功能以传播的信号，但也提供了另一组ITAM，该ITAM被磷酸化并招募更多的ZAP70。例如，这对增加信号强度可以是有用的，并可以增加对低密度抗原的敏感性。在一些实施方案中，融合物可以仅包括具有含ITAM的胞内域的ZAP70 SH2结构域(例如融合物不含有ZAP70激酶结构域)。在其它实施方案中，ZAP70催化结构域(激酶结构域)与ITAM的比例可以变化以影响激活动力学，该动力学响应激活性受体与关联(cognate)靶物相互作用的动态。
ITAM是四个氨基酸的保守序列，其在免疫系统的某些细胞表面蛋白质的细胞质尾部重复两次。该基序含有酪氨酸，其通过任何其它两个氨基酸与亮氨酸或异亮氨酸分隔开，产生签名YxxL/I。两个这些签名通常在分子尾部被6至8个氨基酸分隔开(YxxL/Ix(6-8)YxxL/I)。
ITAM对于免疫细胞中的信号传导是重要的。因此，它们被发现于重要细胞信号传导分子的尾部，如T细胞受体复合物的CD3和ζ-链，B细胞受体复合物的CD79-alpha和-beta链，以及某些Fc受体。这些基序内的酪氨酸残基在受体分子与其配体相互作用后磷酸化，并形成参与细胞信号传导途径的其它蛋白质的停靠位点。
已知数种蛋白质含有具有一个或多个ITAM基序的胞内域。此类蛋白质的例子包括CD3 epsilon链，CD3 gamma链和CD3 delta链等。ITAM基序可以容易地被识别为被任何两个其它氨基酸分隔开的酪氨酸和亮氨酸或异亮氨酸，产生签名YxxL/I。通常，但不总是，两个这些基序在分子尾部被6至8个氨基酸分隔开(YxxL/Ix(6-8)YxxL/I)。因此，本领域技术人员可以容易地找到包含一个或多个ITAM的现有蛋白质以传输激活性信号。此外，鉴于基序是简单的并且不需要复杂的二级结构，本领域技术人员可以设计含有人工ITAM的多肽来传递激活性信号(参见WO 2000063372,其涉及合成的信号传导分子)。
含有ITAM的结构域可以是或包含CD3-zeta胞内域。合适地，含有ITAM的结构域可以包含如SEQ ID NO:13所示的序列或其变体，该变体具有至少80、85、90、95、98或99％序列同一性并保留被磷酸化并招募ZAP70的能力。
SEQ ID NO:13(CD3-zeta胞内域)
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
例如，融合蛋白可以是或包含如SEQ ID NO:14所示的序列，其含有与CD3-zeta胞内域融合的ZAP70-SH2结构域。
SEQ
ID
NO:14
MRRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRSGGGGSGGGGSGGGGSGGGGSMPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA
合适地，融合蛋白可以包含如SEQ ID NO:14所示序列或具有至少80、85、90、95、98或99％序列同一性的其变体。
含有ITIM的结构域
在一个实施方案中，融合蛋白包含PTPN6 SH2结构域和含有基于免疫受体酪氨酸的抑制基序(ITIM)的结构域。
具有含有ITIM的结构域的全长PTPN6的融合物产生放大抑制性免疫信号的结构。这里，融合蛋白被招募到磷酸化的ITIM免疫受体胞内域。PTPN6正常发挥功能以传播信号，但也提供了另一组ITIM，其磷酸化并招募更多的PTPN6。在一些实施方案中，融合物可以仅包括具有含有ITIM的胞内域的PTPN6 SH2结构域(例如融合物不含有PTPN6磷酸酶结构域)。在其它实施方案中，PTPN6催化结构域(激酶结构域)与ITIM的比例可以变化以影响激活动力学，该动力学响应抑制性受体与关联靶物相互作用的动态。
ITIM是保守的氨基酸序列(S/I/V/LxYxxI/V/L)，其存在于免疫系统的许多抑制性受体的细胞质尾部。在具有ITIM的抑制性受体与其配体相互作用后，它们的ITIM基序被Src激酶的酶磷酸化，允许它们经由PTPN6 SH2结构域和磷酸化的ITIM结构域之间的相互作用来招募PTPN6。
含有ITIM的胞内域包括例如来自CD22、LAIR-1、杀伤抑制性受体家族(KIR)、LILRB1、CTLA4、PD-1、BTLA的那些。
来自PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1和KIR3DL3的ITIM胞内域分别如SEQ IDNO:15至24中所示。
SEQ ID NO:15PDCD1胞内域
CSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL
SEQ ID NO:16 BTLA4
KLQRRWKRTQSQQGLQENSSGQSFFVRNKKVRRAPLSEGPHSLGCYNPMMEDGISYTTLRFPEMNIPRTGDAESSEMQRPPPDCDDTVTYSALHKRQVGDYENVIPDFPEDEGIHYSELIQFGVGERPQAQENVDYVILKH
SEQ ID NO:17 LILRB1
LRHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRGLQWRSSPAADAQEENLYAAVKHTQPEDGVEMDTRSPHDEDPQAVTYAEVKHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQDVTYAQLHSLTLRREATEPPPSQEGPSPAVPSIYATLAIH
SEQ ID NO:18 LAIR1
HRQNQIKQGPPRSKDEEQKPQQRPDLAVDVLERTADKATVNGLPEKDRETDTSALAAGSSQEVTYAQLDHWALTQRTARAVSPQSTKPMAESITYAAVARH
SEQ ID NO:19 CTLA4
FLLWILAAVSSGLFFYSFLLTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN
SEQ ID NO:20 KIR2DL1
GNSRHLHVLIGTSVVIIPFAILLFFLLHRWCANKKNAVVMDQEPAGNRTVNREDSDEQDPQEVTYTQLNHCVFTQRKITRPSQRPKTPPTDIIVYTELPNAESRSKVVSCP
SEQ ID NO:21 KIR2DL4
GIARHLHAVIRYSVAIILFTILPFFLLHRWCSKKKENAAVMNQEPAGHRTVNREDSDEQDPQEVTYAQLDHCIFTQRKITGPSQRSKRPSTDTSVCIELPNAEPRALSPAHEHHSQALMGSSRETTALSQTQLASSNVPAAGI
SEQ ID NO:22 KIR2DL5
TGIRRHLHILIGTSVAIILFIILFFFLLHCCCSNKKNAAVMDQEPAGDRTVNREDSDDQDPQEVTYAQLDHCVFTQTKITSPSQRPKTPPTDTTMYMELPNAKPRSLSPAHKHHSQALRGSSRETTALSQNRVASSHVPAAGI
SEQ ID NO:23KIR3DL1
KDPRHLHILIGTSVVIILFILLLFFLLHLWCSNKKNAAVMDQEPAGNRTANSEDSDEQDPEEVTYAQLDHCVFTQRKITRPSQRPKTPPTDTILYTELPNAKPRSKVVSCP
SEQ ID NO:24KIR3DL3
KDPGNSRHLHVLIGTSVVIIPFAILLFFLLHRWCANKKNAVVMDQEPAGNRTVNREDSDEQDPQEVTYAQLNHCVFTQRKITRPSQRPKTPPTDTSV
含有ITIM的结构域可以是或包含PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3胞内域。合适地，含有ITIM的结构域可以包含SEQ IDNO:15至24中任一项所示的序列或其变体，该变体具有至少80、85、90、95、98或99％序列同一性并保留被Src激酶磷酸化并放大抑制性免疫信号的能力。
例如，融合蛋白可以是或包含如SEQ ID NO:25所示的序列，其含有与PD1胞内域融合的PTPN6-SH2结构域。
SEQ ID NO:25
MTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPLSGGGGSGGGGSGGGGSGGGGSMVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPYYATRVNAADIENRVLELNKKQESEDTAKAGFWEEFESLQKQEVKNLHQRLEGQRPENKGKNRYKNILPFDHSRVILQGRDSNIPGSDYINANYIKNQLLGPDENAKTYIASQGCLEATVNDFWQMAWQENSRVIVMTTREVEKGRNKCVPYWPEVGMQRAYGPYSVTNCGEHDTTEYKLRTLQVSPLDNGDLIREIWHYQYLSWPDHGVPSEPGGVLSFLDQINQRQESLPHAGPIIVHCSAGIGRTGTIIVIDMLMENISTKGLDCDIDIQKTIQMVRAQRSGMVQTEAQYKFIYVAIAQFIETTKKKLEVLQSQKGQESEYGNITYPPAMKNAHAKASRTSSKHKEDVYENLHTKNKREEKVKKQRSADKEKSKGSLKRK
合适地，融合蛋白可以包含如SEQ ID NO:25所示的序列或具有至少80、85、90、95、98或99％序列同一性的其变体。
串扰信号(CROSSWIRE SIGNAL)
本发明提供了融合蛋白，其包含：来自ITAM结合蛋白的SH2结构域；和磷酸酶结构域。
本发明还提供了融合蛋白，其包含：来自ITIM结合蛋白的SH2结构域；和激酶结构域。
这些“串扰”信号传导分子将逆转免疫细胞(如T细胞)内的兴奋性或抑制性信号。当T细胞接受兴奋性信号时(例如在通过CAR识别靶抗原或通过TCR识别MHC:肽之后)，第一类串扰分子的存在将导致细胞将兴奋信号解读为抑制信号。
抑制或修正T细胞激活在各种情况下可能是有用的，例如，它可以用于在靶细胞上靶抗原高水平表达情况下的CAR表达T细胞。它可以用于防止可以导致T细胞耗尽和/或激活诱导的细胞死亡的T细胞过度激活。防止T细胞过度活化或过快活化也可防止或减少CAR-T细胞治疗的病理性副作用，如细胞因子释放综合征(CRS)。
相反的情况是当T细胞接收到抑制性信号(例如在与PD1连接后)，且在第二类串扰分子的存在下导致细胞将抑制性信号解读为刺激性信号。
减少或逆转T细胞抑制将帮助细胞克服敌对肿瘤微环境内的抑制性刺激，并且因此应当增加体内T细胞持续性和扩增。
在一个实施方案中，融合蛋白包含PTPN6 SH2结构域与和ZAP70激酶结构域。在另一个实施方案中，本发明的融合蛋白包含与PTPN6激酶结构域融合的ZAP70 SH2结构域。
在涉及与来自PTPN6的磷酸酶结构域融合的ZAP70 SH2结构域的实施方案中，当T细胞接收到兴奋性信号时，其将该信号解读为抑制性信号，因为PTPN6磷酸酶结构域经由ZAP70 SH2结构域招募到激活的ITAM。
在涉及与来自ZAP70的激酶结构域融合的PTPN6 SH2结构域的实施方案中，当T细胞接收到抑制性信号时，其将该信号解读为兴奋性信号，因为ZAP70激酶结构域经由PTPN6结构域招募到激活的ITIM。PTPN6 SH2结构域和ZAP70激酶结构域之间的融合将导致野生型PTPN6竞争磷酸化的ITIM，其阻断抑制性信号，但另外将传输矛盾性的激活信号。这可以在肿瘤微环境中的克服检查点阻断信号中有应用。
人ZAP70激酶、PTPN6磷酸酶和SHP-2磷酸酶结构域的序列分别如SEQ ID NO:26、27和28所示。
SEQ ID NO:26–ZAP70激酶结构域
DPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA
SEQ ID NO:27–PTPN6磷酸酶结构域
FWEEFESLQKQEVKNLHQRLEGQRPENKGKNRYKNILPFDHSRVILQGRDSNIPGSDYINANYIKNQLLGPDENAKTYIASQGCLEATVNDFWQMAWQENSRVIVMTTREVEKGRNKCVPYWPEVGMQRAYGPYSVTNCGEHDTTEYKLRTLQVSPLDNGDLIREIWHYQYLSWPDHGVPSEPGGVLSFLDQINQRQESLPHAGPIIVHCSAGIGRTGTIIVIDMLMENISTKGLDCDIDIQKTIQMVRAQRSGMVQTEAQYKFIYVAIAQFIETTKKKL
SEQ
ID
NO:28–SHP-2磷酸酶结构域
WEEFETLQQQECKLLYSRKEGQRQENKNKNRYKNILPFDHTRVVLHDGDPNEPVSDYINANIIMPEFETKCNNSKPKKSYIATQGCLQNTVNDFWRMVFQENSRVIVMTTKEVERGKSKCVKYWPDEYALKEYGVMRVRNVKESAAHDYTLRELKLSKVGQALLQGNTERTVWQYHFRTWPDHGVPSDPGGVLDFLEEVHHKQESIMDAGPVVVHCSAGIGRTGTFIVIDILIDIIREKGVDCDIDVPKTIQMVRSQRSGMVQTEAQYRFIYMA
ZAP70激酶结构域、PTPN6磷酸酶结构域或SHP-2磷酸酶结构域可以是或包含分别如SEQ ID NO:26，SEQ ID NO:27或SEQ ID NO:28所示的序列；或其变体，该变体具有至少80、85、90、95、98或99％的序列同一性并保留以与野生型激酶/磷酸酶结构域相同的方式磷酸化或去磷酸化下游蛋白的能力。
包含与ZAP70激酶结构域融合的PTPN6 SH2结构域的融合蛋白；包含与PTPN6激酶结构域融合的ZAP70 SH2结构域的融合蛋白；和包含与ZAP70激酶结构域融合的SHP-2 SH2结构域的融合蛋白的实例分别如SEQ ID NO:29，SEQ ID NO:30和SEQ ID NO:61所示。
SEQ ID NO:29–PTPN6 SH2结构域融合:ZAP70激酶结构域
MVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPYYSGGGGSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA
SEQ ID NO:30–ZAP70 SH2结构域融合:PTPN6磷酸酶结构域MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPSGGGGSGGGGSGGGGSGGGGSFWEEFESLQKQEVKNLHQRLEGQRPENKGKNRYKNILPFDHSRVILQGRDSNIPGSDYINANYIKNQLLGPDENAKTYIASQGCLEATVNDFWQMAWQENSRVIVMTTREVEKGRNKCVPYWPEVGMQRAYGPYSVTNCGEHDTTEYKLRTLQVSPLDNGDLIREIWHYQYLSWPDHGVPSEPGGVLSFLDQINQRQESLPHAGPIIVHCSAGIGRTGTIIVIDMLMENISTKGLDCDIDIQKTIQMVRAQRSGMVQTEAQYKFIYVAIAQFIETTKKKL
SEQ ID NO.61–来自SHP-2的双SH2结构域与ZAP70激酶结构域融合
WFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTGDYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPLNCADPTSERWFHGHLSGKEAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYDVGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPLNTTRINPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSL
融合蛋白可以是或包含如SEQ ID NO:29，SEQ ID NO:30或SEQ ID No.61所示的序列或具有至少80、85、90、95、98或99％序列同一性的其变体。
异源信号传导结构域
本融合蛋白可以包含(i)ZAP70，PTPN6或SHP-2 SH2结构域；和(ii)异源信号传导结构域。
如本文所用，术语“异源信号传导结构域”指在野生型ZAP70、PTPN6或SHP-2蛋白中不存在的信号传导结构域。如此，当融合蛋白包含ZAP70 SH2结构域时，其包含不是ZAP70激酶结构域的信号传导结构域。或者，当融合蛋白包含PTPN6 SH2结构域时，其包含不是PTPN6磷酸酶结构域的信号传导结构域。
旁路信号
异源信号传导结构域可以来自通常不被含有ITAM的受体激活的信号传导分子。换言之，异源信号传导结构域可以来自在抗原与TCR结合之后不参与免疫信号1传播的信号分子。免疫信号1足以引发T细胞对同源靶细胞的杀伤，但不能充分激活T细胞以增殖和存活。
在本发明的该方面的一个实施方案中，本发明提供了融合蛋白，其包含(i)来自结合ITAM的蛋白质的SH2结构域；和(ii)异源信号传导结构域。
例如ZAP70与另一信号传导分子(通常不被含有ITAM的受体激活)之间的融合物可以会将信号从一个通路旁通(bypass)到另一个通路。一个例子是共刺激。ZAP70与CD28的胞内域之间的融合物可以传递CD28共刺激信号以及ITAM激活性信号。类似地，ZAP70与41BB或OX40的胞内域之间的融合物可以传递41BB或OX40共刺激信号。也可以招募其他途径，例如ZAP70和AKT激酶结构域之间的融合物可以导致ITAM磷酸化后的AKT信号传递。其他实例可以包括来自JAK的激酶结构域。T细胞可将简单的抗原识别信号解读为传递共刺激信号或甚至细胞因子类型的信号。
此类融合蛋白例如在以下方法中是有用的，该方法中T细胞的重复离体刺激可导致缺乏共刺激表面抗原的群体，且其具有受限的体内增殖能力，导致受限的持久性和效力。共刺激表面抗原的丧失导致T细胞仅通过TCR而激活，其已经与更高程度的激活诱导的细胞死亡相关联，该细胞死亡会对体内效力和持久性产生负面影响。这种效应可以通过表面表达的4-1BB和OX40的活化来逆转，这说明共刺激可以防止激活诱导的细胞死亡并且可以支持肿瘤特异性T细胞的更大扩增。
在本发明的该方面的另一个实施方案中，本发明提供了融合蛋白，其包含(i)来自结合ITIM的蛋白质的SH2结构域；和(ii)异源信号传导结构域。
例如，可以将PTPN6 SH2结构域或SHP-2 SH2结构域与共刺激胞内域融合，使得T细胞将抑制信号解读为共刺激信号。
异源性信号传导结构域可以例如来自CD28、41BB或OX40。
CD28提供有效的共刺激信号-即免疫信号2，其触发T细胞增殖。CD28是CD80(B7.1)和CD86(B7.2)蛋白的受体。
41BB(CD137)是属于TNF超家族的2型跨膜糖蛋白，其在活化的T细胞上表达。41BB的交联增强T细胞增殖，IL-2分泌存活和细胞溶解活性。
OX40(CD134)是在激活后24至72小时后表达的次级共刺激分子，其配体(OX40L)也不在静息抗原提呈细胞上表达，但在该细胞激活后在其上表达。OX40的表达依赖于T细胞的完全激活；没有CD28，OX40的表达被延迟并且低四倍水平。在最初的激活和增殖后，通过OX40的信号传导是延长的T细胞存活所必需的。
CD28、41BB和OX40信号传导结构域(胞内域)分别如SEQ ID NO:31,32和33所示。
SEQ ID NO:31–CD28胞内域
MRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
SEQ ID NO:32–41BB胞内域
MKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
SEQ ID NO:33–OX40胞内域
MRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI
异源信号传导结构域可以是或包含分别如SEQ ID NO:31；SEQ ID NO:32或SEQ IDNO:33所示的序列，或具有至少80、85、90、95、98或99％序列同一性的其变体。
异源信号传导结构域可以是或包含抑制性信号传导结构域。
例如，抑制性信号传导结构域可以包含CD148或CD45的胞内域。已显示CD148和CD45天然地作用于TCR信号传导上游的磷酸化酪氨酸。
CD148是受体样蛋白酪氨酸磷酸酶，其通过干扰PLCγ1和LAT的磷酸化和功能负调节TCR信号传导。
CD45存在于所有造血细胞上，是蛋白酪氨酸磷酸酶，其能够再次通过磷酸化PLCγ1来调节信号转导和功能性应答。
抑制性信号传导结构域可以包含受体样酪氨酸磷酸酶的全部部分。磷酸酶可以干扰参与T细胞信号传导的元件(如PLCγ1和/或LAT)的磷酸化和/或功能。
抑制性信号传导结构域可以是或包含ICOS、CD27、BTLA、CD30、GITR或HVEM的胞内域。
抑制性信号传导结构域可以包含如SEQ ID NO:34至39所示的序列或具有至少80％序列同一性的其变体。
SEQ ID NO:34-ICOS胞内域
CWLTKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL
SEQ ID NO:35-CD27胞内域
QRRKYRSNKGESPVEPAEPCHYSCPREEEGSTIPIQEDYRKPEPACSP
SEQ ID NO:36-BTLA胞内域
RRHQGKQNELSDTAGREINLVDAHLKSEQTEASTRQNSQVLLSETGIYDNDPDLCFRMQEGSEVYSNPCLEENKPGIVYASLNHSVIGPNSRLARNVKEAPTEYASICVRS
SEQ ID NO:37-CD30胞内域
HRRACRKRIRQKLHLCYPVQTSQPKLELVDSRPRRSSTQLRSGASVTEPVAEERGLMSQPLMETCHSVGAAYLESLPLQDASPAGGPSSPRDLPEPRVSTEHTNNKIEKIYIMKADTVIVGTVKAELPEGRGLAGPAEPELEEELEADHTPHYPEQETEPPLGSCSDVMLSVEEEGKEDPLPTAASGK
SEQ ID NO:38-GITR胞内域
QLGLHIWQLRSQCMWPRETQLLLEVPPSTEDARSCQFPEEERGERSAEEKGRLGDLWV
SEQ ID NO:39-HVEM胞内域
CVKRRKPRGDVVKVIVSVQRKRQEAEGEATVIEALQAPPDVTTVAVEETIPSFTGRSPNH
变体序列可以与SEQ ID NO:34至39具有至少80％、85％、90％、95％、98％或99％的序列同一性，条件是该序列提供有效的细胞内信号传导结构域。
合适地，融合蛋白可以是或包含如SEQ ID NO:40至45所示的任何序列。
(SEQ ID NO:40)-CD28胞内域与全长ZAP的氨基末端融合
MRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSSGGGGSGGGGSGGGGSGGGGSMPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA
(SEQ ID NO:41)-41BB胞内域与全长ZAP的氨基末端融合
MKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELSGGGGSGGGGSGGGGSGGGGSMPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA
(SEQ ID NO:42)-OX40胞内域与全长ZAP的氨基末端融合
MRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKISGGGGSGGGGSGGGGSGGGGSMPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGGPLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA
(SEQ ID NO:43)-CD28胞内域与PTPN6 SH2结构域的氨基末端融合MRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSSGGGGSGGGGSGGGGSGGGGSMVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPY
(SEQ ID NO:44)-41BB胞内域与PTPN6 SH2结构域的氨基末端融合MKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELSGGGGSGGGGSGGGGSGGGGSMVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPY
(SEQ ID NO:45)-OX40胞内域与PTPN6 SH2结构域的氨基末端融合MRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKISGGGGSGGGGSGGGGSGGGGSMVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPY
合适地，融合蛋白可以包含如SEQ ID NO:40至45中任一项所示的序列，或具有至少80、85、90、95、98或99％序列同一性的其变体。
激酶结构域
异源信号传导结构域可以是激酶结构域。例如，异源信号传导结构域可以包含AKT激酶结构域或JAK激酶结构域。
Akt(也称为蛋白激酶B(PKB))，是一种丝氨酸/苏氨酸特异性蛋白激酶，在诸如葡萄糖代谢、凋亡、细胞增殖、转录和细胞迁移的多种细胞过程中起着关键的作用。
在TCR的激活后，T细胞分泌支持存活和增殖的IL2。然而，这种分泌是短暂的，并且体外激活和扩增的T细胞依赖异外源性IL2的存活。通过增加与TCR或CAR激活相关的ITAM磷酸化后的AKT磷酸化，可降低或消除激活的T细胞对异源IL2的依赖，并增强其增殖和存活。
Akt激酶结构域如SEQ ID NO:46所示。
SEQ ID NO:46-Akt激酶结构域
AEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
异源信号传导结构域可以是或包含如SEQ ID NO:46所示的序列或具有至少80、85、90、95、98或99％序列同一性的其变体，条件是该序列提供有效的激酶结构域。
例如，融合蛋白可以是或包含SEQ ID NO:47至49和62所示的任何序列，所述序列分别包含直接融合到Akt激酶结构域的ZAP70-SH2结构域、经由接头融合到Akt激酶结构域的ZAP70-SH2结构域、融合到Akt激酶结构域的被突变为无功能的ZAP70-SH2结构域；以及融合到Akt激酶结构域的双SHP-2 SH2结构域。
SEQ ID NO:47-直接融合到Akt激酶结构域的ZAP70-SH2结构域MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
SEQ ID NO:48-经由接头融合到Akt激酶结构域的ZAP70-SH2结构域MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPSGGGGSGGGGSGGGGSGGGGSAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
SEQ ID NO:49-融合到Akt激酶结构域的被突变为无功能的ZAP70-SH2结构域
MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLKPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
SEQ ID NO.62-融合到Akt激酶结构域的双SHP-2 SH2结构域
WFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTGDYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPLNCADPTSERWFHGHLSGKEAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYDVGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPLNTTRINAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
融合蛋白可以包含如SEQ ID NO:47至49或62中任一项所示的序列或具有至少80、85、90、95、98或99％序列同一性的其变体。
Janus激酶(JAK)是细胞内非受体酪氨酸激酶家族，其通过JAK-STAT途径转导细胞因子介导的信号。JAK家族的四个成员是：Janus激酶1(JAK1)；Janus激酶2(JAK2)；Janus激酶3(JAK3)；和酪氨酸激酶2(TYK2)。
SEQ ID NO:50–含有JAK2结构域的激酶
RNEDLIFNESLGQGTFTKIFKGVRREVGDYGQLHETEVLLKVLDKAHRNYSESFFEAASMMSKLSHKHLVLNYGVCVCGDENILVQEFVKFGSLDTYLKKNKNCINILWKLEVAKQLAWAMHFLEENTLIHGNVCAKNILLIREEDRKTGNPPFIKLSDPGISITVLPKDILQERIPWVPPECIENPKNLNLATDKWSFGTTLWEICSGGDKPLSALDSQRKLQFYEDRHQLPAPKWAELANLINNCMDYEPDFRPSFRAIIRDLNSLFTPDYELLTENDMLPNMRIGALGFSGAFEDRDPTQFEERHLKFLQQLGKGNFGSVEMCRYDPLQDNTGEVVAVKKLQHSTEEHLRDFEREIEILKSLQHDNIVKYKGVCYSAGRRNLKLIMEYLPYGSLRDYLQKHKERIDHIKLLQYTSQICKGMEYLGTKRYIHRDLATRNILVENENRVKIGDFGLTKVLPQDKEYYKVKEPGESPIFWYAPESLTESKFSVASDVWSFGVVLYELFTYIEKSKSPPAEFMRMIGNDKQGQMIVFHLIELLKNNGRLPRPDGCPDEIYMIMTECWNNNVNQRPSFRDLALRVDQIRDNM
蛋白酶结构域
本发明还提供了融合蛋白，其包含(i)来自蛋白质的SH2结构域，该蛋白质结合含有ITAM或ITIM的蛋白质，和(ii)蛋白酶结构域。
蛋白酶结构域可以是能够在特定识别序列处切割的任何蛋白酶。因此，蛋白酶结构域可以是任何蛋白酶，其能够通过在特定靶序列处的切割将单个靶多肽分离成两个不同的多肽。
蛋白酶结构域可以是烟草蚀刻病毒(TeV)蛋白酶结构域。
TeV蛋白酶是高度序列特异性的半胱氨酸蛋白酶，其是胰凝乳蛋白酶样蛋白酶。其对其靶切割位点是非常特异的，并因此经常用于体外和体内融合蛋白的受控切割。共有TeV切割位点为ENLYFQ\S(其中‘\’表示切割的肽键)。哺乳动物细胞如人类细胞不表达内源性TeV蛋白酶。
相应的，TeV切割识别位点如SEQ ID NO:51所示。
SEQ ID NO:51–Tev切割位点
ENLYFQS
TeV蛋白酶结构域如SEQ ID NO:52所示。
SEQ ID NO:52
SLFKGPRDYNPISSTICHLTNESDGHTTSLYGIGFGPFIITNKHLFRRNNGTLLVQSLHGVFKVKNTTTLQQHLIDGRDMIIIRMPKDFPPFPQKLKFREPQREERICLVTTNFQTKSMSSMVSDTSCTFPSSDGIFWKHWIQTKDGQCGSPLVSTRDGFIVGIHSASNFTNTNNYFTSVPKNFMELLTNQEAQQWVSGWRLNADSVLWGGHKVFMSKPEEPFQPVKEATQLMNELVYSQ
