CN115551543A - 方法 - Google Patents
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- CN115551543A CN115551543A CN202180034811.1A CN202180034811A CN115551543A CN 115551543 A CN115551543 A CN 115551543A CN 202180034811 A CN202180034811 A CN 202180034811A CN 115551543 A CN115551543 A CN 115551543A
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Abstract
本发明提供了治疗实体癌的方法，其包括向受试者施用细胞的步骤，其中所述细胞包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL‑12)的核酸序列。
Description
发明领域
本发明涉及表达嵌合抗原受体(CAR)的细胞，诸如CAR-T细胞，该细胞分泌白细胞介素-12(IL-12)。编码IL-12的序列位于框架滑动基序(FSM)或翻译通读基序(TRM)的下游使得IL-12以非常低的水平分泌。
发明背景
肿瘤异质性描述了不同的肿瘤细胞可以显示出有区别的形态学和表型概况的观察现象，包括细胞形态、基因表达、代谢、运动性、增殖和转移潜力。
异质性在患者之间、肿瘤之间(肿瘤间异质性)和肿瘤内部(肿瘤内异质性)发生。已经在肿瘤细胞之间观察到多种类型的异质性，源于遗传和非遗传变异性。
由于肿瘤微环境中的异质性，肿瘤细胞之间的异质性可以进一步增加。肿瘤中的区域差异(例如氧气的可用性)对肿瘤细胞施加不同的选择压力，导致在肿瘤的不同空间区域中较宽的优势亚克隆谱。微环境对克隆优势的影响也是在许多患者中看到的原发性和转移性肿瘤之间的异质性以及在具有相同肿瘤类型的患者之间观察到的肿瘤间异质性的可能原因。
癌细胞的异质性为设计有效的治疗策略引入了重大的挑战。
例如，异质性肿瘤可以在不同的克隆群中展现出对细胞毒性药物不同的敏感性。这归因于可抑制或改变治疗功效的克隆相互作用。
在异质性肿瘤中的药物施用很少会杀伤全部肿瘤细胞。最初的异质性肿瘤群可能成为瓶颈，使得很少的药物抗性细胞(如果有的话)会存活。这容许抗性肿瘤群通过分支进化机制复制并生长新的肿瘤。产生的重新增殖的肿瘤是异质性的，并且对所使用的最初药物治疗具有抗性。重新增殖的肿瘤也可能以更有侵略性的方式返回。
因此，需要可替代的方法以解决实体瘤中抗原异质性的问题。
嵌合抗原受体(CAR)
已经描述了许多用于癌症治疗的免疫治疗剂，包括治疗性单克隆抗体(mAb)、双特异性T细胞衔接器和嵌合抗原受体(CAR)。
嵌合抗原受体是将单克隆抗体(mAb)的特异性移植到T细胞的效应子功能的蛋白质。它们的通常形式是I型跨膜域蛋白的形式，其具有抗原识别氨基末端、间隔物、跨膜域，上述结构全部与传递T细胞存活和激活信号的复合胞内域相连。
这些分子最常见的形式是衍生自识别靶抗原的单克隆抗体的单链可变片段(scFv)经由间隔物和跨膜域融合至信号传导胞内域的融合物。此类分子引起T细胞响应scFv对其靶标的识别而激活。当T细胞表达此类CAR时，它们识别并杀伤表达靶抗原的靶细胞。已经开发了几种针对肿瘤相关抗原的CAR，并且使用此类表达CAR的T细胞的过继转移方法目前正在临床试验中，用于治疗多种癌症。
迄今为止，CAR T细胞的成功主要在于血液恶性肿瘤。靶向B细胞抗原CD19的CAR首次成功用于治疗慢性淋巴细胞白血病(CLL)。2017年8月，FDA批准了使用CART19(Kymriah)治疗小儿复发性或难治性急性淋巴细胞白血病(ALL)，并且在同年10月，FDA批准了另一个靶向CD19的CAR(Yescarta)用于成人复发性或难治性大B细胞淋巴瘤。此外，2018年6月欧洲药品管理局(EMA)也批准了这两种药物的使用。然而，尽管进行了大量的研究，实体瘤的CART细胞疗法还远没有那么成功。
克服不利的肿瘤微环境
对于成功的基于细胞的实体癌的免疫治疗性治疗需要克服的关键障碍之一是肿瘤微环境(TME)，其已经被广泛表征为对T细胞不利。对于CAR-T细胞也是如此，对于其他免疫治疗方法诸如使用肿瘤浸润淋巴细胞(TIL)和表达工程化的T细胞受体(TCR)的T细胞也是如此。
肿瘤细胞的糖酵解代谢使环境缺氧、酸性、营养成分低并倾向于氧化应激。在炎症环境中，肿瘤细胞通常上调结合T细胞上抑制性受体的配体，诸如程序性细胞死亡配体1(PD-1)和半乳糖凝集素-9。肿瘤微环境还依赖于基质细胞，如癌症相关成纤维细胞(CAF)和抑制性免疫细胞，包括髓系来源的抑制细胞(MDSC)、肿瘤相关巨噬细胞(TAM)、肿瘤相关中性粒细胞(TAN)、肥大细胞和调节性T细胞(Treg)。这些细胞和肿瘤细胞分泌可溶性因子，如血管内皮生长因子(VEGF)和转化生长因子β(TGFβ)，这些可溶性因子有助于使肿瘤血管系统异常、促进TAM和其他免疫细胞的抗炎极化并参与EMT。它们还产生活性氧种类(ROS)和分子，如乳酸、吲哚胺2,3-双加氧酶(IDO)、前列腺素E2(PGE2)、可溶性Fas和腺苷，这些分子有助于T细胞免疫应答的抑制。
已经在临床前和临床试验中均测试了施用细胞因子使肿瘤环境极化以对T细胞更友好并改善CAR T细胞招募和功能。已经显示诱导炎症性免疫细胞招募的局部IL-12递送增强了在小鼠中过继转移的抗VEGFR-2CAR T细胞的抗肿瘤活性。已经创造了组成型分泌细胞因子诸如IL-12的CAR T细胞(称为“装甲的”CAR)，以增强T细胞在实体瘤中的浸润和功能。然而，这些方法具有局限性：细胞因子的全身性施用可能是有毒性的；细胞因子的组成型产生可能导致不受控制的增殖和转化(Nagarkatti et al(1994)PNAS91:7638-7642；Hassuneh et al(1997)Blood 89:610-620)。
因此，需要可替代的方法来帮助免疫治疗细胞(诸如CAR-T细胞)在实体瘤的不利的微环境中存活并持续存在。
附图说明
图1—显示经典的嵌合抗原受体的示意图。
(a)嵌合抗原受体的基本架构；(b)第一代受体；(c)第二代受体；(d)第三代受体。
图2—框架滑动基序和构建体设计。
(A)示出了框架滑动基序的图形，其中一连串七个尿嘧啶插入到转基因序列中，其促进框架滑动。框架滑动导致替代性地阅读框继续转录/翻译，通常在-1方向，并且产生功能性蛋白质。(B)构建体的结构，显示了转基因、框架滑动基序(SLIP)和2A自切割肽序列的位置。(C)流式细胞术分析转导了构建体的SupT1细胞，该构建体含有RQR8分拣选择标记，之后为对照序列(6xU)或框架滑动基序(7xU)之一和CD22-CD19嵌合蛋白，该嵌合蛋白由融合至CD19的跨膜和截短的胞内域的CD22的胞外域组成。框架滑动基序的引入导致CD22-CD19嵌合物的表达显著降低，而观察到RQR8分拣选择标记相似的水平。
图3—翻译通读基序和构建体设计。
(A)已知的翻译通读基序的示例。(B-G)翻译通读基序构建体的结构。(B)由两个转基因组成的翻译通读构建体，其中翻译通读基序位于第一个转基因的3’和2A自切割肽序列和转基因2的5’。转基因1的表达将显著高于转基因2。(B’)双终止翻译通读构建体，其中将两个终止密码子并入翻译通读基序以降低表达水平，甚至比用单个终止密码子实现的降低表达水平更进一步。(C)通用翻译通读构建体，由侧翼为两个2A自切割肽序列的翻译通读基序组成。该构建体减轻了可能导致不可预测的翻译通读水平的序列依赖性效应。(D)组合方法，其中翻译通读基序与衰减的信号肽序列组合以甚至进一步降低转基因2的表达水平。(E和E’)复合翻译通读基序，其中多个基序串联放置以产生级联减少的转基因表达。(E)多个转基因从使用翻译通读基序和2A自切割肽序列的单个表达盒表达。(E’)使用自切割肽序列以将翻译通读基序分开，上述序列位于转基因2的5’。
图4—示意图示出了用载体转导的细胞中IL-12分泌的剧烈减少，该载体中编码IL-12的序列位于“停止-跳跃”序列(SS)即与终止密码子组合的框架滑动基序或翻译通读基序的下游。
图5—ELISA显示了未转导的细胞(NT)或用以下构建体转导的细胞的上清液中IL-12的浓度：共表达CAR和IL-12的构建体(CAR-2A-IL12)；或共表达CAR和IL-12的构建体，其中IL-12编码序列位于“停止-跳跃”序列的下游(CAR-SS-IL12)。
图6—图表显示了在施用未转导的细胞(NT)或用以下构建体转导的细胞后小鼠的体重：共表达CAR和IL-12的构建体(CAR-2A-IL12)；或共表达CAR和IL-12的构建体，其中IL-12编码序列位于“停止-跳跃”序列的下游(CAR-SS-IL12)。
图7—图表显示了在施用未转导的细胞(NT)或用以下构建体转导的细胞后小鼠中肿瘤大小随时间的变化：单独表达GD2 CAR的构建体(CAR)；共表达GD2 CAR和IL-12的构建体(CAR-2A)；共表达GD2 CAR和IL-12的构建体，其中编码IL-12的序列位于“停止-跳跃”序列的下游(CAR-SS)；或共表达针对不相关的靶抗原的CAR和IL-12的构建体，其中编码IL-12的序列位于“停止-跳跃”序列的下游(MR1-SS)。
发明内容概述
本发明的发明人已经在小鼠模型中显示，施用表达高水平IL-12的工程化的细胞是有毒的。他们还显示，可能通过在编码IL-12的序列的上游包含基序以急剧降低IL-12的表达水平。这些表达超低IL-12的细胞不会在小鼠模型中引起显著的毒性。此外，在实体瘤模型中，表达超低IL-12的CAR-T细胞展现出比单独表达CAR的细胞更有力的抗肿瘤活性。
因此，在第一方面，本发明提供了治疗实体癌的方法，其包括向受试者施用细胞的步骤，其中该细胞包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。
方法可以包括以下步骤：
(i)从受试者中分离细胞样品；
(ii)用位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列转染或转导来自细胞样品的细胞；和
(iii)向受试者施用来自步骤(ii)的转导的或转染的细胞。
编码IL-12的核酸序列可以编码“flexi-IL-12”：IL-12α和IL-12β亚基之间的融合物，通过接头连接。Flexi-IL-12可以包含如SEQ ID No.1所示的序列。
当编码白细胞介素12(IL-12)的核酸序列位于框架滑动基序(FSM)下游时，FSM可以包含尿嘧啶、胸腺嘧啶或鸟嘌呤碱基的重复。例如，FSM可以包含序列UUUUUUU(SEQ IDNo.2)。
FSM还可以包含终止密码子。例如，FSM可以包含以下序列之一：
UUUUUUUGA(SEQ ID NO.3)
UUUUUUUAG(SEQ ID NO.4)
UUUUUUUAA(SEQ ID NO.5)。
当编码白细胞介素12(IL-12)的核酸序列位于翻译通读基序(TRM)下游时，TRM可以包含序列STOP-CUAG或STOP-CAAUUA，其中“STOP”是终止密码子。
翻译通读基序可以包含以下序列之一：
UGA-CUAG(SEQ ID No.6)
UAG-CUAG(SEQ ID No.7)
UAA-CUAG(SEQ ID No.8)
UGA-CAAUUA(SEQ ID No.9)
UAG-CAAUUA(SEQ ID No.10)
UAA-CAAUUA(SEQ ID No.11)。
细胞可以是肿瘤浸润免疫细胞，诸如T细胞、自然杀伤(NK)细胞、NKT细胞、细胞因子诱导的杀伤(CIK)细胞、单核细胞、巨噬细胞或肿瘤浸润淋巴细胞(TIL)。
细胞可以表达嵌合抗原受体(CAR)或工程化的T细胞受体(TCR)，例如，结合以下靶抗原之一的CAR或工程化的TCR：双唾液酸神经节苷脂(GD2)、表皮生长因子受体(EGFR)、上皮细胞粘附分子(EpCAM)、磷脂酰肌醇蛋白聚糖3(GPC3)、人表皮生长因子受体(HER2)、L1CAM、粘蛋白1(MUC1)、前列腺特异性膜抗原(PSMA)。
在本发明的一个实施方案中，细胞表达结合GD2并具有抗原结合域的CAR，该抗原结合域包含
a)重链可变区(VH)，其具有具有以下序列的互补决定区(CDR)：
CDR1–SYNIH(SEQ ID No.12)；
CDR2–VIWAGGSTNYNSALMS(SEQ ID No.13)；
CDR3–RSDDYSWFAY(SEQ ID No.14)；和
b)轻链可变区(VL)，其具有具有以下序列的CDR：
CDR1–RASSSVSSSYLH(SEQ ID No.15)；
CDR2–STSNLAS(SEQ ID No.16)；
CDR3–QQYSGYPIT(SEQ ID No.17)。
在本发明的另一个实施方案中，细胞表达结合PSMA并具有抗原结合域的CAR，该抗原结合域包含
a)重链可变区(VH)，其具有具有以下序列的互补决定区(CDR)：
CDR1–SSWMN(SEQ ID No.18)；
CDR2–RIYPGDGDTNYAQKFQG(SEQ ID No.19)；
CDR3–GTGYLWYFDV(SEQ ID No.20)；和
b)轻链可变区(VL)，其具有具有以下序列的CDR：
CDR1–RASQDINENLA(SEQ ID No.21)；
CDR2–YTSNRAT(SEQ ID No.22)；
CDR3–QQYDNLPFT(SEQ ID No.23)。
细胞还可以表达：
显性负性SHP2；和/或显性负性TGFβ受体；
嵌合细胞因子受体；和/或
一种或多种额外的细胞因子或趋化因子。
细胞可以表达以下一种或多种：IL-7、IL-15、CCL19、CXCL12。特别的，细胞可以表达IL-7和CCL19；或IL-15和/或CXCL12。
编码额外的细胞因子或趋化因子或每种额外的细胞因子或趋化因子的核酸可以位于框架滑动基序(FSM)或翻译通读基序(TRM)的上游。
可替代地，编码额外的细胞因子或趋化因子或每种额外的细胞因子或趋化因子的核酸可以位于框架滑动基序(FSM)或翻译通读基序(TRM)的下游。
本发明的方法可以用于治疗实体癌，诸如：小细胞肺癌(SCLC)、黑色素瘤、肾细胞癌(RCC)、肝细胞癌(HCC)、卵巢癌、胰腺癌、成神经细胞瘤或骨肉瘤。
CAR或工程化的TCR可以结合在实体瘤上具有异质表达的靶抗原。
在第二方面，本发明提供了在受试者诱导在抗肿瘤免疫应答中的表位扩散的方法，其包括向受试者施用多个如本发明第一方面所定义的细胞的步骤。
在第三方面，本发明提供了在受试者中诱导免疫细胞浸润到肿瘤块中的方法，其包括向受试者施用多个如本发明第一方面所定义的细胞的步骤，使得该细胞诱导抗肿瘤免疫应答。
在第四方面，提供了用于治疗实体癌的细胞，该细胞包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。
在第五方面，提供了细胞在制备用于治疗实体癌的药物中的用途，其中该细胞包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。
在第六方面，提供了表达嵌合抗原受体(CAR)的细胞，其包含：
位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列；和
编码一种或多种额外的细胞因子或趋化因子的一种或多种异源核酸序列。
一种或多种异源核酸序列可以编码以下中的一种或多种：IL-7、IL-15、CCL19、CXCL12。
例如，一种或多种异源核酸序列可以编码IL-7和CCL19。
可替代地，一种或多种异源核酸序列可以编码IL-15和/或CXCL12。
编码额外的细胞因子或趋化因子的核酸序列可以位于框架滑动基序(FSM)或翻译通读基序(TRM)的上游或下游。当有两个或更多个编码额外的细胞因子或趋化因子的核酸序列时，一个或多个可能在FSM或TRM的上游，因此它/它们以高水平表达；并且一个或多个可能在FSM或TRM的下游，因此它/它们以低水平表达。
在第七方面，提供了核酸构建体，其包含：
(i)编码嵌合抗原受体(CAR)的核酸序列；和
(ii)位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列；
(vi)如上文所定义的编码一种或多种额外的细胞因子或趋化因子的一种或多种核酸序列。
在第八方面，提供了包含根据本发明第七方面的核酸构建体的载体。
在第九方面，提供了载体试剂盒，每个载体编码一种或多种如上文所定义的核酸序列。
在第十方面，提供了制备根据本发明第六方面的细胞的方法，其包括用根据第七方面的核酸构建体、根据第八方面的载体或根据第九方面的载体试剂盒离体转染或转导细胞的步骤。
本发明提供了用于治疗癌症特别是实体瘤的细胞，该细胞以非常低的水平分泌IL-12。
与先前开发的“装甲的”CAR-T细胞不同，IL-12的分泌水平通过在IL-12编码序列上游并入框架滑动基序或翻译通读基序而降低。本发明的发明人已经显示，低水平IL-12的局部表达极大地增强了抗肿瘤应答而不会引起有问题的毒性水平。
IL-12的局部分泌有两个作用：第一，其提高了CAR-T细胞对不利的肿瘤环境的抗性，提高了CAR-T细胞的增殖和持久性；第二，其具有辅助作用，引起抗肿瘤免疫应答的普遍激活。
在这方面，IL-12的释放在免疫应答过程中具有多种作用，其包括：1)增强T细胞和NK细胞的增殖，2)提高T细胞、NK细胞和巨噬细胞的溶细胞活性，3)激活T辅助细胞1(Th1)细胞，和4)诱导IFN-γ和其他细胞因子的产生。除了激活CAR-T细胞外，认为CAR-T细胞同时局部表达低水平的IL-12将导致“表位扩散”，即启动针对肿瘤细胞上存在的额外的靶抗原的免疫应答。CAR-T细胞的IL-12分泌也可诱导宿主免疫细胞浸润到肿瘤块中。因此，通过CAR-T细胞的直接细胞杀伤、免疫细胞浸润到肿瘤中以及诱导现存的宿主免疫细胞针对其他肿瘤相关抗原的抗癌免疫应答的组合来激活抗肿瘤免疫应答。
表位扩散的诱导对于治疗通常在靶抗原的表达方面表现出异质性的实体瘤特别有用。
其他方面
本发明还提供了在以下编号的段落中概述的另外的方面：
1.治疗小细胞肺癌的方法，其包括向受试者施用细胞的步骤，其中该细胞表达GD2CAR、显性负性SHP2(dnSHP2)和显性负性TGFβRII。
2.根据段落1的方法，其中该细胞还表达嵌合细胞因子受体(CCR)。
3.根据段落2的方法，其中该CCR具有IL-7R胞内域。
4.根据段落1的方法，其中该细胞包含具有以下通式结构的第一核酸构建体：
CAR-coexpr1-dnSHP-coexpr2-dnTGFβR,
dnSHP-coexpr1-CAR-coexpr2-dnTGFβR,
CAR-coexpr1-SG-coexpr2-dnSHP-coexpr3-dnTGFβR,
dnSHP-coexpr1-SG-coexpr2-CAR-coexpr2-dnTGFβR，
其中：
dnSHP是编码显性负性SHP-2的核酸序列；
“coexpr1”、“coexpr2”和“coexpr3”，可以相同或不同，是能够使每个多肽作为分开的实体共表达的核酸序列；
“dnTGFβR”是编码显性负性TGFβ受体的核酸序列；
“CAR”是编码抗GD2嵌合抗原受体的核酸序列；和
“SG”是编码自杀基因诸如RQR8的核酸序列。
5.根据段落2或3的方法，其中该细胞包含具有以下通式结构的第二核酸构建体：
CAR-coexpr1-CCR，或
CAR-coexpr1-SG-coexpr2-CCR
其中：
“CAR”是编码抗GD2嵌合抗原受体的核酸序列；
“coexpr1”和“coexpr2”和“coexpr3”，可以相同或不同，是能够使每个多肽作为分开的实体共表达的核酸序列；
“CCR”是编码嵌合细胞因子受体的核酸序列；和
“SG”是编码自杀基因诸如RQR8的核酸序列。
6.根据段落1的方法，其包括以下步骤：
(i)从受试者中分离含有细胞的样品；
(ii)用表达如段落4所定义的第一核酸构建体的载体转导或转染所述细胞；和
(iii)向受试者施用来自步骤(ii)的细胞。
7.根据段落2或3的方法，其包括以下步骤：
(i)从受试者中分离含有细胞的样品；
(ii)用表达如段落4所定义的第一核酸构建体的第一载体和表达如段落5所定义的第二核酸构建体的第二载体转导或转染所述细胞；和
(iii)向受试者施用来自步骤(ii)的细胞。
