CN107964046A - 对肿瘤细胞有特异性的嵌合抗原受体 - Google Patents
对肿瘤细胞有特异性的嵌合抗原受体 Download PDFInfo
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Abstract
本发明涉及配体如嵌合抗原受体(CAR),其包含对一种或多种抗原有特异性的抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8;表达此类CAR的细胞群体和所述细胞群体用于癌症疗法的用途。
Description
技术领域
本发明涉及配体的用途,所述配体包含对某些抗原有特异性的抗原结合结构域,如嵌合抗原受体(CAR),和/或本发明涉及提供有此类配体的工程改造的细胞用于治疗人类癌症的用途。
背景技术
癌症是涉及失调的细胞生长的一组广泛的疾病。在癌症中,细胞不受控地分裂并生长,形成恶性肿瘤,并且侵入身体的邻近部分。癌症还可通过淋巴系统或血流扩散到身体更远的部分。存在超过200种不同的已知影响人类的癌症。尽管良好的治疗选择可用于许多癌症类型,但是其它癌症类型仍然存在未被满足的医疗需求。
嵌合抗原受体(CAR)的技术对于癌症的过继性细胞免疫疗法可提供有前景的途径。通常,CAR包含对肿瘤相关抗原(TAA)有特异性的抗体单链可变片段(scFv),其经由铰链和跨膜区偶联至T-细胞信号传导分子的胞质结构域。例如,众所周知的淋巴细胞活化部分包括与T-细胞触发(例如,CD3ζ)部分串联的T-细胞共刺激(例如,CD28、CD137、OX40、ICOS和CD27)结构域。CAR介导的过继性免疫疗法允许CAR移植细胞以非HLA限制方式直接识别靶肿瘤细胞上的TAA。
基于CAR的用于癌症的免疫疗法的最重要的是选择对各自肿瘤细胞有特异性的抗原。本发明的目的是提供对癌细胞、特别是对胰腺癌细胞有特异性的此类抗原,以便工程改造杀伤细胞,其然后杀伤/裂解癌细胞,而不攻击非肿瘤细胞。
发明内容
已经发现,不同组的细胞表面抗原在几种人类癌细胞上表达,特别是在人胰腺癌细胞上表达,但在非恶性细胞上不表达或以低水平表达。因此,这些抗原(也称为“标志物”)可用于经由特异性结合标志物的配体来鉴定和/或标记和/或破坏此类癌细胞的逃逸机制和/或使之失能。
因此,本发明涉及一种配体,其包含对一种或多种抗原有特异性的抗原结合结构域,其特征在于所述配体是嵌合抗原受体(CAR),其包含对一种或多种抗原有特异性的抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
本发明的另一个目的是使癌细胞与包含对一种或多种抗原有特异性的抗原结合结构域的配体结合的方法,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
如进一步公开的配体可以是抗体或CAR或表达至少一种此类配体的工程改造的细胞。
本发明的另一个目的是表达至少一种所述配体的工程改造的细胞的群体、包含工程改造的细胞的群体的药物组合物和/或工程改造的细胞的群体或药物组合物用于治疗人类癌症的用途。
附图说明
图1显示能够识别特定靶标的CAR的一般结构。
图2显示CAR的变体,A为单一CAR,B为分开CAR,C为串联CAR,D为来自一种载体的多个CAR。
图3显示源自患者的异种移植物上的高目标标志物,显示异种移植的人胰腺癌细胞上的CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8的表达。
图4显示人PDAC上的高目标标志物,显示原代人胰腺癌细胞和健康肿瘤浸润细胞上的CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8的表达。
图5显示原代人胰腺癌切片上的CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8的表达。
图6中A显示作为转染效力和构建体表达的读数的在表面上表达LNGFR的细胞的百分比。图6中B显示在表面上表达CAR构建体的细胞的百分比。
图7显示CAR T细胞对胰腺癌细胞的杀伤效力。
图8a在(A)中显示门控且图8b在(B)中显示标志物的共表达。
具体实施方式