相应的，蛋白酶结构域可以是或包含如SEQ ID NO:52所示的序列或具有至少80、85、90、95、98或99％序列同一性的其变体，条件是该序列提供有效的蛋白酶功能。
例如，融合蛋白可以是或包含如SEQ ID NO:53或54所示的序列，该序列分别含有与TEV蛋白酶序列融合的ZAP70-SH2结构域或与TEV蛋白酶序列融合的PTPN6-SH2结构域。
SEQ ID NO:53
MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPSGGGGSGGGGSGGGGSGGGGSSLFKGPRDYNPISSTICHLTNESDGHTTSLYGIGFGPFIITNKHLFRRNNGTLLVQSLHGVFKVKNTTTLQQHLIDGRDMIIIRMPKDFPPFPQKLKFREPQREERICLVTTNFQTKSMSSMVSDTSCTFPSSDGIFWKHWIQTKDGQCGSPLVSTRDGFIVGIHSASNFTNTNNYFTSVPKNFMELLTNQEAQQWVSGWRLNADSVLWGGHKVFMSKPEEPFQPVKEATQLMNELVYSQ
SEQ ID NO:54
MVRWFHRDLSGLDAETLLKGRGVHGSFLARPSRKNQGDFSLSVRVGDQVTHIRIQNSGDFYDLYGGEKFATLTELVEYYTQQQGVLQDRDGTIIHLKYPLNCSDPTSERWYHGHMSGGQAETLLQAKGEPWTFLVRESLSQPGDFVLSVLSDQPKAGPGSPLRVTHIKVMCEGGRYTVGGLETFDSLTDLVEHFKKTGIEEASGAFVYLRQPYYSGGGGSSLFKGPRDYNPISSTICHLTNESDGHTTSLYGIGFGPFIITNKHLFRRNNGTLLVQSLHGVFKVKNTTTLQQHLIDGRDMIIIRMPKDFPPFPQKLKFREPQREERICLVTTNFQTKSMSSMVSDTSCTFPSSDGIFWKHWIQTKDGQCGSPLVSTRDGFIVGIHSASNFTNTNNYFTSVPKNFMELLTNQEAQQWVSGWRLNADSVLWGGHKVFMSKPEEPFQPVKEATQLMNELVYSQ
融合蛋白可以包含如SEQ ID NO:53或54所示的序列或具有至少80、85、90、95、98或99％序列同一性的其变体。
融合蛋白的SH2结构域和异源结构域可以通过接头分开，以在空间上分开SH2结构域和异源结构域。
转录信号
包含如前节所述的蛋白酶的融合蛋白可以与具有蛋白酶切割位点的膜栓系蛋白(membrane-tethered protein)在细胞中共表达。在蛋白酶位点处的膜栓系蛋白的切割将释放该蛋白的膜远端部分。
膜栓系蛋白例如可以是膜栓系转录因子。当发生切割时，转录物从其栓系物上释放并自由转运到细胞核。
ZAP70 SH2或PTPN6 SH2结构域与蛋白酶结构域之间的融合将分别导致在ITAM或ITIM磷酸化后蛋白酶的膜近端招募。
ITAM或ITIM结构域的磷酸化导致将分别与蛋白酶结构域融合的ZAP70SH2或PTPN6SH2招募到膜近端区域。这导致转录因子从其栓系物上切割并转移到细胞核。这可能有很多应用：例如，激活后，T细胞可以被编程以表达起到阻止T细胞分化作用的转录因子。例如，激活后T细胞可以被编程以表达细胞因子，如可能起到刺激T细胞增殖和存活作用的IL2、IL7或IL15，或可以将敌对肿瘤微环境转化为更有利于肿瘤免疫排斥的IL12。
具体而言，提供了细胞，其共表达：
(i)包含来自结合磷酸化的ITAM的蛋白质的SH2结构域的融合蛋白；和(ii)膜栓系转录因子
其中当所述转录因子从膜栓系物上释放时，该转录因子增加细胞中IL2，IL7和/或IL15的表达。
还提供了细胞，其共表达：
(i)包含来自结合磷酸化的ITIM的蛋白质的SH2结构域的融合蛋白；和(ii)膜栓系转录因子
其中当所述转录因子从膜栓系物上释放时，该转录因子增加细胞中IL12的表达。
蛋白酶识别位点
蛋白酶识别位点可以是能够使融合蛋白的蛋白酶结构域在膜栓系物和转录因子之间特异性切割膜栓系转录因子的任何氨基酸序列。例如，在一个实施方案中，蛋白酶结构域是TeV蛋白酶结构域并且蛋白酶识别位点是TeV蛋白酶识别位点。
膜栓系物(Membrane tether)
膜栓系物可以是能够将转录因子和蛋白酶识别位点定位在膜近端处的任何序列，信号或结构域。例如，膜栓系物可以是myrsitylation信号或跨膜域。
合适地，跨膜域可以是在膜中热力学稳定的任何蛋白质结构。这通常是由几个疏水性残基组成的alpha螺旋。任何跨膜蛋白的跨膜域均可用于提供跨膜部分。任何跨膜蛋白的跨膜域可以用于提供本发明的跨膜部分。本领域技术人员可以使用TMHMM算法(http://www.cbs.dtu.dk/services/TMHMM-2.0/)确定蛋白的跨膜域的存在和跨度。此外，考虑到蛋白的跨膜域是相对简单的结构，即预测形成足够长度的疏水alpha螺旋以跨越膜的多肽序列，也可以使用人工设计的TM结构域(US 7052906B1描述了合成跨膜组分)。
跨膜域可以来源于CD28，其产生良好的受体稳定性。
转录因子
转录因子可以是任何转录因子，其选择为在相关ITAM或ITIM基序磷酸化后刺激所需的应答。
转录因子可以是天然的或人工的。人工转录因子可以来源于例如TALEN、锌指组装物或CrispR/CAS9，后者与指导mRNA共表达。
优选地，转录因子将含有核定位信号以在蛋白酶结构域切割后帮助其转运至核酸酶。
例如，核酸序列(ii)(其编码包含膜栓系转录因子的蛋白质，该膜栓系转录因子包含：(i)膜栓系物；(ii)蛋白酶识别位点；和(iii)转录因子)可以编码蛋白质，该蛋白质由如SEQ ID NO:55所示序列组成或包含该序列，其中SEQ ID NO:55所示序列含有RQR8结构域；CD4-Endotox1跨膜域，TEV蛋白酶识别位点和VP16-GAL4转录因子。
SEQ ID NO:55
MGTSLLCWMALCLLGADHADACPYSNPSLCSGGGGSELPTQGTFSNVSTNVSPAKPTTTACPYSNPSLCSGGGGSPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDMALIVLGGVAGLLLFIGLGIFFCVRCRHRRRQAERMAQIKRVVSEKKTAQAPHRFQKTCSPISGGGGSENLYFQMPKKKRKVAPPTDVSLGDELHLDGEDVAMAHADALDDFDLDMLGDGDSPGPGFTPHDSAPYGALDMADFEFEQMFTDALGIDEYGGSGGGSMQILVASDATMKLLSSIEQACDICRLKKLKCSKEKPKCAKCLKNNWECRYSPKTKRSPLTRAHLTEVESRLERLEQLFLLIFPREDLDMILKMDSLQDIKALLTGLFVQDNVNKDAVTDRLASVETDMPLTLRQHRISATSSSEESSNKGQRQLTV
适当地，所述蛋白质可以包含如SEQ ID NO:55所示的序列；或具有至少80、85、90、95、98或99％序列同一性的其变体。
受体
本发明还提供了核酸构建体，其包含(a)编码根据本发明第一方面的包含PTPN6SH2结构域的融合蛋白的核酸序列，或编码根据本发明的第三方面的截短的蛋白质的核酸序列；和(b)编码包含含有ITIM的胞内域的受体的核酸序列。
去势信号(CASTRATION SIGNAL)
包含上述蛋白酶的融合蛋白可以与包含细胞内蛋白酶切割位点的靶受体在细胞中共表达。靶受体在蛋白酶位点处的切割将释放靶受体的细胞内膜远端部分。
靶受体可以是例如T细胞受体(TCR)或嵌合抗原受体(CAR)。
受体可以包含位于蛋白质的细胞内部分末端处的激活性或共刺激性胞内域。然后，在蛋白酶切割位点处切割从靶CAR除去激活性或共刺激性胞内域，减少或阻止靶受体介导的T细胞激活。
或者，靶受体可以包含位于蛋白质的细胞内部分末端的抑制性胞内域。然后，在蛋白酶切割位点处的切割从靶CAR除去抑制性胞内域，“开通(switching-on)”靶受体介导的T细胞活化的潜能。
抑制性胞内域例如可以包含CD148或CD45胞内域或来自蛋白质的含有ITIM的胞内域，所述蛋白质如PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3。
例如，靶受体可以包含如SEQ ID NO:56所示序列，其包含含有来自PD-1的ITIM胞内域的针对CD33的CAR。
SEQ ID NO:56
MAVPTQVLGLLLLWLTDARCDIQMTQSPSSLSASVGDRVTITCRASEDIYFNLVWYQQKPGKAPKLLIYDTNRLADGVPSRFSGSGSGTQYTLTISSLQPEDFATYYCQHYKNYPLTFGQGTKLEIKRSGGGGSGGGGSGGGGSGGGGSRSEVQLVESGGGLVQPGGSLRLSCAASGFTLSNYGMHWIRQAPGKGLEWVSSISLNGGSTYYRDSVKGRFTISRDNAKSTLYLQMNSLRAEDTAVYYCAAQDAYTGGYFDYWGQGTLVTVSSMDPATTTKPVLRTPSPVHPTGTSQPQRPEDCRPRGSVKGTGLDFACDIYVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL
适当地，蛋白质可以包含如SEQ ID NO:56所示序列；或具有至少80、85、90、95、98或99％序列同一性的其变体。
当受体包含跨膜域和激活性胞内域之间的蛋白酶切割位点时，去势信号融合蛋白可用来抑制受体。例如，可以构建第一CAR，其中其胞内域通过蛋白酶切割位点与跨膜域分开。识别不同抗原的第二CAR可包含含有ITIM的胞内域。第二受体对关联抗原的识别将导致将去势信号融合蛋白招募到膜，并且随后在蛋白酶识别位点处切割。此类切割将使激活性胞内域与第一受体相分离，并阻止来自所述受体的激活和信号传播。
这将导致“与非(AND NOT)”型逻辑门，其中只有当第一个CAR被单独激活时才会传输持续的信号(即，当第一个CAR结合其关联抗原但第二个CAR不结合其关联抗原时)。例如，此类“逻辑门”可能是有用的，因为单个抗原的存在(或不存在)有效地描述癌症是相对罕见的，其可导致缺乏特异性。靶向在正常细胞上表达的抗原导致靶向肿瘤外毒性(on-target,off-tumour toxicity)。在一些癌症中，通过存在一种抗原(通常是组织特异性抗原)和不存在另一种存在于正常细胞上的抗原来最好地定义肿瘤。例如，急性骨髓性白血病(AML)细胞表达CD33。正常干细胞表达CD33，但也表达CD34，而AML细胞通常是CD34阴性的。仅靶向CD33来治疗AML与显著的毒性相关，因为其消耗正常的干细胞。然而，特异性靶向CD33阳性但不是CD34阳性的细胞将避免这种相当大的脱靶(off-target)毒性。
表2中显示了用于此类“与非”门的潜在抗原对。
表2
例如，包含在跨膜域和激活性胞内域之间处的蛋白酶切割位点的受体可以是如SEQ ID NO:57所示的序列，其含有具有可切割的CD3-zeta胞内域的针对CD19的CAR。
SEQ ID NO:57
MSLPVTALLLPLALLLHAARPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITKAGGGGSGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIFWVLVVVGGVLACYSLLVTVAFIIFWVRCRHRRRQAERMAQIKRVVSEKKTAQAPHRFQKTCSPISGGGGSENLYFQMRRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
适当地，所述蛋白质可以包含如SEQ ID NO:57所示的序列或具有至少80、85、90、95、98或99％序列同一性的其变体。
其中受体包含经由蛋白酶切割位点与抑制胞内域融合的激活性胞内域，去势信号融合蛋白可用于激活人工信号传导结构域。例如，可以构建第一CAR，其中其胞内域包含经由蛋白酶切割位点与抑制性胞内域融合的激活性胞内域。识别不同的抗原的第二CAR可以包含含有ITIM的胞内域。第二受体对关联抗原的识别将导致将去势信号融合蛋白招募至膜并随后从第一受体的激活性胞内域上切割抑制性胞内域。从激活性胞内域上切割和分离抑制性胞内域将允许抗原结合后的第一CAR的激活并因此经由第一受体激活信号传导。
这将导致“与”型CAR逻辑门，其中只有当第一和第二受体被激活时才会发生有效的信号传导。例如，此类“逻辑门”是有用的，因为大多数癌症不能基于单一抗原与正常组织区分开来。因此，发生相当大的“靶向肿瘤外”毒性，由此正常组织被治疗破坏。对于一些癌症来说，靶向两种癌症抗原的存在可以比靶向一种更有选择性并因此更有效。例如，B-慢性淋巴细胞性白血病(B-CLL)是目前通过靶向CD19来治疗的常见白血病。这治疗淋巴瘤，但也消耗整个B细胞部分，使得治疗有相当的毒性作用。B-CLL具有不同寻常的表型，因为CD5和CD19是共表达的。通过仅靶向表达CD5和CD19的细胞，有可能显著降低靶向肿瘤外毒性。
表3中显示了用于此类“与”逻辑门的潜在抗原对
表3
| 癌症类型 | 抗原 |
| 慢性淋巴细胞白血病 | CD5,CD19 |
| 神经母细胞瘤 | ALK,GD2 |
| 胶质瘤 | EGFR,波形蛋白 |
| 多发性骨髓瘤 | BCMA,CD138 |
| 肾细胞癌 | 碳酸酐酶IX,G250 |
| T-ALL | CD2,N-钙粘蛋白 |
| 前列腺癌 | PSMA,hepsin(或其他) |
例如，包含经由蛋白酶切割位点融合到抑制性胞内域的激活性胞内域的受体可以是如SEQ ID NO:58所示的序列；该序列含有具有CD3-zeta胞内域和可切割CD148的针对CD19的CAR。
SEQ ID NO:58
MSLPVTALLLPLALLLHAARPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITKAGGGGSGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIFWVLVVVGGVLACYSLLVTVAFIIFWVRRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRENLYFQMAVFGCIFGALVIVTVGGFIFWRKKRKDAKNNEVSFSQIKPKKSKLIRVENFEAYFKKQQADSNCGFAEEYEDLKLVGISQPKYAAELAENRGKNRYNNVLPYDISRVKLSVQTHSTDDYINANYMPGYHSKKDFIATQGPLPNTLKDFWRMVWEKNVYAIIMLTKCVEQGRTKCEEYWPSKQAQDYGDITVAMTSEIVLPEWTIRDFTVKNIQTSESHPLRQFHFTSWPDHGVPDTTDLLINFRYLVRDYMKQSPPESPILVHCSAGVGRTGTFIAIDRLIYQIENENTVDVYGIVYDLRMHRPLMVQTEDQYVFLNQCVLDIVRSQKDSKVDLIYQNTTAMTIYENLAPVTTFGKTNGYIA
适当地，受体可以包含如SEQ ID NO:58所示的序列；或具有至少80、85、90、95、98或99％序列同一性的其变体。
阻断信号
本发明提供了截短的蛋白质，其包含来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质的SH2结构域，但缺少激酶结构域。
例如，截短的蛋白可以包含ZAP70 SH2结构域但缺少ZAP70激酶结构域。换而言之，本发明提供了截短的蛋白质，其：(i)包含如SEQ ID NO:2所示的序列，但不包含如SEQ IDNO:26所示的序列。
ZAP70 SH2结构域的过表达导致与全长/野生型ZAP70的竞争。由于截短的ZAP70不能传播信号，信号传递随着野生型ZAP70和截短蛋白之间的比率成比例地降低。这对于降低T细胞激活的强度，例如防止可以导致T细胞耗竭、活化诱导的细胞死亡以临床上可能导致细胞因子风暴(cytokine storms)的T细胞过度激活可以是有用的。
本发明还提供了截短的蛋白质，其包含来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域，但缺少磷酸酶结构域。
例如，截短的蛋白质可以包含PTPN6 SH2结构域但缺少PTPN6磷酸酶结构域。换而言之，本发明提供了截短的蛋白质，其：(i)包含如SEQ ID NO:6所示的序列，但不包含如SEQID NO:27所示的序列。
在这种情况下，ITIM信号传导可以随着野生型PTPN6和截短蛋白之间的比率成比例地降低。这可以有助于减少抑制性信号，如PD1信号。当T细胞靶向过表达PDL1(或类似的抑制性受体)以逃避免疫排斥的肿瘤时，这可以是有用的。
上述阻断信号或串扰信号的使用相对于通常用抗体阻断单个配体/受体相互作用(例如PD-L1/PD1)的传统免疫检查点阻断方法提供了显著的优势。如上所述，抑制性免疫受体类型包含许多具有随T细胞状态而波动的冗余和表达模式的成员。抗体或重组配体/受体的使用可以有效地阻断一种抑制性受体，但不会影响其他传输的抑制信号。个别抑制性受体的基因组编辑(Menger et al,Cancer Res.2016Apr 15；76(8):2087-93)具有类似的限制。个别抑制性受体与共刺激结构域之间融合的策略也受到类似的限制(Liu et al,Cancer Res.2016Mar 15；76(6):1578-90)。
本发明的方法将阻断(并取决于策略重新解释)经由ITIM传送的抑制性信号。因此调制了整个类别的抑制性信号。在Odorizzi和Wherry(2012)J.Immunol.188:2957-2965的表II中提供了通过ITIM发信号的抑制性受体的列表。它们包括：PD1、BTLA、2B4、CTLA-4、GP49B、Lair-1、Pir-B、PECAM-1、CD22、Siglec 7、Siglec 9、KLRG1、ILT2、CD94-NKG2A和CD5。
核酸
一方面，本发明提供了编码根据本发明的融合蛋白或截短的蛋白的核酸。
如本文所用，术语“多核苷酸”、“核苷酸”和“核酸”旨在是彼此同义的。
本领域的技术人员将理解由于遗传密码的简并性，许多不同的多核苷酸和核酸可以编码相同的多肽。另外，本领域的技术人员应当理解使用常规技术，可以制备核苷酸取代，其不影响由此处所述的多核苷酸编码的多肽序列，以反映多肽将在其中表达的任意特定宿主生物中的密码子选择。
根据本发明的核酸可以包括DNA或RNA。它们可以是单链的或双链的。它们也可以是在它们之中包括合成的或修饰的核苷酸的多核苷酸。对寡核苷酸的一些不同类型的修饰是本领域已知的。这些包括膦酸甲酯和硫代磷酸酯骨架，在分子的3’和/或5’末端的吖啶(acridine)或聚赖氨酸链的添加。为了如本文所述的用途的目的，应当理解可以通过本领域可用的任意方法修饰多核苷酸。为了提高感兴趣的多核苷酸的体内活性或寿命可以进行此类修饰。
术语“变体”、“同源物”或“衍生物”关于核苷酸序列包括来自序列或对序列的一个(或多个)核酸的任意取代，变异，修饰，置换，缺失或添加。
核酸构建体
一方面，本发明提供了将本发明的截短的蛋白或融合蛋白质与另一种蛋白质共表达的核酸构建体。核酸构建体可以包含：编码本发明的截短的蛋白或融合蛋白的核酸序列；和编码另一种蛋白质的核酸。
本发明提供了将本发明的截短蛋白或融合蛋白质与嵌合抗原受体共表达的核酸构建体。核酸构建体可以包含：(i)编码本发明的截短的蛋白或融合蛋白的核酸序列；和(ii)编码嵌合抗原受体的核酸。
嵌合抗原受体(CAR)可以是包含含有ITAM的胞内域(如CD3 zeta)的激活性CAR。CAR可以是包含“连接关闭(ligation-off)”胞内域的抑制性CAR，如WO2015/075469中所述，该CAR可以包含来自受体样酪氨酸磷酸酶(如CD148或CD45)的全部或部分胞内域。CAR可以是包含“连接开启(ligation-on)”胞内域的抑制性CAR，如WO2015/075469中所述，其可以包含ITIM结构域。
本发明的融合蛋白和截短的蛋白可以与表达两种或更多种CAR的“逻辑门”组合的细胞一起使用。或(OR)门包含两种激活性CAR，如WO2015/075468中所述。和(AND)门包含激活性CAR和“连接关闭(igation-off)”抑制性CAR，如WO2015/075469中所述。
因此，本发明提供了核酸构建体，其包含：
(i)编码本发明的截短的蛋白或融合蛋白的核酸序列；
(ii)第一嵌合抗原受体(CAR)；和
(iii)第二嵌合抗原受体。
参照本发明的转录信号方面，这里提供了核酸构建体，其包含(i)编码包含SH2结构域和蛋白酶结构域的融合蛋白的核酸序列；和(ii)编码膜栓系转录因子的核酸序列，该膜栓系转录因子包含：膜栓系物；蛋白酶识别位点；和转录因子。
参照本发明的去势信号方面，这里提供了核酸构建体，其包含(i)编码包含SH2结构域和蛋白酶结构域(如TeV结构域)的融合蛋白的核酸序列；和(ii)编码包含蛋白酶切割位点的受体的核酸序列。
例如，本发明提供了核酸构建体，其包含：(a)编码融合蛋白的核酸序列，所述融合蛋白包含(i)PTPN6 SH2结构域；和(ii)蛋白酶结构域(如TeV结构域)；(b)编码包含蛋白酶切割位点的受体的核酸序列；和(c)编码包含含有ITIM的胞内域的受体的核酸序列。
受体可以是T细胞受体(TCR)或嵌合抗原受体(CAR)。
适当地，由核酸序列(b)编码的蛋白质可以是T细胞受体(TCR)或嵌合抗原受体(CAR)，其包含(i)跨膜结构域和激活性胞内域之间的蛋白酶切割位点；或(ii)经由蛋白酶切割位点融合到抑制性胞内域的激活性胞内域。
在本发明的核酸构建体生产独立的多肽例如当其共表达本发明的融合蛋白和CAR的情况下，其还可以包含使两种蛋白质能够表达的核酸序列。例如，其可以包含编码两个核酸序列之间的切割位点的序列。切割位点可以是自切割的，使得当产生新生多肽时，它立即被切割成两种蛋白质，而不需要任何外部切割活性。各种自切割位点是已知的，包括口蹄疫病毒(FMDV)2a自切割肽，其具有以下示出的序列：
SEQ ID NO:59
RAEGRGSLLTCGDVEENPGP
或
SEQ ID NO:60
QCTNYALLKLAGDVESNPGP
共表达序列可以是内部核糖体进入序列(IRES)。共表达序列可以是内部启动子。
嵌合抗原受体(CAR)
在图13中示意性显示的CAR是嵌合的I型跨膜蛋白质，其将胞外抗原识别域(结合剂)连接至胞内信号传导域(胞内域)。结合物通常为来源于单克隆抗体(mAb)的单链可变片段(scFv)，但它可以是基于包含抗体样抗原结合位点的其他形式。为将结合物与膜分离并允许它具有合适的方向，间隔域通常是必需的。常用的间隔域是IgG1的Fc。取决于抗原，更紧凑的间隔区可以足够，例如来自CD8α的茎部和甚至是仅IgG1的铰链。跨膜域将蛋白质锚定在细胞膜中，并将间隔区连接至胞内域。
早期的CAR设计具有来源于FcεR1或CD3ζ的γ链的细胞内部分的胞内域。因此，这些第一代受体传输免疫信号1，其足以触发相关靶细胞的T细胞杀死，但未能充分激活T细胞以增殖和存活。为了克服此限制，已构建了复合胞内域:T细胞共刺激分子的胞内部分与CD3ζ的胞内部分的融合导致了可在抗原识别后同时传输激活和共刺激信号的第二代受体。最常使用的共刺激域是CD28的共刺激域。这提供最有效的共刺激信号-即触发T细胞增殖的免疫信号2。也已经描述了包括TNF受体家族胞内域的一些受体，例如密切相关的传输存活信号的OX40和41BB。甚至现在已经描述了更强大的第三代CAR，其具有能够传输激活，增殖和存活信号的胞内域。
使用例如逆转录病毒载体可以将CAR编码核酸转移到T细胞。可使用慢病毒载体。通过这种方式可产生用于过继性细胞转移的大量的癌特异性T细胞。当CAR结合靶抗原时，这导致活化信号传输到表达所述CAR的T细胞上。因此，CAR指导T细胞的针对表达靶抗原的肿瘤细胞的特异性和细胞毒性。
因此，CAR通常包含：(i)抗原结合域；(ii)间隔区；(iii)跨膜域；和(iii)包含信号传导域或与信号传导域相关的胞内域。
抗原结合域
抗原结合域是CAR的识别抗原的部分。众多的抗原结合域是本领域公知的，包括基于抗体，抗体模拟物和T细胞受体的抗原结合位点的那些抗原结合域。例如，抗原结合域可以包含：由单克隆抗体衍生的单链可变片段(scFv)；靶抗原的天然配体；具有针对靶标的足够亲和性的肽；单域抗体；人工单结合剂诸如Darpin(设计的锚蛋白重复蛋白)；或T细胞受体衍生的单链。
抗原结合域可包含不基于抗体的抗原结合位点的域。例如，抗原结合域可包含基于蛋白质/肽的域，所述蛋白质/肽为肿瘤细胞表面受体的可溶性配体(例如可溶性肽，如细胞因子或趋化因子)；或膜锚定配体或者受体的胞外域，对于所述配体或者受体，结合对对应物表达在肿瘤细胞上。
抗原结合结构域可以基于抗原的天然配体。
抗原结合结构域可以包含来自组合文库的亲和肽或从头设计的亲和蛋白/肽。
间隔区结构域
CAR包含间隔区序列以连接抗原结合域与跨膜域并且在空间上分离来自胞内域的抗原结合域。柔性间隔区允许抗原结合域在不同方向上定向以促进结合。
在需要种CAR的本发明的方面中，第一和第二CAR可以包含不同的间隔区分子。例如，间隔区序列可以例如包含IgG1Fc区，IgG1铰链或人CD8茎或小鼠CD8茎。间隔区可以备选地包含备选的接头序列，其具有与gG1Fc区，IgG1铰链或CD8茎相似的长度和/或域间距性质。可以改变人IgG1间隔区以除去Fc结合基序。
上面提到的所有间隔域都是同源二聚体。然而，机制不限于使用同源二聚体受体并也应当适用于单体受体，只要间隔区足够刚性即可。此类间隔区的例子为CD2或截短的CD22。
由于CAR通常是同源二聚体(参见图13a)，交叉配对可能导致异源二聚体嵌合抗原受体。由于各种原因，这是不希望的，例如：(1)靶细胞上的表位可能不处于相同的“水平”使得交叉配对的CAR可以只能与一个抗原结合；(2)来自两种不同scFv的VH和VL可以互换并且要么不能识别靶标，要么更糟糕地识别意想不到的和不可预测的抗原。对于如上描述的“与”和“与非”门，为了避免交叉配对但与共同定位足够相似，第一CAR的间隔区可以与第二CAR的间隔区充分不同。可以使用成对的直系同源间隔区序列。例子是鼠和人CD8茎部，或者可选地是单体的间隔区结构域--如CD2的胞内域。
下表中示出了共定位的间隔区对的示例：
跨膜域
跨膜域是CAR的跨越膜的序列。
跨膜域可以是在膜中热力学稳定的任何蛋白质结构。这通常是由几个疏水性残基构成的螺旋。可以将任何跨膜蛋白质的跨膜域用于提供本发明的跨膜部分。蛋白质的跨膜域的存在和跨度可以通过本领域的技术人员使用TMHMM算法(http://www.cbs.dtu.dk/services/TMHMM-2.0/)来确定。此外，考虑到蛋白质的跨膜域是相对简单的结构，即预测形成足够长的疏水alpha螺旋以跨越膜的多肽序列，也可以使用人工设计的TM域(US 7052906B1描述了合成的跨膜组分)。
跨膜域可以源自CD28，其提供了良好的受体稳定性。
激活性胞内域
胞内域是CAR的信号传输部分。它可以是CAR细胞内结构域的一部分或与之相关联。在抗原识别后，受体聚簇，天然CD45和CD148被排除在突触外，并且将信号传输到细胞。最常用的胞内域组分是含有3个ITAM的CD3-zeta的胞内域。这在结合抗原后将激活信号传输到T细胞。CD3-zeta可能不能提供完全有能力(competent)的激活信号，并且可能需要额外的共刺激信号。例如，可以将嵌合CD28和OX40与CD3-zeta一起用于传输增殖/存活信号，或全部三种可以一起使用。
在CAR包含及活性胞内域的情况下，它可以仅包含CD3-Zeta胞内域，CD3-Zeta胞内域与CD28或OX40的胞内域，或CD28胞内域和OX40和CD3-Zeta胞内域。
任何含有ITAM基序的胞内域都可以作为本发明中的激活性胞内域。本文描述了含有ITAM基序的合适的胞内域。
抑制性胞内域
在上面称为“与”门的实施方案中，第一CAR可以包含经由蛋白酶切割位点融合到抑制性胞内域的激活性胞内域。使得在不存在第二CAR的激活的情况下，抑制性胞内域抑制通过第一CAR的T细胞激活。激活第二CAR后，第二CAR的胞内域中的ITIM被磷酸化并且PTPN6/磷酸酶结构域融合蛋白被招募到膜。这导致第一CAR在激活性胞内域和抑制性胞内域之间处的切割，因此使T细胞激活。
当处于相同胞内域时，抑制性胞内域可以包含抑制通过激活性CAR的T细胞信号传导的任何序列。
抑制胞内域可以是或包含酪氨酸磷酸酶，如受体样酪氨酸磷酸酶。抑制性胞内域可以是或包含当与CAR的激活性胞内域共定位时能够抑制TCR信号传导的任何酪氨酸磷酸酶。抑制性胞内域可以是或包含对于磷酸化ITAM具有足够快的催化速率的任何酪氨酸磷酸酶，所述磷酸化的ITAM当与CAR的激活性胞内域共定位时能够抑制TCR信号传导。
载体
本发明还提供载体，或载体的试剂盒，其包括根据本发明的一个或多个核酸序列或构建体。此类载体可以用于将核酸序列或构建体导入宿主细胞中，使得其表达由核酸序列或构建体编码的蛋白质。
载体可以是例如质粒或病毒载体，如逆转录病毒载体或慢病毒载体，或基于转座子的载体或合成的mRNA。
载体可以能够转染或转导T细胞。
细胞
本发明还涉及免疫细胞，所述细胞包含本发明的融合蛋白、截短的蛋白质、核酸和/或核酸构建体。
细胞可以是细胞溶解免疫细胞。
细胞溶解免疫细胞可以是T细胞或T淋巴细胞，其是在细胞介导的免疫中起中心作用的淋巴细胞类型。通过细胞表面上的T细胞受体(TCR)的存在，可以将它们与其它淋巴细胞，如B细胞和天然杀伤细胞(NK细胞)区分。存在多种类型的T细胞，如下文总结的。
辅助T辅助细胞(TH细胞)在免疫过程中协助其它白细胞，包括B细胞成熟成为浆细胞和记忆B细胞，和细胞毒性T细胞和巨噬细胞的激活。TH细胞在它们的表面上表达CD4。当抗原提呈细胞(APC)表面上的MHC II类分子将肽抗原呈递至TH细胞时，它们变得激活。可以将这些细胞分化成几个亚型的一种，包括TH1、TH2、TH3、TH17、Th9，或TFH，其分泌不同的细胞因子以促进不同类型的免疫应答。
细胞溶解T细胞(TC细胞，或CTL)破坏病毒感染的细胞和肿瘤细胞，并也牵连在移植排斥中。CTL在它们表面上表达CD8。这些细胞通过结合与MHC I类联合的抗原识别它们的靶标，所述MHC I类存在于所有有核细胞的表面上。通过由调节T细胞分泌的IL-10、腺苷和其它分子，CD8+细胞可以失活为无变应性状态，其防止自身免疫性疾病，如实验性自身免疫性脑脊髓炎。
记忆T细胞是抗原特异性T细胞的子集，其在感染已经解决之后长期持续。它们在再次暴露于其同源(cognate)抗原后迅速扩增为大量效应T细胞，从而为免疫系统提供了针对过去感染的“记忆”。记忆T细胞包括三种亚型：中央记忆T细胞(TCM细胞)和两种类型的效应记忆T细胞(TEM细胞和TEMRA细胞)。记忆细胞可以是CD4+或CD8+。记忆T细胞通常表达细胞表面蛋白CD45RO。
调节T细胞(Treg细胞)，以前称为抑制T细胞，对于免疫耐受的维持是重要的。它们主要的作用是关闭T细胞介导的免疫朝向免疫反应的结束和抑制逃脱胸腺中的阴性选择过程的自身反应T细胞。
已经描述了两类主要的CD4+ Treg细胞--天然存在的Treg细胞和适应性Treg细胞。
天然存在的Treg细胞(也称为CD4+CD25+FoxP3+ Treg细胞)在胸腺中产生，并已经与形成中的T细胞和已经使用TSLP激活的髓样(CD11c+)以及浆细胞样(CD123+)树突细胞两者之间的相互作用相连。可以通过称为FoxP3的细胞内分子的存在，将天然发生的Treg细胞与其它T细胞区分。FOXP3基因的突变可以阻止调节性T细胞的发育，导致致命的自身免疫病IPEX.
适应性Treg细胞(也称为Tr1细胞或Th3细胞)可以在正常免疫应答期间起源。
自然杀伤细胞(或NK细胞)是一种构成先天免疫系统的一部分的细胞溶解细胞。NK细胞以不依赖MHC的方式提供对来自病毒感染细胞的固有信号的快速应答。