8.用于治疗小细胞肺癌(SCLC)的细胞，其中该细胞表达GD2CAR、显性负性SHP2(dnSHP2)和显性负性TGFβRII。
9.细胞在制备用于治疗小细胞肺癌(SCLC)的药物中的用途，其中该细胞表达GD2CAR、显性负性SHP2(dnSHP2)和显性负性TGFβRII。
以下详细描述，当其涉及核酸和多肽序列、多肽组分、载体、细胞、方法等，关于权利要求书中本发明的方面，同样适用于上文段落中展示的方面。
发明详述
本发明提供了以非常低的水平表达白细胞介素12(IL-12)的细胞。该细胞包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码IL-12的核酸序列。
IL-12和其他细胞因子/趋化因子
本发明提供了细胞，其包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。该细胞还可以包含编码除IL-12以外的细胞因子和/或趋化因子的异源核酸序列。
白细胞介素12(IL-12)是由树突状细胞、巨噬细胞、中性粒细胞和人类B淋巴母样细胞响应抗原刺激而天然产生的白细胞介素。IL-12参与幼稚T细胞分化成Th1细胞。它被称为T细胞刺激因子，可以刺激T细胞的生长和功能。它刺激T细胞和自然杀伤(NK)细胞产生干扰素-γ(IFN-γ)和肿瘤坏死因子-α(TNF-α)，并减少IL-4介导的IFN-γ抑制。
IL-12在自然杀伤细胞和T淋巴细胞的活动中起重要作用。IL-12介导NK细胞和CD8+细胞毒性T淋巴细胞的细胞毒活性的增强。
IL-12是有力的免疫调节细胞因子，对于调节肿瘤微环境，从而重定向针对癌症的免疫反应特别令人感兴趣。IL-12具有全身毒性，因此局部产生IL-12的方法是令人感兴趣的。
IL-12是异二聚体细胞因子，由两个单独的基因IL-12A(p35)和IL-12B(p40)编码。在蛋白质合成后形成活性的异二聚体(称为“p70”)。
本发明的细胞可以包含编码IL-12A和/或IL-12B的异源核酸序列。人IL-12A的序列可从Uniprot登录号P29459获得。该序列的缺少信号肽的部分如下文SEQ ID No.24所示。人IL-12B的序列可从Uniprot登录号P29460获得。该序列的缺少信号肽的部分如下文SEQID No.25所示。
SEQ ID No.24(人IL-12A)
SEQ ID No.25(人IL-12B)
异源核酸序列可以编码“flexi-IL-12”，其是人IL-12α(p35)和IL-12β(p40)亚基之间的融合物，通过接头连接。合适的flexi-IL-12序列如下文SEQ ID No.1所示。
SEQ ID No.1(flexi-IL-12序列)
在SEQ ID No.1中，信号肽(来自鼠κ链V-III区MOPC 63(Uniprot P01661)的信号肽)以粗体显示；丝氨酸-甘氨酸接头以粗体和下划线显示。Flexi-IL12可以包含SEQ IDNo.1中所示的IL-12A和B序列，但具有不同的信号肽和/或接头序列。它可以具有通式结构：
SP-IL12A-L-IL12B
其中SP是信号肽，IL12A是人IL-12A；L是接头序列，诸如甘氨酸-丝氨酸接头；IL12B是人IL-12B。
异源核酸序列可以编码如SEQ ID No.1、24或25所示的序列之一或其变体。变体序列可以与SEQ ID No.1、24或25具有至少80、85、90、95、98或99％的序列同一性，条件是该变体序列在体内表达时保留IL-12功能。例如，变体序列可以保留增强体内细胞毒性T细胞活性的能力和/或变体序列可以刺激T细胞产生干扰素-γ(IFN-γ)。
细胞可以包含编码除了IL-12之外的一种或多种细胞因子的一种或多种异源核酸。例如，一种或多种核酸序列可以编码增强炎症反应和/或提高CAR-T细胞疗法功效的细胞因子。细胞因子可以选自以下：IL-7、IL15、IL-17A、IL-18、IL-2、GM-CSF和IL-21。特别地，额外的细胞因子可以是IL-7。
IL-7
IL-7是对B细胞和T细胞发育重要的细胞因子。IL-7刺激多能(multipotent)(多能性(pluripotent))造血干细胞分化为淋巴祖细胞，并刺激淋巴谱系中所有细胞(B细胞、T细胞和NK细胞)的增殖。
IL-7和肝细胞生长因子(HGF)形成异二聚体，其作为pre-pro-B细胞生长刺激因子发挥功能。发现这种细胞因子是早期T细胞发育过程中T细胞受体β(TCRβ)的V(D)J重排的辅因子。人IL-7的氨基酸序列可从UniProt(登录号P13232)获得，如下文SEQ ID No.26所示。
SEQ ID No.26(人IL-7)
IL-15
白细胞介素-15(IL-15)是与白细胞介素-2(IL-2)结构相似的细胞因子。与IL-2相似，IL-15与由IL-2/IL-15受体β链和共同的γ链构成的复合物结合并通过该复合物传导信号。被一种或多种病毒感染后IL-15在由单核吞噬细胞和其他细胞分泌，并调节T细胞和自然杀伤(NK)细胞的活化和增殖。
人IL-15的氨基酸序列可从UniProt(登录号P40933)获得，如下文SEQ ID No.27所示。
SEQ ID No.27(人IL-15)
IL-17A、IL-18、IL-2、粒细胞-巨噬细胞集落刺激因子(GM-CSF)和IL-21的氨基酸序列可从UniProt获得，如下表所示。
| 细胞因子 | UniProt登录号 |
| IL-17A | Q16552 |
| IL-18 | Q14116 |
| IL-2 | P60568 |
| GM-CSF | P04141 |
| IL-21 | Q9HBE4 |
一种或多种异源核酸序列可以编码一种或多种趋化因子。
趋化因子是由细胞分泌的小细胞因子家族。它们的名字来源于它们在附近的反应性细胞中诱导定向的趋化性的能力；它们是趋化性细胞因子。由受感染的或受损的细胞释放的趋化因子形成浓度梯度。被吸引的细胞通过梯度向更高浓度的趋化因子移动。
趋化因子的质量均约为8-10千道尔顿，并且在保守位置具有四个半胱氨酸残基，这是形成其三维形状的关键。一些趋化因子被认为是促炎性的，并且可以在免疫应答期间被诱导以将免疫系统的细胞招募到感染的部位。实例为：CXCL-8、CCL2、CCL3、CCL4、CCL5、CCL11、CXCL10。其他趋化因子被认为是恒定性的，并且在组织维持或发育的正常过程中参与控制细胞的迁移。这些趋化因子包括：CCL14、CCL19、CCL20、CCL21、CCL25、CCL27、CXCL12和CXCL13。这种分类不严格，例如，CCL20也可以充当促炎性趋化因子。
已经将趋化因子分为四个主要亚家族：CXC、CC、CX3C和XC。所有这些蛋白质都通过与G蛋白连接的跨膜受体(称为趋化因子受体)相互作用来发挥其生物学作用，这些受体选择性地存在于其靶细胞表面。
细胞可以表达恒定性趋化因子，诸如CCL19或CXCL12。
趋化因子(CC基序)配体19(CCL19)是属于CC趋化因子家族的小细胞因子，也称为EBI1配体趋化因子(ELC)和巨噬细胞炎性蛋白-3-β(MIP-3-β)。CCL19通过与趋化因子受体CCR7结合而引发对其靶细胞的影响。它吸引免疫系统的某些细胞，包括树突状细胞和抗原结合的B细胞和CCR7+中央记忆T细胞。人CCL19的氨基酸序列可从UniProt(登录号Q99731)获得，并如下文SEQ ID No.28所示。
SEQ ID No.28(CCL19)
C-X-C基序趋化因子12(CXCL12)，即基质细胞衍生因子1(SDF1)，通过同一基因的可变剪接以两种形式(CXCL12a和CXCL12b)产生。趋化因子的特征在于存在四个保守的半胱氨酸，它们形成两个二硫键。CXCL12蛋白属于CXC趋化因子组，其半胱氨酸的初始对由一个中间氨基酸隔开。此外，CXCL12 N末端的前8个残基充当受体结合位点，环区的RFFESH基序(残基12-17，SEQ ID NO:102)充当CXCL12受体结合的对接位点。
CXCL12在小鼠的许多组织中表达，包括脑、胸腺、心脏、肺、肝、肾、脾和骨髓。CXCL12对淋巴细胞具有很强的趋化性。人CXCL12的氨基酸序列可从UniProt(登录号P48061)获得，并如下文SEQ ID No.29所示。
SEQ ID No.29(CXCL12)
停止跳跃基序
框架滑动
在转录过程中，RNA聚合酶基于与DNA模板互补而催化核苷酸并入生长的RNA链中。然而，当RNA聚合酶遇到一段重复的碱基时，会发生滑动或“打滑”。在自然界中利用了转录滑动，例如，用于调节大肠杆菌pyrBI和codBA操纵子、副粘液病毒中P基因的表达和嗜热栖热菌(Thermus thermophiles)的细胞dnaX基因的解码。
当RNA聚合酶滑动时，这会导致合成编码替代性的阅读框的mRNA，因为它缺少一个(或可能两个)重复碱基。
本发明的核酸构建体可以包含转录框架滑动位点，使得下游转基因的转录仅在RNA聚合酶滑移产生编码替代性的阅读框的mRNA的情况下发生。
将mRNA序列翻译成蛋白质是一个复杂的过程，涉及核糖体、起始和延伸因子、氨酰转移RNA(aa-tRNA)、氨酰tRNA合成酶和释放因子的协调。当一系列因子与mRNA的5'末端结合时翻译起始，然后导致40S核糖体的招募和mRNA的扫描。当一系列起始因子和40S核糖体遇到编码氨基酸甲硫氨酸的密码子(核苷酸三联体)(AUG密码子)时，60S核糖体被招募，多肽合成从装载有适当氨基酸的同源tRNA配对开始。翻译的起始可以在AUG以外的可替代的起始密码子处发生，但AUG是最常用的起始密码子。多肽的延伸以循环方式发生，其中tRNA与其同源密码子结合，在新添加的氨基酸和延伸的多肽之间形成肽键，并且多肽易位以暴露下一个密码子。
在翻译期间，在核糖体阻滞在特定密码子处时核糖体停滞可能发生。核糖体停滞可以通过核苷酸水解(nucleocytic)途径促进mRNA降解，或者它可以诱导-1或-2方向的滑动。已知mRNA中的重复序列(诸如UUUUUUA)可诱导翻译框架滑动，并且该序列存在于人类免疫缺陷病毒(HIV)的组特异性抗原基因(gag)和聚合酶(pol)基因的3'端。HIV gag/pol基因的-1翻译框架滑动导致Gag-Pol多聚蛋白的表达。
本发明的核酸构建体可以包含翻译框架滑动位点，使得下游转录本的翻译仅在如果有核糖体的框架滑动时发生。
框架滑动位点可以包含一段相同类型的碱基。
可以将框架滑动基序放置在核酸构建体中切割位点的上游和/或下游。框架滑动基序位于核酸构建体中的第一和第二转基因之间。
框架滑动基序可以单独使用。在这个实施方案中，可以将第二转基因放置在框架滑动位点下游的框外，使得第二转基因的转录或翻译需要框架滑动。
该基序可以例如包含5、7、8、10或11个碱基的一段。例如，该位点可以包含尿嘧啶、腺苷或鸟嘌呤碱基的重复。例如，该位点可以包含如SEQ ID No.2所示的序列
UUUUUUU(SEQ ID No.2)。
可替代地，框架滑动位点可以与终止密码子组合使用。在这个实施方案中，可以将终止密码子放置在框架滑动位点下游的框内，使得需要框架滑动来忽略终止密码子。
终止密码子可以是UGA、UAG或UAA。框架滑动位点可以包含三个的倍数的尿嘧啶、腺苷或鸟嘌呤碱基的重复，例如3、6或9个尿嘧啶、腺苷或鸟嘌呤碱基的重复。
框架滑动位点/终止密码子组合的实例如SEQ ID No.3、4和5所示。
UUUUUUUGA(SEQ ID NO.3)
UUUUUUUAG(SEQ ID NO.4)
UUUUUUUAA(SEQ ID NO.5)。
翻译通读
当核糖体遇到UGA、UAG或UAA终止密码子时翻译终止。此时，释放因子识别终止密码子并促进核糖体的解离和再循环。由于释放因子和近同源tRNA之间的竞争，随着终止密码子的解码，翻译终止通常以高保真度发生，并且多肽的持续延伸仅在0.1％的时间发生。然而，据报道，某些基因中的终止密码子解码水平升高导致翻译通读。在某些情况下，这会导致产生具有额外功能基序的更长的多肽，这一过程称为功能通读。
当释放因子1(RF1)无法识别终止密码子并且近同源的aa-tRNA将氨基酸插入延伸的多肽中时，会发生翻译通读，从而抑制终止密码子。释放因子和aa-tRNA的局部浓度影响终止密码子抑制和翻译通读的水平，低浓度的释放因子促进翻译通读。在哺乳动物中，UAG终止密码子的抑制导致色氨酸、精氨酸或半胱氨酸残基的插入。
最早发现的终止密码子抑制的实例之一是兔β珠蛋白基因，其中翻译通读导致在蛋白质3的C端添加22个氨基酸。
翻译通读的频率取决于许多因素，包括：1)使用的终止密码子(UGA、UAG或UAA)；2)终止密码子两侧紧接的序列，终止密码子上游和下游的六个核苷酸特别重要；以及3)在mRNA的3'端顺式作用序列的存在。
三个终止密码子的终止效率不同，其中UAA是最强的终止密码子，UGA是最弱的终止密码子，终止效率的等级定义为UAA>UAG>UGA。因此，UGA终止密码子展现出最高水平的翻译通读，UAA终止密码子展现出最低水平的翻译通读。
对展现出翻译通读的基因的序列分析已经鉴定出至少两种促进终止密码子抑制和维持翻译的不同基序：STOP-CUAG和STOP-CAAUUA(其中STOP可以是UGA、UAG或UAA)。翻译通读的水平取决于所使用的终止密码子：UGA支持最高水平的翻译通读，并且从UAG和UAA终止密码子获得递减的通读水平，因此通读的整体等级是UGA>UAG>UAA。
本发明的核酸构建体可以包含如SEQ ID No.6至11所示的序列之一。
UGACUAG(SEQ ID No.6)
UAGCUAG(SEQ ID No.7)
UAACUAG(SEQ ID No.8)
UGACAAUUA(SEQ ID No.9)
UAGCAAUUA(SEQ ID No.10)
UAACAAUUA(SEQ ID No.11)
翻译通读位点可以位于核酸构建体中的第一转基因和第二转基因之间。可以将翻译通读位点放置在核酸构建体中切割位点的上游和/或下游。翻译通读位点的两侧可以是切割位点(图3C)。可以使用两个或更多个翻译通读位点，例如，彼此相邻放置(图3B')，或者位于切割位点的两侧(图E')。
为了进一步降低下游转基因的表达水平，可以在翻译通读基序的5'插入多个终止密码子(图2B)。多个终止翻译通读基序的实例如SEQ ID NO.30所示，其中将两个UGA终止密码子放置在CUAG通读基序的5'。
UGAUGACUAG(SEQ ID No.30)。
上述序列以RNA的形式呈现，但在构建体中，它们可以是一旦转录就产生这些RNA序列的等同的DNA序列，对于上述SEQ ID No.6-11其将是：
TGACTAG(SEQ ID No.31)
TAGCTAG(SEQ ID No.32)
TAACTAG(SEQ ID No.33)
TGACAATTA(SEQ ID No.34)
TAGCAATTA(SEQ ID No.35)
TAACAATTA(SEQ ID No.36)
特别地，编码TRM的DNA序列可以具有如SEQ ID No.37所示的序列，其编码STOP；亮氨酸；丙氨酸。
TGACTAGCA(SEQ ID No.37)
在核酸构建体包含超过两个转基因的情况下，可以将复合翻译通读基序串联放置在编码切割位点的序列的5'。这使得多个转基因能够以不同的比率表达。对于每个额外的通读基序，表达水平相对于上游转基因应该降低10到50倍。
可以将编码IL-12的核酸序列放置在框架滑动基序(FSM)或翻译通读基序(TRM)的下游。核酸构建体可以具有通式结构：
CAR-FSM/TRM-coexpr-IL12
其中：
“CAR”是编码嵌合抗原受体的核酸序列；
“FSM/TRM”是框架滑动基序或翻译通读基序；
“coexpr”是能够使CAR和IL-12作为分开的多肽共表达的序列；并且
“IL-12”是编码IL-12或flexi-IL12的核酸序列。
在包含编码另一种细胞因子或趋化因子或趋化因子的核酸序列的构建体中，也可将其放置在FSM或TRM的下游，使得一种或多种其他细胞因子或一种或多种趋化因子的表达水平也降低(与在没有FSM或TRM序列的情况下获得的表达水平相比)。在这一方面，一种或多种其他细胞因子或一种或多种趋化因子的表达水平降低可与IL-12的表达水平降低相当。此类构建体可以具有通式结构：
CAR-FSM/TRM-coexpr1-IL12-coexpr2-CC；或
CAR-FSM/TRM-coexpr1-CC-coexpr2-IL12
其中：
“CAR”是编码嵌合抗原受体的核酸序列；
“FSM/TRM”是框架滑动基序或翻译通读基序；
“coexpr1”和“coexpr2”，可以相同或不同，是能够使CAR、IL-12和细胞因子或趋化因子作为分开的多肽共表达的序列；
“IL-12”是编码IL-12或flexi-IL12的核酸序列；和
“CC”是编码细胞因子(除IL-12以外)或趋化因子的核酸序列。
可替代地，可以将编码其他细胞因子或编码趋化因子的核酸序列放置在FSM或TRM的上游或单独的构建体上，使得其表达不受FSM或TRM的影响。通过这样的排列，一种或多种其他细胞因子或一种或多种趋化因子的表达水平将超过IL-12的表达水平。此类构建体可以具有通式结构：
CAR-coexpr1-CC-FSM/TRM-coexpr2-IL12；或
CC-coexpr1-CAR-FSM/TRM-coexpr2-IL12
其中：
“CAR”是编码嵌合抗原受体的核酸序列；
“FSM/TRM”是框架滑动基序或翻译通读基序；
“coexpr1”和“coexpr2”，可以相同或不同，是能够使CAR、IL-12和细胞因子或趋化因子作为分开的多肽共表达的序列；
“IL-12”是编码IL-12或flexi-IL12的核酸序列；和
“CC”是编码细胞因子(除IL-12以外)或趋化因子的核酸序列。
第三种选择是可以将编码一种或多种其他细胞因子或一种或多种趋化因子的核酸序列放置于与IL-12编码序列上游的FSM或TRM不同的FSM或TRM的下游。这可具有“复合”作用。例如，具有复合翻译通读基序的核酸构建体可以具有结构：
CAR-FSM/TRM1-coexpr1-CC-FSM/TRM2-coexpr2-IL12
其中：
“CAR”是编码嵌合抗原受体的核酸序列；
“FSM/TRM1”和“FSM/TRM2”，可以相同或不同，是框架滑动基序或翻译通读基序；
“coexpr1”和“coexpr2”，可以相同或不同，是能够使CAR、IL-12和细胞因子或趋化因子作为分开的多肽共表达的序列；
“IL-12”是编码IL-12或flexi-IL12的核酸序列；并且
“CC”是编码细胞因子(除IL-12以外)或趋化因子的核酸序列。
在这种排列下，CAR的表达水平将高于细胞因子/趋化因子的表达水平，细胞因子/趋化因子的表达水平将高于IL-12的表达水平。
改变的信号肽
虽然翻译通读基序会显著降低转基因的表达，但在某些情况下，可能有必要进一步降低表达水平。对于分泌的蛋白质，可以通过将翻译通读基序与改变的信号肽序列组合来实现表达的进一步降低。在这种情况下，将改变的信号肽和第二个转基因放置在翻译通读基序和自切割肽序列的3'(图3D)。
信号肽是短肽，通常5-30个氨基酸长，存在于大多数注定要进入分泌途径的新合成的蛋白质的N末端。这些蛋白质包括驻留在某些细胞器(例如，内质网、高尔基体或内体)内的蛋白质、从细胞分泌的蛋白质和跨膜蛋白质。
信号肽通常含有核心序列，该核心序列是一长段具有形成单个α-螺旋的趋势的疏水性氨基酸。信号肽可以以一短段带正电荷的氨基酸开始，这有助于在转移过程中加强多肽合适的拓扑结构。在信号肽的端部，通常有被信号肽酶识别和切割的一段氨基酸。信号肽酶可以在转移过程中或转移完成后切割以产生游离的信号肽和成熟蛋白。然后特定的蛋白酶消化游离的信号肽。
信号肽通常位于分子的氨基末端，尽管一些羧基末端的信号肽是已知的。
在WO2016/174409中对改变的信号肽有详细的描述，其通过引用并入本文。改变的信号肽可以包含一个或多个突变，诸如取代或缺失，使得它具有比衍生它的野生型信号肽更少的疏水性氨基酸。术语“野生型”是指衍生改变的信号肽的天然蛋白质中存在的信号肽序列。
在核酸构建体包含两个均编码跨膜蛋白的转基因的情况下，由下游转基因编码的蛋白质(其具有较低的相对表达)可以包含比由上游转基因编码的蛋白质(其具有较高的相对表达)更少的疏水性氨基酸。
为了改变信号肽效率而突变的疏水性氨基酸可以是：丙氨酸(A)、缬氨酸(V)、异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、苯丙氨酸(P)、酪氨酸(Y)或色氨酸(W)。