在本发明的第一个实施方案中,配体包含对至少两种不同抗原有特异性的至少两种不同抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。例如,所述配体可以包含对CLA和CD66c有特异性或对CLA和TSPAN8有特异性的抗原结合结构域。
在结合癌细胞的优选方法中,癌细胞(或癌细胞群体)与包含对至少两种不同抗原有特异性的至少两种不同抗原结合结构域的配体结合,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。再次,所述配体可以包含对CLA和CD66c有特异性或对CLA和TSPAN8有特异性的抗原结合结构域。
定义
术语“肿瘤”在医学上称为瘤(neoplasm)。不是所有肿瘤都是癌性的;良性肿瘤不侵入邻近组织并且不扩散到整个身体。
术语“癌症”在医学上称为恶性肿瘤。癌症是涉及失调的细胞生长的一组广泛的疾病。在癌症中,细胞(癌细胞)不受控地分裂和生长,形成恶性肿瘤,并且侵入身体的邻近部分。癌症还可通过淋巴系统或血流扩散到身体的更远端的部分。
术语“分离的”意指从天然状态改变或移除。例如,分离的细胞群体意指此类细胞的富集和从其它细胞分开,所述其它细胞在其天然存在状态下通常与所述分离的细胞相关联。分离的细胞群体意指基本上纯化的细胞群体,其为均质细胞群体。
关于配体如抗体、其片段或CAR的抗原结合结构域的术语“特异性结合”或“对……有特异性”是指识别并结合特异性抗原,但基本上不识别或结合样品中的其它分子的抗原结合结构域。特异性结合来自一个物种的抗原的抗原结合结构域也可结合来自另一个物种的那种抗原。这种物种间交叉反应性不违背该抗原结合结构域具有特异性的定义。特异性结合抗原的抗原结合结构域还可结合该抗原的不同等位基因形式(等位基因变体、剪接变体、同种型等)。该交叉反应性不违背该抗原结合结构域具有特异性的定义。
如本文所用的术语“工程改造的细胞”和“遗传修饰的细胞”可互换使用。该术语意指含有和/或表达外源基因或核酸序列,其进而改变细胞或其后代的基因型或表型。特别地,该术语是指通过本领域众所周知的重组方法操作以稳定或瞬时地表达在天然状态下不在这些细胞中表达的肽或蛋白的细胞(优先为T细胞)。例如,T细胞被工程改造以在其细胞表面上表达人工构建体,诸如嵌合抗原受体。例如,编码CAR的序列可使用逆转录病毒或慢病毒载体递送至细胞中。
分别在SEQ ID NO:1-32(以氨基酸的单字母代码)中给出的氨基酸序列应当是指保留如定义的各自氨基酸序列的预期功能的各自氨基酸序列的所有群集。因此,在序列表中定义的在氨基酸序列水平具有至少70%或至少75%、80%、85%、90%、95%、97%、98%或99%的序列同一性的氨基酸序列的所有变体都被包括在本发明的范围内。在本发明的上下文中,可以采用本领域众所周知的氨基酸序列的比对程序使用成对比对确定“序列同一性”。
T细胞或T淋巴细胞是在细胞介导的免疫中起核心作用的淋巴细胞类型。通过在细胞表面上T细胞受体(TCR)的存在,它们可以与其它淋巴细胞诸如B细胞和天然杀伤细胞(NK细胞)区分开。存在几个T细胞子集,各自具有不同的功能。
T辅助细胞(TH细胞)在免疫过程中辅助其它白细胞,包括B细胞成熟为浆细胞和记忆B细胞,以及活化细胞毒性T细胞和巨噬细胞。这些细胞也称为CD4+T细胞,因为它们在其表面上表达CD4糖蛋白。当辅助T细胞通过在抗原递呈细胞(APC)表面上表达的MHC II类分子递呈肽抗原时,其变为活化的。一旦被活化,它们迅速分裂并分泌称为细胞因子的小蛋白(其调节或辅助主动免疫应答)。这些细胞可以分化为分泌不同细胞因子的几种亚型(包括TH1、TH2、TH3、TH17、Th9或TFH)之一,以触发不同类型的免疫应答。来自APC的信号传导将T细胞引导至特定亚型。
细胞毒性T细胞(TC细胞或CTL)破坏感染的细胞和肿瘤细胞,并且还参与移植排斥。这些细胞也称为CD8+T细胞,因为它们在其表面表达CD8糖蛋白。这些细胞通过结合至与在所有有核细胞的表面上存在的MHC I类分子相关的抗原而识别它们的靶标。
记忆T细胞是抗原特异性T细胞的子集,其在感染消退后长期存在。它们在重新暴露于其同源抗原后快速扩增成大量的效应T细胞,因此为免疫系统提供针对过去的感染的“记忆”。记忆T细胞包含三种亚型: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分子CD45RO。