NK细胞(属于固有淋巴样细胞组)定义为大颗粒淋巴细胞(LGL)并构成第三种细胞，其与产生B和T淋巴细胞的共同淋巴样前体细胞区分。已知NK细胞在骨髓、淋巴结、脾、扁桃体和胸腺中分化并成熟，然后它们在那里进入循环。
本发明的细胞可以是上述任意细胞类型。
可以离体从患者自身的外周血(第一方)，或在来自供体外周血的造血干细胞移植物的背景(第二方)中，或来自无关联供体的外周血(第三方)创建表达本发明的分子的T或NK细胞。
或者，表达本发明的分子的T或NK细胞可以来源于可诱导祖细胞或胚胎祖细胞离体分化为T或NK细胞。或者，可以使用保留了其溶解功能并可以起治疗剂作用的永生化的T细胞系。
在所有这些实施方案中，通过许多方法的一种导入编码CAR的DNA或RNA生成CAR细胞，所述方法包括使用病毒载体转导，使用DNA或RNA转染。
本发明的细胞可以是来自受试者的离体T或NK细胞。T或NK细胞可以来自外周血单核细胞(PBMC)样品。在使用本发明的核酸转导之前，可以激活和/或扩增T或NK细胞，例如通过使用抗CD3单克隆抗体处理。
本发明的T或NK细胞可以通过以下制成：
(i)从受试者或以上列出的其它来源分离含有T或NK细胞的样品；和
(ii)使用根据本发明的一种或多种核酸序列转导或转染T或NK细胞。
接着，可以纯化T细胞或NK细胞，例如基于抗原结合多肽的抗原结合域的表达选择。
本发明还提供了包含本发明的融合蛋白或截短的蛋白和嵌合抗原受体(CAR)的细胞。
嵌合抗原受体(CAR)可以是包含含有ITAM的胞内域(例如CD3 zeta)的激活性CAR。CAR可以是包含“连接关闭(ligation-off)”胞内域的抑制性CAR，如WO2015/075469中所述，所述抑制性CAR可以包含来自受体样酪氨酸磷酸酶(如CD148或CD45)的全部或部分胞内域。CAR可以是包含“连接开启(ligation-on)”胞内域的抑制性CAR，如WO2015/075470中所述，所述抑制性CAR可以包含ITIM结构域。
本发明的融合蛋白和截短的蛋白可以与表达两种或更多种CAR的“逻辑门”组合的细胞一起使用。或(OR)门包含两种激活性CAR，如WO2015/075468中所述。和(AND)门包含激活性CAR和“连接关闭(ligation-off)”抑制性CAR,如WO2015/075469中所述。And not包含激活性CAR和“连接开启”抑制性CAR，如WO2015/075470中所述。
因此，本发明提供了细胞，其包含：
(i)编码本发明的截短蛋的白或融合蛋白的核酸序列；
(ii)第一嵌合抗原受体(CAR)；和
(iii)第二嵌合抗原受体。
参照本发明的转录信号方面，这里提供了细胞，其包含(i)包含SH2结构域和蛋白酶的融合蛋白；和(ii)膜栓系转录因子，其包含：膜栓系物；蛋白酶识别位点；和转录因子。
参照本发明的去势信号方面，这里提供了细胞，其包含(i)包含SH2结构域和蛋白酶的融合蛋白；和(ii)包含蛋白酶切割位点的受体。
受体可以例如是T细胞受体(TCR)或嵌合抗原受体(CAR)，其包含(i)在跨膜域和激活性胞内域之间的蛋白酶切割位点；或(ii)经由蛋白酶切割位点融合到抑制性胞内域的激活性胞内域。
组合物
本发明还涉及含有多个本发明的细胞的药物组合物。药物组合物可另外包含药学上可接受的载体，稀释剂或赋形剂。药物组合物可任选包含一种或多种其它药物活性多肽和/或化合物。此类制剂可以例如是适合于静脉内输注的形式。
治疗方法
本发明的细胞可以能够杀死靶细胞，例如癌细胞。
本发明的细胞可用于感染(如病毒感染)的治疗。
本发明的细胞也可以用于控制病原性免疫应答，例如，自身免疫性疾病，变态反应和移植物抗宿主排斥。
本发明的细胞可以用于治疗癌性疾病，如膀胱癌，乳腺癌，结肠癌，子宫内膜癌，肾癌(肾细胞)，白血病，肺癌，黑素瘤，非霍奇金淋巴瘤，胰腺癌，前列腺癌和甲状腺癌。
本发明的细胞可用于治疗：口腔和咽的癌症，包括舌癌、口腔癌和咽癌；消化系统的癌症，其包括食管癌，胃癌和结肠直肠癌；肝脏和胆道系统的癌症，其包括肝细胞癌和胆管癌；呼吸系统的癌症，其包括支气管癌和咽癌；骨和关节的癌症，其包括骨肉瘤；皮肤癌，其包括黑素瘤；乳腺癌；生殖道的癌症，其包括在女性中的子宫癌，卵巢癌和宫颈癌，以及在男性中的前列腺癌和睾丸癌；肾道的癌症，其包括肾细胞癌，尿道或膀胱的移行细胞癌；脑癌，其包括胶质瘤，多形性胶质母细胞瘤和髓母细胞瘤(medullobastomas)；内分泌系统的癌症，包括甲状腺癌，肾上腺癌和与多发性内分泌腺新生物综合征相关的癌症；淋巴瘤，其包括霍奇金淋巴瘤和非霍奇金淋巴瘤；多发性骨髓瘤和浆细胞瘤；急性和慢性白血病，髓样或淋巴性白血病；以及其他的未指明位点的癌症，包括神经母细胞瘤。
用本发明的细胞进行的治疗可以帮助防止在标准方法中经常发生的肿瘤细胞的逃逸或释放。
现在将通过实施例进一步描述本发明，所述实施例意在用于协助本领域普通技术人员中实施本发明，并且不是意在以任何方式限制本发明的范围。
实施例
实施例1：将T细胞激活途径征用于(subjugation)增强的或非生理性信号
测试了参与早期T细胞信号激活的一些SH2结构域以确定T细胞激活信号是否可以被征用(subjugate)或“劫持”，使得当T细胞被激活时，可以调制或重新传输信号。
发明人通过将AKT的激酶结构域连接到来自Zap70，Grap，Grb2和PLCγ的SH2结构域而产生了数种嵌合AKT构建体(图8)。
在未转导的(NT)T细胞中，在用OKT3处理以诱导TCR的交联和活化后，可检测到非常低水平的内源性AKT的磷酸化水平(图10b：上图)。然而，在表达Zap-AKT构建体的细胞中，观察到显著水平的磷酸化-AKT(图10B：下图)。
活化T细胞的接头(LAT)是ZAP70的下游靶物，并且通过数种含有SH2的蛋白(如Grb2，Grap和PLCγ)结合。预计来自这些LAT结合物中的每个的SH2结构域也将允许劫持来自CD3-zeta的激活信号。但是，事实并非如此。
当AKT激酶结构域连接至来自Grb2，Grap或PLCγ的SH2结构域时，没有观察到比NTT细胞观察到的更高水平的AKT激酶结构域的TCR-依赖性磷酸化(图9a)。
这说明了该T细胞信号传导劫持系统特别需要来自诸如Zap70或酪氨酸蛋白磷酸酶非受体6型(PTPN6)的非常早期的T细胞信号传导分子的串联SH2结构域。
实施例2：转录控制
将TetV蛋白酶融合到Zap70SH2结构域。膜结合的转录因子也如下克隆：与VP16/GAL4转录因子框内克隆RQR8，其通过TeV切割位点分开。该融合蛋白允许在TeV切割时释放VP16/GAL4转录因子(其含有核定位信号)。
这些蛋白质均在还表达CD19特异性嵌合抗原受体的T细胞中表达。为了证明需要ZAP70-TeV方法，该转录因子也与用TeV替换了其胞内域的CD19 CAR共表达(图11)。
将T细胞暴露于CD19阴性和阳性靶物。通过响应于GALv/VP16的萤光素酶基因盒来测量转录激活。只有在标准CD19 CAR与ZAP-TeV和膜栓系转录因子共表达的条件下，才导致CD19识别后的选择性转录激活。直接与TeV融合的CD19 CAR导致组成型转录激活(图12)。
实施例3：使用截短的SHP-1(PTPN6)或截短的SHP-2的PD-1信号阻断
如下表所示转导PBMC细胞：
将细胞与用CD19，PDL1或两者转导的SupT1细胞共培养48小时，并通过ELISA测量IFNγ释放。结果示于图15。
SupT1靶细胞上存在PDL1导致IFNγ释放减少。与仅表达CAR的那些PBMC相比，用表达CAR和截短的SHP-1或截短的SHP-2构建体的PBMC增加了IFNγ的释放。这说明截短的SHp-1和SHP-2构建体成功地抑制了来自靶细胞的PDL1抑制性信号。
实施例4：使用SHP-2 SH2结构域与Zap70激酶的融合物的PD-1信号劫持
如下表所示转导PBMC细胞：
将细胞与用CD19或PDL1转导的SupT1细胞以1:1的比例共培养24小时。通过ELISA测量IFNγ释放(图16A)。与CAR+ PD1转导的T细胞相比，在CAR-SHP2.Zap70+ PD1转导的T细胞与PDL1 SupT1靶细胞的共培养物中观察到IFN-γ生产的增加。
还进行了细胞毒性测定，其中通过FACS来定量SupT1细胞的杀伤(图16B)。在PDL1阳性靶细胞与CAR-SHP2.Zap70+ PD1转导的T细胞的共培养物中观察到对PDL1 SupT1靶物几乎完全杀伤。相反，用CAR+ PD1的单独构建体没有看到杀伤。这说明用Zap70的激酶结构域替换SHP2的磷酸酶结构域成功地将抑制性PD1信号转化为激活性信号。因此，SHP-2-Zap激酶融合蛋白成功地劫持了抑制性PDL1-PD1信号并将其转变为T细胞激活信号。
上述说明书中提及的所有出版物通过引用并入本文。在不脱离本发明的范围和精神的情况下，本发明的所述方法和系统的各种修改和变化对于本领域技术人员将是显而易见的。虽然已经结合具体的优选实施例描述了本发明，但是应当理解，所要求保护的本发明不应被不适当地限于这些具体实施例。实际上，对于分子生物学，细胞生物学或相关领域的技术人员显而易见的用于实施本发明的所述模式的各种修改意图在所附权利要求的范围内。
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<151> 2015-06-01
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Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 14
<211> 754
<212> PRT
<213> 人工序列
<220>
<223> ZAP70-SH2结构域融合到CD3-zeta胞内域
<400> 14
Met Arg Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
1 5 10 15
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
20 25 30
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
35 40 45
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
50 55 60
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
65 70 75 80
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
85 90 95
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
100 105 110
Pro Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Met Pro Asp Pro Ala Ala His Leu Pro
130 135 140
Phe Phe Tyr Gly Ser Ile Ser Arg Ala Glu Ala Glu Glu His Leu Lys
145 150 155 160
Leu Ala Gly Met Ala Asp Gly Leu Phe Leu Leu Arg Gln Cys Leu Arg
165 170 175
Ser Leu Gly Gly Tyr Val Leu Ser Leu Val His Asp Val Arg Phe His
180 185 190
His Phe Pro Ile Glu Arg Gln Leu Asn Gly Thr Tyr Ala Ile Ala Gly
195 200 205
Gly Lys Ala His Cys Gly Pro Ala Glu Leu Cys Glu Phe Tyr Ser Arg
210 215 220
Asp Pro Asp Gly Leu Pro Cys Asn Leu Arg Lys Pro Cys Asn Arg Pro
225 230 235 240
Ser Gly Leu Glu Pro Gln Pro Gly Val Phe Asp Cys Leu Arg Asp Ala
245 250 255
Met Val Arg Asp Tyr Val Arg Gln Thr Trp Lys Leu Glu Gly Glu Ala
260 265 270
Leu Glu Gln Ala Ile Ile Ser Gln Ala Pro Gln Val Glu Lys Leu Ile
275 280 285
Ala Thr Thr Ala His Glu Arg Met Pro Trp Tyr His Ser Ser Leu Thr
290 295 300
Arg Glu Glu Ala Glu Arg Lys Leu Tyr Ser Gly Ala Gln Thr Asp Gly
305 310 315 320
Lys Phe Leu Leu Arg Pro Arg Lys Glu Gln Gly Thr Tyr Ala Leu Ser
325 330 335
Leu Ile Tyr Gly Lys Thr Val Tyr His Tyr Leu Ile Ser Gln Asp Lys
340 345 350
Ala Gly Lys Tyr Cys Ile Pro Glu Gly Thr Lys Phe Asp Thr Leu Trp
355 360 365
Gln Leu Val Glu Tyr Leu Lys Leu Lys Ala Asp Gly Leu Ile Tyr Cys
370 375 380
Leu Lys Glu Ala Cys Pro Asn Ser Ser Ala Ser Asn Ala Ser Gly Ala
385 390 395 400
Ala Ala Pro Thr Leu Pro Ala His Pro Ser Thr Leu Thr His Pro Gln
405 410 415
Arg Arg Ile Asp Thr Leu Asn Ser Asp Gly Tyr Thr Pro Glu Pro Ala
420 425 430
Arg Ile Thr Ser Pro Asp Lys Pro Arg Pro Met Pro Met Asp Thr Ser
435 440 445
Val Tyr Glu Ser Pro Tyr Ser Asp Pro Glu Glu Leu Lys Asp Lys Lys
450 455 460
Leu Phe Leu Lys Arg Asp Asn Leu Leu Ile Ala Asp Ile Glu Leu Gly
465 470 475 480
Cys Gly Asn Phe Gly Ser Val Arg Gln Gly Val Tyr Arg Met Arg Lys
485 490 495
Lys Gln Ile Asp Val Ala Ile Lys Val Leu Lys Gln Gly Thr Glu Lys
500 505 510
Ala Asp Thr Glu Glu Met Met Arg Glu Ala Gln Ile Met His Gln Leu
515 520 525
Asp Asn Pro Tyr Ile Val Arg Leu Ile Gly Val Cys Gln Ala Glu Ala
530 535 540
Leu Met Leu Val Met Glu Met Ala Gly Gly Gly Pro Leu His Lys Phe
545 550 555 560
Leu Val Gly Lys Arg Glu Glu Ile Pro Val Ser Asn Val Ala Glu Leu
565 570 575
Leu His Gln Val Ser Met Gly Met Lys Tyr Leu Glu Glu Lys Asn Phe
580 585 590
Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Leu Val Asn Arg His
595 600 605
Tyr Ala Lys Ile Ser Asp Phe Gly Leu Ser Lys Ala Leu Gly Ala Asp
610 615 620
Asp Ser Tyr Tyr Thr Ala Arg Ser Ala Gly Lys Trp Pro Leu Lys Trp
625 630 635 640
Tyr Ala Pro Glu Cys Ile Asn Phe Arg Lys Phe Ser Ser Arg Ser Asp
645 650 655
Val Trp Ser Tyr Gly Val Thr Met Trp Glu Ala Leu Ser Tyr Gly Gln
660 665 670
Lys Pro Tyr Lys Lys Met Lys Gly Pro Glu Val Met Ala Phe Ile Glu
675 680 685
Gln Gly Lys Arg Met Glu Cys Pro Pro Glu Cys Pro Pro Glu Leu Tyr
690 695 700
Ala Leu Met Ser Asp Cys Trp Ile Tyr Lys Trp Glu Asp Arg Pro Asp
705 710 715 720
Phe Leu Thr Val Glu Gln Arg Met Arg Ala Cys Tyr Tyr Ser Leu Ala
725 730 735
Ser Lys Val Glu Gly Pro Pro Gly Ser Thr Gln Lys Ala Glu Ala Ala
740 745 750
Cys Ala
<210> 15
<211> 97
<212> PRT
<213> 人工序列
<220>
<223> PDCD1 胞内域
<400> 15
Cys Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln
1 5 10 15
Pro Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr
20 25 30
Gly Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val
35 40 45
Pro Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser
50 55 60
Gly Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro
65 70 75 80
Arg Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro
85 90 95
Leu
<210> 16
<211> 141
<212> PRT
<213> 人工序列
<220>
<223> BTLA4 胞内域
<400> 16
Lys Leu Gln Arg Arg Trp Lys Arg Thr Gln Ser Gln Gln Gly Leu Gln
1 5 10 15
Glu Asn Ser Ser Gly Gln Ser Phe Phe Val Arg Asn Lys Lys Val Arg
20 25 30
Arg Ala Pro Leu Ser Glu Gly Pro His Ser Leu Gly Cys Tyr Asn Pro
35 40 45
Met Met Glu Asp Gly Ile Ser Tyr Thr Thr Leu Arg Phe Pro Glu Met
50 55 60
Asn Ile Pro Arg Thr Gly Asp Ala Glu Ser Ser Glu Met Gln Arg Pro
65 70 75 80
Pro Pro Asp Cys Asp Asp Thr Val Thr Tyr Ser Ala Leu His Lys Arg
85 90 95
Gln Val Gly Asp Tyr Glu Asn Val Ile Pro Asp Phe Pro Glu Asp Glu
100 105 110
Gly Ile His Tyr Ser Glu Leu Ile Gln Phe Gly Val Gly Glu Arg Pro
115 120 125
Gln Ala Gln Glu Asn Val Asp Tyr Val Ile Leu Lys His
130 135 140
<210> 17
<211> 168
<212> PRT
<213> 人工序列
<220>
<223> LILRB1 胞内域
<400> 17
Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys
1 5 10 15
Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp
20 25 30
Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu
35 40 45
Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu
50 55 60
Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr
65 70 75 80
Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro
85 90 95
Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu
100 105 110
Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln
115 120 125
Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala
130 135 140
Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser
145 150 155 160
Ile Tyr Ala Thr Leu Ala Ile His
165
<210> 18
<211> 101
<212> PRT
<213> 人工序列
<220>
<223> LAIR1 胞内域
<400> 18
His Arg Gln Asn Gln Ile Lys Gln Gly Pro Pro Arg Ser Lys Asp Glu
1 5 10 15
Glu Gln Lys Pro Gln Gln Arg Pro Asp Leu Ala Val Asp Val Leu Glu
20 25 30
Arg Thr Ala Asp Lys Ala Thr Val Asn Gly Leu Pro Glu Lys Asp Arg
35 40 45
Glu Thr Asp Thr Ser Ala Leu Ala Ala Gly Ser Ser Gln Glu Val Thr
50 55 60
Tyr Ala Gln Leu Asp His Trp Ala Leu Thr Gln Arg Thr Ala Arg Ala
65 70 75 80
Val Ser Pro Gln Ser Thr Lys Pro Met Ala Glu Ser Ile Thr Tyr Ala
85 90 95
Ala Val Ala Arg His
100
<210> 19
<211> 62
<212> PRT
<213> 人工序列
<220>
<223> CTLA4 胞内域
<400> 19
Phe Leu Leu Trp Ile Leu Ala Ala Val Ser Ser Gly Leu Phe Phe Tyr
1 5 10 15
Ser Phe Leu Leu Thr Ala Val Ser Leu Ser Lys Met Leu Lys Lys Arg
20 25 30
Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu Pro
35 40 45
Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn
50 55 60
<210> 20
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> KIR2DL1 胞内域
<400> 20
Gly Asn Ser Arg His Leu His Val Leu Ile Gly Thr Ser Val Val Ile
1 5 10 15
Ile Pro Phe Ala Ile Leu Leu Phe Phe Leu Leu His Arg Trp Cys Ala
20 25 30
Asn Lys Lys Asn Ala Val Val Met Asp Gln Glu Pro Ala Gly Asn Arg
35 40 45
Thr Val Asn Arg Glu Asp Ser Asp Glu Gln Asp Pro Gln Glu Val Thr
50 55 60
Tyr Thr Gln Leu Asn His Cys Val Phe Thr Gln Arg Lys Ile Thr Arg
65 70 75 80
Pro Ser Gln Arg Pro Lys Thr Pro Pro Thr Asp Ile Ile Val Tyr Thr
85 90 95
Glu Leu Pro Asn Ala Glu Ser Arg Ser Lys Val Val Ser Cys Pro
100 105 110
<210> 21
<211> 143
<212> PRT
<213> 人工序列
<220>
<223> KIR2DL4 胞内域
<400> 21
Gly Ile Ala Arg His Leu His Ala Val Ile Arg Tyr Ser Val Ala Ile
1 5 10 15
Ile Leu Phe Thr Ile Leu Pro Phe Phe Leu Leu His Arg Trp Cys Ser
20 25 30
Lys Lys Lys Glu Asn Ala Ala Val Met Asn Gln Glu Pro Ala Gly His
35 40 45
Arg Thr Val Asn Arg Glu Asp Ser Asp Glu Gln Asp Pro Gln Glu Val
50 55 60
Thr Tyr Ala Gln Leu Asp His Cys Ile Phe Thr Gln Arg Lys Ile Thr
65 70 75 80
Gly Pro Ser Gln Arg Ser Lys Arg Pro Ser Thr Asp Thr Ser Val Cys
85 90 95
Ile Glu Leu Pro Asn Ala Glu Pro Arg Ala Leu Ser Pro Ala His Glu
100 105 110
His His Ser Gln Ala Leu Met Gly Ser Ser Arg Glu Thr Thr Ala Leu
115 120 125
Ser Gln Thr Gln Leu Ala Ser Ser Asn Val Pro Ala Ala Gly Ile
130 135 140
<210> 22
<211> 143
<212> PRT
<213> 人工序列
<220>
<223> KIR2DL5 胞内域
<400> 22
Thr Gly Ile Arg Arg His Leu His Ile Leu Ile Gly Thr Ser Val Ala
1 5 10 15
Ile Ile Leu Phe Ile Ile Leu Phe Phe Phe Leu Leu His Cys Cys Cys
20 25 30
Ser Asn Lys Lys Asn Ala Ala Val Met Asp Gln Glu Pro Ala Gly Asp
35 40 45
Arg Thr Val Asn Arg Glu Asp Ser Asp Asp Gln Asp Pro Gln Glu Val
50 55 60
Thr Tyr Ala Gln Leu Asp His Cys Val Phe Thr Gln Thr Lys Ile Thr
65 70 75 80
Ser Pro Ser Gln Arg Pro Lys Thr Pro Pro Thr Asp Thr Thr Met Tyr
85 90 95
Met Glu Leu Pro Asn Ala Lys Pro Arg Ser Leu Ser Pro Ala His Lys
100 105 110
His His Ser Gln Ala Leu Arg Gly Ser Ser Arg Glu Thr Thr Ala Leu
115 120 125
Ser Gln Asn Arg Val Ala Ser Ser His Val Pro Ala Ala Gly Ile
130 135 140
<210> 23
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> KIR3DL1 胞内域
<400> 23
Lys Asp Pro Arg His Leu His Ile Leu Ile Gly Thr Ser Val Val Ile
1 5 10 15
Ile Leu Phe Ile Leu Leu Leu Phe Phe Leu Leu His Leu Trp Cys Ser
20 25 30
Asn Lys Lys Asn Ala Ala Val Met Asp Gln Glu Pro Ala Gly Asn Arg
35 40 45
Thr Ala Asn Ser Glu Asp Ser Asp Glu Gln Asp Pro Glu Glu Val Thr
50 55 60
Tyr Ala Gln Leu Asp His Cys Val Phe Thr Gln Arg Lys Ile Thr Arg
65 70 75 80
Pro Ser Gln Arg Pro Lys Thr Pro Pro Thr Asp Thr Ile Leu Tyr Thr
85 90 95
Glu Leu Pro Asn Ala Lys Pro Arg Ser Lys Val Val Ser Cys Pro
100 105 110
<210> 24
<211> 97
<212> PRT
<213> 人工序列
<220>
<223> KIR3DL3 胞内域
<400> 24
Lys Asp Pro Gly Asn Ser Arg His Leu His Val Leu Ile Gly Thr Ser
1 5 10 15
Val Val Ile Ile Pro Phe Ala Ile Leu Leu Phe Phe Leu Leu His Arg
20 25 30
Trp Cys Ala Asn Lys Lys Asn Ala Val Val Met Asp Gln Glu Pro Ala
35 40 45
Gly Asn Arg Thr Val Asn Arg Glu Asp Ser Asp Glu Gln Asp Pro Gln
50 55 60
Glu Val Thr Tyr Ala Gln Leu Asn His Cys Val Phe Thr Gln Arg Lys
65 70 75 80
Ile Thr Arg Pro Ser Gln Arg Pro Lys Thr Pro Pro Thr Asp Thr Ser
85 90 95
Val
<210> 25
<211> 701
<212> PRT
<213> 人工序列
<220>
<223> PTPN6-SH2结构域融合到PD1 胞内域
<400> 25
Met Thr Gly Gln Pro Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe
1 5 10 15
Ser Val Asp Tyr Gly Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro
20 25 30
Glu Pro Pro Val Pro Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile
35 40 45
Val Phe Pro Ser Gly Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser
50 55 60
Ala Asp Gly Pro Arg Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His
65 70 75 80
Cys Ser Trp Pro Leu Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
85 90 95
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Val Arg Trp Phe His
100 105 110
Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr Leu Leu Lys Gly Arg Gly
115 120 125
Val His Gly Ser Phe Leu Ala Arg Pro Ser Arg Lys Asn Gln Gly Asp
130 135 140
Phe Ser Leu Ser Val Arg Val Gly Asp Gln Val Thr His Ile Arg Ile
145 150 155 160
Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr Gly Gly Glu Lys Phe Ala
165 170 175
Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr Gln Gln Gln Gly Val Leu
180 185 190
Gln Asp Arg Asp Gly Thr Ile Ile His Leu Lys Tyr Pro Leu Asn Cys
195 200 205
Ser Asp Pro Thr Ser Glu Arg Trp Tyr His Gly His Met Ser Gly Gly
210 215 220
Gln Ala Glu Thr Leu Leu Gln Ala Lys Gly Glu Pro Trp Thr Phe Leu
225 230 235 240
Val Arg Glu Ser Leu Ser Gln Pro Gly Asp Phe Val Leu Ser Val Leu
245 250 255
Ser Asp Gln Pro Lys Ala Gly Pro Gly Ser Pro Leu Arg Val Thr His
260 265 270
Ile Lys Val Met Cys Glu Gly Gly Arg Tyr Thr Val Gly Gly Leu Glu
275 280 285
Thr Phe Asp Ser Leu Thr Asp Leu Val Glu His Phe Lys Lys Thr Gly
290 295 300
Ile Glu Glu Ala Ser Gly Ala Phe Val Tyr Leu Arg Gln Pro Tyr Tyr
305 310 315 320
Ala Thr Arg Val Asn Ala Ala Asp Ile Glu Asn Arg Val Leu Glu Leu
325 330 335
Asn Lys Lys Gln Glu Ser Glu Asp Thr Ala Lys Ala Gly Phe Trp Glu
340 345 350
Glu Phe Glu Ser Leu Gln Lys Gln Glu Val Lys Asn Leu His Gln Arg
355 360 365
Leu Glu Gly Gln Arg Pro Glu Asn Lys Gly Lys Asn Arg Tyr Lys Asn
370 375 380
Ile Leu Pro Phe Asp His Ser Arg Val Ile Leu Gln Gly Arg Asp Ser
385 390 395 400
Asn Ile Pro Gly Ser Asp Tyr Ile Asn Ala Asn Tyr Ile Lys Asn Gln
405 410 415
Leu Leu Gly Pro Asp Glu Asn Ala Lys Thr Tyr Ile Ala Ser Gln Gly
420 425 430
Cys Leu Glu Ala Thr Val Asn Asp Phe Trp Gln Met Ala Trp Gln Glu
435 440 445
Asn Ser Arg Val Ile Val Met Thr Thr Arg Glu Val Glu Lys Gly Arg
450 455 460
Asn Lys Cys Val Pro Tyr Trp Pro Glu Val Gly Met Gln Arg Ala Tyr
465 470 475 480
Gly Pro Tyr Ser Val Thr Asn Cys Gly Glu His Asp Thr Thr Glu Tyr
485 490 495
Lys Leu Arg Thr Leu Gln Val Ser Pro Leu Asp Asn Gly Asp Leu Ile
500 505 510
Arg Glu Ile Trp His Tyr Gln Tyr Leu Ser Trp Pro Asp His Gly Val
515 520 525
Pro Ser Glu Pro Gly Gly Val Leu Ser Phe Leu Asp Gln Ile Asn Gln
530 535 540
Arg Gln Glu Ser Leu Pro His Ala Gly Pro Ile Ile Val His Cys Ser
545 550 555 560
Ala Gly Ile Gly Arg Thr Gly Thr Ile Ile Val Ile Asp Met Leu Met
565 570 575
Glu Asn Ile Ser Thr Lys Gly Leu Asp Cys Asp Ile Asp Ile Gln Lys
580 585 590
Thr Ile Gln Met Val Arg Ala Gln Arg Ser Gly Met Val Gln Thr Glu
595 600 605
Ala Gln Tyr Lys Phe Ile Tyr Val Ala Ile Ala Gln Phe Ile Glu Thr
610 615 620
Thr Lys Lys Lys Leu Glu Val Leu Gln Ser Gln Lys Gly Gln Glu Ser
625 630 635 640
Glu Tyr Gly Asn Ile Thr Tyr Pro Pro Ala Met Lys Asn Ala His Ala
645 650 655
Lys Ala Ser Arg Thr Ser Ser Lys His Lys Glu Asp Val Tyr Glu Asn
660 665 670
Leu His Thr Lys Asn Lys Arg Glu Glu Lys Val Lys Lys Gln Arg Ser
675 680 685
Ala Asp Lys Glu Lys Ser Lys Gly Ser Leu Lys Arg Lys
690 695 700
<210> 26
<211> 299
<212> PRT
<213> 人工序列
<220>
<223> ZAP70激酶结构域
<400> 26
Asp Pro Glu Glu Leu Lys Asp Lys Lys Leu Phe Leu Lys Arg Asp Asn
1 5 10 15
Leu Leu Ile Ala Asp Ile Glu Leu Gly Cys Gly Asn Phe Gly Ser Val
20 25 30
Arg Gln Gly Val Tyr Arg Met Arg Lys Lys Gln Ile Asp Val Ala Ile
35 40 45
Lys Val Leu Lys Gln Gly Thr Glu Lys Ala Asp Thr Glu Glu Met Met
50 55 60
Arg Glu Ala Gln Ile Met His Gln Leu Asp Asn Pro Tyr Ile Val Arg
65 70 75 80
Leu Ile Gly Val Cys Gln Ala Glu Ala Leu Met Leu Val Met Glu Met
85 90 95
Ala Gly Gly Gly Pro Leu His Lys Phe Leu Val Gly Lys Arg Glu Glu
100 105 110
Ile Pro Val Ser Asn Val Ala Glu Leu Leu His Gln Val Ser Met Gly
115 120 125
Met Lys Tyr Leu Glu Glu Lys Asn Phe Val His Arg Asp Leu Ala Ala
130 135 140
Arg Asn Val Leu Leu Val Asn Arg His Tyr Ala Lys Ile Ser Asp Phe
145 150 155 160
Gly Leu Ser Lys Ala Leu Gly Ala Asp Asp Ser Tyr Tyr Thr Ala Arg
165 170 175
Ser Ala Gly Lys Trp Pro Leu Lys Trp Tyr Ala Pro Glu Cys Ile Asn
180 185 190
Phe Arg Lys Phe Ser Ser Arg Ser Asp Val Trp Ser Tyr Gly Val Thr
195 200 205
Met Trp Glu Ala Leu Ser Tyr Gly Gln Lys Pro Tyr Lys Lys Met Lys
210 215 220
Gly Pro Glu Val Met Ala Phe Ile Glu Gln Gly Lys Arg Met Glu Cys
225 230 235 240
Pro Pro Glu Cys Pro Pro Glu Leu Tyr Ala Leu Met Ser Asp Cys Trp
245 250 255
Ile Tyr Lys Trp Glu Asp Arg Pro Asp Phe Leu Thr Val Glu Gln Arg
260 265 270
Met Arg Ala Cys Tyr Tyr Ser Leu Ala Ser Lys Val Glu Gly Pro Pro
275 280 285
Gly Ser Thr Gln Lys Ala Glu Ala Ala Cys Ala
290 295
<210> 27
<211> 280
<212> PRT
<213> 人工序列
<220>
<223> PTPN6磷酸酶结构域
<400> 27
Phe Trp Glu Glu Phe Glu Ser Leu Gln Lys Gln Glu Val Lys Asn Leu
1 5 10 15
His Gln Arg Leu Glu Gly Gln Arg Pro Glu Asn Lys Gly Lys Asn Arg
20 25 30
Tyr Lys Asn Ile Leu Pro Phe Asp His Ser Arg Val Ile Leu Gln Gly
35 40 45
Arg Asp Ser Asn Ile Pro Gly Ser Asp Tyr Ile Asn Ala Asn Tyr Ile
50 55 60
Lys Asn Gln Leu Leu Gly Pro Asp Glu Asn Ala Lys Thr Tyr Ile Ala
65 70 75 80
Ser Gln Gly Cys Leu Glu Ala Thr Val Asn Asp Phe Trp Gln Met Ala
85 90 95
Trp Gln Glu Asn Ser Arg Val Ile Val Met Thr Thr Arg Glu Val Glu
100 105 110
Lys Gly Arg Asn Lys Cys Val Pro Tyr Trp Pro Glu Val Gly Met Gln
115 120 125
Arg Ala Tyr Gly Pro Tyr Ser Val Thr Asn Cys Gly Glu His Asp Thr
130 135 140
Thr Glu Tyr Lys Leu Arg Thr Leu Gln Val Ser Pro Leu Asp Asn Gly
145 150 155 160
Asp Leu Ile Arg Glu Ile Trp His Tyr Gln Tyr Leu Ser Trp Pro Asp
165 170 175
His Gly Val Pro Ser Glu Pro Gly Gly Val Leu Ser Phe Leu Asp Gln
180 185 190
Ile Asn Gln Arg Gln Glu Ser Leu Pro His Ala Gly Pro Ile Ile Val
195 200 205
His Cys Ser Ala Gly Ile Gly Arg Thr Gly Thr Ile Ile Val Ile Asp
210 215 220
Met Leu Met Glu Asn Ile Ser Thr Lys Gly Leu Asp Cys Asp Ile Asp
225 230 235 240
Ile Gln Lys Thr Ile Gln Met Val Arg Ala Gln Arg Ser Gly Met Val
245 250 255
Gln Thr Glu Ala Gln Tyr Lys Phe Ile Tyr Val Ala Ile Ala Gln Phe
260 265 270
Ile Glu Thr Thr Lys Lys Lys Leu
275 280
<210> 28
<211> 274
<212> PRT
<213> 人工序列
<220>
<223> SHP-2 磷酸酶结构域
<400> 28
Trp Glu Glu Phe Glu Thr Leu Gln Gln Gln Glu Cys Lys Leu Leu Tyr
1 5 10 15
Ser Arg Lys Glu Gly Gln Arg Gln Glu Asn Lys Asn Lys Asn Arg Tyr
20 25 30
Lys Asn Ile Leu Pro Phe Asp His Thr Arg Val Val Leu His Asp Gly
35 40 45
Asp Pro Asn Glu Pro Val Ser Asp Tyr Ile Asn Ala Asn Ile Ile Met
50 55 60
Pro Glu Phe Glu Thr Lys Cys Asn Asn Ser Lys Pro Lys Lys Ser Tyr
65 70 75 80
Ile Ala Thr Gln Gly Cys Leu Gln Asn Thr Val Asn Asp Phe Trp Arg
85 90 95
Met Val Phe Gln Glu Asn Ser Arg Val Ile Val Met Thr Thr Lys Glu
100 105 110
Val Glu Arg Gly Lys Ser Lys Cys Val Lys Tyr Trp Pro Asp Glu Tyr
115 120 125
Ala Leu Lys Glu Tyr Gly Val Met Arg Val Arg Asn Val Lys Glu Ser
130 135 140
Ala Ala His Asp Tyr Thr Leu Arg Glu Leu Lys Leu Ser Lys Val Gly
145 150 155 160
Gln Ala Leu Leu Gln Gly Asn Thr Glu Arg Thr Val Trp Gln Tyr His
165 170 175
Phe Arg Thr Trp Pro Asp His Gly Val Pro Ser Asp Pro Gly Gly Val
180 185 190
Leu Asp Phe Leu Glu Glu Val His His Lys Gln Glu Ser Ile Met Asp
195 200 205
Ala Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly Arg Thr Gly
210 215 220
Thr Phe Ile Val Ile Asp Ile Leu Ile Asp Ile Ile Arg Glu Lys Gly
225 230 235 240
Val Asp Cys Asp Ile Asp Val Pro Lys Thr Ile Gln Met Val Arg Ser
245 250 255
Gln Arg Ser Gly Met Val Gln Thr Glu Ala Gln Tyr Arg Phe Ile Tyr
260 265 270
Met Ala
<210> 29
<211> 519
<212> PRT
<213> 人工序列
<220>
<223> PTPN6 SH2结构域融合物: ZAP70激酶结构域
<400> 29
Met Val Arg Trp Phe His Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr
1 5 10 15
Leu Leu Lys Gly Arg Gly Val His Gly Ser Phe Leu Ala Arg Pro Ser
20 25 30
Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Val Arg Val Gly Asp Gln
35 40 45
Val Thr His Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr
50 55 60
Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr
65 70 75 80
Gln Gln Gln Gly Val Leu Gln Asp Arg Asp Gly Thr Ile Ile His Leu
85 90 95
Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Ser Glu Arg Trp Tyr His
100 105 110
Gly His Met Ser Gly Gly Gln Ala Glu Thr Leu Leu Gln Ala Lys Gly
115 120 125
Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln Pro Gly Asp
130 135 140
Phe Val Leu Ser Val Leu Ser Asp Gln Pro Lys Ala Gly Pro Gly Ser
145 150 155 160
Pro Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly Gly Arg Tyr
165 170 175
Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Leu Thr Asp Leu Val Glu
180 185 190
His Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala Phe Val Tyr
195 200 205
Leu Arg Gln Pro Tyr Tyr Ser Gly Gly Gly Gly Ser Asp Pro Glu Glu
210 215 220
Leu Lys Asp Lys Lys Leu Phe Leu Lys Arg Asp Asn Leu Leu Ile Ala
225 230 235 240
Asp Ile Glu Leu Gly Cys Gly Asn Phe Gly Ser Val Arg Gln Gly Val
245 250 255
Tyr Arg Met Arg Lys Lys Gln Ile Asp Val Ala Ile Lys Val Leu Lys
260 265 270
Gln Gly Thr Glu Lys Ala Asp Thr Glu Glu Met Met Arg Glu Ala Gln
275 280 285
Ile Met His Gln Leu Asp Asn Pro Tyr Ile Val Arg Leu Ile Gly Val
290 295 300
Cys Gln Ala Glu Ala Leu Met Leu Val Met Glu Met Ala Gly Gly Gly
305 310 315 320
Pro Leu His Lys Phe Leu Val Gly Lys Arg Glu Glu Ile Pro Val Ser
325 330 335
Asn Val Ala Glu Leu Leu His Gln Val Ser Met Gly Met Lys Tyr Leu
340 345 350
Glu Glu Lys Asn Phe Val His Arg Asp Leu Ala Ala Arg Asn Val Leu
355 360 365
Leu Val Asn Arg His Tyr Ala Lys Ile Ser Asp Phe Gly Leu Ser Lys
370 375 380
Ala Leu Gly Ala Asp Asp Ser Tyr Tyr Thr Ala Arg Ser Ala Gly Lys
385 390 395 400
Trp Pro Leu Lys Trp Tyr Ala Pro Glu Cys Ile Asn Phe Arg Lys Phe
405 410 415
Ser Ser Arg Ser Asp Val Trp Ser Tyr Gly Val Thr Met Trp Glu Ala
420 425 430
Leu Ser Tyr Gly Gln Lys Pro Tyr Lys Lys Met Lys Gly Pro Glu Val
435 440 445
Met Ala Phe Ile Glu Gln Gly Lys Arg Met Glu Cys Pro Pro Glu Cys
450 455 460
Pro Pro Glu Leu Tyr Ala Leu Met Ser Asp Cys Trp Ile Tyr Lys Trp
465 470 475 480
Glu Asp Arg Pro Asp Phe Leu Thr Val Glu Gln Arg Met Arg Ala Cys
485 490 495
Tyr Tyr Ser Leu Ala Ser Lys Val Glu Gly Pro Pro Gly Ser Thr Gln
500 505 510
Lys Ala Glu Ala Ala Cys Ala
515
<210> 30
<211> 581
<212> PRT
<213> 人工序列
<220>
<223> ZAP70 SH2结构域融合物: PTPN6 磷酸酶结构域
<400> 30
Met Pro Asp Pro Ala Ala His Leu Pro Phe Phe Tyr Gly Ser Ile Ser
1 5 10 15
Arg Ala Glu Ala Glu Glu His Leu Lys Leu Ala Gly Met Ala Asp Gly
20 25 30
Leu Phe Leu Leu Arg Gln Cys Leu Arg Ser Leu Gly Gly Tyr Val Leu
35 40 45
Ser Leu Val His Asp Val Arg Phe His His Phe Pro Ile Glu Arg Gln
50 55 60
Leu Asn Gly Thr Tyr Ala Ile Ala Gly Gly Lys Ala His Cys Gly Pro
65 70 75 80
Ala Glu Leu Cys Glu Phe Tyr Ser Arg Asp Pro Asp Gly Leu Pro Cys
85 90 95
Asn Leu Arg Lys Pro Cys Asn Arg Pro Ser Gly Leu Glu Pro Gln Pro
100 105 110
Gly Val Phe Asp Cys Leu Arg Asp Ala Met Val Arg Asp Tyr Val Arg
115 120 125
Gln Thr Trp Lys Leu Glu Gly Glu Ala Leu Glu Gln Ala Ile Ile Ser
130 135 140
Gln Ala Pro Gln Val Glu Lys Leu Ile Ala Thr Thr Ala His Glu Arg
145 150 155 160
Met Pro Trp Tyr His Ser Ser Leu Thr Arg Glu Glu Ala Glu Arg Lys
165 170 175
Leu Tyr Ser Gly Ala Gln Thr Asp Gly Lys Phe Leu Leu Arg Pro Arg
180 185 190
Lys Glu Gln Gly Thr Tyr Ala Leu Ser Leu Ile Tyr Gly Lys Thr Val
195 200 205
Tyr His Tyr Leu Ile Ser Gln Asp Lys Ala Gly Lys Tyr Cys Ile Pro
210 215 220
Glu Gly Thr Lys Phe Asp Thr Leu Trp Gln Leu Val Glu Tyr Leu Lys
225 230 235 240
Leu Lys Ala Asp Gly Leu Ile Tyr Cys Leu Lys Glu Ala Cys Pro Asn
245 250 255
Ser Ser Ala Ser Asn Ala Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala
260 265 270
His Pro Ser Thr Leu Thr His Pro Ser Gly Gly Gly Gly Ser Gly Gly
275 280 285
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Phe Trp Glu
290 295 300
Glu Phe Glu Ser Leu Gln Lys Gln Glu Val Lys Asn Leu His Gln Arg
305 310 315 320
Leu Glu Gly Gln Arg Pro Glu Asn Lys Gly Lys Asn Arg Tyr Lys Asn
325 330 335
Ile Leu Pro Phe Asp His Ser Arg Val Ile Leu Gln Gly Arg Asp Ser
340 345 350
Asn Ile Pro Gly Ser Asp Tyr Ile Asn Ala Asn Tyr Ile Lys Asn Gln
355 360 365
Leu Leu Gly Pro Asp Glu Asn Ala Lys Thr Tyr Ile Ala Ser Gln Gly
370 375 380
Cys Leu Glu Ala Thr Val Asn Asp Phe Trp Gln Met Ala Trp Gln Glu
385 390 395 400
Asn Ser Arg Val Ile Val Met Thr Thr Arg Glu Val Glu Lys Gly Arg
405 410 415
Asn Lys Cys Val Pro Tyr Trp Pro Glu Val Gly Met Gln Arg Ala Tyr
420 425 430
Gly Pro Tyr Ser Val Thr Asn Cys Gly Glu His Asp Thr Thr Glu Tyr
435 440 445
Lys Leu Arg Thr Leu Gln Val Ser Pro Leu Asp Asn Gly Asp Leu Ile
450 455 460
Arg Glu Ile Trp His Tyr Gln Tyr Leu Ser Trp Pro Asp His Gly Val
465 470 475 480
Pro Ser Glu Pro Gly Gly Val Leu Ser Phe Leu Asp Gln Ile Asn Gln
485 490 495
Arg Gln Glu Ser Leu Pro His Ala Gly Pro Ile Ile Val His Cys Ser
500 505 510
Ala Gly Ile Gly Arg Thr Gly Thr Ile Ile Val Ile Asp Met Leu Met
515 520 525
Glu Asn Ile Ser Thr Lys Gly Leu Asp Cys Asp Ile Asp Ile Gln Lys
530 535 540
Thr Ile Gln Met Val Arg Ala Gln Arg Ser Gly Met Val Gln Thr Glu
545 550 555 560
Ala Gln Tyr Lys Phe Ile Tyr Val Ala Ile Ala Gln Phe Ile Glu Thr
565 570 575
Thr Lys Lys Lys Leu
580
<210> 31
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> CD28 胞内域
<400> 31
Met Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met
1 5 10 15
Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala
20 25 30
Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 32
<211> 43
<212> PRT
<213> 人工序列
<220>
<223> 41BB 胞内域
<400> 32
Met Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
1 5 10 15
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
20 25 30
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 33
<211> 37
<212> PRT
<213> 人工序列
<220>
<223> OX40 胞内域
<400> 33
Met Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
1 5 10 15
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
20 25 30
Thr Leu Ala Lys Ile
35
<210> 34
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> ICOS 胞内域