改变的信号肽可以包含1、2、3、4或5个疏水性氨基酸的氨基酸缺失或疏水性氨基酸的取代。可以用非疏水性氨基酸诸如亲水性或中性氨基酸替换疏水性氨基酸。
切割位点
本发明提供了核酸构建体，其包含：
(i)编码嵌合抗原受体(CAR)的核酸序列；和
(ii)位于FSM/TRM下游的编码白细胞介素12(IL-12)的核酸序列。
核酸构建体还可以包含以下中的一种或多种：
(iii)编码显性负性SHP2的核酸序列；
(iv)编码显性负性TGFβ受体的核酸序列；
(v)编码嵌合细胞因子受体的核酸序列；
(vi)编码一种或多种额外的细胞因子或趋化因子的一种或多种核酸序列。
为了使CAR和IL-12以及任选的一种或多种额外的组分可以作为分开的多肽表达，构建体可以包含编码切割位点的序列，该切割位点位于编码两个多肽的核酸序列之间。
切割位点可以是使通过核酸构建体的翻译产生的多肽能够分裂或变为分开的任何序列。
为方便起见，本文使用术语“切割”，但切割位点可能导致两个多肽通过不同于经典切割的机制分开成单独的实体。例如，对于口蹄疫病毒(FMDV)2A自切割肽(参见下文)，已经提出了各种模型来解释“切割”活性：宿主细胞蛋白酶的蛋白水解、自身蛋白水解或翻译效应(Donnelly et al(2001)J.Gen.Virol.82:1027-1041)。此类“切割”的确切机制对于本发明的目的并不重要，只要切割位点在位于编码第一和第二多肽的核酸序列之间时，导致第一和第二多肽作为分开的实体表达。
切割位点可以是弗林蛋白酶(furin)切割位点。
弗林蛋白酶是属于枯草杆菌蛋白酶样蛋白前体转换酶家族的酶。该家族的成员是将潜在的前体蛋白加工成其生物活性产物的蛋白前体转换酶。弗林蛋白酶是一种钙依赖性丝氨酸内切蛋白酶，可以在其配对的碱性氨基酸加工位点有效地切割前体蛋白。弗林蛋白酶底物的实例包括甲状旁腺激素原、转化生长因子β1前体、白蛋白原、β分泌酶原、1型膜基质金属蛋白酶、神经生长因子原的β亚基和血管性血友病因子。弗林蛋白酶恰好在碱性氨基酸靶序列(规范地，Arg-X-(Arg/Lys)-Arg'(SEQ ID No.38))下游切割蛋白质，并在高尔基体中富集。
切割位点可以是烟草蚀刻病毒(TEV)切割位点。
TEV蛋白酶是具有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。它对其靶切割位点非常特异，因此经常用于体外和体内融合蛋白的受控切割。一致的TEV切割位点是ENLYFQ\S(SEQ ID No.39)(其中“\”表示被切割的肽键)。哺乳动物细胞(诸如人类细胞)不表达TEV蛋白酶。因此，在本发明的核酸构建体包含TEV切割位点并在哺乳动物细胞中表达的实施方案中—外源TEV蛋白酶也必须在哺乳动物细胞中表达。
切割位点可以编码自切割肽。
“自切割肽”是指这样的肽，其发挥功能使得当产生包含第一和第二多肽以及自切割肽的多肽时，该多肽立即“被切割”或分开成为不同的和分离的第一和第二多肽，而不需要任何外部切割活性。
自切割肽可以是来自口疮病毒属或心病毒属的2A自切割肽。口疮病毒属和心病毒属的主要2A/2B切割由2A在其自身的C末端的“切割”介导。在口疮病毒属中，诸如口蹄疫病毒(FMDV)和马鼻炎A病毒，2A区域是约18个氨基酸的一小段，其连同蛋白质2B的N末端残基(保守的脯氨酸残基)代表能够在其自身的C末端介导“切割”的自主元件。
较长的心病毒属蛋白的C末端19个氨基酸连同2B的N末端脯氨酸以大约等于口疮病毒属FMDV 2a序列的效率介导“切割”。心病毒属包括脑心肌炎病毒(EMCV)和泰勒氏鼠脑炎病毒(TMEV)。
EMCV和FMDV 2A的突变分析揭示了基序DxExNPGP(SEQ ID No.40)与“切割”活性密切相关(如上文Donelly et al(2001))。
本发明的切割位点可以包含氨基酸序列：
Dx1Ex2NPGP，其中x1和x2是任何氨基酸。X1可以选自以下组：I、V、M和S。X2可以选自以下组：T、M、S、L、E、Q和F。
例如，切割位点可以包含表1中所示的氨基酸序列之一。
表1
基于2A序列的切割位点可以是例如15-22个氨基酸长度。序列可以包含2A蛋白的C末端，随后是脯氨酸残基(其对应于2B的N末端脯氨酸)。
突变研究还显示，除了天然存在的2A序列外，一些变体也具有活性。切割位点可以对应于来自天然存在的2A多肽的变体序列，具有一个、两个或三个氨基酸取代，该变体序列保留了诱导多蛋白序列“切割”成两个或更多个分开的蛋白质的能力。
切割序列可以选自以下序列，这些序列均已显示在一定程度上具有活性(如上文Donnelly et al(2001))：
LLNFDLLKLAGDVESNPGP(SEQ ID No.50)
LLNFDLLKLAGDVQSNPGP(SEQ ID No.51)
LLNFDLLKLAGDVEINPGP(SEQ ID No.52)
LLNFDLLKLAGDVEFNPGP(SEQ ID No.53)
LLNFDLLKLAGDVESHPGP(SEQ ID No.54)
LLNFDLLKLAGDVESEPGP(SEQ ID No.55)
LLNFDLLKLAGDVESQPGP(SEQ ID No.56)
LLNFDLLKLAGDVESNPGG(SEQ ID No.57)。
基于DxExNPGP基序的序列，除了口疮病毒属或心病毒属、“小核糖核酸病毒样”昆虫病毒、C型轮状病毒和锥体虫属种内的重复序列和细菌序列以外，已经在小核糖核酸病毒中发现了“2A样”序列(如上文Donnelly et al(2001))。切割位点可以包含这些2A样序列之一，诸如：
YHADYYKQRLIHDVEMNPGP(SEQ ID No.58)
HYAGYFADLLIHDIETNPGP(SEQ ID No.59)
QCTNYALLKLAGDVESNPGP(SEQ ID No.60)
ATNFSLLKQAGDVEENPGP(SEQ ID No.61)
AARQMLLLLSGDVETNPGP(SEQ ID No.62)
RAEGRGSLLTCGDVEENPGP(SEQ ID No.63)
TRAEIEDELIRAGIESNPGP(SEQ ID No.64)
TRAEIEDELIRADIESNPGP(SEQ ID No.65)
AKFQIDKILISGDVELNPGP(SEQ ID No.66)
SSIIRTKMLVSGDVEENPGP(SEQ ID No.67)
CDAQRQKLLLSGDIEQNPGP(SEQ ID No.68)
YPIDFGGFLVKADSEFNPGP(SEQ ID No.69)
切割位点可以包含如SEQ ID No.63(RAEGRGSLLTCGDVEENPGP)所示的2A样序列或来自Thosea asigna病毒衣壳蛋白的2A肽，该2A肽具有序列EGRGSLLTCGDVEENPGP(SEQ IDNo.70)。
已经显示包括5至39个氨基酸之间的N末端“延伸”可以增加活性(如上文Donnellyet al(2001))。特别地，切割序列可以包含以下序列之一或其变体，例如，该变体具有最多5个氨基酸变化，其保留切割位点活性：
嵌合抗原受体(CAR)
图1中示意性显示的CAR是嵌合的I型跨膜蛋白，其将细胞外抗原识别域(结合物)连接至细胞内信号传导域(胞内域)。结合物通常是衍生自单克隆抗体(mAb)的单链可变片段(scFv)，但它可以基于包含抗体样抗原结合位点的其他形式。间隔物域通常是将结合物与膜分开并容许其具有合适的方向所必需的。常用的间隔物域是IgG1的Fc。取决于抗原，更紧凑的间隔物可以足够，例如来自CD8α的茎，甚至只是单独的IgG1铰链。跨膜域将蛋白质锚定在细胞膜上并将间隔物连接至胞内域。
早期的CAR设计具有衍生自FcεR1或CD3ζ的γ链的细胞内部分的胞内域。因此，这些第一代受体传递免疫信号1，其足以触发同源靶细胞的T细胞杀伤，但是不能完全激活T细胞增殖和存活。为了克服这一限制，已经构建了复合胞内域：将T细胞共刺激分子的细胞内部分与CD3ζ的细胞内部分融合产生第二代受体，其可以在抗原识别后同时传递激活和共刺激信号。最常用的共刺激域是CD28的共刺激域。这提供了最有力的共刺激信号—即触发T细胞增殖的免疫信号2。还描述了一些包括TNF受体家族胞内域在内的受体，诸如传递存活信号的密切相关的OX40和41BB。现在已经描述了甚至更有力的第三代CAR，其具有能够传递激活、增殖和存活信号的胞内域。
可以使用例如逆转录病毒载体或慢病毒载体将编码CAR的核酸转移至T细胞以产生用于过继细胞转移的癌症特异性T细胞。当CAR结合靶抗原时，这导致激活信号传递到表达CAR的T细胞。因此，CAR将T细胞的特异性和细胞毒性引导至表达靶抗原的肿瘤细胞。
已经开发了双特异性CAR(称为串联CAR或TanCAR)以同时靶向两种或更多种癌症特异性标志物。在TanCAR中，细胞外域包含两个串联的抗原结合特异性，通过接头连接。因此两个结合特异性(scFv)均连接至单个跨膜部分：一个scFv位于膜附近，另一个位于远处位置。当TanCAR结合一个或两个靶抗原时，这导致激活信号传递到表达TanCAR的细胞。
抗原结合域
抗原结合域是识别抗原的CAR的部分。本领域已知许多抗原结合域，包括基于抗体的抗原结合位点、抗体类似物和T细胞受体的抗原结合域。例如，抗原结合域可以包含：衍生自单克隆抗体的单链可变片段(scFv)、靶抗原的天然配体、对靶标具有足够亲和力的肽、单域抗体、人工单个结合物诸如Darpin(设计的锚蛋白重复蛋白)或衍生自T细胞受体的单链。
在经典的CAR中，抗原结合域包含：衍生自单克隆抗体的单链可变片段(scFv)。还用域抗体(dAb)或VHH抗原结合域或包含例如单克隆抗体的Fab片段产生CAR。FabCAR包含两条链：一条具有抗体样轻链可变区(VL)和恒定区(CL)，一条具有重链可变区(VH)和恒定区(CH)。一条链还包含跨膜域和细胞内信号传导域。CL和CH之间的缔合引起受体的组装。
Fab CAR的两条链可以具有通式结构：
VH-CH-间隔物-跨膜域-胞内信号传导域；以及
VL-CL
或
VL-CL-间隔物-跨膜域-胞内信号传导域；以及
VH-CH。
对于Fab型嵌合受体，抗原结合域由来自一条多肽链的VH和来自另一条多肽链的VL组成。
多肽链可以包含VH/VL域和CH/CL域之间的接头。接头可以是柔性的并且用来在空间上将VH/VL域与CH/CL域分开。
CAR的抗原结合域可以结合肿瘤相关抗原。已知各种肿瘤相关抗原(TAA)，例如如下表2所示。
表2
CAR可以结合下表3中总结的靶标之一。特别地，CAR可以结合以下靶抗原之一：双唾液酸神经节苷脂(GD2)、表皮生长因子受体(EGFR)、上皮细胞粘附分子(EpCAM)、磷脂酰肌醇蛋白聚糖3(GPC3)、人表皮生长因子受体(HER2)、L1CAM、粘蛋白1(MUC1)或前列腺特异性膜抗原(PSMA)。
在本发明的一个实施方案中，CAR可以结合除了PSMA以外的抗原。CAR可以结合表3中列出的不是PSMA的靶抗原之一。例如，CAR可以结合以下靶抗原之一：双唾液酸神经节苷脂(GD2)、表皮生长因子受体(EGFR)、上皮细胞粘附分子(EpCAM)、磷脂酰肌醇蛋白聚糖3(GPC3)、人表皮生长因子受体(HER2)、L1CAM和粘蛋白1(MUC1)。
双唾液酸神经节苷脂GD2
已经开发了结合双唾液酸神经节苷脂(GD2)的CAR，该双唾液酸神经节苷脂是含有唾液酸的鞘糖脂。例如，此类CAR可以基于WO2015/132604中所描述的GD2结合物14g2a或huK666。
结合GD2的CAR可以具有抗原结合域，该抗原结合域包含：
a)重链可变区(VH)，其具有具有以下序列的互补决定区(CDR)：
CDR1–SYNIH(SEQ ID No.12)；
CDR2–VIWAGGSTNYNSALMS(SEQ ID No.13)；
CDR3–RSDDYSWFAY(SEQ ID No.14)；和
b)轻链可变区(VL)，其具有具有以下序列的CDR：
CDR1–RASSSVSSSYLH(SEQ ID No.15)；
CDR2–STSNLAS(SEQ ID No.16)；
CDR3–QQYSGYPIT(SEQ ID No.17)。
GD2结合域可以包含具有如SEQ ID No.75所示序列的VH域；和/或具有如SEQ IDNo 76所示序列的VL域。
SEQ ID No.75(人源化KM666VH序列)
SEQ ID No.76(人源化KM666 VL序列)
CAR的抗原结合域可以包含与SEQ ID NO:75或76的变体，该变体具有至少80、85、90、95、98或99％序列同一性，条件是该变体序列保留结合GD2的能力。
表皮生长因子受体(EGFR)
表皮生长因子受体(EGFR、ErbB-1、人中的HER1)是跨膜蛋白，其是细胞外蛋白配体的表皮生长因子家族(EGF家族)的成员的受体。人EpCAM的氨基酸序列可从UniProt登录号P00533获得。EGFR进行从无活性的单体形式到有活性同二聚体的转变。EGFR二聚化刺激其内在的细胞内蛋白-酪氨酸激酶的活性，导致C末端域中的几个酪氨酸(Y)残基自磷酸化，包括Y992、Y1045、Y1068、Y1148和Y1173。自磷酸化通过几个其他的蛋白引发下游激活和信号传导，这些其他的蛋白通过其自身的磷酸酪氨酸结合SH2域与这些磷酸化的酪氨酸结合。这些下游信号传导蛋白起始若干信号转导级联反应，主要是MAPK、Akt和JNK通路，导致DNA合成和细胞增殖。
EGFR的过表达与极其多种肿瘤的发展有关。导致EGFR过表达(称为上调或扩增)的突变与许多癌症有关，包括肺腺癌(40％的情况)、肛门癌、胶质母细胞瘤(50％)和头颈部上皮肿瘤(80-100％)。这些涉及EGFR的体细胞突变导致其持续激活，从而产生不受控制的细胞分裂。在胶质母细胞瘤中，经常观察到称为EGFRvIII的EGFR特定突变。EGFR或家族成员的突变、扩增或失调参与全部上皮癌的大约30％。
已知若干抗EGFR抗体，例如，西妥昔单抗、帕尼单抗、扎鲁木单抗、尼妥珠单抗和马妥珠单抗。
上皮细胞粘附分子(EpCAM)
上皮细胞粘附分子(EpCAM)是跨膜糖蛋白，其介导上皮细胞中不依赖Ca2+的同型细胞-细胞粘附。EpCAM还参与细胞信号传导、迁移、增殖和分化。此外，EpCAM通过其上调c-myc、e-fabp和细胞周期蛋白A&E的能力具有致癌潜力。由于EpCAM仅在上皮和衍生自上皮的肿瘤中表达，EpCAM可以用作多种癌症的诊断标志物。它似乎在癌的肿瘤发生和转移中发挥作用，因此它也可以充当预后标志物和免疫治疗策略的靶标。EpCAM通常在某些癌中过表达，包括在乳腺癌、结肠癌和皮肤基底细胞癌中。
EpCAM是糖基化的30至40kDa的I型膜蛋白。人EpCAM的氨基酸序列可从UniProt登录号P16422获得。EpCAM可以被切割，从而赋予该分子致癌潜力。切割后，细胞外域(EpEX)被释放到细胞周围的区域，细胞内域(EpICD)被释放到细胞的细胞质中。EpICD与细胞核内部的蛋白FHL2、β-连环蛋白和Lef形成复合物。然后该复合物与DNA结合并促进多种基因的转录。上调的靶标包括c-myc、e-fabp和细胞周期蛋白A&E。这具有促进肿瘤生长的作用。此外，已被切割的EpEX可以刺激额外的EpCAM分子的切割，引起正反馈回路。EpCAM也可以在肿瘤的上皮间质转化(EMT)中发挥作用。
由于EpCAM主要在正常上皮细胞的基底外侧膜上表达，它应该比癌组织中的EpCAM更不容易被抗体接近，在癌组织中EpCAM均匀分布在癌细胞表面。除了在许多癌中过表达外，EpCAM在癌症干细胞中也表达，使得EpCAM成为免疫治疗的有吸引力的靶标。然而，EpCAM在癌中的异质性表达以及EpCAM不是肿瘤特异性的事实(即，它存在于正常上皮细胞中)迄今为止阻碍了针对EpCAM的免疫治疗方法的发展。
已知若干种抗EpCAM抗体，分别包括鼠IgG2a依决洛单抗(edrecolomab)及其鼠/人嵌合IgG1抗体型式，以及人源化的、人工程化的和全人IgG1抗体3622W94、ING-1和阿德木单抗(adecatumumab)(MT201)。
磷脂酰肌醇蛋白聚糖3(GPC3)
磷脂酰肌醇蛋白聚糖3在控制细胞分裂和生长调节中发挥作用。GPC3的蛋白质核心由两个亚基组成，其中N末端亚基的大小约为40kDa，C末端亚基的大小约为30kDa。人GPC3的氨基酸序列可从UniProt登录号P51654获得。
已在哺乳动物中鉴定出六种磷脂酰肌醇蛋白聚糖(GPC1-6)。细胞表面硫酸乙酰肝素蛋白聚糖由膜相关蛋白核心构成，该核心被可变数量的硫酸乙酰肝素链取代。磷脂酰肌醇蛋白聚糖相关的整合膜蛋白聚糖家族(GRIPS)的成员包含通过糖基磷脂酰肌醇连接锚定到细胞质膜的核心蛋白。GPC3与Wnt和卷曲蛋白(FZD)均相互作用形成复合物并引发下游信号传导。
GPC3是治疗肝癌的有希望的治疗靶标。已经开发了若干种治疗性抗GPC3抗体，包括GC33、HN3和YP7。YP7及其人源化形式hYP7与GPC3的C-lobe结合；单域抗体HN3靶向GPC3的N-lobe；而人单克隆抗体靶向GPC3的硫酸乙酰肝素部分。正在不同阶段开发基于GC33、hYP7和HN3的嵌合抗原受体(CAR)T细胞免疫疗法用于治疗肝癌。
人表皮生长因子受体(HER2)
HER2(来自人类表皮生长因子受体2)也称为HER2/neu、受体酪氨酸蛋白激酶erbB-2、CD340(分化簇340)、原癌基因Neu、Erbb2(啮齿类)和ERBB2(人)。
HER2是人表皮生长因子受体(HER/EGFR/ERBB)家族的成员。已经显示这种癌基因的扩增或过表达在某些具有攻击性的类型的乳腺癌的发展和进展中起重要作用。近年来，该蛋白质已经成为约30％的乳腺癌患者的重要生物标志物和治疗靶标。
ErbB家族由四种质膜结合受体酪氨酸激酶组成。其中之一是erbB-2，其他成员是表皮生长因子受体、erbB-3(神经调节蛋白结合；缺乏激酶域)和erbB-4。所有四种都含有细胞外配体结合域、跨膜域和胞内域，胞内域可以与众多的信号传导分子相互作用并展现出配体依赖性和配体非依赖性活性。HER2可以与其他三种受体中的任何一种进行异二聚化，并且认为HER2是其他ErbB受体的优选的二聚化配偶体。二聚化导致受体的胞质域内酪氨酸残基的自磷酸化并起始各种信号传导通路。人HER2的氨基酸序列可从UniProt登录号P04626获得。
HER2是单克隆抗体曲妥珠单抗(作为赫赛汀销售)的靶标。曲妥珠单抗仅对HER2过表达的癌症有效。曲妥珠单抗与HER2结合的一个重要的下游效应是阻止细胞增殖的蛋白质p27增加。抑制HER2和HER3受体二聚化的另一种单克隆抗体帕妥珠单抗，于2012年6月获得FDA批准与曲妥珠单抗组合使用。
L1细胞粘附分子(L1CAM)
L1CAM，又称为L1，是L1蛋白家族的跨膜蛋白成员，由L1CAM基因编码。这种蛋白质为200-220kDa，由六个免疫球蛋白域后面跟着五个纤连蛋白III型域形成，五个纤连蛋白III型域通过跨膜螺旋连接到小的胞内域。人L1CAM的氨基酸序列可从UniProt登录号P32004获得。
L1CAM是一种神经元细胞粘附分子，在细胞迁移、粘附、神经突增生、髓鞘形成和神经元分化中具有强烈影响。L1CAM位于整个神经系统的神经元表面。它沿着细胞膜放置，使蛋白质的一端留在神经细胞内部，而另一端留在神经元的外表面上。这种定位容许该蛋白质激活通过神经元传播的化学信号。
极其多种细胞表达L1CAM，包括未成熟的少突胶质细胞和施旺细胞，这些细胞是为神经元提供支持和保护并形成髓鞘的非神经元细胞；T细胞，该T细胞是参与细胞介导的免疫的淋巴细胞；其他类型的淋巴细胞，诸如B细胞和单核细胞。L1CAM在多种肿瘤类型中表达，例如黑色素瘤和肺癌细胞。
Wolterink et al(2010)Cancer Res 15:2504-2515描述了一系列针对L1CAM胞外域的新型单克隆抗体(mAb)的产生，包括抗体L1-9.3。
粘蛋白1(MUC1)
细胞表面相关的粘蛋白1(MUC1)，也称为多态性上皮粘蛋白(PEM)或上皮膜抗原或EMA，是由人类MUC1基因编码的粘蛋白。MUC1是其细胞外域具有广泛的O连接糖基化的糖蛋白。粘蛋白排列在肺、胃、肠、眼睛和一些其他器官的上皮细胞的顶部表面。粘蛋白保护身体免受与细胞外域中的寡糖结合的病原体的感染，防止病原体到达细胞表面。MUC1的过表达通常与结肠癌、乳腺癌、卵巢癌、肺癌和胰腺癌有关。人MUC1的氨基酸序列可从UniProt登录号P15941获得。