以前称为抑制性T细胞的调节性T细胞(Treg细胞)对维持免疫耐受性至关重要。它们的主要作用是在免疫反应即将结束时关闭T细胞介导的免疫,并抑制逃避胸腺中的负选择过程的自身反应性T细胞。已经描述了两种主要的CD4+Treg细胞类别:Foxp3+Treg细胞和Foxp3-Treg细胞。
天然杀伤T细胞(NKT细胞)使适应性免疫系统与先天免疫系统桥接。不同于识别由主要组织相容性复合体(MHC)分子递呈的肽抗原的常规T细胞,NKT细胞识别由称为CD1d的分子递呈的糖脂抗原。一旦被活化,这些细胞可以行使归属于Th和Tc细胞二者的功能(即细胞因子产生和细胞裂解/细胞杀伤分子的释放)。
免疫疗法是定义为“通过诱导、增强或抑制免疫应答而治疗疾病”的医学术语。设计用于引发或扩增免疫应答的免疫疗法被归类为活化免疫疗法,而减少或抑制免疫应答的免疫疗法被归类为抑制免疫疗法。作为活化性免疫疗法的癌症免疫疗法尝试刺激免疫系统以排斥和破坏肿瘤。过继性细胞转移利用基于细胞(诸如基于T细胞)的细胞毒性反应攻击癌细胞。对患者的癌症具有天然的或基因工程改造的反应性的T细胞在体外产生,然后转移返回到癌症患者体内。
术语“生物标志物”或“标志物”在本领域中是普遍的,并且可广泛地表示生物分子和/或其可检测部分(例如核酸、肽或脂质,诸如糖脂),其在个体中的定性和/或定量评估对于所述个体的表型和/或基因型的一个或多个方面是预测性的或提供信息(例如,预测性的、诊断性的和/或预后性的)。例如,生物标志物对于个体中癌症的化疗治疗的结果是预测性的或提供信息。如果生物标志物可用本领域已知的方法检测,则该生物标志物被表达(“生物标志物的表达”)。因此,生物标志物的表达不仅包括在核酸水平(DNA和/或RNA)和蛋白水平的表达,而且包括在细胞上或细胞中的其它生物结构的表达(存在),诸如糖脂或者蛋白活性。
如本文所用的术语“靶标”是指与应由抗原结合结构域(例如,抗体的或CAR的抗原结合结构域)特异性识别的细胞相关的抗原或表位。用于抗体识别的抗原或表位可以结合至细胞表面,但也可以是分泌的、细胞外膜的部分或从细胞脱落。
如本文所用的术语“抗体”是指多克隆或单克隆抗体及其片段,其可以通过本领域技术人员众所周知的方法产生。抗体可以是任何物种的,例如,小鼠、大鼠、绵羊、人。对于治疗目的,如果待使用非人抗原结合片段,它们可以通过本领域已知的任何方法人源化。抗体还可以是修饰的抗体(例如,寡聚体、还原的抗体、氧化的抗体和标记的抗体)。
如本文所用的术语“杀伤细胞”是指可以杀伤/裂解另一细胞、例如癌细胞的细胞。最常见的是,T细胞、NK细胞、树突状细胞和巨噬细胞可用作杀伤细胞。
如本文所用的术语“工程改造的杀伤细胞”是指被遗传修饰以允许特异性杀伤靶细胞的杀伤细胞,例如,用针对靶标的CAR修饰以杀伤表达各自靶标的肿瘤细胞的细胞。
嵌合抗原受体(CAR)
根据本发明的嵌合抗原受体(CAR)可以包含与跨膜结构域和/或细胞内信号传导结构域缀合的抗原结合结构域,如例如图1中所示。
在本发明的第一个实施方案中,所述配体是嵌合抗原受体(CAR),其包含对一种或多种抗原有特异性的抗原结合结构域,所述一种或多种抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
在本发明的第二个实施方案中,所述配体是CAR,其包含对CLA以及一种或多种抗原有特异性的抗原结合结构域,所述一种或多种抗原选自CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
在本发明的第三个实施方案中,所述配体是CAR,其包含抗原结合结构域、跨膜结构域和/或细胞内信号传导结构域,并且包含与相同或不同的跨膜结构域和/或细胞内信号传导结构域缀合的对两种不同抗原有特异性的至少两种抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