<400> 34
Cys Trp Leu Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro Asn
1 5 10 15
Gly Glu Tyr Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser Arg
20 25 30
Leu Thr Asp Val Thr Leu
35
<210> 35
<211> 48
<212> PRT
<213> 人工序列
<220>
<223> CD27 胞内域
<400> 35
Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser Pro Val Glu Pro
1 5 10 15
Ala Glu Pro Cys His Tyr Ser Cys Pro Arg Glu Glu Glu Gly Ser Thr
20 25 30
Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro Ala Cys Ser Pro
35 40 45
<210> 36
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> BTLA 胞内域
<400> 36
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> 37
<211> 188
<212> PRT
<213> 人工序列
<220>
<223> CD30 胞内域
<400> 37
His Arg Arg Ala Cys Arg Lys Arg Ile Arg Gln Lys Leu His Leu Cys
1 5 10 15
Tyr Pro Val Gln Thr Ser Gln Pro Lys Leu Glu Leu Val Asp Ser Arg
20 25 30
Pro Arg Arg Ser Ser Thr Gln Leu Arg Ser Gly Ala Ser Val Thr Glu
35 40 45
Pro Val Ala Glu Glu Arg Gly Leu Met Ser Gln Pro Leu Met Glu Thr
50 55 60
Cys His Ser Val Gly Ala Ala Tyr Leu Glu Ser Leu Pro Leu Gln Asp
65 70 75 80
Ala Ser Pro Ala Gly Gly Pro Ser Ser Pro Arg Asp Leu Pro Glu Pro
85 90 95
Arg Val Ser Thr Glu His Thr Asn Asn Lys Ile Glu Lys Ile Tyr Ile
100 105 110
Met Lys Ala Asp Thr Val Ile Val Gly Thr Val Lys Ala Glu Leu Pro
115 120 125
Glu Gly Arg Gly Leu Ala Gly Pro Ala Glu Pro Glu Leu Glu Glu Glu
130 135 140
Leu Glu Ala Asp His Thr Pro His Tyr Pro Glu Gln Glu Thr Glu Pro
145 150 155 160
Pro Leu Gly Ser Cys Ser Asp Val Met Leu Ser Val Glu Glu Glu Gly
165 170 175
Lys Glu Asp Pro Leu Pro Thr Ala Ala Ser Gly Lys
180 185
<210> 38
<211> 58
<212> PRT
<213> 人工序列
<220>
<223> GITR 胞内域
<400> 38
Gln Leu Gly Leu His Ile Trp Gln Leu Arg Ser Gln Cys Met Trp Pro
1 5 10 15
Arg Glu Thr Gln Leu Leu Leu Glu Val Pro Pro Ser Thr Glu Asp Ala
20 25 30
Arg Ser Cys Gln Phe Pro Glu Glu Glu Arg Gly Glu Arg Ser Ala Glu
35 40 45
Glu Lys Gly Arg Leu Gly Asp Leu Trp Val
50 55
<210> 39
<211> 60
<212> PRT
<213> 人工序列
<220>
<223> HVEM 胞内域
<400> 39
Cys Val Lys Arg Arg Lys Pro Arg Gly Asp Val Val Lys Val Ile Val
1 5 10 15
Ser Val Gln Arg Lys Arg Gln Glu Ala Glu Gly Glu Ala Thr Val Ile
20 25 30
Glu Ala Leu Gln Ala Pro Pro Asp Val Thr Thr Val Ala Val Glu Glu
35 40 45
Thr Ile Pro Ser Phe Thr Gly Arg Ser Pro Asn His
50 55 60
<210> 40
<211> 682
<212> PRT
<213> 人工序列
<220>
<223> CD28 胞内域 融合到全长ZAP的氨基末端
<400> 40
Met Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met
1 5 10 15
Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala
20 25 30
Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met
50 55 60
Pro Asp Pro Ala Ala His Leu Pro Phe Phe Tyr Gly Ser Ile Ser Arg
65 70 75 80
Ala Glu Ala Glu Glu His Leu Lys Leu Ala Gly Met Ala Asp Gly Leu
85 90 95
Phe Leu Leu Arg Gln Cys Leu Arg Ser Leu Gly Gly Tyr Val Leu Ser
100 105 110
Leu Val His Asp Val Arg Phe His His Phe Pro Ile Glu Arg Gln Leu
115 120 125
Asn Gly Thr Tyr Ala Ile Ala Gly Gly Lys Ala His Cys Gly Pro Ala
130 135 140
Glu Leu Cys Glu Phe Tyr Ser Arg Asp Pro Asp Gly Leu Pro Cys Asn
145 150 155 160
Leu Arg Lys Pro Cys Asn Arg Pro Ser Gly Leu Glu Pro Gln Pro Gly
165 170 175
Val Phe Asp Cys Leu Arg Asp Ala Met Val Arg Asp Tyr Val Arg Gln
180 185 190
Thr Trp Lys Leu Glu Gly Glu Ala Leu Glu Gln Ala Ile Ile Ser Gln
195 200 205
Ala Pro Gln Val Glu Lys Leu Ile Ala Thr Thr Ala His Glu Arg Met
210 215 220
Pro Trp Tyr His Ser Ser Leu Thr Arg Glu Glu Ala Glu Arg Lys Leu
225 230 235 240
Tyr Ser Gly Ala Gln Thr Asp Gly Lys Phe Leu Leu Arg Pro Arg Lys
245 250 255
Glu Gln Gly Thr Tyr Ala Leu Ser Leu Ile Tyr Gly Lys Thr Val Tyr
260 265 270
His Tyr Leu Ile Ser Gln Asp Lys Ala Gly Lys Tyr Cys Ile Pro Glu
275 280 285
Gly Thr Lys Phe Asp Thr Leu Trp Gln Leu Val Glu Tyr Leu Lys Leu
290 295 300
Lys Ala Asp Gly Leu Ile Tyr Cys Leu Lys Glu Ala Cys Pro Asn Ser
305 310 315 320
Ser Ala Ser Asn Ala Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala His
325 330 335
Pro Ser Thr Leu Thr His Pro Gln Arg Arg Ile Asp Thr Leu Asn Ser
340 345 350
Asp Gly Tyr Thr Pro Glu Pro Ala Arg Ile Thr Ser Pro Asp Lys Pro
355 360 365
Arg Pro Met Pro Met Asp Thr Ser Val Tyr Glu Ser Pro Tyr Ser Asp
370 375 380
Pro Glu Glu Leu Lys Asp Lys Lys Leu Phe Leu Lys Arg Asp Asn Leu
385 390 395 400
Leu Ile Ala Asp Ile Glu Leu Gly Cys Gly Asn Phe Gly Ser Val Arg
405 410 415
Gln Gly Val Tyr Arg Met Arg Lys Lys Gln Ile Asp Val Ala Ile Lys
420 425 430
Val Leu Lys Gln Gly Thr Glu Lys Ala Asp Thr Glu Glu Met Met Arg
435 440 445
Glu Ala Gln Ile Met His Gln Leu Asp Asn Pro Tyr Ile Val Arg Leu
450 455 460
Ile Gly Val Cys Gln Ala Glu Ala Leu Met Leu Val Met Glu Met Ala
465 470 475 480
Gly Gly Gly Pro Leu His Lys Phe Leu Val Gly Lys Arg Glu Glu Ile
485 490 495
Pro Val Ser Asn Val Ala Glu Leu Leu His Gln Val Ser Met Gly Met
500 505 510
Lys Tyr Leu Glu Glu Lys Asn Phe Val His Arg Asp Leu Ala Ala Arg
515 520 525
Asn Val Leu Leu Val Asn Arg His Tyr Ala Lys Ile Ser Asp Phe Gly
530 535 540
Leu Ser Lys Ala Leu Gly Ala Asp Asp Ser Tyr Tyr Thr Ala Arg Ser
545 550 555 560
Ala Gly Lys Trp Pro Leu Lys Trp Tyr Ala Pro Glu Cys Ile Asn Phe
565 570 575
Arg Lys Phe Ser Ser Arg Ser Asp Val Trp Ser Tyr Gly Val Thr Met
580 585 590
Trp Glu Ala Leu Ser Tyr Gly Gln Lys Pro Tyr Lys Lys Met Lys Gly
595 600 605
Pro Glu Val Met Ala Phe Ile Glu Gln Gly Lys Arg Met Glu Cys Pro
610 615 620
Pro Glu Cys Pro Pro Glu Leu Tyr Ala Leu Met Ser Asp Cys Trp Ile
625 630 635 640
Tyr Lys Trp Glu Asp Arg Pro Asp Phe Leu Thr Val Glu Gln Arg Met
645 650 655
Arg Ala Cys Tyr Tyr Ser Leu Ala Ser Lys Val Glu Gly Pro Pro Gly
660 665 670
Ser Thr Gln Lys Ala Glu Ala Ala Cys Ala
675 680
<210> 41
<211> 683
<212> PRT
<213> 人工序列
<220>
<223> 41BB 胞内域融合到全长ZAP的氨基末端
<400> 41
Met Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
1 5 10 15
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
20 25 30
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
50 55 60
Met Pro Asp Pro Ala Ala His Leu Pro Phe Phe Tyr Gly Ser Ile Ser
65 70 75 80
Arg Ala Glu Ala Glu Glu His Leu Lys Leu Ala Gly Met Ala Asp Gly
85 90 95
Leu Phe Leu Leu Arg Gln Cys Leu Arg Ser Leu Gly Gly Tyr Val Leu
100 105 110
Ser Leu Val His Asp Val Arg Phe His His Phe Pro Ile Glu Arg Gln
115 120 125
Leu Asn Gly Thr Tyr Ala Ile Ala Gly Gly Lys Ala His Cys Gly Pro
130 135 140
Ala Glu Leu Cys Glu Phe Tyr Ser Arg Asp Pro Asp Gly Leu Pro Cys
145 150 155 160
Asn Leu Arg Lys Pro Cys Asn Arg Pro Ser Gly Leu Glu Pro Gln Pro
165 170 175
Gly Val Phe Asp Cys Leu Arg Asp Ala Met Val Arg Asp Tyr Val Arg
180 185 190
Gln Thr Trp Lys Leu Glu Gly Glu Ala Leu Glu Gln Ala Ile Ile Ser
195 200 205
Gln Ala Pro Gln Val Glu Lys Leu Ile Ala Thr Thr Ala His Glu Arg
210 215 220
Met Pro Trp Tyr His Ser Ser Leu Thr Arg Glu Glu Ala Glu Arg Lys
225 230 235 240
Leu Tyr Ser Gly Ala Gln Thr Asp Gly Lys Phe Leu Leu Arg Pro Arg
245 250 255
Lys Glu Gln Gly Thr Tyr Ala Leu Ser Leu Ile Tyr Gly Lys Thr Val
260 265 270
Tyr His Tyr Leu Ile Ser Gln Asp Lys Ala Gly Lys Tyr Cys Ile Pro
275 280 285
Glu Gly Thr Lys Phe Asp Thr Leu Trp Gln Leu Val Glu Tyr Leu Lys
290 295 300
Leu Lys Ala Asp Gly Leu Ile Tyr Cys Leu Lys Glu Ala Cys Pro Asn
305 310 315 320
Ser Ser Ala Ser Asn Ala Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala
325 330 335
His Pro Ser Thr Leu Thr His Pro Gln Arg Arg Ile Asp Thr Leu Asn
340 345 350
Ser Asp Gly Tyr Thr Pro Glu Pro Ala Arg Ile Thr Ser Pro Asp Lys
355 360 365
Pro Arg Pro Met Pro Met Asp Thr Ser Val Tyr Glu Ser Pro Tyr Ser
370 375 380
Asp Pro Glu Glu Leu Lys Asp Lys Lys Leu Phe Leu Lys Arg Asp Asn
385 390 395 400
Leu Leu Ile Ala Asp Ile Glu Leu Gly Cys Gly Asn Phe Gly Ser Val
405 410 415
Arg Gln Gly Val Tyr Arg Met Arg Lys Lys Gln Ile Asp Val Ala Ile
420 425 430
Lys Val Leu Lys Gln Gly Thr Glu Lys Ala Asp Thr Glu Glu Met Met
435 440 445
Arg Glu Ala Gln Ile Met His Gln Leu Asp Asn Pro Tyr Ile Val Arg
450 455 460
Leu Ile Gly Val Cys Gln Ala Glu Ala Leu Met Leu Val Met Glu Met
465 470 475 480
Ala Gly Gly Gly Pro Leu His Lys Phe Leu Val Gly Lys Arg Glu Glu
485 490 495
Ile Pro Val Ser Asn Val Ala Glu Leu Leu His Gln Val Ser Met Gly
500 505 510
Met Lys Tyr Leu Glu Glu Lys Asn Phe Val His Arg Asp Leu Ala Ala
515 520 525
Arg Asn Val Leu Leu Val Asn Arg His Tyr Ala Lys Ile Ser Asp Phe
530 535 540
Gly Leu Ser Lys Ala Leu Gly Ala Asp Asp Ser Tyr Tyr Thr Ala Arg
545 550 555 560
Ser Ala Gly Lys Trp Pro Leu Lys Trp Tyr Ala Pro Glu Cys Ile Asn
565 570 575
Phe Arg Lys Phe Ser Ser Arg Ser Asp Val Trp Ser Tyr Gly Val Thr
580 585 590
Met Trp Glu Ala Leu Ser Tyr Gly Gln Lys Pro Tyr Lys Lys Met Lys
595 600 605
Gly Pro Glu Val Met Ala Phe Ile Glu Gln Gly Lys Arg Met Glu Cys
610 615 620
Pro Pro Glu Cys Pro Pro Glu Leu Tyr Ala Leu Met Ser Asp Cys Trp
625 630 635 640
Ile Tyr Lys Trp Glu Asp Arg Pro Asp Phe Leu Thr Val Glu Gln Arg
645 650 655
Met Arg Ala Cys Tyr Tyr Ser Leu Ala Ser Lys Val Glu Gly Pro Pro
660 665 670
Gly Ser Thr Gln Lys Ala Glu Ala Ala Cys Ala
675 680
<210> 42
<211> 677
<212> PRT
<213> 人工序列
<220>
<223> OX40 胞内域融合到全长ZAP的氨基末端
<400> 42
Met Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
1 5 10 15
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
20 25 30
Thr Leu Ala Lys Ile Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Pro Asp Pro Ala Ala
50 55 60
His Leu Pro Phe Phe Tyr Gly Ser Ile Ser Arg Ala Glu Ala Glu Glu
65 70 75 80
His Leu Lys Leu Ala Gly Met Ala Asp Gly Leu Phe Leu Leu Arg Gln
85 90 95
Cys Leu Arg Ser Leu Gly Gly Tyr Val Leu Ser Leu Val His Asp Val
100 105 110
Arg Phe His His Phe Pro Ile Glu Arg Gln Leu Asn Gly Thr Tyr Ala
115 120 125
Ile Ala Gly Gly Lys Ala His Cys Gly Pro Ala Glu Leu Cys Glu Phe
130 135 140
Tyr Ser Arg Asp Pro Asp Gly Leu Pro Cys Asn Leu Arg Lys Pro Cys
145 150 155 160
Asn Arg Pro Ser Gly Leu Glu Pro Gln Pro Gly Val Phe Asp Cys Leu
165 170 175
Arg Asp Ala Met Val Arg Asp Tyr Val Arg Gln Thr Trp Lys Leu Glu
180 185 190
Gly Glu Ala Leu Glu Gln Ala Ile Ile Ser Gln Ala Pro Gln Val Glu
195 200 205
Lys Leu Ile Ala Thr Thr Ala His Glu Arg Met Pro Trp Tyr His Ser
210 215 220
Ser Leu Thr Arg Glu Glu Ala Glu Arg Lys Leu Tyr Ser Gly Ala Gln
225 230 235 240
Thr Asp Gly Lys Phe Leu Leu Arg Pro Arg Lys Glu Gln Gly Thr Tyr
245 250 255
Ala Leu Ser Leu Ile Tyr Gly Lys Thr Val Tyr His Tyr Leu Ile Ser
260 265 270
Gln Asp Lys Ala Gly Lys Tyr Cys Ile Pro Glu Gly Thr Lys Phe Asp
275 280 285
Thr Leu Trp Gln Leu Val Glu Tyr Leu Lys Leu Lys Ala Asp Gly Leu
290 295 300
Ile Tyr Cys Leu Lys Glu Ala Cys Pro Asn Ser Ser Ala Ser Asn Ala
305 310 315 320
Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala His Pro Ser Thr Leu Thr
325 330 335
His Pro Gln Arg Arg Ile Asp Thr Leu Asn Ser Asp Gly Tyr Thr Pro
340 345 350
Glu Pro Ala Arg Ile Thr Ser Pro Asp Lys Pro Arg Pro Met Pro Met
355 360 365
Asp Thr Ser Val Tyr Glu Ser Pro Tyr Ser Asp Pro Glu Glu Leu Lys
370 375 380
Asp Lys Lys Leu Phe Leu Lys Arg Asp Asn Leu Leu Ile Ala Asp Ile
385 390 395 400
Glu Leu Gly Cys Gly Asn Phe Gly Ser Val Arg Gln Gly Val Tyr Arg
405 410 415
Met Arg Lys Lys Gln Ile Asp Val Ala Ile Lys Val Leu Lys Gln Gly
420 425 430
Thr Glu Lys Ala Asp Thr Glu Glu Met Met Arg Glu Ala Gln Ile Met
435 440 445
His Gln Leu Asp Asn Pro Tyr Ile Val Arg Leu Ile Gly Val Cys Gln
450 455 460
Ala Glu Ala Leu Met Leu Val Met Glu Met Ala Gly Gly Gly Pro Leu
465 470 475 480
His Lys Phe Leu Val Gly Lys Arg Glu Glu Ile Pro Val Ser Asn Val
485 490 495
Ala Glu Leu Leu His Gln Val Ser Met Gly Met Lys Tyr Leu Glu Glu
500 505 510
Lys Asn Phe Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Leu Val
515 520 525
Asn Arg His Tyr Ala Lys Ile Ser Asp Phe Gly Leu Ser Lys Ala Leu
530 535 540
Gly Ala Asp Asp Ser Tyr Tyr Thr Ala Arg Ser Ala Gly Lys Trp Pro
545 550 555 560
Leu Lys Trp Tyr Ala Pro Glu Cys Ile Asn Phe Arg Lys Phe Ser Ser
565 570 575
Arg Ser Asp Val Trp Ser Tyr Gly Val Thr Met Trp Glu Ala Leu Ser
580 585 590
Tyr Gly Gln Lys Pro Tyr Lys Lys Met Lys Gly Pro Glu Val Met Ala
595 600 605
Phe Ile Glu Gln Gly Lys Arg Met Glu Cys Pro Pro Glu Cys Pro Pro
610 615 620
Glu Leu Tyr Ala Leu Met Ser Asp Cys Trp Ile Tyr Lys Trp Glu Asp
625 630 635 640
Arg Pro Asp Phe Leu Thr Val Glu Gln Arg Met Arg Ala Cys Tyr Tyr
645 650 655
Ser Leu Ala Ser Lys Val Glu Gly Pro Pro Gly Ser Thr Gln Lys Ala
660 665 670
Glu Ala Ala Cys Ala
675
<210> 43
<211> 276
<212> PRT
<213> 人工序列
<220>
<223> CD28 胞内域融合到PTPN6 SH2结构域的氨基末端
<400> 43
Met Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met
1 5 10 15
Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala
20 25 30
Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met
50 55 60
Val Arg Trp Phe His Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr Leu
65 70 75 80
Leu Lys Gly Arg Gly Val His Gly Ser Phe Leu Ala Arg Pro Ser Arg
85 90 95
Lys Asn Gln Gly Asp Phe Ser Leu Ser Val Arg Val Gly Asp Gln Val
100 105 110
Thr His Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr Gly
115 120 125
Gly Glu Lys Phe Ala Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr Gln
130 135 140
Gln Gln Gly Val Leu Gln Asp Arg Asp Gly Thr Ile Ile His Leu Lys
145 150 155 160
Tyr Pro Leu Asn Cys Ser Asp Pro Thr Ser Glu Arg Trp Tyr His Gly
165 170 175
His Met Ser Gly Gly Gln Ala Glu Thr Leu Leu Gln Ala Lys Gly Glu
180 185 190
Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln Pro Gly Asp Phe
195 200 205
Val Leu Ser Val Leu Ser Asp Gln Pro Lys Ala Gly Pro Gly Ser Pro
210 215 220
Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly Gly Arg Tyr Thr
225 230 235 240
Val Gly Gly Leu Glu Thr Phe Asp Ser Leu Thr Asp Leu Val Glu His
245 250 255
Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala Phe Val Tyr Leu
260 265 270
Arg Gln Pro Tyr
275
<210> 44
<211> 277
<212> PRT
<213> 人工序列
<220>
<223> 41BB 胞内域融合到PTPN6 SH2结构域的氨基末端
<400> 44
Met Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
1 5 10 15
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
20 25 30
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
50 55 60
Met Val Arg Trp Phe His Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr
65 70 75 80
Leu Leu Lys Gly Arg Gly Val His Gly Ser Phe Leu Ala Arg Pro Ser
85 90 95
Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Val Arg Val Gly Asp Gln