已经开发并表征了许多抗粘蛋白1(抗MUC1)抗体，包括1B2和12D10，这些抗体识别PDT*R基序(星号代表O-糖基化位点，SEQ ID N:104)处的特定O-聚糖结构。1B2识别GalNAc残基的具有未取代的O-6位置的O-聚糖(Tn、T和23ST)，而12D10在相同位置识别Neu5Ac(STn、26ST和dST)。
前列腺特异性膜抗原(PSMA)
前列腺特异性膜抗原(PSMA)，也称为谷氨酸羧肽酶II(GCPII)、N-乙酰-L-天冬氨酰-L-谷氨酸肽酶I(NAALADase I)或NAAG肽酶，是锌金属酶。它是催化N-乙酰天冬氨酰谷氨酸(NAAG)水解为谷氨酸和N-乙酰天冬氨酸(NAA)的II类膜糖蛋白。人MUC1的氨基酸序列可从UniProt登录号Q04609获得。
人PSMA在前列腺中高度表达，大约比在大多数其他组织中高一百倍。在一些前列腺癌中，PSMA是第二大上调的基因产物，比非癌性前列腺细胞中的水平增加8到12倍。由于这种高表达，正在开发PSMA作为一些癌症治疗和成像的潜在生物标志物。在人前列腺癌中，较高表达的肿瘤与较快的进展时间和患者遭受复发的较大百分比相关。使用具有降低的PSMA水平的前列腺和乳腺癌细胞系的体外研究显示细胞的增殖、迁移、侵袭、粘附和存活显著降低。
表达对前列腺特异性膜抗原(PSMA)具有特异性的CAR的T细胞目前处于在治疗前列腺癌的临床试验中(Junhans et al(2016)Prostate 76:1257-1270)。
英国专利申请号1919019.8描述了适用于CAR的各种PSMA抗原结合域。
结合PSMA的CAR可以具有抗原结合域，该抗原结合域包含：
a)重链可变区(VH)，其具有具有以下序列的互补决定区(CDR)：
CDR1–SSWMN(SEQ ID No.18)；
CDR2–RIYPGDGDTNYAQKFQG(SEQ ID No.19)；
CDR3–GTGYLWYFDV(SEQ ID No.20)；和
b)轻链可变区(VL)，其具有具有以下序列的CDR：
CDR1–RASQDINENLA(SEQ ID No.21)；
CDR2–YTSNRAT(SEQ ID No.22)；
CDR3–QQYDNLPFT(SEQ ID No.23)。
PSMA结合域可以包含具有如SEQ ID No.77所示的序列的VH域；和/或具有如SEQID No.78所示的序列的VL域。
SEQ ID No.77(人源化7A12VH序列)
SEQ ID No.78(人源化7A12 VL序列)
CAR的抗原结合域可以包含SEQ ID NO:77或78的变体，该变体具有至少80、85、90、95、98或99％序列同一性，条件是该变体序列保留结合PSMA的能力。
然而，在本发明的一个实施方案中，CAR与除了PSMA以外的抗原结合。CAR可以具有非PSMA特异性抗原结合域。
细胞内T细胞信号传导域(胞内域)
CAR可以包含激活的胞内域CAR的信号传递部分或与激活的胞内域CAR的信号传递部分缔合。抗原识别后，受体聚集并将信号传递给细胞。最常用的胞内域组分是含有3个ITAM的CD3-ζ。这在抗原结合后将激活信号传递给T细胞。CD3-ζ可能无法提供完全有能力的激活信号，可能需要额外的共刺激信号。例如，嵌合的CD28和OX40可以与CD3-ζ一起使用以传递增殖/存活信号，或者所有三个可以一起使用。
CAR的胞内域可以包含CD28胞内域和CD3-ζ胞内域。这些胞内域的序列分别如下文SEQ ID No.79和80所示：
SEQ ID No.79(CD28胞内域)
SEQ ID No.80(CD3z胞内域)
胞内域可以包含：
(i)含有ITAM的胞内域，诸如来自CD3ζ的胞内域；和/或
(ii)共刺激域，诸如来自CD28的胞内域；和/或
(iii)传递生存信号的域，例如TNF受体家族胞内域，诸如OX-40或4-1BB。
含有ITAM基序的胞内域可以充当本发明中的激活胞内域。已知若干蛋白质含有具有一个或多个ITAM基序的胞内域。此类蛋白质的实例包括CD3ε链、CD3γ链和CD3δ链等等。可以将ITAM基序很容易地识别为通过任何两个其他氨基酸将酪氨酸与亮氨酸或异亮氨酸分开，产生特征YxxL/I(SeQ ID NO.81)。通常，但并非总是如此，这些基序中的两个在分子尾部被6到8个氨基酸分开(YxxL/Ix(6-8)YxxL/I)。因此，本领域技术人员可以容易地发现含有一个或多个ITAM以传递激活信号的现有的蛋白质。此外，鉴于该基序简单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的多肽以传递激活信号(参见WO2000/063372，其涉及合成的信号传导分子)。
已经描述了许多系统，其中CAR的抗原识别部分位于与信号传递部分分开的分子上，诸如WO015/150771、WO2016/124930和WO2016/030691中描述的那些系统。本发明的方法中使用的一种或多种病毒载体可以编码此类“分裂的CAR”。可替代地，一种载体可以包含编码抗原识别部分的核酸序列，并且一种载体可以包含编码细胞内信号传导域的核酸序列。
信号肽
载体中的一条或多条核酸序列可以编码信号肽，使得当CAR、细胞因子或趋化因子在细胞内部表达时，将新生蛋白引导至内质网并且随后引导至细胞表面，其在此处表达(或在细胞因子或趋化因子的情况下分泌)。
信号肽的核心可以含有一长段倾向于形成单个α-螺旋的疏水性氨基酸。信号肽可以以一短段带正电荷的氨基酸开始，这有助于在转移过程中加强多肽的合适拓扑结构。在信号肽的端部，通常有被信号肽酶识别和切割的一段氨基酸。信号肽酶可以在转移过程中或转移完成后切割以产生游离的信号肽和成熟蛋白。然后特定的蛋白酶消化游离的信号肽。
信号肽可以在分子的氨基末端。
CAR可以具有通用公式：
信号肽-抗原结合域-间隔物域-跨膜域-细胞内T细胞信号传导域(胞内域)。
间隔物
CAR可以包含间隔物序列以将抗原结合域与跨膜域连接并将抗原结合域与胞内域在空间上分开。柔性间隔物容许抗原结合域朝向不同方向以促进抗原结合。
例如，间隔物序列可以包含IgG1Fc区、IgG1铰链或CD8茎或其组合。间隔物可以替代地包含具有与IgG1 Fc区、IgG1铰链或CD8茎相似的长度和/或域间隔特性的替代序列。
当病毒载体的组合物包括超过一种包含编码CAR的核酸序列的载体时，CAR可以具有不同的间隔物。
或门
本发明的细胞组合物可以包含两种或更多种CAR。这可以是用两种或更多种载体转导的结果，每种载体包含编码CAR的核酸序列；或者这可以是用包含编码两种或更多种CAR的核酸构建体的单一载体转导的结果。
CAR可以与一种或多种其他活化性或抑制性嵌合抗原受体组合使用。例如，它们可以以“逻辑门”的形式与一种或多种其他CAR组合使用，这种CAR组合在由细胞(诸如T细胞)表达时，能够检测至少两种靶抗原的特定表达样式。如果将至少两种靶抗原任意地表示为抗原A和抗原B，则三种可能的选择如下：
“或门”—当抗原A或抗原B存在于靶细胞上时，T细胞触发
“与门”—只有当抗原A和B均存在于靶细胞上时，T细胞触发
“与非门”—如果抗原A单独存在于靶细胞上，T细胞触发，但如果抗原A和B均存在于靶细胞上，T细胞不会触发
基于癌细胞上两种或更多种标志物的特定表达(或缺乏表达)，可以对表达这些CAR组合的工程化的T细胞进行定制，使其对癌细胞具有敏锐的特异性。
例如，在WO2015/075469、WO2015/075470和WO2015/075470中描述了此类“逻辑门”。
“或门”包含两种或更多种激活性CAR，每种针对由靶细胞表达的不同的靶抗原。或门的优点是靶细胞上的有效可靶向抗原增加，因为其实际上是抗原A+抗原B。这对于在靶细胞上以可变或低密度表达的抗原尤其重要，因为单个抗原的水平可能低于CAR-T细胞有效靶向所需的阈值。同时，它避免了抗原逃逸的现象。
转基因T细胞受体(TCR)
本发明的细胞可以表达转基因TCR。
T细胞受体(TCR)是在T细胞表面发现的分子，其负责将抗原片段识别为与主要组织相容性复合物(MHC)分子结合的肽。
TCR是由两条不同的蛋白质链组成的异二聚体。在人中，在95％的T细胞中TCR由alpha(α)链和beta(β)链(分别由TRA和TRB编码)组成，而在5％的T细胞中TCR由gamma和delta(γ/δ)链(分别由TRG和TRD编码)组成。
当TCR与抗原肽和MHC(肽/MHC)结合时，T淋巴细胞通过信号转导被激活。
与常规的抗体导向的靶抗原相比，TCR识别的抗原可以包括整个潜在的细胞内蛋白质阵列，这些蛋白质被加工并作为肽/MHC复合物递送到细胞表面。
可以通过使用载体将TRA和TRB基因、或TRG和TRD基因人工引入细胞，工程化改造细胞以表达异源(即非天然)TCR分子。例如，可以将工程化TCR的基因引入自体T细胞并转移回患者用于T细胞过继疗法。此类“异源”TCR在本文中也可以称为“转基因TCR”或工程化TCR。
本发明的细胞可以包含一种或多种编码TRA和TRB基因的异源核酸序列；或一种或多种编码TRG和TRD基因的异源核酸序列。
显性负性SHP-2
本发明的细胞可以表达显性负性SHP-2。
WO2016/193696描述了SHP-1和SHP-2的截短型式，该截短形式阻断或减少由抑制性免疫受体诸如CTLA4、PD-1、LAG-3、2B4或BTLA 1介导的抑制。SHP-1或SHP-2的截短型式包含一个或两个SH2域，但缺乏磷酸酶域。当在CAR-T细胞中表达时，这些分子充当野生型SHP-1和SHP-2的显性负性型式，与内源分子竞争结合磷酸化的ITIM。
本发明的细胞可以表达截短的蛋白质，其包含来自结合磷酸化的免疫受体酪氨酸抑制基序(ITIM)的蛋白质的SH2域但缺乏SHP-1磷酸酶域。截短的蛋白质可以包含一个或两个SHP-1SH2域，但缺乏SHP-1磷酸酶域。可替代地，截短的蛋白质可以包含一个或两个SHP-2SH2域，但缺乏SHP-2磷酸酶域。
SHP-1
含有Src同源区2域的磷酸酶-1(SHP-1)是蛋白质酪氨酸磷酸酶家族的成员。它也被称为PTPN6。
SHP-1的N末端区含有两个串联的SH2域，其介导SHP-1与其底物的相互作用。C末端区含有酪氨酸蛋白磷酸酶域。
SHP-1能够与许多抑制性免疫受体或含有ITIM的受体结合并从中传播信号。此类受体的实例包括但不限于：PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1和KIR3DL3。
人SHP-1蛋白具有UniProtKB登录号P29350。
活性调节物可以包含如下文SEQ ID NO:82所示的SHP-1串联SH2域或由其组成。
SHP-1 SH2完整域(SEQ ID NO:82)
SHP-1在序列的N末端具有两个SH2域，位于残基4-100和110-213。活性调节物可以包含如SEQ ID No.83和84所示的序列之一或两者。
SHP-1 SH2 1(SEQ ID NO:83)
SHP-1 SH2 2(SEQ ID No.84)
细胞可以表达SEQ ID NO:82、83或84的变体，其具有至少80、85、90、95、98或99％的序列同一性，条件是改编题序列是具有所需特性的SH2域序列。换言之，变体序列应该能够与下列至少一种分子的细胞质尾部中的磷酸化的酪氨酸残基结合以容许SHP-1的招募：PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3。
SHP-2
SHP-2，也称为PTPN11、PTP-1D和PTP-2C，是蛋白质酪氨酸磷酸酶(PTP)家族的成员。与PTPN6类似，SHP-2具有由在其N末端的两个串联的SH2域后面跟着蛋白质酪氨酸磷酸酶(PTP)域组成的域结构。在非活性状态下，N末端SH2域与PTP域结合并阻断潜在底物进入活性位点。因此，SHP-2是自动抑制的。在与目标磷酸酪氨酰残基结合后，N末端SH2域从PTP域中释放，通过解除自动抑制来催化性地激活该酶。
人SHP-2具有UniProtKB登录号P35235-1。
活性调节物可以包含如以下SEQ ID NO:87所示的SHP-1串联SH2域或由其组成。SHP-1在序列的N末端具有两个SH2域，位于残基6-102和112。活性调节物可以包含如SEQ IDNo.85和86所示的序列之一或两者。
SHP-2第一SH2域(SEQ ID NO:85)
SHP-2第二SH2域(SEQ ID No.86)
SHP-2两个SH2域(SEQ ID No.87)
细胞可以表达SEQ ID NO:85、86或87的变体，其具有至少80、85、90、95、98或99％的序列同一性，条件是该变体序列是具有所需特性的SH2域序列。换言之，变体序列应该能够与下列至少一种分子的细胞质尾部中的磷酸化的酪氨酸残基结合以容许SHP-2的招募：PD1、PDCD1、BTLA4、LILRB1、LAIR1、CTLA4、KIR2DL1、KIR2DL4、KIR2DL5、KIR3DL1或KIR3DL3。
显性负性TGFβ受体
本发明的细胞可以表达显性负性TGFβ受体。
工程化的细胞面临限制过继免疫疗法的不利微环境。肿瘤微环境内的主要抑制机制之一是转化生长因子β(TGFβ)。TGFβ信号传导通路在控制多种细胞过程的调节性信号传导中具有关键作用。TGFβ还在T细胞稳态和细胞功能控制中发挥核心作用。特别地，TGFβ信号传导与T细胞的具有减少的增殖和激活的免疫抑制状态相关。TGFβ的表达与肿瘤的免疫抑制微环境有关。
已知多种癌性肿瘤细胞直接产生TGFβ。除了癌性细胞产生TGFβ外，存在于肿瘤部位的极其多种非癌性细胞可以产生TGFβ，诸如肿瘤相关T细胞、自然杀伤(NK)细胞、巨噬细胞、上皮细胞和基质细胞。
转化生长因子β受体是丝氨酸/苏氨酸激酶受体的超家族。这些受体结合生长因子TGFβ超家族的成员和细胞因子信号传导蛋白。存在五种II型受体(它们是激活性受体)和七种I型受体(它们是信号传播受体)。
还存在辅助共受体(也称为III型受体)。TGFβ配体超家族的每个亚家族都与I型和II型受体结合。
三种转化生长因子有许多活性。TGFβ1和2牵涉癌症，其中它们可刺激癌症干细胞、增加纤维化/促纤维增生反应，和抑制肿瘤的免疫识别。
活性的TGFβ受体(TβR)是异四聚体，由两个TGFβ受体I(TβRI)和两个TGFβ受体II(TβRII)组成。TGFβ1以潜伏形式分泌，并通过多种机制被激活。一旦被激活，它与TβRII TβRI形成复合物，磷酸化并激活TβRI。
本发明的细胞可以表达显性负性TGFβ受体。显性负性TGFβ受体可以缺乏激酶域。
例如，显性负性TGFβ受体可以包含如SEQ ID No.88所示的序列或由其组成，其是TGF受体II的单体型式。
SEQ ID No.88(dn TGFβRII)
已经报道了显性负性TGF-βRII(dnTGF-βRII)以增强靶向PSMA的CAR-T细胞增殖、细胞因子分泌、抵抗耗竭、长期体内持久性以及诱导攻击性人前列腺癌小鼠模型中的肿瘤根除(Kloss et al(2018)Mol.Ther.26:1855-1866)。
嵌合细胞因子受体
本发明的细胞可以表达嵌合细胞因子受体。
WO2017/029512描述了嵌合细胞因子受体(CCR)，其包含：与非细胞因子配体结合的外域；和细胞因子受体胞内域。
非细胞因子配体可以选自肿瘤分泌的因子、趋化因子和细胞表面抗原。
嵌合细胞因子受体可以包含两种多肽：
(i)第一多肽，其包含：
(a)结合配体的第一表位的第一抗原结合域
(b)细胞因子受体胞内域的第一链；和
(ii)第二多肽，其包含：
(a)结合配体的第二表位的第二抗原结合域
(b)细胞因子受体胞内域的第二链。
可替代的嵌合细胞因子受体，其包含两种多肽：
(i)第一多肽，其包含：
(a)重链可变域(VH)
(b)细胞因子受体胞内域的第一链；和
(ii)第二多肽，其包含：
(a)轻链可变域(VL)
(b)细胞因子受体胞内域的第二链。
例如，细胞因子受体胞内域可以包含：
(i)IL-2受体β链胞内域
(ii)IL-7受体α链胞内域；
(iii)IL-15受体α链胞内域；或
(iv)共用γ链受体胞内域。
细胞因子受体胞内域可以包含(i)、(ii)或(iii)；和(iv)。
细胞因子受体胞内域可以包含来自粒细胞-巨噬细胞集落刺激因子受体(GMCSF-R)的α-链胞内域和β-链胞内域。
配体可以是肿瘤分泌的因子，例如选自以下的肿瘤分泌的因子：前列腺特异性抗原(PSA)、癌胚抗原(CEA)、血管内皮生长因子(VEGF)和CA125。
配体可以是趋化因子，例如选自以下的趋化因子：CXCL12、CCL2、CCL4、CCL5和CCL22。
配体可以是细胞表面分子，诸如跨膜蛋白。例如，配体可以是CD22。
组成型活性嵌合细胞因子受体
本发明的细胞可以表达组成型活性嵌合细胞因子受体。组成型活性嵌合细胞因子受体可以包含两条链，它们自发地二聚化或在将两个细胞因子受体胞内域结合在一起的剂(二聚化的化学诱导物或CID)的存在下二聚化。
因此，组成型活性嵌合细胞因子受体可以包含二聚化域；和细胞因子受体胞内域。
二聚化可以自发地发生，在这种情况下嵌合跨膜蛋白将具有组成型活性。可替代地，二聚化可以仅在二聚化的化学诱导物(CID)存在下发生，在这种情况下跨膜蛋白仅在CID的存在下引起细胞因子类型的信号传导。
WO2015/150771中描述了合适的二聚化域和CID，其内容通过引用并入本文。
在二聚化域自发地异二聚化的情况下，其可以基于抗体的二聚化域。特别地，它可以包含重链恒定域(CH)和轻链恒定域(CL)的二聚化部分。恒定域的“二聚化部分”是形成链间二硫键的序列的部分。
嵌合细胞因子受体可以包含抗体的Fab部分作为外域。在这方面，嵌合抗原可以包含两种多肽：
(i)第一多肽，其包含：
(a)重链恒定域(CH)
(b)细胞因子受体胞内域的第一链；和
(ii)第二多肽，其包含：
(a)轻链恒定域(CL)
(b)细胞因子受体胞内域的第二链。
细胞因子受体胞内域可以包含：
(i)IL-2受体β链胞内域
(ii)IL-7受体α链胞内域；或
(iii)IL-15受体α链胞内域；和/或
(iv)共用γ链受体胞内域。
细胞因子受体胞内域可以包含来自粒细胞-巨噬细胞集落刺激因子受体(GMCSF-R)的α-链胞内域和β-链胞内域。
具有IL-2、IL-7或GM-CSF受体胞内域的组成型活性CCR可以具有以下结构之一：
Fab_CCR_IL2：
Fab_CCR_IL7：
Fab_CCR_GMCSF：
其中：
HuLightKappa是人轻κ链
IL2RgTM是来自人IL2R共用γ链的跨膜域
IL2RgEndo是衍生自人IL2R共用γ链的胞内域
2A是能够使两条多肽共表达的序列，其可以是自切割肽，诸如2A肽
HuCH1是人CH1
IL2bTM是来自人IL-2Rβ的跨膜域
IL2RbENDO是来自人IL2Rβ的胞内域
IL7RaTM是来自人IL-7Rα的跨膜域
IL7RaENDO是来自人IL-7Rα的胞内域
GMCSFRbTM是来自人GM-CSFR共用β链的跨膜域
GMCSFRbEndo是来自GM-CSFR共用β链的胞内域
GMCSFRaTM是来自人GF-CSFRα的跨膜域
GMCSFRaENDO是衍生自人GM-CSFRα的胞内域
用于制备组成型活性细胞因子受体的组分的序列如下文SEQ ID NO.89至101所示。
SEQ ID No.89(人Igκ恒定域)
SEQ ID No.90(人铰链)
SEQ ID No.91(人IgG1CH1域)
SEQ ID No.92(来自人IL2R共用γ链的跨膜域)
SEQ ID No.93(来自人IL-2Rβ的跨膜域)
SEQ ID No.94(来自人IL-7Rα的跨膜域)
SEQ ID No.95(来自人GF-CSFRα的跨膜域)
SEQ ID No.96(来自人GM-CSFR共用β链的跨膜域)
SEQ ID No.97(来自人IL2R共用γ链的胞内域)
SEQ ID No.98(来自人IL-2Rβ的胞内域)
SEQ ID No.99(来自人IL-7Rα的胞内域)
SEQ ID No.100(衍生自人GM-CSFRα的胞内域)
SEQ ID No.101(来自GM-CSFR共用β链的胞内域)
组成型活性CCR可以包含SEQ ID NO:89至101中的一个或多个的变体，其具有至少80、85、90、95、98或99％序列同一性，条件是该变体序列具有所需的特性。例如，变体CH或CL序列应该保留与含有CL/CH的链的二聚化的能力。来自该细胞因子受体胞内域的变体链应该保留当与细胞因子受体的相互链偶联时触发细胞因子介导的信号传导的能力。
核酸序列
本发明提供了位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。