在本发明的另一个实施方案中,CAR的抗原结合结构域结合与多肽偶联的半抗原(“半抗原化的”多肽),其中所述多肽可以结合肿瘤相关抗原。此类CAR例如公开于US9233125B2中,并且在本领域中被称为“抗标签”CAR。类似地,本发明的CAR的细胞外部分可以包含接头/标记表位(LLE)结合结构域作为抗原结合结构域,其结合作为靶细胞结合分子的一部分的接头/标记表位(LLE)。此类“抗LLE CAR”公开于欧洲专利申请号EP16196487.9中。两种类型的CAR是通用和/或可调节的CAR。半抗原和LLE两者都是直接或间接与多肽偶联的“标签”(标记的多肽),其中所述多肽可以结合靶细胞的(细胞)表面上表达的肿瘤相关抗原。
在该实施方案中,所述配体包含对一种或多种抗原有特异性的抗原结合结构域,其特征在于所述配体是嵌合抗原受体(CAR),其包含抗标签结合区,所述抗标签结合区可以结合与对一种或多种抗原有特异性的抗原结合结构域偶联的标签,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。合适的标签是例如但不限于生物素、其它半抗原、FITC或其它荧光染料分子、FLAG、HIS、YOL MYC、葡聚糖、FcR、抗体-同种型、人工工程改造的表位、FAB或FAB2结合物。
CAR的跨膜结构域可以包含4-1BB、CD8和/或CD28的跨膜结构域的序列;并且细胞内信号传导结构域包含CD28、CD137和CD3ζ中的一种或多种的细胞内信号传导结构域的序列。
在该实施方案的一个优选变体中,嵌合抗原受体(CAR)包含对CLA有特异性的抗原结合结构域,而没有额外的抗原结合结构域或额外CAR,其中所述抗原结合结构域与一个跨膜结构域和一个或多个信号传导结构域缀合。该变体通过实例的方式显示于图2的A中。
在本发明的第二个变体中,所述嵌合抗原受体(CAR)包含对两种或更多种抗原有特异性的至少两种不同抗原结合结构域,所述抗原选自CLA(皮肤淋巴细胞抗原)、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8,其中所述抗原结合结构域与不同的跨膜结构域和/或信号传导结构域缀合。该变体通过实例的方式显示于图2的B中。
在本发明的第三个变体中,所述嵌合抗原受体(CAR)包含对两种或更多种抗原有特异性的至少两种不同抗原结合结构域,所述抗原选自CLA(皮肤淋巴细胞抗原)、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8,其中所述抗原结合结构域与相同(一个)跨膜结构域和信号传导结构域缀合。该变体通过实例的方式显示于图2的C中。
在本发明的第四个变体中,所述嵌合抗原受体(CAR)包含对两种或更多种抗原有特异性的至少两种不同抗原结合结构域,所述抗原选自CLA(皮肤淋巴细胞抗原)、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8,其中所述抗原结合结构域与不同的跨膜结构域和信号传导结构域缀合,并且所述抗原结合结构域源自一个载体。该变体通过实例的方式显示于图2的D中。
CLA是皮肤淋巴细胞相关抗原(CLA),P-选择素糖蛋白配体-1(PSGL-1)的专用糖型。其充当选择素(包括CD62E(ELAM-1)和CD62L(LECAM-1))的配体。CLA是独特的皮肤归巢受体,并且主要发现在渗透皮肤的人类T细胞的次要子集上。这种PSGL-1的翻译后修饰被认为充当调节CD4+和CD8+记忆/效应T细胞从外周血到皮肤的组织特异性归巢的机制,其在许多炎性和某些恶性皮肤疾病中起重要作用。
在外周血中,CLA不仅被发现在皮肤归巢记忆/效应T细胞上,而且还被发现在记忆/效应B细胞、NK细胞、血液树突状细胞和单核细胞上表达。CLA还被发现在皮肤中的朗格汉斯细胞上。
为了增强癌细胞的特异性识别,嵌合抗原受体(CAR)可以包含对CLA以及一种或多种(如两种、三种或四种)抗原有特异性的抗原结合结构域,所述抗原选自CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。对胰腺癌有特异性的优选组合是CLA与TSPAN8以及CLA与CD66c。
所述CAR的抗原结合结构域可包含,例如,全长重链、Fab片段、单链Fv(scFv)片段、二价单链抗体或双特异抗体(diabody),其各自对靶抗原CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8中的一种或多种是特异性的。