100 105 110
Val Thr His Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr
115 120 125
Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr
130 135 140
Gln Gln Gln Gly Val Leu Gln Asp Arg Asp Gly Thr Ile Ile His Leu
145 150 155 160
Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Ser Glu Arg Trp Tyr His
165 170 175
Gly His Met Ser Gly Gly Gln Ala Glu Thr Leu Leu Gln Ala Lys Gly
180 185 190
Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln Pro Gly Asp
195 200 205
Phe Val Leu Ser Val Leu Ser Asp Gln Pro Lys Ala Gly Pro Gly Ser
210 215 220
Pro Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly Gly Arg Tyr
225 230 235 240
Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Leu Thr Asp Leu Val Glu
245 250 255
His Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala Phe Val Tyr
260 265 270
Leu Arg Gln Pro Tyr
275
<210> 45
<211> 271
<212> PRT
<213> 人工序列
<220>
<223> OX40 胞内域 融合到PTPN6 SH2结构域的氨基末端
<400> 45
Met Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
1 5 10 15
Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
20 25 30
Thr Leu Ala Lys Ile Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Val Arg Trp Phe His
50 55 60
Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr Leu Leu Lys Gly Arg Gly
65 70 75 80
Val His Gly Ser Phe Leu Ala Arg Pro Ser Arg Lys Asn Gln Gly Asp
85 90 95
Phe Ser Leu Ser Val Arg Val Gly Asp Gln Val Thr His Ile Arg Ile
100 105 110
Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr Gly Gly Glu Lys Phe Ala
115 120 125
Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr Gln Gln Gln Gly Val Leu
130 135 140
Gln Asp Arg Asp Gly Thr Ile Ile His Leu Lys Tyr Pro Leu Asn Cys
145 150 155 160
Ser Asp Pro Thr Ser Glu Arg Trp Tyr His Gly His Met Ser Gly Gly
165 170 175
Gln Ala Glu Thr Leu Leu Gln Ala Lys Gly Glu Pro Trp Thr Phe Leu
180 185 190
Val Arg Glu Ser Leu Ser Gln Pro Gly Asp Phe Val Leu Ser Val Leu
195 200 205
Ser Asp Gln Pro Lys Ala Gly Pro Gly Ser Pro Leu Arg Val Thr His
210 215 220
Ile Lys Val Met Cys Glu Gly Gly Arg Tyr Thr Val Gly Gly Leu Glu
225 230 235 240
Thr Phe Asp Ser Leu Thr Asp Leu Val Glu His Phe Lys Lys Thr Gly
245 250 255
Ile Glu Glu Ala Ser Gly Ala Phe Val Tyr Leu Arg Gln Pro Tyr
260 265 270
<210> 46
<211> 350
<212> PRT
<213> 人工序列
<220>
<223> Akt 激酶结构域
<400> 46
Ala Glu Glu Met Glu Val Ser Leu Ala Lys Pro Lys His Arg Val Thr
1 5 10 15
Met Asn Glu Phe Glu Tyr Leu Lys Leu Leu Gly Lys Gly Thr Phe Gly
20 25 30
Lys Val Ile Leu Val Lys Glu Lys Ala Thr Gly Arg Tyr Tyr Ala Met
35 40 45
Lys Ile Leu Lys Lys Glu Val Ile Val Ala Lys Asp Glu Val Ala His
50 55 60
Thr Leu Thr Glu Asn Arg Val Leu Gln Asn Ser Arg His Pro Phe Leu
65 70 75 80
Thr Ala Leu Lys Tyr Ser Phe Gln Thr His Asp Arg Leu Cys Phe Val
85 90 95
Met Glu Tyr Ala Asn Gly Gly Glu Leu Phe Phe His Leu Ser Arg Glu
100 105 110
Arg Val Phe Ser Glu Asp Arg Ala Arg Phe Tyr Gly Ala Glu Ile Val
115 120 125
Ser Ala Leu Asp Tyr Leu His Ser Glu Lys Asn Val Val Tyr Arg Asp
130 135 140
Leu Lys Leu Glu Asn Leu Met Leu Asp Lys Asp Gly His Ile Lys Ile
145 150 155 160
Thr Asp Phe Gly Leu Cys Lys Glu Gly Ile Lys Asp Gly Ala Thr Met
165 170 175
Lys Thr Phe Cys Gly Thr Pro Glu Tyr Leu Ala Pro Glu Val Leu Glu
180 185 190
Asp Asn Asp Tyr Gly Arg Ala Val Asp Trp Trp Gly Leu Gly Val Val
195 200 205
Met Tyr Glu Met Met Cys Gly Arg Leu Pro Phe Tyr Asn Gln Asp His
210 215 220
Glu Lys Leu Phe Glu Leu Ile Leu Met Glu Glu Ile Arg Phe Pro Arg
225 230 235 240
Thr Leu Gly Pro Glu Ala Lys Ser Leu Leu Ser Gly Leu Leu Lys Lys
245 250 255
Asp Pro Lys Gln Arg Leu Gly Gly Gly Ser Glu Asp Ala Lys Glu Ile
260 265 270
Met Gln His Arg Phe Phe Ala Gly Ile Val Trp Gln His Val Tyr Glu
275 280 285
Lys Lys Leu Ser Pro Pro Phe Lys Pro Gln Val Thr Ser Glu Thr Asp
290 295 300
Thr Arg Tyr Phe Asp Glu Glu Phe Thr Ala Gln Met Ile Thr Ile Thr
305 310 315 320
Pro Pro Asp Gln Asp Asp Ser Met Glu Cys Val Asp Ser Glu Arg Arg
325 330 335
Pro His Phe Pro Gln Phe Ser Tyr Ser Ala Ser Gly Thr Ala
340 345 350
<210> 47
<211> 630
<212> PRT
<213> 人工序列
<220>
<223> 直接融合到Akt激酶结构域的ZAP70-SH2结构域
<400> 47
Met Pro Asp Pro Ala Ala His Leu Pro Phe Phe Tyr Gly Ser Ile Ser
1 5 10 15
Arg Ala Glu Ala Glu Glu His Leu Lys Leu Ala Gly Met Ala Asp Gly
20 25 30
Leu Phe Leu Leu Arg Gln Cys Leu Arg Ser Leu Gly Gly Tyr Val Leu
35 40 45
Ser Leu Val His Asp Val Arg Phe His His Phe Pro Ile Glu Arg Gln
50 55 60
Leu Asn Gly Thr Tyr Ala Ile Ala Gly Gly Lys Ala His Cys Gly Pro
65 70 75 80
Ala Glu Leu Cys Glu Phe Tyr Ser Arg Asp Pro Asp Gly Leu Pro Cys
85 90 95
Asn Leu Arg Lys Pro Cys Asn Arg Pro Ser Gly Leu Glu Pro Gln Pro
100 105 110
Gly Val Phe Asp Cys Leu Arg Asp Ala Met Val Arg Asp Tyr Val Arg
115 120 125
Gln Thr Trp Lys Leu Glu Gly Glu Ala Leu Glu Gln Ala Ile Ile Ser
130 135 140
Gln Ala Pro Gln Val Glu Lys Leu Ile Ala Thr Thr Ala His Glu Arg
145 150 155 160
Met Pro Trp Tyr His Ser Ser Leu Thr Arg Glu Glu Ala Glu Arg Lys
165 170 175
Leu Tyr Ser Gly Ala Gln Thr Asp Gly Lys Phe Leu Leu Arg Pro Arg
180 185 190
Lys Glu Gln Gly Thr Tyr Ala Leu Ser Leu Ile Tyr Gly Lys Thr Val
195 200 205
Tyr His Tyr Leu Ile Ser Gln Asp Lys Ala Gly Lys Tyr Cys Ile Pro
210 215 220
Glu Gly Thr Lys Phe Asp Thr Leu Trp Gln Leu Val Glu Tyr Leu Lys
225 230 235 240
Leu Lys Ala Asp Gly Leu Ile Tyr Cys Leu Lys Glu Ala Cys Pro Asn
245 250 255
Ser Ser Ala Ser Asn Ala Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala
260 265 270
His Pro Ser Thr Leu Thr His Pro Ala Glu Glu Met Glu Val Ser Leu
275 280 285
Ala Lys Pro Lys His Arg Val Thr Met Asn Glu Phe Glu Tyr Leu Lys
290 295 300
Leu Leu Gly Lys Gly Thr Phe Gly Lys Val Ile Leu Val Lys Glu Lys
305 310 315 320
Ala Thr Gly Arg Tyr Tyr Ala Met Lys Ile Leu Lys Lys Glu Val Ile
325 330 335
Val Ala Lys Asp Glu Val Ala His Thr Leu Thr Glu Asn Arg Val Leu
340 345 350
Gln Asn Ser Arg His Pro Phe Leu Thr Ala Leu Lys Tyr Ser Phe Gln
355 360 365
Thr His Asp Arg Leu Cys Phe Val Met Glu Tyr Ala Asn Gly Gly Glu
370 375 380
Leu Phe Phe His Leu Ser Arg Glu Arg Val Phe Ser Glu Asp Arg Ala
385 390 395 400
Arg Phe Tyr Gly Ala Glu Ile Val Ser Ala Leu Asp Tyr Leu His Ser
405 410 415
Glu Lys Asn Val Val Tyr Arg Asp Leu Lys Leu Glu Asn Leu Met Leu
420 425 430
Asp Lys Asp Gly His Ile Lys Ile Thr Asp Phe Gly Leu Cys Lys Glu
435 440 445
Gly Ile Lys Asp Gly Ala Thr Met Lys Thr Phe Cys Gly Thr Pro Glu
450 455 460
Tyr Leu Ala Pro Glu Val Leu Glu Asp Asn Asp Tyr Gly Arg Ala Val
465 470 475 480
Asp Trp Trp Gly Leu Gly Val Val Met Tyr Glu Met Met Cys Gly Arg
485 490 495
Leu Pro Phe Tyr Asn Gln Asp His Glu Lys Leu Phe Glu Leu Ile Leu
500 505 510
Met Glu Glu Ile Arg Phe Pro Arg Thr Leu Gly Pro Glu Ala Lys Ser
515 520 525
Leu Leu Ser Gly Leu Leu Lys Lys Asp Pro Lys Gln Arg Leu Gly Gly
530 535 540
Gly Ser Glu Asp Ala Lys Glu Ile Met Gln His Arg Phe Phe Ala Gly
545 550 555 560
Ile Val Trp Gln His Val Tyr Glu Lys Lys Leu Ser Pro Pro Phe Lys
565 570 575
Pro Gln Val Thr Ser Glu Thr Asp Thr Arg Tyr Phe Asp Glu Glu Phe
580 585 590
Thr Ala Gln Met Ile Thr Ile Thr Pro Pro Asp Gln Asp Asp Ser Met
595 600 605
Glu Cys Val Asp Ser Glu Arg Arg Pro His Phe Pro Gln Phe Ser Tyr
610 615 620
Ser Ala Ser Gly Thr Ala
625 630
<210> 48
<211> 651
<212> PRT
<213> 人工序列
<220>
<223> 经由接头融合到Akt激酶结构域的ZAP70-SH2结构域
<400> 48
Met Pro Asp Pro Ala Ala His Leu Pro Phe Phe Tyr Gly Ser Ile Ser
1 5 10 15
Arg Ala Glu Ala Glu Glu His Leu Lys Leu Ala Gly Met Ala Asp Gly
20 25 30
Leu Phe Leu Leu Arg Gln Cys Leu Arg Ser Leu Gly Gly Tyr Val Leu
35 40 45
Ser Leu Val His Asp Val Arg Phe His His Phe Pro Ile Glu Arg Gln
50 55 60
Leu Asn Gly Thr Tyr Ala Ile Ala Gly Gly Lys Ala His Cys Gly Pro
65 70 75 80
Ala Glu Leu Cys Glu Phe Tyr Ser Arg Asp Pro Asp Gly Leu Pro Cys
85 90 95
Asn Leu Arg Lys Pro Cys Asn Arg Pro Ser Gly Leu Glu Pro Gln Pro
100 105 110
Gly Val Phe Asp Cys Leu Arg Asp Ala Met Val Arg Asp Tyr Val Arg
115 120 125
Gln Thr Trp Lys Leu Glu Gly Glu Ala Leu Glu Gln Ala Ile Ile Ser
130 135 140
Gln Ala Pro Gln Val Glu Lys Leu Ile Ala Thr Thr Ala His Glu Arg
145 150 155 160
Met Pro Trp Tyr His Ser Ser Leu Thr Arg Glu Glu Ala Glu Arg Lys
165 170 175
Leu Tyr Ser Gly Ala Gln Thr Asp Gly Lys Phe Leu Leu Arg Pro Arg
180 185 190
Lys Glu Gln Gly Thr Tyr Ala Leu Ser Leu Ile Tyr Gly Lys Thr Val
195 200 205
Tyr His Tyr Leu Ile Ser Gln Asp Lys Ala Gly Lys Tyr Cys Ile Pro
210 215 220
Glu Gly Thr Lys Phe Asp Thr Leu Trp Gln Leu Val Glu Tyr Leu Lys
225 230 235 240
Leu Lys Ala Asp Gly Leu Ile Tyr Cys Leu Lys Glu Ala Cys Pro Asn
245 250 255
Ser Ser Ala Ser Asn Ala Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala
260 265 270
His Pro Ser Thr Leu Thr His Pro Ser Gly Gly Gly Gly Ser Gly Gly
275 280 285
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Glu
290 295 300
Met Glu Val Ser Leu Ala Lys Pro Lys His Arg Val Thr Met Asn Glu
305 310 315 320
Phe Glu Tyr Leu Lys Leu Leu Gly Lys Gly Thr Phe Gly Lys Val Ile
325 330 335
Leu Val Lys Glu Lys Ala Thr Gly Arg Tyr Tyr Ala Met Lys Ile Leu
340 345 350
Lys Lys Glu Val Ile Val Ala Lys Asp Glu Val Ala His Thr Leu Thr
355 360 365
Glu Asn Arg Val Leu Gln Asn Ser Arg His Pro Phe Leu Thr Ala Leu
370 375 380
Lys Tyr Ser Phe Gln Thr His Asp Arg Leu Cys Phe Val Met Glu Tyr
385 390 395 400
Ala Asn Gly Gly Glu Leu Phe Phe His Leu Ser Arg Glu Arg Val Phe
405 410 415
Ser Glu Asp Arg Ala Arg Phe Tyr Gly Ala Glu Ile Val Ser Ala Leu
420 425 430
Asp Tyr Leu His Ser Glu Lys Asn Val Val Tyr Arg Asp Leu Lys Leu
435 440 445
Glu Asn Leu Met Leu Asp Lys Asp Gly His Ile Lys Ile Thr Asp Phe
450 455 460
Gly Leu Cys Lys Glu Gly Ile Lys Asp Gly Ala Thr Met Lys Thr Phe
465 470 475 480
Cys Gly Thr Pro Glu Tyr Leu Ala Pro Glu Val Leu Glu Asp Asn Asp
485 490 495
Tyr Gly Arg Ala Val Asp Trp Trp Gly Leu Gly Val Val Met Tyr Glu
500 505 510
Met Met Cys Gly Arg Leu Pro Phe Tyr Asn Gln Asp His Glu Lys Leu
515 520 525
Phe Glu Leu Ile Leu Met Glu Glu Ile Arg Phe Pro Arg Thr Leu Gly
530 535 540
Pro Glu Ala Lys Ser Leu Leu Ser Gly Leu Leu Lys Lys Asp Pro Lys
545 550 555 560
Gln Arg Leu Gly Gly Gly Ser Glu Asp Ala Lys Glu Ile Met Gln His
565 570 575
Arg Phe Phe Ala Gly Ile Val Trp Gln His Val Tyr Glu Lys Lys Leu
580 585 590
Ser Pro Pro Phe Lys Pro Gln Val Thr Ser Glu Thr Asp Thr Arg Tyr
595 600 605
Phe Asp Glu Glu Phe Thr Ala Gln Met Ile Thr Ile Thr Pro Pro Asp
610 615 620
Gln Asp Asp Ser Met Glu Cys Val Asp Ser Glu Arg Arg Pro His Phe
625 630 635 640
Pro Gln Phe Ser Tyr Ser Ala Ser Gly Thr Ala
645 650
<210> 49
<211> 630
<212> PRT
<213> 人工序列
<220>
<223> 融合到Akt激酶结构域的被突变为无功能的ZAP70-SH2结构域
<400> 49
Met Pro Asp Pro Ala Ala His Leu Pro Phe Phe Tyr Gly Ser Ile Ser
1 5 10 15
Arg Ala Glu Ala Glu Glu His Leu Lys Leu Ala Gly Met Ala Asp Gly
20 25 30
Leu Phe Leu Leu Arg Gln Cys Leu Arg Ser Leu Gly Gly Tyr Val Leu
35 40 45
Ser Leu Val His Asp Val Arg Phe His His Phe Pro Ile Glu Arg Gln
50 55 60
Leu Asn Gly Thr Tyr Ala Ile Ala Gly Gly Lys Ala His Cys Gly Pro
65 70 75 80
Ala Glu Leu Cys Glu Phe Tyr Ser Arg Asp Pro Asp Gly Leu Pro Cys
85 90 95
Asn Leu Arg Lys Pro Cys Asn Arg Pro Ser Gly Leu Glu Pro Gln Pro
100 105 110
Gly Val Phe Asp Cys Leu Arg Asp Ala Met Val Arg Asp Tyr Val Arg
115 120 125
Gln Thr Trp Lys Leu Glu Gly Glu Ala Leu Glu Gln Ala Ile Ile Ser
130 135 140
Gln Ala Pro Gln Val Glu Lys Leu Ile Ala Thr Thr Ala His Glu Arg
145 150 155 160
Met Pro Trp Tyr His Ser Ser Leu Thr Arg Glu Glu Ala Glu Arg Lys
165 170 175
Leu Tyr Ser Gly Ala Gln Thr Asp Gly Lys Phe Leu Leu Lys Pro Arg
180 185 190
Lys Glu Gln Gly Thr Tyr Ala Leu Ser Leu Ile Tyr Gly Lys Thr Val
195 200 205
Tyr His Tyr Leu Ile Ser Gln Asp Lys Ala Gly Lys Tyr Cys Ile Pro
210 215 220
Glu Gly Thr Lys Phe Asp Thr Leu Trp Gln Leu Val Glu Tyr Leu Lys
225 230 235 240
Leu Lys Ala Asp Gly Leu Ile Tyr Cys Leu Lys Glu Ala Cys Pro Asn
245 250 255
Ser Ser Ala Ser Asn Ala Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala
260 265 270
His Pro Ser Thr Leu Thr His Pro Ala Glu Glu Met Glu Val Ser Leu
275 280 285
Ala Lys Pro Lys His Arg Val Thr Met Asn Glu Phe Glu Tyr Leu Lys
290 295 300
Leu Leu Gly Lys Gly Thr Phe Gly Lys Val Ile Leu Val Lys Glu Lys
305 310 315 320
Ala Thr Gly Arg Tyr Tyr Ala Met Lys Ile Leu Lys Lys Glu Val Ile
325 330 335
Val Ala Lys Asp Glu Val Ala His Thr Leu Thr Glu Asn Arg Val Leu
340 345 350
Gln Asn Ser Arg His Pro Phe Leu Thr Ala Leu Lys Tyr Ser Phe Gln
355 360 365
Thr His Asp Arg Leu Cys Phe Val Met Glu Tyr Ala Asn Gly Gly Glu
370 375 380
Leu Phe Phe His Leu Ser Arg Glu Arg Val Phe Ser Glu Asp Arg Ala
385 390 395 400
Arg Phe Tyr Gly Ala Glu Ile Val Ser Ala Leu Asp Tyr Leu His Ser
405 410 415
Glu Lys Asn Val Val Tyr Arg Asp Leu Lys Leu Glu Asn Leu Met Leu
420 425 430
Asp Lys Asp Gly His Ile Lys Ile Thr Asp Phe Gly Leu Cys Lys Glu
435 440 445
Gly Ile Lys Asp Gly Ala Thr Met Lys Thr Phe Cys Gly Thr Pro Glu
450 455 460
Tyr Leu Ala Pro Glu Val Leu Glu Asp Asn Asp Tyr Gly Arg Ala Val
465 470 475 480
Asp Trp Trp Gly Leu Gly Val Val Met Tyr Glu Met Met Cys Gly Arg
485 490 495
Leu Pro Phe Tyr Asn Gln Asp His Glu Lys Leu Phe Glu Leu Ile Leu
500 505 510
Met Glu Glu Ile Arg Phe Pro Arg Thr Leu Gly Pro Glu Ala Lys Ser
515 520 525
Leu Leu Ser Gly Leu Leu Lys Lys Asp Pro Lys Gln Arg Leu Gly Gly
530 535 540
Gly Ser Glu Asp Ala Lys Glu Ile Met Gln His Arg Phe Phe Ala Gly
545 550 555 560
Ile Val Trp Gln His Val Tyr Glu Lys Lys Leu Ser Pro Pro Phe Lys
565 570 575
Pro Gln Val Thr Ser Glu Thr Asp Thr Arg Tyr Phe Asp Glu Glu Phe
580 585 590
Thr Ala Gln Met Ile Thr Ile Thr Pro Pro Asp Gln Asp Asp Ser Met
595 600 605
Glu Cys Val Asp Ser Glu Arg Arg Pro His Phe Pro Gln Phe Ser Tyr
610 615 620
Ser Ala Ser Gly Thr Ala
625 630
<210> 50
<211> 590
<212> PRT
<213> 人工序列
<220>
<223> 含有JAK2结构域的激酶
<400> 50
Arg Asn Glu Asp Leu Ile Phe Asn Glu Ser Leu Gly Gln Gly Thr Phe
1 5 10 15
Thr Lys Ile Phe Lys Gly Val Arg Arg Glu Val Gly Asp Tyr Gly Gln
20 25 30
Leu His Glu Thr Glu Val Leu Leu Lys Val Leu Asp Lys Ala His Arg
35 40 45
Asn Tyr Ser Glu Ser Phe Phe Glu Ala Ala Ser Met Met Ser Lys Leu
50 55 60
Ser His Lys His Leu Val Leu Asn Tyr Gly Val Cys Val Cys Gly Asp
65 70 75 80
Glu Asn Ile Leu Val Gln Glu Phe Val Lys Phe Gly Ser Leu Asp Thr
85 90 95