可以将核酸序列引入细胞中使得该细胞以非常低的水平分泌IL-12。
核酸序列可以编码包含如SEQ ID No 1、24或25所示序列的多肽。
如本文所用，术语“多核苷酸”、“核苷酸”和“核酸”旨在彼此同义。
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，应当理解，技术人员可以使用常规的技术进行不影响本文所述的多核苷酸编码的多肽序列的核苷酸取代，以反映要在其中表达多肽的任何特定宿主生物体的密码子使用。
根据本发明的核酸可以包含DNA或RNA。它们可以是单链的或双链的。它们也可以是其中包括合成的或修饰的核苷酸的多核苷酸。本领域已知许多不同类型的对寡核苷酸的修饰。这些修饰包括甲基膦酸酯和硫代磷酸酯主链，在分子的3’和/或5’端添加吖啶或聚赖氨酸链。为了本文所述的用途，应当理解多核苷酸可以通过本领域可用的任何方法修饰。可以进行此类修饰以增强目的多核苷酸的体内活性或寿命。
与核苷酸序列有关的术语“变体”、“同源物”或“衍生物”包括来自或对序列的一个(或多个)核酸的任何取代、变异、修饰、置换、删除或添加。
核酸构建体
本发明提供了包含本发明的核酸序列的核酸构建体。核酸构建体还可以包含编码嵌合抗原受体(CAR)或转基因TCR的核酸序列。
根据的核酸构建体还可以包含以下中的一种或多种：
编码显性负性SHP2的核酸序列；
编码显性负性TGFβ受体的核酸序列；
编码嵌合细胞因子受体的核酸序列；
编码一种或多种额外的细胞因子或趋化因子的一种或多种核酸序列。
本发明提供了核酸构建体，其包含：
(i)编码嵌合抗原受体(CAR)的核酸序列；
(ii)位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列；和
(iii)编码IL-15的核酸序列；和/或
(iv)编码CXCL12的核酸序列。
本发明提供了核酸构建体，其包含：
(i)编码嵌合抗原受体(CAR)的核酸序列；
(ii)位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列；和
(iii)编码IL-7的核酸序列；和/或
(iv)编码CCL19的核酸序列。
核酸构建体可以在核酸序列之间包含共表达序列，使得共表达序列上游和下游的转基因作为分开的多肽由细胞表达。共表达序列可以编码自切割肽，其在上文更详细地描述。
如上文所述，用于共表达CAR与低水平的IL-12的核酸构建体可以具有通式结构：
CAR-FSM/TRM-coexpr-IL12
其中：
“CAR”是编码嵌合抗原受体的核酸序列；
“FSM/TRM”是框架滑动基序或翻译通读基序；
“coexpr”是能够使CAR和IL-12作为分开的多肽共表达的序列；并且
“IL-12”是编码IL-12或flexi-IL12的核酸序列。
包含编码另一种细胞因子或趋化因子或趋化因子的核酸序列的构建体可以具有通式结构：
CAR-FSM/TRM-coexpr1-IL12-coexpr2-CC；或
CAR-FSM/TRM-coexpr1-CC-coexpr2-IL12；
CAR-coexpr1-CC-FSM/TRM-coexpr2-IL12；
CC-coexpr1-CAR-FSM/TRM-coexpr2-IL12
其中：
“CAR”是编码嵌合抗原受体的核酸序列；
“FSM/TRM”是框架滑动基序或翻译通读基序；
“coexpr1”和“coexpr2”，可以相同或不同，是能够使CAR、IL-12和细胞因子或趋化因子作为分开的多肽共表达的序列；
“IL-12”是编码IL-12或flexi-IL12的核酸序列；并且
“CC”是编码细胞因子(除IL-12以外)或趋化因子的核酸序列。
具有复合翻译通读基序的核酸构建体可以具有结构：
CAR-FSM/TRM1-coexpr1-CC-FSM/TRM2-coexpr2-IL12
其中：
“CAR”是编码嵌合抗原受体的核酸序列；
“FSM/TRM1”和“FSM/TRM2”，可以相同或不同，是框架滑动基序或翻译通读基序；
“coexpr1”和“coexpr2”，可以相同或不同，是能够使CAR、IL-12和细胞因子或趋化因子作为分开的多肽共表达的序列；
“IL-12”是编码IL-12或flexi-IL12的核酸序列；并且
“CC”是编码细胞因子(除IL-12以外)或趋化因子的核酸序列。
载体
本发明还提供了包含本发明的核酸序列或核酸构建体的载体。
此类载体可用于将核酸序列或构建体引入宿主细胞使其表达低水平的IL-12。
例如，载体可以是质粒或病毒载体，诸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哺乳动物细胞，例如T细胞或NK细胞。
载体试剂盒
本发明还提供了包含多个载体的试剂盒，其中至少一个载体包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。
所述试剂盒中的所述载体或其他载体可以包含以下中的一种或多种：
编码CAR或转基因TCR的核酸序列；
编码显性负性SHP2的核酸序列；
编码显性负性TGFβ受体的核酸序列；
编码嵌合细胞因子受体的核酸序列；
编码一种或多种额外的细胞因子或趋化因子的一种或多种核酸序列。
试剂盒可以包含：
第一载体，所述第一载体包含编码CAR的核酸序列和位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列；和
第二载体，所述第二载体包含编码CAR的核酸序列、编码显性负性SHP2的核酸序列和编码显性负性TGFβ的核酸序列。
细胞
本发明提供了包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列的细胞。
细胞可以是肿瘤浸润免疫细胞，诸如T细胞、自然杀伤(NK)细胞、NKT细胞、细胞因子诱导的杀伤(CIK)细胞、单核细胞、巨噬细胞、肿瘤浸润淋巴细胞(TIL)、树突状细胞、中性粒细胞、肥大细胞、嗜酸性粒细胞或嗜碱性粒细胞。
细胞可以是溶细胞性免疫细胞，诸如T细胞和/或NK细胞。
T细胞或T淋巴细胞是一类在细胞介导的免疫中起核心作用的淋巴细胞。它们可以通过在细胞表面上T细胞受体(TCR)的存在而与其他淋巴细胞，诸如B细胞和自然杀伤细胞(NK细胞)区分开。存在多种类型的T细胞，总结如下。
辅助性T辅助细胞(TH细胞)在免疫过程中协助其他白血细胞，包括B细胞成熟为浆细胞和记忆B细胞，以及激活细胞毒性T细胞和巨噬细胞。TH细胞在其表面表达CD4。当肽抗原被抗原呈递细胞(APC)的表面上的MHC II类分子呈递给TH细胞时，TH细胞变为活化。这些细胞可以分化成几种亚型之一，包括TH1、TH2、TH3、TH17、Th9或TFH，它们分泌不同的细胞因子以促进不同类型的免疫应答。
溶细胞性T细胞(TC细胞或CTL)破坏病毒感染的细胞和肿瘤细胞，并且还参与移植排斥。CTL在其表面表达CD8。这些细胞通过与存在于所有有核细胞表面的与MHC I类缔合的抗原结合来识别它们的靶标。通过调节性T细胞分泌的IL-10、腺苷和其他分子，可以使CD8+细胞失活至无能状态，这预防自身免疫性疾病，诸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，其在感染解决后长期存在。当再次暴露于其同源抗原后它们迅速扩增成大量效应T细胞，从而为免疫系统提供针对过去感染的“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。
调节性T细胞(Treg细胞)，以前称为抑制性T细胞，对于维持免疫耐受至关重要。它们的主要作用是在免疫反应末期关闭T细胞介导的免疫，以及抑制胸腺中逃脱负向选择过程的自反应性T细胞。
已经描述了两种主要类型的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)出现在胸腺中，并且与发育中的T细胞与已被TSLP激活的髓样(CD11c+)和浆细胞样(CD123+)树突状细胞之间的相互作用有关。通过称为FoxP3的细胞内分子的存在，可以将天然存在的Treg细胞与其他T细胞区分开。FOXP3基因的突变能够阻止调节性T细胞发育，导致致命的自身免疫性疾病IPEX。
适应性Treg细胞(也称为Tr1细胞或Th3细胞)可能起源于正常的免疫应答期间。
自然杀伤细胞(或NK细胞)形成先天免疫系统的一部分。NK细胞以不依赖于MHC的方式对来自被病毒感染的细胞的先天信号提供快速应答。
NK细胞(属于先天淋巴样细胞组)被定义为大颗粒淋巴细胞(LGL)，构成从产生B和T淋巴细胞的共同淋巴样祖细胞分化而来的第三种细胞。已知NK细胞在骨髓、淋巴结、脾脏、扁桃体和胸腺中分化和成熟，然后它们进入循环。
自然杀伤T(NKT)细胞是一组异质的T细胞，它们共享T细胞和自然杀伤细胞的特性。这些细胞中的许多识别非多态性CD1d分子，该分子是结合自身和外来脂质和糖脂的抗原呈递分子。它们仅构成所有外周血T细胞的约0.1％。
NKT细胞是共表达αβT细胞受体的T细胞的子集，但也表达多种通常与NK细胞相关的分子标记，诸如NK1.1。最著名的NKT细胞与传统的αβT细胞的区别在于它们的T细胞受体在多样性方面受到更多限制(“不变”或“1型”NKT)。它们和其他CD1d限制性T细胞(“2型”NKT)识别由CD1d分子(抗原呈递分子CD1家族的成员)呈递的脂质和糖脂，而不识别肽-主要组织相容性复合物(MHC)。因此，NKT细胞在识别来自生物体(诸如导致结核病的分枝杆菌)的糖脂方面是重要的。
NKT细胞包括NK1.1+和NK1.1-，以及CD4+、CD4-、CD8+和CD8-细胞。自然杀伤T细胞还可以与NK细胞共享其他特征，诸如CD16和CD56表达和颗粒酶产生。
细胞因子诱导的杀伤细胞(CIK)细胞是一组具有混合T细胞样和自然杀伤(NK)细胞样表型的特征的免疫效应细胞。它们是通过将人外周血单核细胞(PBMC)或脐带血单核细胞与干扰素-γ(IFN-γ)、抗CD3抗体、重组人白细胞介素(IL-)1和重组人白细胞介素(IL)-2离体孵育产生的。
通常，免疫细胞检测存在于受感染的细胞表面上的主要组织相容性复合物(MHC)，从而触发细胞因子释放，导致裂解或细胞凋亡。然而，CIK细胞能够在不存在抗体和MHC的情况下识别受感染的细胞甚至是恶性细胞，容许快速和无偏的免疫反应。这特别重要，因为缺少MHC标记的有害细胞无法被其他免疫细胞诸如T淋巴细胞追踪和攻击。作为特殊的特征，终末分化的CD3+CD56+CIK细胞具有MHC限制性和MHC非限制性的抗肿瘤细胞毒性的能力。这些特性尤其使CIK细胞具有作为癌症和病毒感染的潜在疗法的吸引力。
在体外和体内都已经产生了NK细胞的新亚类。这些被称为细胞因子诱导的记忆样自然杀伤细胞的NK细胞是使用细胞因子诱导的，最常用的是IL-12、IL-15和IL-18的混合。这些NK细胞被这些细胞因子激活以刺激感染并诱导适应性免疫应答。如果与靶细胞诸如肿瘤靶标共培养，这些NK细胞具有记忆样能力，并且在建立防御方面更具适应性和有效性。
本发明的细胞可以是上文提及的任何细胞类型。
细胞可以衍生自血液样品，例如来自白细胞单采术。细胞可以是或包含外周血单核细胞(PBMC)。
细胞可以从患者自己的外周血(第一方)离体产生，或者在造血干细胞移植的环境中从供体外周血(第二方)离体产生，或者从来自无关联供体的外周血(第三方)离体产生。
可替代地，细胞可以衍生自诱导型祖细胞或胚胎祖细胞离体分化为例如T或NK细胞。可替代地，可以使用保留其溶解功能并且可以充当治疗剂的永生化T细胞系。
可以在用本发明第一方面的编码提供根据嵌合多肽的分子的核酸转导之前活化和/或扩增细胞，例如通过用抗CD3单克隆抗体处理。
药物组合物
本发明的细胞可以作为药物组合物向患者施用。
药物组合物可以额外包含药学上可接受的载体、稀释剂或赋形剂。药物组合物可以任选地包含一种或多种另外的有药学活性的多肽和/或化合物。例如，此类制剂可以是适合静脉输注的形式。
制备细胞的方法
在另一方面，本发明提供了制备根据本发明的细胞的方法，其包括将本发明的核酸序列、核酸构建体、载体或载体试剂盒引入细胞的步骤。
核酸序列、核酸构建体、载体或载体试剂盒可以例如通过体外或离体转导或转染引入。
细胞可以是从受试者分离的细胞，例如从受试者分离的T细胞或NK细胞。
细胞可以是自体的或同种异体的。
治疗方法
本发明提供了治疗疾病的方法，其包括向受试者施用本发明的细胞组合物(例如在如上文所述的药物组合物中)的步骤。
治疗疾病的方法涉及本发明的细胞组合物的治疗用途。可以向患有现有疾病或病症的受试者施用细胞组合物，以减轻、减少或改善与疾病相关的至少一种症状和/或减缓、减少或阻断疾病的进展。
预防疾病的方法涉及本发明的细胞组合物的预防用途。可以向尚未患病和/或未显示出任何疾病症状的受试者施用细胞组合物，以预防或削弱疾病的病因或减少或预防与疾病相关的至少一种症状的发展。受试者可以具有该疾病的易感性或被认为有发展该疾病的风险。
方法可以涉及以下步骤：
(i)分离含有细胞的样品；
(ii)用至少两种病毒载体的混合物转导此细胞；
(iii)向受试者施用来自(ii)的细胞。
本发明还提供了用于治疗和/或预防疾病的本发明的细胞组合物。
本发明还涉及本发明的细胞组合物在制备用于治疗疾病的药物中的用途。
通过本发明的方法治疗的疾病可以是癌性疾病，诸如膀胱癌、乳腺癌、结肠癌、子宫内膜癌、肾癌(肾细胞)、白血病、肺癌、黑色素瘤、非霍奇金淋巴瘤、胰腺癌、前列腺癌和甲状腺癌。
本发明组合物的细胞可以能够杀伤靶细胞，诸如癌细胞。靶细胞的特征可以在于靶细胞附近存在肿瘤分泌的配体或趋化因子配体。靶细胞的特征可以在于可溶性配体的存在以及肿瘤相关抗原(TAA)在靶细胞表面的表达。
特别地，本发明的细胞可以用于治疗实体癌。实体癌是形成分离的肿瘤块的恶性肿瘤，例如脑、乳腺、前列腺、结直肠、肾、肉瘤、黑色素瘤，其与可以弥漫性浸润组织而不形成肿块的淋巴增殖性恶性肿瘤白血病不同。
本发明的细胞可以用于治疗表3中所列的癌症之一。
表3-示例性实体癌靶标及其相关适应症
特别地，本发明的细胞可以用于治疗小细胞肺癌(SCLC)、黑色素瘤、肾细胞癌(RCC)、肝细胞癌(HCC)、卵巢癌、胰腺癌、成神经细胞瘤、骨肉瘤。在这些实施方案中，细胞可以表达GD2特异性CAR。
癌症异质性和表位扩散
癌症可以是异质的。在这方面，CAR靶向的抗原的表达水平可以在癌细胞之间不同。肿瘤中表达CAR靶向的抗原的细胞比例可以小于100％，例如在肿瘤中小于约95、90、80、70、60、50、40、30、20或10％的细胞可以以可检测的水平或以CAR-T细胞可识别的水平表达靶抗原。实体癌的一些细胞可以是抗原阴性的或抗原暗淡的，即表达低水平的靶抗原。“抗原暗淡的”靶细胞平均每个细胞可以表达少于约1000、750、500或250个拷贝的靶抗原。
由于IL-12的辅助作用，本发明的细胞特别适合靶向异质的肿瘤。IL-12通过激活幼稚T细胞和巨噬细胞来激活抗肿瘤免疫应答。已经显示其1)增强T细胞和NK细胞的增殖，2)增加T细胞、NK细胞和巨噬细胞的溶细胞活性，3)激活T辅助1(Th1)细胞，以及4)诱导IFN-γ和其他细胞因子的产生。IL-12激活邻近的CAR-T细胞并增强其细胞毒性，增强其杀伤具有低水平靶抗原的肿瘤细胞的能力。
CAR T细胞疗法的机制是通过表达CAR的T细胞直接杀伤表达靶抗原的细胞。不希望受理论束缚，本发明的发明人相信，由CAR-T细胞同时局部表达IL-12将导致“表位扩散”，即引发针对肿瘤细胞上存在的额外的靶抗原的免疫应答。CAR-T细胞分泌IL-12也可以诱导宿主免疫细胞浸润到肿瘤块中。
因此，从T细胞分泌的IL-12不仅克服了由肿瘤细胞介导的免疫抑制，而且还为表位扩散提供了有利的环境，在该环境中免疫细胞多样化以除原始抗原还攻击多种肿瘤相关靶标。肿瘤根除的作用机制是通过CAR-T细胞直接的细胞杀伤、免疫细胞浸润到肿瘤中以及诱导现有的宿主免疫细胞针对其他肿瘤相关抗原的抗癌免疫应答的组合。
表位扩散对于异质肿瘤的治疗是重要的，因为它能够杀伤靶抗原暗淡的或阴性的细胞。此外，它有助于防止肿瘤从CAR-T细胞疗法中免疫逃逸，从而防止恶性肿瘤可能作为抗原阴性群体复发。
现在将通过实施例的方式进一步描述本发明，这些实施例旨在用来帮助本领域的普通技术人员实施本发明并且不旨在以任何方式限制本发明的范围。
实施例
实施例1—CAR-T细胞表达IL-12
在编码两种转基因的构建体中包含自切割肽诸如FMDV衍生的2A肽序列，导致两种多肽的大致相等的表达。在构建体共表达CAR和IL-12的情况下，这将导致CAR-T细胞分泌高水平的IL-12(在图4A左图中示意性示出)。
然而，在IL-12编码序列上游加入“停止-跳跃”序列应该会急剧减少CAR-T细胞产生的IL-12的量(在图4A左图中示意性示出)。
为了实验性证明，用编码以下构建体的病毒转导外周血单核细胞(PBMC)：
CAR-2A-IL-12：包含CAR编码序列、2A自切割肽和编码flexi-IL-12的序列(具有如SEQ ID No.1所示的序列)，和
CAR-SS-IL-12：包含CAR编码序列、停止-跳跃序列(具有如SEQ ID No.37所示的序列)和位于停止-跳跃序列下游的编码flexi-IL-12的序列。
将未转导的细胞(NT)和用每种构建体转导的PBMC以1x10E6个细胞/mL铺入96孔板中，48小时后，收集培养基用于通过ELISA对释放的IL-12进行定量。结果如图4B所示。
当将编码IL-12的序列放置在停止-跳跃序列的下游时，转导的细胞产生的IL-12急剧减少，但仍可检测到。
实施例2—研究表达IL-12的CAR-T细胞的体内抗肿瘤活性
接下来，使用具有免疫能力的小鼠模型研究了SS-IL12模块在体内的功能。
通过用表达以下构建体的载体转导鼠PBMC产生表达CAR的细胞：
其中“Thy1.1”是转导标记；“aGD2_muK666-muCD8STK-muCD28Z”是第二代鼠GD2CAR；“mfIL-12”是鼠flexi-IL-12；“SKIP_TGACAATTA”是位于鼠flexi-IL-12编码序列上游的翻译通读基序；“aEGFRvIII_MR1-muCD8STK-muCD28Z”是针对aEGFRvIII的第二代鼠CAR，用作阴性对照。
在幻灯片的右侧可以看到，在图表中CAR-2A-IL12组的体重急剧下降，这是由于IL-12的全身毒性并且不得不对这些小鼠实施安乐死。关于肿瘤生长控制，在右侧我们可以看到在单独CAR组中肿瘤生长根本没有得到控制；而注射了CAR-SS-IL12的小鼠显著下降，是对肿瘤生长的控制，却没有CAR-2A-IL12小鼠组中显示的毒性。
我们可以得出结论，在具有挑战性的小鼠模型中，SS-IL12模块防止毒性同时保持有力的抗肿瘤活性。
在鼠B16黑色素瘤模型中，使用体内测定法研究表达GD2以及表达或不表达IL-12的T细胞的抗肿瘤活性。
在第0天将B16.F10.GD2(0.1x106)皮下施用于小鼠。7天后，将3x106个CAR-T细胞经静脉内施用，并且在接下来的14天监测肿瘤生长。
如图6所示，CAR-2A-IL12组，即接受表达CAR与IL-12组合但没有停止-跳跃序列的细胞的小鼠，由于IL-12的全身毒性而显示出急剧的体重减轻。第12天之前不得不对这些小鼠实施安乐死。CAR-SS-IL12组，即接受表达CAR与超低水平IL-12组合的细胞的小鼠没有显示出任何显著的体重减轻或IL-12相关的毒性。
肿瘤生长测定结果如图7所示。仅表达简单GD2CAR的CAR T细胞的静脉内递送对肿瘤生长没有显著影响(图7“CAR”)。引入表达IL-12而没有控制表达水平的翻译通读基序的CAR-T细胞，对小鼠具有致命毒性(图7“CAR-2A”)。然而，共表达超低水平IL-12(其中将IL-12编码序列放置在翻译通读基序的下游)的CAR T细胞的静脉内递送，展现出有力的抗肿瘤活性并延长了小鼠的存活期(图7“CAR-SS”)。
实施例3—研究表达超低IL-12的CAR-T细胞在免疫应答期间诱导表位扩散的能力
为了检查ssIL12模块在体内诱导表位扩散反应的能力，从鼠黑色素瘤细胞系B16.F10产生了靶细胞系，该鼠黑色素瘤细胞系B16.F10经转导以表达在质膜上合成GD2所需的两种前体酶(GD2和GD3合酶)。该靶细胞系的GD2表达为100％阳性的，并且用于通过以固定的比例添加非转导的B16.F10细胞来制备异质靶细胞群。
生成的异质靶细胞群为10％、30％、50％、70％或90％GD2阳性，并且与100％GD2阳性细胞的同质对照进行比较。将1E5个靶细胞经皮下注射到自体受体中并且容许植入持续6天后施用5戈瑞(Gray)全身照射。
次日，经静脉注射3E6个CAR T细胞。定期监测小鼠的毒性体征(体重、血清细胞因子和一般状况)和功效(肿瘤大小的卡尺测量)。
在取下时，取小鼠脾脏用于分析CAR细胞、CD4+T细胞、CD8+T细胞、B细胞、NK细胞和单核细胞的比例。收集取下时任何剩余的肿瘤用于免疫组织化学分析(以评估免疫浸润和肿瘤形态)和流式细胞术(以评估免疫浸润和GD2阳性肿瘤的比例和表达水平)。
通过模块消除来自受体小鼠的异质靶标的能力和/或模块诱导免疫浸润在肿瘤块中的能力来确定表位扩散程度。
上述说明书中提及的所有出版物均通过引用并入本文。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。尽管已经结合具体的优选实施方案描述了本发明，但应当理解，所要求保护的本发明不应被过度地限制于此类具体的实施方案。实际上，对分子生物学或相关领域的技术人员来说显而易见的用于实施本发明的所述模式的各种修改旨在落入所附权利要求的范围内。
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50 55 60
Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu Leu
65 70 75 80
Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys Asp
85 90 95
Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys Asn
100 105 110
Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr Asp
115 120 125
Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln Gly
130 135 140
Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly Asp
145 150 155 160
Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala Cys
165 170 175
Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala Val
180 185 190
His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg Asp
195 200 205
Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu Lys
210 215 220
Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp Ser
225 230 235 240
Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln Gly
245 250 255
Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr Ser
260 265 270
Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala Gln
275 280 285
Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro Cys
290 295 300
<210> 26
<211> 177
<212> PRT
<213> 智人
<400> 26
Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile
1 5 10 15
Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys
20 25 30
Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu
35 40 45
Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe
50 55 60
Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Glu Gly Met Phe
65 70 75 80
Leu Phe Arg Ala Ala Arg Lys Leu Arg Gln Phe Leu Lys Met Asn Ser
85 90 95
Thr Gly Asp Phe Asp Leu His Leu Leu Lys Val Ser Glu Gly Thr Thr
100 105 110
Ile Leu Leu Asn Cys Thr Gly Gln Val Lys Gly Arg Lys Pro Ala Ala
115 120 125
Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu Asn Lys Ser Leu
130 135 140
Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu Lys Arg Leu Leu
145 150 155 160
Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met Gly Thr Lys Glu
165 170 175
His
<210> 27
<211> 162
<212> PRT
<213> 智人
<400> 27
Met Arg Ile Ser Lys Pro His Leu Arg Ser Ile Ser Ile Gln Cys Tyr
1 5 10 15
Leu Cys Leu Leu Leu Asn Ser His Phe Leu Thr Glu Ala Gly Ile His
20 25 30
Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro Lys Thr Glu Ala
35 40 45
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
50 55 60
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
65 70 75 80
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
85 90 95
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
100 105 110
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
115 120 125
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
130 135 140
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
145 150 155 160
Thr Ser
<210> 28
<211> 98
<212> PRT
<213> 智人
<400> 28
Met Ala Leu Leu Leu Ala Leu Ser Leu Leu Val Leu Trp Thr Ser Pro
1 5 10 15
Ala Pro Thr Leu Ser Gly Thr Asn Asp Ala Glu Asp Cys Cys Leu Ser
20 25 30
Val Thr Gln Lys Pro Ile Pro Gly Tyr Ile Val Arg Asn Phe His Tyr
35 40 45
Leu Leu Ile Lys Asp Gly Cys Arg Val Pro Ala Val Val Phe Thr Thr
50 55 60
Leu Arg Gly Arg Gln Leu Cys Ala Pro Pro Asp Gln Pro Trp Val Glu
65 70 75 80
Arg Ile Ile Gln Arg Leu Gln Arg Thr Ser Ala Lys Met Lys Arg Arg
85 90 95
Ser Ser
<210> 29
<211> 93
<212> PRT
<213> 智人
<400> 29
Met Asn Ala Lys Val Val Val Val Leu Val Leu Val Leu Thr Ala Leu
1 5 10 15
Cys Leu Ser Asp Gly Lys Pro Val Ser Leu Ser Tyr Arg Cys Pro Cys
20 25 30
Arg Phe Phe Glu Ser His Val Ala Arg Ala Asn Val Lys His Leu Lys
35 40 45
Ile Leu Asn Thr Pro Asn Cys Ala Leu Gln Ile Val Ala Arg Leu Lys
50 55 60
Asn Asn Asn Arg Gln Val Cys Ile Asp Pro Lys Leu Lys Trp Ile Gln
65 70 75 80
Glu Tyr Leu Glu Lys Ala Leu Asn Lys Arg Phe Lys Met
85 90
<210> 30
<211> 10
<212> RNA
<213> 人工序列
<220>
<223> 多个终止翻译通读基序
<400> 30
ugaugacuag 10
<210> 31
<211> 7
<212> DNA
<213> 人工序列
<220>
<223> 编码TRM的构建体DNA序列
<400> 31
tgactag 7
<210> 32
<211> 7
<212> DNA
<213> 人工序列
<220>
<223> 编码TRM的构建体DNA序列
<400> 32
tagctag 7
<210> 33
<211> 7
<212> DNA
<213> 人工序列
<220>
<223> 编码TRM的构建体DNA序列
<400> 33
taactag 7
<210> 34
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 编码TRM的构建体DNA序列
<400> 34
tgacaatta 9
<210> 35
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 编码TRM的构建体DNA序列
<400> 35
tagcaatta 9
<210> 36
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 编码TRM的构建体DNA序列
<400> 36
taacaatta 9
<210> 37
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 编码TRM的构建体DNA序列
<400> 37
tgactagca 9
<210> 38
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 碱性氨基酸弗林蛋白酶靶序列
<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> (3)..(3)
<223> Xaa可以是Arg或Lys
<400> 38
Arg Xaa Xaa Arg
1
<210> 39
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 一致的烟草蚀刻病毒(TEV)切割位点
<400> 39
Glu Asn Leu Tyr Phe Gln Ser
1 5
<210> 40
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 涉及切割活性的基序
<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)..(4)
<223> Xaa可以是任何天然存在的氨基酸
<400> 40
Asp Xaa Glu Xaa Asn Pro Gly Pro
1 5
<210> 41
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 41
Asp Ile Glu Thr Asn Pro Gly Pro
1 5
<210> 42
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 42
Asp Val Glu Thr Asn Pro Gly Pro
1 5
<210> 43
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 43
Asp Val Glu Met Asn Pro Gly Pro
1 5
<210> 44
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 44
Asp Val Glu Ser Asn Pro Gly Pro
1 5
<210> 45
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 45
Asp Met Glu Ser Asn Pro Gly Pro
1 5
<210> 46
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 46
Asp Val Glu Glu Asn Pro Gly Pro
1 5
<210> 47
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 47
Asp Ile Glu Leu Asn Pro Gly Pro
1 5
<210> 48
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 48
Asp Ile Glu Gln Asn Pro Gly Pro
1 5
<210> 49
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 49
Asp Ser Glu Phe Asn Pro Gly Pro
1 5
<210> 50
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 50
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn
1 5 10 15
Pro Gly Pro
<210> 51
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 51
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Gln Ser Asn
1 5 10 15
Pro Gly Pro
<210> 52
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 52
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ile Asn
1 5 10 15
Pro Gly Pro
<210> 53
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 53
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Phe Asn
1 5 10 15
Pro Gly Pro
<210> 54
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 54
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser His
1 5 10 15
Pro Gly Pro
<210> 55
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 55
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Glu
1 5 10 15
Pro Gly Pro
<210> 56
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 56
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Gln
1 5 10 15
Pro Gly Pro
<210> 57
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 57
Leu Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn
1 5 10 15
Pro Gly Gly
<210> 58
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 58
Tyr His Ala Asp Tyr Tyr Lys Gln Arg Leu Ile His Asp Val Glu Met
1 5 10 15
Asn Pro Gly Pro
20
<210> 59
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 59
His Tyr Ala Gly Tyr Phe Ala Asp Leu Leu Ile His Asp Ile Glu Thr
1 5 10 15
Asn Pro Gly Pro
20
<210> 60
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<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> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 61
Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn
1 5 10 15
Pro Gly Pro
<210> 62
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 62
Ala Ala Arg Gln Met Leu Leu Leu Leu Ser Gly Asp Val Glu Thr Asn
1 5 10 15
Pro Gly Pro
<210> 63
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 63
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> 64
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 64
Thr Arg Ala Glu Ile Glu Asp Glu Leu Ile Arg Ala Gly Ile Glu Ser
1 5 10 15
Asn Pro Gly Pro
20
<210> 65
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 65
Thr Arg Ala Glu Ile Glu Asp Glu Leu Ile Arg Ala Asp Ile Glu Ser
1 5 10 15
Asn Pro Gly Pro