Tyr Leu Lys Lys Asn Lys Asn Cys Ile Asn Ile Leu Trp Lys Leu Glu
100 105 110
Val Ala Lys Gln Leu Ala Trp Ala Met His Phe Leu Glu Glu Asn Thr
115 120 125
Leu Ile His Gly Asn Val Cys Ala Lys Asn Ile Leu Leu Ile Arg Glu
130 135 140
Glu Asp Arg Lys Thr Gly Asn Pro Pro Phe Ile Lys Leu Ser Asp Pro
145 150 155 160
Gly Ile Ser Ile Thr Val Leu Pro Lys Asp Ile Leu Gln Glu Arg Ile
165 170 175
Pro Trp Val Pro Pro Glu Cys Ile Glu Asn Pro Lys Asn Leu Asn Leu
180 185 190
Ala Thr Asp Lys Trp Ser Phe Gly Thr Thr Leu Trp Glu Ile Cys Ser
195 200 205
Gly Gly Asp Lys Pro Leu Ser Ala Leu Asp Ser Gln Arg Lys Leu Gln
210 215 220
Phe Tyr Glu Asp Arg His Gln Leu Pro Ala Pro Lys Trp Ala Glu Leu
225 230 235 240
Ala Asn Leu Ile Asn Asn Cys Met Asp Tyr Glu Pro Asp Phe Arg Pro
245 250 255
Ser Phe Arg Ala Ile Ile Arg Asp Leu Asn Ser Leu Phe Thr Pro Asp
260 265 270
Tyr Glu Leu Leu Thr Glu Asn Asp Met Leu Pro Asn Met Arg Ile Gly
275 280 285
Ala Leu Gly Phe Ser Gly Ala Phe Glu Asp Arg Asp Pro Thr Gln Phe
290 295 300
Glu Glu Arg His Leu Lys Phe Leu Gln Gln Leu Gly Lys Gly Asn Phe
305 310 315 320
Gly Ser Val Glu Met Cys Arg Tyr Asp Pro Leu Gln Asp Asn Thr Gly
325 330 335
Glu Val Val Ala Val Lys Lys Leu Gln His Ser Thr Glu Glu His Leu
340 345 350
Arg Asp Phe Glu Arg Glu Ile Glu Ile Leu Lys Ser Leu Gln His Asp
355 360 365
Asn Ile Val Lys Tyr Lys Gly Val Cys Tyr Ser Ala Gly Arg Arg Asn
370 375 380
Leu Lys Leu Ile Met Glu Tyr Leu Pro Tyr Gly Ser Leu Arg Asp Tyr
385 390 395 400
Leu Gln Lys His Lys Glu Arg Ile Asp His Ile Lys Leu Leu Gln Tyr
405 410 415
Thr Ser Gln Ile Cys Lys Gly Met Glu Tyr Leu Gly Thr Lys Arg Tyr
420 425 430
Ile His Arg Asp Leu Ala Thr Arg Asn Ile Leu Val Glu Asn Glu Asn
435 440 445
Arg Val Lys Ile Gly Asp Phe Gly Leu Thr Lys Val Leu Pro Gln Asp
450 455 460
Lys Glu Tyr Tyr Lys Val Lys Glu Pro Gly Glu Ser Pro Ile Phe Trp
465 470 475 480
Tyr Ala Pro Glu Ser Leu Thr Glu Ser Lys Phe Ser Val Ala Ser Asp
485 490 495
Val Trp Ser Phe Gly Val Val Leu Tyr Glu Leu Phe Thr Tyr Ile Glu
500 505 510
Lys Ser Lys Ser Pro Pro Ala Glu Phe Met Arg Met Ile Gly Asn Asp
515 520 525
Lys Gln Gly Gln Met Ile Val Phe His Leu Ile Glu Leu Leu Lys Asn
530 535 540
Asn Gly Arg Leu Pro Arg Pro Asp Gly Cys Pro Asp Glu Ile Tyr Met
545 550 555 560
Ile Met Thr Glu Cys Trp Asn Asn Asn Val Asn Gln Arg Pro Ser Phe
565 570 575
Arg Asp Leu Ala Leu Arg Val Asp Gln Ile Arg Asp Asn Met
580 585 590
<210> 51
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 共有烟草蚀刻病毒(TEV)切割位点
<400> 51
Glu Asn Leu Tyr Phe Gln Ser
1 5
<210> 52
<211> 240
<212> PRT
<213> 人工序列
<220>
<223> TeV 蛋白酶结构域
<400> 52
Ser Leu Phe Lys Gly Pro Arg Asp Tyr Asn Pro Ile Ser Ser Thr Ile
1 5 10 15
Cys His Leu Thr Asn Glu Ser Asp Gly His Thr Thr Ser Leu Tyr Gly
20 25 30
Ile Gly Phe Gly Pro Phe Ile Ile Thr Asn Lys His Leu Phe Arg Arg
35 40 45
Asn Asn Gly Thr Leu Leu Val Gln Ser Leu His Gly Val Phe Lys Val
50 55 60
Lys Asn Thr Thr Thr Leu Gln Gln His Leu Ile Asp Gly Arg Asp Met
65 70 75 80
Ile Ile Ile Arg Met Pro Lys Asp Phe Pro Pro Phe Pro Gln Lys Leu
85 90 95
Lys Phe Arg Glu Pro Gln Arg Glu Glu Arg Ile Cys Leu Val Thr Thr
100 105 110
Asn Phe Gln Thr Lys Ser Met Ser Ser Met Val Ser Asp Thr Ser Cys
115 120 125
Thr Phe Pro Ser Ser Asp Gly Ile Phe Trp Lys His Trp Ile Gln Thr
130 135 140
Lys Asp Gly Gln Cys Gly Ser Pro Leu Val Ser Thr Arg Asp Gly Phe
145 150 155 160
Ile Val Gly Ile His Ser Ala Ser Asn Phe Thr Asn Thr Asn Asn Tyr
165 170 175
Phe Thr Ser Val Pro Lys Asn Phe Met Glu Leu Leu Thr Asn Gln Glu
180 185 190
Ala Gln Gln Trp Val Ser Gly Trp Arg Leu Asn Ala Asp Ser Val Leu
195 200 205
Trp Gly Gly His Lys Val Phe Met Ser Lys Pro Glu Glu Pro Phe Gln
210 215 220
Pro Val Lys Glu Ala Thr Gln Leu Met Asn Glu Leu Val Tyr Ser Gln
225 230 235 240
<210> 53
<211> 541
<212> PRT
<213> 人工序列
<220>
<223> 融合到TEV蛋白酶序列的ZAP70-SH2结构域
<400> 53
Met Pro Asp Pro Ala Ala His Leu Pro Phe Phe Tyr Gly Ser Ile Ser
1 5 10 15
Arg Ala Glu Ala Glu Glu His Leu Lys Leu Ala Gly Met Ala Asp Gly
20 25 30
Leu Phe Leu Leu Arg Gln Cys Leu Arg Ser Leu Gly Gly Tyr Val Leu
35 40 45
Ser Leu Val His Asp Val Arg Phe His His Phe Pro Ile Glu Arg Gln
50 55 60
Leu Asn Gly Thr Tyr Ala Ile Ala Gly Gly Lys Ala His Cys Gly Pro
65 70 75 80
Ala Glu Leu Cys Glu Phe Tyr Ser Arg Asp Pro Asp Gly Leu Pro Cys
85 90 95
Asn Leu Arg Lys Pro Cys Asn Arg Pro Ser Gly Leu Glu Pro Gln Pro
100 105 110
Gly Val Phe Asp Cys Leu Arg Asp Ala Met Val Arg Asp Tyr Val Arg
115 120 125
Gln Thr Trp Lys Leu Glu Gly Glu Ala Leu Glu Gln Ala Ile Ile Ser
130 135 140
Gln Ala Pro Gln Val Glu Lys Leu Ile Ala Thr Thr Ala His Glu Arg
145 150 155 160
Met Pro Trp Tyr His Ser Ser Leu Thr Arg Glu Glu Ala Glu Arg Lys
165 170 175
Leu Tyr Ser Gly Ala Gln Thr Asp Gly Lys Phe Leu Leu Arg Pro Arg
180 185 190
Lys Glu Gln Gly Thr Tyr Ala Leu Ser Leu Ile Tyr Gly Lys Thr Val
195 200 205
Tyr His Tyr Leu Ile Ser Gln Asp Lys Ala Gly Lys Tyr Cys Ile Pro
210 215 220
Glu Gly Thr Lys Phe Asp Thr Leu Trp Gln Leu Val Glu Tyr Leu Lys
225 230 235 240
Leu Lys Ala Asp Gly Leu Ile Tyr Cys Leu Lys Glu Ala Cys Pro Asn
245 250 255
Ser Ser Ala Ser Asn Ala Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala
260 265 270
His Pro Ser Thr Leu Thr His Pro Ser Gly Gly Gly Gly Ser Gly Gly
275 280 285
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Leu Phe
290 295 300
Lys Gly Pro Arg Asp Tyr Asn Pro Ile Ser Ser Thr Ile Cys His Leu
305 310 315 320
Thr Asn Glu Ser Asp Gly His Thr Thr Ser Leu Tyr Gly Ile Gly Phe
325 330 335
Gly Pro Phe Ile Ile Thr Asn Lys His Leu Phe Arg Arg Asn Asn Gly
340 345 350
Thr Leu Leu Val Gln Ser Leu His Gly Val Phe Lys Val Lys Asn Thr
355 360 365
Thr Thr Leu Gln Gln His Leu Ile Asp Gly Arg Asp Met Ile Ile Ile
370 375 380
Arg Met Pro Lys Asp Phe Pro Pro Phe Pro Gln Lys Leu Lys Phe Arg
385 390 395 400
Glu Pro Gln Arg Glu Glu Arg Ile Cys Leu Val Thr Thr Asn Phe Gln
405 410 415
Thr Lys Ser Met Ser Ser Met Val Ser Asp Thr Ser Cys Thr Phe Pro
420 425 430
Ser Ser Asp Gly Ile Phe Trp Lys His Trp Ile Gln Thr Lys Asp Gly
435 440 445
Gln Cys Gly Ser Pro Leu Val Ser Thr Arg Asp Gly Phe Ile Val Gly
450 455 460
Ile His Ser Ala Ser Asn Phe Thr Asn Thr Asn Asn Tyr Phe Thr Ser
465 470 475 480
Val Pro Lys Asn Phe Met Glu Leu Leu Thr Asn Gln Glu Ala Gln Gln
485 490 495
Trp Val Ser Gly Trp Arg Leu Asn Ala Asp Ser Val Leu Trp Gly Gly
500 505 510
His Lys Val Phe Met Ser Lys Pro Glu Glu Pro Phe Gln Pro Val Lys
515 520 525
Glu Ala Thr Gln Leu Met Asn Glu Leu Val Tyr Ser Gln
530 535 540
<210> 54
<211> 460
<212> PRT
<213> 人工序列
<220>
<223> 融合到TEV蛋白酶序列的PTPN6-SH2结构域
<400> 54
Met Val Arg Trp Phe His Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr
1 5 10 15
Leu Leu Lys Gly Arg Gly Val His Gly Ser Phe Leu Ala Arg Pro Ser
20 25 30
Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Val Arg Val Gly Asp Gln
35 40 45
Val Thr His Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr
50 55 60
Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr
65 70 75 80
Gln Gln Gln Gly Val Leu Gln Asp Arg Asp Gly Thr Ile Ile His Leu
85 90 95
Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Ser Glu Arg Trp Tyr His
100 105 110
Gly His Met Ser Gly Gly Gln Ala Glu Thr Leu Leu Gln Ala Lys Gly
115 120 125
Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln Pro Gly Asp
130 135 140
Phe Val Leu Ser Val Leu Ser Asp Gln Pro Lys Ala Gly Pro Gly Ser
145 150 155 160
Pro Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly Gly Arg Tyr
165 170 175
Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Leu Thr Asp Leu Val Glu
180 185 190
His Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala Phe Val Tyr
195 200 205
Leu Arg Gln Pro Tyr Tyr Ser Gly Gly Gly Gly Ser Ser Leu Phe Lys
210 215 220
Gly Pro Arg Asp Tyr Asn Pro Ile Ser Ser Thr Ile Cys His Leu Thr
225 230 235 240
Asn Glu Ser Asp Gly His Thr Thr Ser Leu Tyr Gly Ile Gly Phe Gly
245 250 255
Pro Phe Ile Ile Thr Asn Lys His Leu Phe Arg Arg Asn Asn Gly Thr
260 265 270
Leu Leu Val Gln Ser Leu His Gly Val Phe Lys Val Lys Asn Thr Thr
275 280 285
Thr Leu Gln Gln His Leu Ile Asp Gly Arg Asp Met Ile Ile Ile Arg
290 295 300
Met Pro Lys Asp Phe Pro Pro Phe Pro Gln Lys Leu Lys Phe Arg Glu
305 310 315 320
Pro Gln Arg Glu Glu Arg Ile Cys Leu Val Thr Thr Asn Phe Gln Thr
325 330 335
Lys Ser Met Ser Ser Met Val Ser Asp Thr Ser Cys Thr Phe Pro Ser
340 345 350
Ser Asp Gly Ile Phe Trp Lys His Trp Ile Gln Thr Lys Asp Gly Gln
355 360 365
Cys Gly Ser Pro Leu Val Ser Thr Arg Asp Gly Phe Ile Val Gly Ile
370 375 380
His Ser Ala Ser Asn Phe Thr Asn Thr Asn Asn Tyr Phe Thr Ser Val
385 390 395 400
Pro Lys Asn Phe Met Glu Leu Leu Thr Asn Gln Glu Ala Gln Gln Trp
405 410 415
Val Ser Gly Trp Arg Leu Asn Ala Asp Ser Val Leu Trp Gly Gly His
420 425 430
Lys Val Phe Met Ser Lys Pro Glu Glu Pro Phe Gln Pro Val Lys Glu
435 440 445
Ala Thr Gln Leu Met Asn Glu Leu Val Tyr Ser Gln
450 455 460
<210> 55
<211> 438
<212> PRT
<213> 人工序列
<220>
<223> 膜栓系转录因子
<400> 55
Met Gly Thr Ser Leu Leu Cys Trp Met Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Ala Asp Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly
20 25 30
Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser
35 40 45
Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser
50 55 60
Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Pro Ala Pro Arg Pro
65 70 75 80
Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro
85 90 95
Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu
100 105 110
Asp Phe Ala Cys Asp Met Ala Leu Ile Val Leu Gly Gly Val Ala Gly
115 120 125
Leu Leu Leu Phe Ile Gly Leu Gly Ile Phe Phe Cys Val Arg Cys Arg
130 135 140
His Arg Arg Arg Gln Ala Glu Arg Met Ala Gln Ile Lys Arg Val Val
145 150 155 160
Ser Glu Lys Lys Thr Ala Gln Ala Pro His Arg Phe Gln Lys Thr Cys
165 170 175
Ser Pro Ile Ser Gly Gly Gly Gly Ser Glu Asn Leu Tyr Phe Gln Met
180 185 190
Pro Lys Lys Lys Arg Lys Val Ala Pro Pro Thr Asp Val Ser Leu Gly
195 200 205
Asp Glu Leu His Leu Asp Gly Glu Asp Val Ala Met Ala His Ala Asp
210 215 220
Ala Leu Asp Asp Phe Asp Leu Asp Met Leu Gly Asp Gly Asp Ser Pro
225 230 235 240
Gly Pro Gly Phe Thr Pro His Asp Ser Ala Pro Tyr Gly Ala Leu Asp
245 250 255
Met Ala Asp Phe Glu Phe Glu Gln Met Phe Thr Asp Ala Leu Gly Ile
260 265 270
Asp Glu Tyr Gly Gly Ser Gly Gly Gly Ser Met Gln Ile Leu Val Ala
275 280 285
Ser Asp Ala Thr Met Lys Leu Leu Ser Ser Ile Glu Gln Ala Cys Asp
290 295 300
Ile Cys Arg Leu Lys Lys Leu Lys Cys Ser Lys Glu Lys Pro Lys Cys
305 310 315 320
Ala Lys Cys Leu Lys Asn Asn Trp Glu Cys Arg Tyr Ser Pro Lys Thr
325 330 335
Lys Arg Ser Pro Leu Thr Arg Ala His Leu Thr Glu Val Glu Ser Arg
340 345 350
Leu Glu Arg Leu Glu Gln Leu Phe Leu Leu Ile Phe Pro Arg Glu Asp
355 360 365
Leu Asp Met Ile Leu Lys Met Asp Ser Leu Gln Asp Ile Lys Ala Leu
370 375 380
Leu Thr Gly Leu Phe Val Gln Asp Asn Val Asn Lys Asp Ala Val Thr
385 390 395 400
Asp Arg Leu Ala Ser Val Glu Thr Asp Met Pro Leu Thr Leu Arg Gln
405 410 415
His Arg Ile Ser Ala Thr Ser Ser Ser Glu Glu Ser Ser Asn Lys Gly
420 425 430
Gln Arg Gln Leu Thr Val
435
<210> 56
<211> 438
<212> PRT
<213> 人工序列
<220>
<223> 靶受体
<400> 56
Met Ala Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asp
35 40 45
Ile Tyr Phe Asn Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Asp Thr Asn Arg Leu Ala Asp Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Tyr Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr Lys
100 105 110
Asn Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Arg Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Leu Ser Asn Tyr Gly Met His Trp Ile Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Leu Asn Gly Gly Ser
195 200 205
Thr Tyr Tyr Arg Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Ser Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gln Asp Ala Tyr Thr Gly Gly
245 250 255
Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Met
260 265 270
Asp Pro Ala Thr Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val
275 280 285
His Pro Thr Gly Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro
290 295 300
Arg Gly Ser Val Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr
305 310 315 320
Val Gly Val Val Gly Gly Leu Leu Gly Ser Leu Val Leu Leu Val Trp
325 330 335
Val Leu Ala Val Ile Cys Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala
340 345 350
Arg Arg Thr Gly Gln Pro Leu Lys Glu Asp Pro Ser Ala Val Pro Val
355 360 365
Phe Ser Val Asp Tyr Gly Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr
370 375 380
Pro Glu Pro Pro Val Pro Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr
385 390 395 400
Ile Val Phe Pro Ser Gly Met Gly Thr Ser Ser Pro Ala Arg Arg Gly
405 410 415
Ser Ala Asp Gly Pro Arg Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly
420 425 430
His Cys Ser Trp Pro Leu
435
<210> 57
<211> 509
<212> PRT
<213> 人工序列
<220>
<223> 含有具有可切割CD3-zeta胞内域的针对CD19的CAR的受体
<400> 57
Met Ser Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Lys Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu Ser Gly Pro Gly
145 150 155 160
Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly
165 170 175
Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg
180 185 190
Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr
195 200 205
Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser
210 215 220
Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr
225 230 235 240
Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala
245 250 255
Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Asp Pro
260 265 270
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
275 280 285
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
290 295 300
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Phe Trp
305 310 315 320
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
325 330 335
Thr Val Ala Phe Ile Ile Phe Trp Val Arg Cys Arg His Arg Arg Arg
340 345 350
Gln Ala Glu Arg Met Ala Gln Ile Lys Arg Val Val Ser Glu Lys Lys
355 360 365
Thr Ala Gln Ala Pro His Arg Phe Gln Lys Thr Cys Ser Pro Ile Ser
370 375 380
Gly Gly Gly Gly Ser Glu Asn Leu Tyr Phe Gln Met Arg Arg Val Lys
385 390 395 400
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
405 410 415
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
420 425 430
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
435 440 445
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
450 455 460
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
465 470 475 480
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
485 490 495
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505
<210> 58
<211> 827
<212> PRT
<213> 人工序列
<220>
<223> 含有具有CD3-zeta胞内域和可切割CD148胞内域的针对CD19的CAR的受体
<400> 58
Met Ser Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Lys Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu Ser Gly Pro Gly
145 150 155 160
Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly
165 170 175
Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg
180 185 190
Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr
195 200 205
Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser
210 215 220
Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr
225 230 235 240
Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala
245 250 255
Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Asp Pro
260 265 270
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
275 280 285
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
290 295 300
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Phe Trp
305 310 315 320
Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val
325 330 335
Thr Val Ala Phe Ile Ile Phe Trp Val Arg Arg Val Lys Phe Ser Arg
340 345 350
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
355 360 365
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
370 375 380
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
385 390 395 400
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
405 410 415
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
420 425 430
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
435 440 445
Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu Asn Leu Tyr Phe Gln
450 455 460
Met Ala Val Phe Gly Cys Ile Phe Gly Ala Leu Val Ile Val Thr Val
465 470 475 480
Gly Gly Phe Ile Phe Trp Arg Lys Lys Arg Lys Asp Ala Lys Asn Asn
485 490 495
Glu Val Ser Phe Ser Gln Ile Lys Pro Lys Lys Ser Lys Leu Ile Arg
500 505 510
Val Glu Asn Phe Glu Ala Tyr Phe Lys Lys Gln Gln Ala Asp Ser Asn
515 520 525
Cys Gly Phe Ala Glu Glu Tyr Glu Asp Leu Lys Leu Val Gly Ile Ser
530 535 540
Gln Pro Lys Tyr Ala Ala Glu Leu Ala Glu Asn Arg Gly Lys Asn Arg
545 550 555 560
Tyr Asn Asn Val Leu Pro Tyr Asp Ile Ser Arg Val Lys Leu Ser Val
565 570 575
Gln Thr His Ser Thr Asp Asp Tyr Ile Asn Ala Asn Tyr Met Pro Gly
580 585 590
Tyr His Ser Lys Lys Asp Phe Ile Ala Thr Gln Gly Pro Leu Pro Asn
595 600 605
Thr Leu Lys Asp Phe Trp Arg Met Val Trp Glu Lys Asn Val Tyr Ala
610 615 620
Ile Ile Met Leu Thr Lys Cys Val Glu Gln Gly Arg Thr Lys Cys Glu
625 630 635 640
Glu Tyr Trp Pro Ser Lys Gln Ala Gln Asp Tyr Gly Asp Ile Thr Val
645 650 655
Ala Met Thr Ser Glu Ile Val Leu Pro Glu Trp Thr Ile Arg Asp Phe
660 665 670
Thr Val Lys Asn Ile Gln Thr Ser Glu Ser His Pro Leu Arg Gln Phe
675 680 685
His Phe Thr Ser Trp Pro Asp His Gly Val Pro Asp Thr Thr Asp Leu
690 695 700
Leu Ile Asn Phe Arg Tyr Leu Val Arg Asp Tyr Met Lys Gln Ser Pro
705 710 715 720
Pro Glu Ser Pro Ile Leu Val His Cys Ser Ala Gly Val Gly Arg Thr
725 730 735
Gly Thr Phe Ile Ala Ile Asp Arg Leu Ile Tyr Gln Ile Glu Asn Glu
740 745 750
Asn Thr Val Asp Val Tyr Gly Ile Val Tyr Asp Leu Arg Met His Arg
755 760 765
Pro Leu Met Val Gln Thr Glu Asp Gln Tyr Val Phe Leu Asn Gln Cys
770 775 780
Val Leu Asp Ile Val Arg Ser Gln Lys Asp Ser Lys Val Asp Leu Ile
785 790 795 800
Tyr Gln Asn Thr Thr Ala Met Thr Ile Tyr Glu Asn Leu Ala Pro Val
805 810 815
Thr Thr Phe Gly Lys Thr Asn Gly Tyr Ile Ala
820 825
<210> 59
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 2a 自切割肽
<400> 59
Arg Ala Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu
1 5 10 15
Asn Pro Gly Pro
20
<210> 60
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 2a 自切割肽
<400> 60
Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp Val Glu Ser
1 5 10 15
Asn Pro Gly Pro
20
<210> 61
<211> 563
<212> PRT
<213> 人工序列
<220>
<223> 来自融合到ZAP70激酶结构域的SHP-2的双SH2结构域
<400> 61
Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala Glu Asn Leu Leu Leu
1 5 10 15
Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg Pro Ser Lys Ser Asn
20 25 30
Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn Gly Ala Val Thr His
35 40 45
Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp Leu Tyr Gly Gly Glu
50 55 60
Lys Phe Ala Thr Leu Ala Glu Leu Val Gln Tyr Tyr Met Glu His His
65 70 75 80
Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile Glu Leu Lys Tyr Pro
85 90 95
Leu Asn Cys Ala Asp Pro Thr Ser Glu Arg Trp Phe His Gly His Leu
100 105 110
Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu Lys Gly Lys His Gly
115 120 125
Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro Gly Asp Phe Val Leu
130 135 140
Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser Asn Asp Gly Lys Ser
145 150 155 160
Lys Val Thr His Val Met Ile Arg Cys Gln Glu Leu Lys Tyr Asp Val
165 170 175
Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp Leu Val Glu His Tyr
180 185 190
Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr Val Leu Gln Leu Lys
195 200 205
Gln Pro Leu Asn Thr Thr Arg Ile Asn Pro Asn Ser Ser Ala Ser Asn
210 215 220
Ala Ser Gly Ala Ala Ala Pro Thr Leu Pro Ala His Pro Ser Thr Leu
225 230 235 240
Thr His Pro Gln Arg Arg Ile Asp Thr Leu Asn Ser Asp Gly Tyr Thr
245 250 255
Pro Glu Pro Ala Arg Ile Thr Ser Pro Asp Lys Pro Arg Pro Met Pro
260 265 270
Met Asp Thr Ser Val Tyr Glu Ser Pro Tyr Ser Asp Pro Glu Glu Leu
275 280 285
Lys Asp Lys Lys Leu Phe Leu Lys Arg Asp Asn Leu Leu Ile Ala Asp
290 295 300
Ile Glu Leu Gly Cys Gly Asn Phe Gly Ser Val Arg Gln Gly Val Tyr
305 310 315 320
Arg Met Arg Lys Lys Gln Ile Asp Val Ala Ile Lys Val Leu Lys Gln
325 330 335
Gly Thr Glu Lys Ala Asp Thr Glu Glu Met Met Arg Glu Ala Gln Ile
340 345 350
Met His Gln Leu Asp Asn Pro Tyr Ile Val Arg Leu Ile Gly Val Cys
355 360 365
Gln Ala Glu Ala Leu Met Leu Val Met Glu Met Ala Gly Gly Gly Pro
370 375 380
Leu His Lys Phe Leu Val Gly Lys Arg Glu Glu Ile Pro Val Ser Asn
385 390 395 400
Val Ala Glu Leu Leu His Gln Val Ser Met Gly Met Lys Tyr Leu Glu
405 410 415
Glu Lys Asn Phe Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Leu
420 425 430
Val Asn Arg His Tyr Ala Lys Ile Ser Asp Phe Gly Leu Ser Lys Ala
435 440 445
Leu Gly Ala Asp Asp Ser Tyr Tyr Thr Ala Arg Ser Ala Gly Lys Trp
450 455 460
Pro Leu Lys Trp Tyr Ala Pro Glu Cys Ile Asn Phe Arg Lys Phe Ser
465 470 475 480
Ser Arg Ser Asp Val Trp Ser Tyr Gly Val Thr Met Trp Glu Ala Leu
485 490 495
Ser Tyr Gly Gln Lys Pro Tyr Lys Lys Met Lys Gly Pro Glu Val Met
500 505 510
Ala Phe Ile Glu Gln Gly Lys Arg Met Glu Cys Pro Pro Glu Cys Pro
515 520 525
Pro Glu Leu Tyr Ala Leu Met Ser Asp Cys Trp Ile Tyr Lys Trp Glu
530 535 540
Asp Arg Pro Asp Phe Leu Thr Val Glu Gln Arg Met Arg Ala Cys Tyr
545 550 555 560
Tyr Ser Leu
<210> 62
<211> 567
<212> PRT
<213> 人工序列
<220>
<223> 融合到Akt激酶结构域的双SHP-2 SH2结构域
<400> 62
Trp Phe His Pro Asn Ile Thr Gly Val Glu Ala Glu Asn Leu Leu Leu
1 5 10 15
Thr Arg Gly Val Asp Gly Ser Phe Leu Ala Arg Pro Ser Lys Ser Asn
20 25 30
Pro Gly Asp Phe Thr Leu Ser Val Arg Arg Asn Gly Ala Val Thr His
35 40 45
Ile Lys Ile Gln Asn Thr Gly Asp Tyr Tyr Asp Leu Tyr Gly Gly Glu
50 55 60
Lys Phe Ala Thr Leu Ala Glu Leu Val Gln Tyr Tyr Met Glu His His
65 70 75 80
Gly Gln Leu Lys Glu Lys Asn Gly Asp Val Ile Glu Leu Lys Tyr Pro
85 90 95
Leu Asn Cys Ala Asp Pro Thr Ser Glu Arg Trp Phe His Gly His Leu
100 105 110
Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr Glu Lys Gly Lys His Gly
115 120 125
Ser Phe Leu Val Arg Glu Ser Gln Ser His Pro Gly Asp Phe Val Leu
130 135 140
Ser Val Arg Thr Gly Asp Asp Lys Gly Glu Ser Asn Asp Gly Lys Ser
145 150 155 160
Lys Val Thr His Val Met Ile Arg Cys Gln Glu Leu Lys Tyr Asp Val
165 170 175
Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr Asp Leu Val Glu His Tyr
180 185 190
Lys Lys Asn Pro Met Val Glu Thr Leu Gly Thr Val Leu Gln Leu Lys
195 200 205
Gln Pro Leu Asn Thr Thr Arg Ile Asn Ala Glu Glu Met Glu Val Ser
210 215 220
Leu Ala Lys Pro Lys His Arg Val Thr Met Asn Glu Phe Glu Tyr Leu
225 230 235 240
Lys Leu Leu Gly Lys Gly Thr Phe Gly Lys Val Ile Leu Val Lys Glu
245 250 255
Lys Ala Thr Gly Arg Tyr Tyr Ala Met Lys Ile Leu Lys Lys Glu Val
260 265 270
Ile Val Ala Lys Asp Glu Val Ala His Thr Leu Thr Glu Asn Arg Val
275 280 285
Leu Gln Asn Ser Arg His Pro Phe Leu Thr Ala Leu Lys Tyr Ser Phe
290 295 300
Gln Thr His Asp Arg Leu Cys Phe Val Met Glu Tyr Ala Asn Gly Gly
305 310 315 320
Glu Leu Phe Phe His Leu Ser Arg Glu Arg Val Phe Ser Glu Asp Arg
325 330 335
Ala Arg Phe Tyr Gly Ala Glu Ile Val Ser Ala Leu Asp Tyr Leu His
340 345 350
Ser Glu Lys Asn Val Val Tyr Arg Asp Leu Lys Leu Glu Asn Leu Met
355 360 365
Leu Asp Lys Asp Gly His Ile Lys Ile Thr Asp Phe Gly Leu Cys Lys
370 375 380
Glu Gly Ile Lys Asp Gly Ala Thr Met Lys Thr Phe Cys Gly Thr Pro
385 390 395 400
Glu Tyr Leu Ala Pro Glu Val Leu Glu Asp Asn Asp Tyr Gly Arg Ala
405 410 415
Val Asp Trp Trp Gly Leu Gly Val Val Met Tyr Glu Met Met Cys Gly
420 425 430
Arg Leu Pro Phe Tyr Asn Gln Asp His Glu Lys Leu Phe Glu Leu Ile
435 440 445
Leu Met Glu Glu Ile Arg Phe Pro Arg Thr Leu Gly Pro Glu Ala Lys
450 455 460
Ser Leu Leu Ser Gly Leu Leu Lys Lys Asp Pro Lys Gln Arg Leu Gly
465 470 475 480
Gly Gly Ser Glu Asp Ala Lys Glu Ile Met Gln His Arg Phe Phe Ala
485 490 495
Gly Ile Val Trp Gln His Val Tyr Glu Lys Lys Leu Ser Pro Pro Phe
500 505 510
Lys Pro Gln Val Thr Ser Glu Thr Asp Thr Arg Tyr Phe Asp Glu Glu
515 520 525
Phe Thr Ala Gln Met Ile Thr Ile Thr Pro Pro Asp Gln Asp Asp Ser
530 535 540
Met Glu Cys Val Asp Ser Glu Arg Arg Pro His Phe Pro Gln Phe Ser
545 550 555 560
Tyr Ser Ala Ser Gly Thr Ala
565
<210> 63
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> ITIM保守序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa may be Ser, Ile, Val or Leu
<220>
<221> misc_feature
<222> (2)..(2)
<223> Xaa 可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (4)..(5)
<223> Xaa 可以是任何天然存在的氨基酸
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa 可以是Ile, Val 或 Leu
<400> 63
Xaa Xaa Tyr Xaa Xaa Xaa
1 5
Claims (53)
1.细胞，其包含嵌合抗原受体(CAR)和信号传导修饰蛋白，所述信号传导修饰蛋白选自以下之一：
(i)截短的蛋白质，其包含SH2结构域，但缺少激酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质；
(ii)截短的蛋白质，其包含SH2结构域，但缺少磷酸酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质；
(iii)融合蛋白质，其包含(a)SH2结构域；和(ii)异源结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质。
2.根据权利要求1的细胞，其中所述信号传导修饰蛋白是包含ZAP70SH2结构域但缺少ZAP70激酶结构域的截短的蛋白质。
3.根据权利要求1的细胞，其中所述信号传导修饰蛋白是包含PTPN6SH2但缺少PTPN6磷酸酶结构域的截短的蛋白质。
4.根据权利要求1的细胞，其中所述信号传导修饰蛋白是包含SHP-2SH2结构域但缺少SHP-2磷酸酶结构域的截短的蛋白质。
5.根据权利要求1的细胞，其中所述信号传导修饰蛋白是融合蛋白质，该融合蛋白质包含(i)SH2结构域；和(ii)磷酸酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质。
6.根据权利要求5的细胞，其中所述融合蛋白质包含ZAP70SH2结构域。
7.根据权利要求5或6的细胞，其中所述融合蛋白质包含PTPN6或SHP-2磷酸酶结构域。
8.根据权利要求1的细胞，其中所述信号传导修饰蛋白是融合蛋白质，该融合蛋白质包含(i)来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质的SH2结构域；和(ii)激酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质。
9.根据权利要求8的细胞，其中所述融合蛋白质包含来自PTPN6或SHP-2的SH2结构域。
10.根据权利要求8或9的细胞，其中所述融合蛋白质包含Zap70激酶结构域。
11.根据权利要求8或9的细胞，其中所述融合蛋白质包含AKT或JAK激酶结构域。
12.根据权利要求1的细胞，其中所述信号传导修饰蛋白是融合蛋白质，该融合蛋白质包含(i)SH2结构域；和(ii)异源信号传导结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质。
13.根据权利要求12的细胞，其中所述融合蛋白质包含来自ZAP70、PTPN6或SHP-2的SH2结构域。
14.根据权利要求12或13的细胞，其中所述异源信号传导结构域来自通常不被含有ITAM或ITIM的受体激活的信号传导分子。
15.根据权利要求12、13或14的细胞，其中所述异源信号传导结构域是共刺激性结构域。
16.根据权利要求15的细胞，其中所述融合蛋白质包含CD28、OX40或41BB共刺激性结构域。
17.根据权利要求12、13或14的细胞，其中所述异源信号传导结构域是抑制性结构域。
18.根据权利要求17的细胞，其中所述抑制性结构域包含CD148或CD45的胞内域(endodomain)。
19.根据权利要求17的细胞，其中所述异源信号传导结构域是或包含ICOS、CD27、BTLA、CD30、GITR或HVEM的胞内域。
20.根据权利要求1的细胞，其中所述信号传导修饰蛋白是融合蛋白质，该融合蛋白质包含(i)SH2结构域；和(ii)含有ITAM的结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质。
21.根据权利要求20的细胞，其中所述融合蛋白质包含ZAP70SH2结构域。
22.根据权利要求20或21的细胞，其中所述含有ITAM的结构域是或包含CD3-Zeta的胞内域。
23.根据权利要求1的细胞，其中所述信号传导修饰蛋白是融合蛋白质，该融合蛋白质包含(i)SH2结构域；和(ii)含有ITIM的结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质。
24.根据权利要求23的细胞，其中所述融合蛋白质包含来自PTPN6或SHP-2的SH2结构域。
25.根据权利要求23或24的细胞，其中所述含有ITIM的结构域是或包含来自PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3的胞内域。
26.根据权利要求1的细胞，其中所述信号传导修饰蛋白是融合蛋白质，该融合蛋白质包含(i)SH2结构域；和(ii)蛋白酶结构域，所述SH2结构域来自与磷酸化的基于免疫受体酪氨酸的激活基序(ITAM)结合的蛋白质，或来自与磷酸化的基于免疫受体酪氨酸的抑制基序(ITIM)结合的蛋白质。
27.根据权利要求26细胞，其中所述融合蛋白质包含来自ZAP70、PTPN6或SHP-2的SH2结构域。
28.根据权利要求26或27细胞，其中所述蛋白酶结构域是或包含烟草蚀刻病毒蛋白酶(TeV)。
29.根据权利要求26至28中任一项的细胞，其还包含具有蛋白酶切割位点的膜栓系转录因子(membrane-tethered transcription factor)。
30.根据权利要求29的细胞，其中在所述蛋白酶切割位点处的切割释放转录因子而导致靶基因的表达增加。
31.根据权利要求30的细胞，其中所述靶基因编码细胞因子。
32.根据权利要求31的细胞，其中所述细胞因子选自下组：IL-2、IL-7、IL-15和IL-12。
33.根据权利要求26至28中任一项的细胞，其中所述嵌合抗原受体(CAR)是包含细胞内蛋白酶切割位点的靶CAR。
34.根据权利要求33的细胞，其中所述靶CAR包含激活性或共刺激性胞内域，并且在所述蛋白酶切割位点处的切割从所述靶CAR除去所述胞内域。
35.根据权利要求33的细胞，其中所述靶CAR包含抑制性胞内域，并且在所述蛋白酶切割位点处的切割从所述靶CAR除去所述抑制性胞内域。
36.根据权利要求35的细胞，其中所述抑制性胞内域包含CD148或CD45胞内域。
37.根据权利要求1的细胞，其包含两种CAR：包含含有ITAM的胞内域的激活性CAR；和如权利要求33至36中任一项所定义的靶CAR。
38.根据权利要求1的细胞，其包含两种CAR：包含含有ITIM的胞内域的抑制性CAR；和如权利要求33至36中任一项所定义的靶CAR。
39.核酸构建体，其包含：
编码嵌合抗原受体的第一核酸序列；和
编码如前述任一项权利要求中所定义的截短的蛋白质或融合蛋白质的第二核酸序列。
40.根据权利要求39的核酸构建体，其还包含编码如权利要求29至32中任一项所定义的膜栓系转录因子的第三核酸序列。
41.根据权利要求39的核酸构建体，其还包含编码如权利要求33至36中任一项所定义的靶CAR的第三核酸序列。
42.根据权利要求41的核酸构建体，其还包含编码如权利要求37中所定义的激活性CAR或如权利要求38中所定义的抑制性CAR的第四核酸序列。
43.载体，其包含根据权利要求39至42中任一项的核酸构建体或者如权利要求39至42中任一项所定义的第一和第二，以及任选地第三和/或第四核酸序列。
44.载体组，其包含如权利要求39至42中任一项所定义的第一和第二，以及任选地第三和/或第四核酸序列。
45.根据权利要求43或44的载体或载体组，其是逆转录病毒或慢病毒载体。
46.药物组合物，其包含多个根据权利要求1至38中任一项的细胞。
47.根据权利要求46的药物组合物，其用于治疗和/或预防疾病。
48.治疗和/或预防疾病的方法，其包括向受试者施用根据权利要求46的药物组合物的步骤。
49.根据权利要求48的方法，其包括以下步骤：
(i)从受试者分离含有细胞的样品；
(ii)用根据权利要求41或42的核酸构建体，根据权利要求43至45中任一项的载体或载体组转导或转染所述细胞；并且
(iii)向受试者施用来自(ii)的所述细胞。
50.根据权利要求46的药物组合物在制备用于治疗和/或预防疾病的药物中的用途。
51.根据权利要求47使用的药物组合物或根据权利要求48或49的方法或根据权利要求50的用途，其中所述疾病是癌症。
52.制备根据权利要求1至38中任一项的细胞的方法，其包括向所述细胞导入以下项的步骤：根据权利要求41或42的核酸构建体，根据权利要求43至45中任一项的载体或载体组。
53.根据权利要求52的方法，其中所述细胞来自从受试者分离的样品。
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