20
<210> 66
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 66
Ala Lys Phe Gln Ile Asp Lys Ile Leu Ile Ser Gly Asp Val Glu Leu
1 5 10 15
Asn Pro Gly Pro
20
<210> 67
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 67
Ser Ser Ile Ile Arg Thr Lys Met Leu Val Ser Gly Asp Val Glu Glu
1 5 10 15
Asn Pro Gly Pro
20
<210> 68
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 68
Cys Asp Ala Gln Arg Gln Lys Leu Leu Leu Ser Gly Asp Ile Glu Gln
1 5 10 15
Asn Pro Gly Pro
20
<210> 69
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 切割位点，2A样序列
<400> 69
Tyr Pro Ile Asp Phe Gly Gly Phe Leu Val Lys Ala Asp Ser Glu Phe
1 5 10 15
Asn Pro Gly Pro
20
<210> 70
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 来自Thosea asigna病毒衣壳蛋白的2A肽
<400> 70
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
1 5 10 15
Gly Pro
<210> 71
<211> 57
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 71
Val Thr Glu Leu Leu Tyr Arg Met Lys Arg Ala Glu Thr Tyr Cys Pro
1 5 10 15
Arg Pro Leu Ala Ile His Pro Thr Glu Ala Arg His Lys Gln Lys Ile
20 25 30
Val Ala Pro Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala
35 40 45
Gly Asp Val Glu Ser Asn Pro Gly Pro
50 55
<210> 72
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 72
Leu Leu Ala Ile His Pro Thr Glu Ala Arg His Lys Gln Lys Ile Val
1 5 10 15
Ala Pro Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly
20 25 30
Asp Val Glu Ser Asn Pro Gly Pro
35 40
<210> 73
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 73
Glu Ala Arg His Lys Gln Lys Ile Val Ala Pro Val Lys Gln Thr Leu
1 5 10 15
Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn Pro Gly
20 25 30
Pro
<210> 74
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 切割序列
<400> 74
Ala Pro Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly
1 5 10 15
Asp Val Glu Ser Asn Pro Gly Pro
20
<210> 75
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化KM666 VH序列
<400> 75
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ala Ser Tyr
20 25 30
Asn Ile His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Phe Leu
65 70 75 80
Lys Met Ser Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Arg Ser Asp Asp Tyr Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 76
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化KM666 VL序列
<400> 76
Glu Asn Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Lys Ala Pro Lys Val Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 77
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化7A12 VH序列
<400> 77
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Gly Tyr Leu Trp Tyr Phe Asp Val Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 78
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化7A12 VL序列
<400> 78
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Asn Glu Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Arg Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 79
<211> 41
<212> PRT
<213> 人工序列
<220>
<223> CD28胞内域
<400> 79
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 80
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3z胞内域
<400> 80
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
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> 81
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> ITAM（免疫受体酪氨酸激活基序）
<220>
<221> misc_feature
<222> (2)..(3)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa可以是Leu或Ile
<400> 81
Tyr Xaa Xaa Xaa
1
<210> 82
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> SHP-1 SH2完整域
<400> 82
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
210
<210> 83
<211> 97
<212> PRT
<213> 人工序列
<220>
<223> SHP-1 SH2域1
<400> 83
Trp Phe His Arg Asp Leu Ser Gly Leu Asp Ala Glu Thr Leu Leu Lys
1 5 10 15
Gly Arg Gly Val His Gly Ser Phe Leu Ala Arg Pro Ser Arg Lys Asn
20 25 30
Gln Gly Asp Phe Ser Leu Ser Val Arg Val Gly Asp Gln Val Thr His
35 40 45
Ile Arg Ile Gln Asn Ser Gly Asp Phe Tyr Asp Leu Tyr Gly Gly Glu
50 55 60
Lys Phe Ala Thr Leu Thr Glu Leu Val Glu Tyr Tyr Thr Gln Gln Gln
65 70 75 80
Gly Val Leu Gln Asp Arg Asp Gly Thr Ile Ile His Leu Lys Tyr Pro
85 90 95
Leu
<210> 84
<211> 104
<212> PRT
<213> 人工序列
<220>
<223> SHP-1 SH2域2
<400> 84
Trp Tyr His Gly His Met Ser Gly Gly Gln Ala Glu Thr Leu Leu Gln
1 5 10 15
Ala Lys Gly Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Leu Ser Gln
20 25 30
Pro Gly Asp Phe Val Leu Ser Val Leu Ser Asp Gln Pro Lys Ala Gly
35 40 45
Pro Gly Ser Pro Leu Arg Val Thr His Ile Lys Val Met Cys Glu Gly
50 55 60
Gly Arg Tyr Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Leu Thr Asp
65 70 75 80
Leu Val Glu His Phe Lys Lys Thr Gly Ile Glu Glu Ala Ser Gly Ala
85 90 95
Phe Val Tyr Leu Arg Gln Pro Tyr
100
<210> 85
<211> 97
<212> PRT
<213> 人工序列
<220>
<223> SHP-2第一SH2域
<400> 85
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
<210> 86
<211> 105
<212> PRT
<213> 人工序列
<220>
<223> SHP-2第二SH2域
<400> 86
Trp Phe His Gly His Leu Ser Gly Lys Glu Ala Glu Lys Leu Leu Thr
1 5 10 15
Glu Lys Gly Lys His Gly Ser Phe Leu Val Arg Glu Ser Gln Ser His
20 25 30
Pro Gly Asp Phe Val Leu Ser Val Arg Thr Gly Asp Asp Lys Gly Glu
35 40 45
Ser Asn Asp Gly Lys Ser Lys Val Thr His Val Met Ile Arg Cys Gln
50 55 60
Glu Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Phe Asp Ser Leu Thr
65 70 75 80
Asp Leu Val Glu His Tyr Lys Lys Asn Pro Met Val Glu Thr Leu Gly
85 90 95
Thr Val Leu Gln Leu Lys Gln Pro Leu
100 105
<210> 87
<211> 211
<212> PRT
<213> 人工序列
<220>
<223> SHP-2串联SH2域
<400> 87
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
210
<210> 88
<211> 177
<212> PRT
<213> 人工序列
<220>
<223> 显性负性TGFβ受体II
<400> 88
Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val
1 5 10 15
Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys
20 25 30
Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn
35 40 45
Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala
50 55 60
Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His
65 70 75 80
Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser
85 90 95
Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe
100 105 110
Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser
115 120 125
Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln
130 135 140
Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val
145 150 155 160
Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser
165 170 175
Ser
<210> 89
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人Igκ恒定域
<400> 89
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 90
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人铰链
<400> 90
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 91
<211> 97
<212> PRT
<213> 人工序列
<220>
<223> 人IgG1 CH1域
<400> 91
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
1 5 10 15
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
20 25 30
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
35 40 45
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
50 55 60
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
65 70 75 80
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
85 90 95
Val
<210> 92
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 来自人IL2R共用γ链的跨膜域
<400> 92
Val Val Ile Ser Val Gly Ser Met Gly Leu Ile Ile Ser Leu Leu Cys
1 5 10 15
Val Tyr Phe Trp Leu
20
<210> 93
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 来自人IL-2R β的跨膜域
<400> 93
Ile Pro Trp Leu Gly His Leu Leu Val Gly Leu Ser Gly Ala Phe Gly
1 5 10 15
Phe Ile Ile Leu Val Tyr Leu Leu Ile
20 25
<210> 94
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 来自人IL-7R α的跨膜域
<400> 94
Pro Ile Leu Leu Thr Ile Ser Ile Leu Ser Phe Phe Ser Val Ala Leu
1 5 10 15
Leu Val Ile Leu Ala Cys Val Leu Trp
20 25
<210> 95
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 来自人GF-CSFR α的跨膜域
<400> 95
Asn Leu Gly Ser Val Tyr Ile Tyr Val Leu Leu Ile Val Gly Thr Leu
1 5 10 15
Val Cys Gly Ile Val Leu Gly Phe Leu Phe
20 25
<210> 96
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 来自人GM-CSFR共用β链的跨膜域
<400> 96
Val Leu Ala Leu Ile Val Ile Phe Leu Thr Ile Ala Val Leu Leu Ala
1 5 10 15
Leu
<210> 97
<211> 86
<212> PRT
<213> 人工序列
<220>
<223> 来自人IL2R共用γ链的胞内域
<400> 97
Glu Arg Thr Met Pro Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu
1 5 10 15
Val Thr Glu Tyr His Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys
20 25 30
Gly Leu Ala Glu Ser Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu
35 40 45
Val Ser Glu Ile Pro Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly
50 55 60
Ala Ser Pro Cys Asn Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr
65 70 75 80
Thr Leu Lys Pro Glu Thr
85
<210> 98
<211> 286
<212> PRT
<213> 人工序列
<220>
<223> 来自人IL-2R β的胞内域
<400> 98
Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys Asn
1 5 10 15
Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser Ser Glu His Gly
20 25 30
Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe
35 40 45
Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu Glu Val Leu Glu
50 55 60
Arg Asp Lys Val Thr Gln Leu Leu Leu Gln Gln Asp Lys Val Pro Glu
65 70 75 80
Pro Ala Ser Leu Ser Ser Asn His Ser Leu Thr Ser Cys Phe Thr Asn
85 90 95
Gln Gly Tyr Phe Phe Phe His Leu Pro Asp Ala Leu Glu Ile Glu Ala
100 105 110
Cys Gln Val Tyr Phe Thr Tyr Asp Pro Tyr Ser Glu Glu Asp Pro Asp
115 120 125
Glu Gly Val Ala Gly Ala Pro Thr Gly Ser Ser Pro Gln Pro Leu Gln
130 135 140
Pro Leu Ser Gly Glu Asp Asp Ala Tyr Cys Thr Phe Pro Ser Arg Asp
145 150 155 160
Asp Leu Leu Leu Phe Ser Pro Ser Leu Leu Gly Gly Pro Ser Pro Pro
165 170 175
Ser Thr Ala Pro Gly Gly Ser Gly Ala Gly Glu Glu Arg Met Pro Pro
180 185 190
Ser Leu Gln Glu Arg Val Pro Arg Asp Trp Asp Pro Gln Pro Leu Gly
195 200 205
Pro Pro Thr Pro Gly Val Pro Asp Leu Val Asp Phe Gln Pro Pro Pro
210 215 220
Glu Leu Val Leu Arg Glu Ala Gly Glu Glu Val Pro Asp Ala Gly Pro
225 230 235 240
Arg Glu Gly Val Ser Phe Pro Trp Ser Arg Pro Pro Gly Gln Gly Glu
245 250 255
Phe Arg Ala Leu Asn Ala Arg Leu Pro Leu Asn Thr Asp Ala Tyr Leu
260 265 270
Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr His Leu Val
275 280 285
<210> 99
<211> 195
<212> PRT
<213> 人工序列
<220>
<223> 来自人IL-7R α的胞内域
<400> 99
Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys
1 5 10 15
Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val
20 25 30
Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp
35 40 45
Asp Ile Gln Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp Thr Phe
50 55 60
Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln Arg Leu Gly Gly Asp Val
65 70 75 80
Gln Ser Pro Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro Glu Ser
85 90 95
Phe Gly Arg Asp Ser Ser Leu Thr Cys Leu Ala Gly Asn Val Ser Ala
100 105 110
Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu
115 120 125
Ser Gly Lys Asn Gly Pro His Val Tyr Gln Asp Leu Leu Leu Ser Leu
130 135 140
Gly Thr Thr Asn Ser Thr Leu Pro Pro Pro Phe Ser Leu Gln Ser Gly
145 150 155 160
Ile Leu Thr Leu Asn Pro Val Ala Gln Gly Gln Pro Ile Leu Thr Ser
165 170 175
Leu Gly Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr
180 185 190
Gln Asn Gln
195
<210> 100
<211> 54
<212> PRT
<213> 人工序列
<220>
<223> 衍生自人GM-CSFR α的胞内域
<400> 100
Lys Arg Phe Leu Arg Ile Gln Arg Leu Phe Pro Pro Val Pro Gln Ile
1 5 10 15
Lys Asp Lys Leu Asn Asp Asn His Glu Val Glu Asp Glu Ile Ile Trp
20 25 30
Glu Glu Phe Thr Pro Glu Glu Gly Lys Gly Tyr Arg Glu Glu Val Leu
35 40 45
Thr Val Lys Glu Ile Thr
50
<210> 101
<211> 437
<212> PRT
<213> 人工序列
<220>
<223> 来自GM-CSFR共用β链的胞内域
<400> 101
Arg Phe Cys Gly Ile Tyr Gly Tyr Arg Leu Arg Arg Lys Trp Glu Glu
1 5 10 15
Lys Ile Pro Asn Pro Ser Lys Ser His Leu Phe Gln Asn Gly Ser Ala
20 25 30
Glu Leu Trp Pro Pro Gly Ser Met Ser Ala Phe Thr Ser Gly Ser Pro
35 40 45
Pro His Gln Gly Pro Trp Gly Ser Arg Phe Pro Glu Leu Glu Gly Val
50 55 60
Phe Pro Val Gly Phe Gly Asp Ser Glu Val Ser Pro Leu Thr Ile Glu
65 70 75 80
Asp Pro Lys His Val Cys Asp Pro Pro Ser Gly Pro Asp Thr Thr Pro
85 90 95
Ala Ala Ser Asp Leu Pro Thr Glu Gln Pro Pro Ser Pro Gln Pro Gly
100 105 110
Pro Pro Ala Ala Ser His Thr Pro Glu Lys Gln Ala Ser Ser Phe Asp
115 120 125
Phe Asn Gly Pro Tyr Leu Gly Pro Pro His Ser Arg Ser Leu Pro Asp
130 135 140
Ile Leu Gly Gln Pro Glu Pro Pro Gln Glu Gly Gly Ser Gln Lys Ser
145 150 155 160
Pro Pro Pro Gly Ser Leu Glu Tyr Leu Cys Leu Pro Ala Gly Gly Gln
165 170 175
Val Gln Leu Val Pro Leu Ala Gln Ala Met Gly Pro Gly Gln Ala Val
180 185 190
Glu Val Glu Arg Arg Pro Ser Gln Gly Ala Ala Gly Ser Pro Ser Leu
195 200 205
Glu Ser Gly Gly Gly Pro Ala Pro Pro Ala Leu Gly Pro Arg Val Gly
210 215 220
Gly Gln Asp Gln Lys Asp Ser Pro Val Ala Ile Pro Met Ser Ser Gly
225 230 235 240
Asp Thr Glu Asp Pro Gly Val Ala Ser Gly Tyr Val Ser Ser Ala Asp
245 250 255
Leu Val Phe Thr Pro Asn Ser Gly Ala Ser Ser Val Ser Leu Val Pro
260 265 270
Ser Leu Gly Leu Pro Ser Asp Gln Thr Pro Ser Leu Cys Pro Gly Leu
275 280 285
Ala Ser Gly Pro Pro Gly Ala Pro Gly Pro Val Lys Ser Gly Phe Glu
290 295 300
Gly Tyr Val Glu Leu Pro Pro Ile Glu Gly Arg Ser Pro Arg Ser Pro
305 310 315 320
Arg Asn Asn Pro Val Pro Pro Glu Ala Lys Ser Pro Val Leu Asn Pro
325 330 335
Gly Glu Arg Pro Ala Asp Val Ser Pro Thr Ser Pro Gln Pro Glu Gly
340 345 350
Leu Leu Val Leu Gln Gln Val Gly Asp Tyr Cys Phe Leu Pro Gly Leu
355 360 365
Gly Pro Gly Pro Leu Ser Leu Arg Ser Lys Pro Ser Ser Pro Gly Pro
370 375 380
Gly Pro Glu Ile Lys Asn Leu Asp Gln Ala Phe Gln Val Lys Lys Pro
385 390 395 400
Pro Gly Gln Ala Val Pro Gln Val Pro Val Ile Gln Leu Phe Lys Ala
405 410 415
Leu Lys Gln Gln Asp Tyr Leu Ser Leu Pro Pro Trp Glu Val Asn Lys
420 425 430
Pro Gly Glu Val Cys
435
<210> 102
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CXCL12环区基序
<400> 102
Arg Phe Phe Glu Ser His
1 5
<210> 103
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 切割位点基序
<400> 103
Asp Val Glu Leu Asn Pro Gly Pro
1 5
<210> 104
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 粘蛋白1基序
<400> 104
Pro Asp Thr Arg
1
Claims (40)
1.治疗实体癌的方法，其包括向受试者施用细胞的步骤，其中所述细胞包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。
2.根据权利要求1的方法，其包括以下步骤：
(i)从受试者中分离细胞样品；
(ii)用位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列转染或转导来自所述细胞样品的细胞；和
(iii)向所述受试者施用来自步骤(ii)的转导的或转染的细胞。
3.根据权利要求1或2的方法，其中所述编码IL-12的核酸序列编码“flexi-IL-12”：通过接头连接的IL-12α和IL-12β亚基之间的融合物。
4.根据权利要求3的方法，其中flexi-IL-12包含如SEQ ID No.1所示的序列。
5.根据前述权利要求中任一项的方法，其中所述编码白细胞介素(IL-12)的核酸序列位于框架滑动基序(FSM)的下游，并且所述FSM包含尿嘧啶、胸腺嘧啶或鸟嘌呤碱基的重复。
6.根据权利要求5的方法，其中所述FSM包含序列UUUUUUU(SEQ ID No.2)。
7.根据权利要求5或6的方法，其中所述FSM还包含终止密码子。
8.根据权利要求7的方法，其中所述FSM包含以下序列之一：
UUUUUUUGA(SEQ ID NO.3)
UUUUUUUAG(SEQ ID NO.4)
UUUUUUUAA(SEQ ID NO.5)。
9.根据权利要求1至4中任一项的方法，其中所述编码白细胞介素(IL-12)的核酸序列位于翻译通读基序(TRM)的下游，所述TRM包含序列STOP-CUAG或STOP-CAAUUA，其中“STOP”是终止密码子。
10.根据权利要求9的方法，其中所述翻译通读基序包含以下序列之一：
UGA-CUAG(SEQ ID No.6)
UAG-CUAG(SEQ ID No.7)
UAA-CUAG(SEQ ID No.8)
UGA-CAAUUA(SEQ ID No.9)
UAG-CAAUUA(SEQ ID No.10)
UAA-CAAUUA(SEQ ID No.11)。
11.根据前述权利要求中任一项的方法，其中所述细胞是肿瘤浸润免疫细胞。
12.根据权利要求11的方法，其中所述细胞是T细胞、自然杀伤(NK)细胞、NKT细胞、细胞因子诱导的杀伤(CIK)细胞、单核细胞、巨噬细胞或肿瘤浸润淋巴细胞(TIL)。
13.根据前述权利要求中任一项的方法，其中所述细胞表达嵌合抗原受体(CAR)或工程化的T细胞受体(TCR)。
14.根据权利要求12或13的方法，其中所述CAR或工程化的TCR结合以下靶抗原之一：双唾液酸神经节苷脂(GD2)、表皮生长因子受体(EGFR)、上皮细胞粘附分子(EpCAM)、磷脂酰肌醇蛋白聚糖3(GPC3)、人表皮生长因子受体(HER2)、L1CAM、粘蛋白1(MUC1)、前列腺特异性膜抗原(PSMA)。
15.根据权利要求14的方法，其中所述细胞表达结合GD2并具有抗原结合域的CAR，所述抗原结合域包含
a)重链可变区(VH)，所述重链可变区包含具有以下序列的互补决定区(CDR)：
CDR1–SYNIH(SEQ ID No.12)；
CDR2–VIWAGGSTNYNSALMS(SEQ ID No.13)；
CDR3–RSDDYSWFAY(SEQ ID No.14)；和
b)轻链可变区(VL)，所述轻链可变区包含具有以下序列的CDR：
CDR1–RASSSVSSSYLH(SEQ ID No.15)；
CDR2–STSNLAS(SEQ ID No.16)；
CDR3–QQYSGYPIT(SEQ ID No.17)。
16.根据权利要求14的方法，其中所述细胞表达结合PSMA并具有抗原结合域的CAR，所述抗原结合域包含
a)重链可变区(VH)，所述重链可变区包含具有以下序列的互补决定区(CDR)：
CDR1–SSWMN(SEQ ID No.18)；
CDR2–RIYPGDGDTNYAQKFQG(SEQ ID No.19)；
CDR3–GTGYLWYFDV(SEQ ID No.20)；和
b)轻链可变区(VL)，所述轻链可变区包含具有以下序列的CDR：
CDR1–RASQDINENLA(SEQ ID No.21)；
CDR2–YTSNRAT(SEQ ID No.22)；
CDR3–QQYDNLPFT(SEQ ID No.23)。
17.根据前述权利要求中任一项的方法，其中所述细胞还表达显性负性SHP2；和/或显性负性TGFβ受体。
18.根据前述权利要求中任一项的方法，其中所述细胞还表达嵌合细胞因子受体。
19.根据前述权利要求中任一项的方法，其中所述细胞还表达一种或多种额外的细胞因子或趋化因子。
20.根据权利要求19的方法，其中所述细胞表达以下中的一种或多种：IL-7、IL-15、CCL19和CXCL12。
21.根据权利要求20的方法，其中所述细胞表达IL-7和CCL19。
22.根据权利要求20的方法，其中所述细胞表达IL-15和/或CXCL12。
23.根据权利要求19至22中任一项的方法，其中编码所述一种或多种额外的细胞因子或趋化因子或每种额外的细胞因子或趋化因子的所述核酸位于框架滑动基序(FSM)或翻译通读基序(TRM)的上游。
24.根据权利要求19至22中任一项的方法，其中编码所述一种或多种额外的细胞因子或趋化因子或每种额外的细胞因子或趋化因子的所述核酸位于框架滑动基序(FSM)或翻译通读基序(TRM)的下游。
25.根据前述权利要求中任一项的方法，其用于治疗小细胞肺癌(SCLC)、黑色素瘤、肾细胞癌(RCC)、肝细胞癌(HCC)、卵巢癌、胰腺癌、成神经细胞瘤或骨肉瘤。
26.根据前述权利要求中任一项的方法，其中所述细胞表达结合靶抗原的CAR或工程化的TCR，并且所述靶抗原在所述实体瘤上的表达是异质的。
27.在受试者中诱导抗肿瘤免疫应答中的表位扩散的方法，其包括向所述受试者施用多个如前述权利要求中任一项所定义的细胞的步骤。
28.在受试者中诱导免疫细胞浸润到肿瘤块中的方法，其包括向所述受试者施用多个如前述权利要求中任一项所定义的细胞，使得所述细胞诱导抗肿瘤免疫应答的步骤。
29.治疗实体癌中使用的细胞，所述细胞包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。
30.细胞在制备用于治疗实体癌的药物中的用途，其中所述细胞包含位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列。
31.表达嵌合抗原受体(CAR)的细胞，其包含：
位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列；和
编码一种或多种额外的细胞因子或趋化因子的一种或多种异源核酸序列。
32.根据权利要求25的细胞，其中所述一种或多种异源核酸序列编码以下中的一种或多种：IL-7、IL-15、CCL19和CXCL12。
33.根据权利要求25的细胞，其中所述一种或多种异源核酸序列编码IL-7和CCL19。
34.根据权利要求25的细胞，其中所述一种或多种异源核酸序列编码IL-15和/或CXCL12。
35.根据权利要求31至34中任一项的细胞，其中编码一种或多种额外的细胞因子或趋化因子的所述异源核酸序列中的一种或多种位于框架滑动基序(FSM)或翻译通读基序(TRM)的上游。
36.根据权利要求31至34中任一项的细胞，其中编码一种或多种额外的细胞因子或趋化因子的所述异源核酸序列中的一种或多种位于框架滑动基序(FSM)或翻译通读基序(TRM)的下游。
37.核酸构建体，其包含：
(i)编码嵌合抗原受体(CAR)的核酸序列；和
(ii)位于框架滑动基序(FSM)或翻译通读基序(TRM)下游的编码白细胞介素12(IL-12)的核酸序列；
(vi)如权利要求32至36中任一项所定义的编码一种或多种额外的细胞因子或趋化因子的一种或多种核酸序列。
38.载体，其包含根据权利要求37的核酸构建体。
39.载体试剂盒，每个载体编码一种或多种如权利要求37所定义的核酸序列。
40.制备根据权利要求31至36中任一项的细胞的方法，其包括用根据权利要求37所述的核酸构建体、根据权利要求38所述的载体或根据权利要求39所述的载体试剂盒离体转染或转导细胞的步骤。
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| GB201403972D0 (en) | 2014-03-06 | 2014-04-23 | Ucl Business Plc | Chimeric antigen receptor |
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