所述CAR的抗原结合结构域可包含SEQ ID NO:1和SEQ ID NO:2的氨基酸序列。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。所述CAR的抗原结合结构域可包含scFv,所述scFv包含SEQ ID NO:17或SEQ ID NO:18的氨基酸序列。
本发明还涵盖包含编码对公开的标志物有特异性的CAR的氨基酸序列的序列的核酸(DNA或RNA)构建体。
在本发明的一个实施方案中,产生编码对公开的标志物有特异性CAR的DNA构建体(载体、质粒)。至少将编码对公开的标志物有特异性的抗原结合结构域的核酸序列与编码跨膜结构域的核酸序列、且随后与编码细胞内结构域的核酸序列融合。此类表达载体的构建可以通过本领域众所周知的重组方法进行。或者,可以合成产生所述核酸序列。
或者,CAR可由另外的部分(诸如接头和/或铰链)构成和/或可构成为如下所述的双链或多链CAR。
通常如图1和2中所示,CAR可包含含有抗原结合结构域的细胞外结构域、跨膜结构域和细胞内信号传导结构域。细胞外结构域可通过接头连接到跨膜结构域。细胞外结构域还可连接至信号肽。
“信号肽”是指引导细胞内的蛋白转运和定位例如到某些细胞器(诸如内质网)和/或细胞表面的肽序列。
“抗原结合结构域”是指特异性结合抗原(并且因此能够靶向含有抗原的细胞)的CAR的区域。本发明的CAR可包含一个或多个抗原结合结构域。通常,CAR上的抗原结合结构域是细胞外的。抗原结合结构域可包含抗体或其片段。抗原结合结构域可包含,例如,全长重链、Fab片段、单链Fv(scFv)片段、二价单链抗体或双特异抗体。特异性结合给定抗原的任何分子(诸如来自天然存在的受体的亲合体(affibodies)或配体结合结构域)均可用作抗原结合结构域。通常抗原结合结构域是scFv。通常,在scFv中,免疫球蛋白重链和轻链的可变部分通过柔性接头融合以形成scFv。此接头可以是例如“(G4/S1)3-接头”。
在一些情况下,抗原结合结构域源自CAR将在其中使用的相同物种是有益的。例如,如果计划在人类中治疗性地使用,则CAR的抗原结合结构域包含人或人源化抗体或其片段可能是有益的。人或人源化抗体或其片段可通过本领域众所周知的多种方法制造。
如本文所用,“间隔区”或“铰链”是指在抗原结合结构域和跨膜结构域之间的亲水性区域。本发明的CAR可包含细胞外间隔结构域,但也可能省略此间隔区。间隔区可包括抗体或其片段的Fc片段、抗体或其片段的铰链区、抗体的CH2或CH3区、辅助蛋白、人工间隔区序列或其组合。间隔区的一个突出实例是CD8α铰链。
CAR的跨膜结构域可源自此结构域的任何期望的天然或合成来源。如果该来源是天然的,则结构域可源自任何膜结合的或跨膜蛋白。跨膜结构域可源自例如CD8α或CD28。
本发明的CAR的胞质结构域或细胞内信号传导结构域造成其中表达该CAR的免疫细胞的至少一种正常效应子功能的活化。"效应子功能"意指细胞的专门化功能,例如在T细胞中,效应子功能可以是细胞裂解活性或辅助细胞活性,包括细胞因子的分泌。细胞内信号传导结构域是指转导效应子功能信号并且引导表达本发明的CAR的细胞行使专门化功能的蛋白部分。细胞内信号传导结构域可包括足以转导效应子功能信号的给定蛋白的细胞内信号传导结构域的任何完整或截断部分。
用于CAR中的细胞内信号传导结构域的突出实例包括在抗原受体接合之后协同作用以启动信号转导的T细胞受体(TCR)和辅助受体的胞质序列。
通常,T细胞活化可以由两种不同类别的胞质信号传导序列介导,第一是通过TCR启动抗原依赖性初级活化的那些(初级胞质信号传导序列),且第二是以非抗原依赖性方式起作用以提供次级或共刺激信号的那些(次级胞质信号传导序列)。
以刺激方式起作用的初级胞质信号传导序列可以含有ITAM(基于免疫受体酪氨酸的活化基序信号传导基序)。
经常用于CAR中的含ITAM的初级胞质信号传导序列的实例来源于TCRζ、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b和CD66d。
CAR的胞质结构域可以被设计为包含CD3-ζ信号传导结构域本身或与任何其它所需的胞质结构域组合的CD3-ζ信号传导结构域。CAR的胞质结构域可以包含CD3ζ链部分和共刺激信号传导区。共刺激信号传导区是指包含共刺激分子的细胞内结构域的CAR的部分。共刺激分子是淋巴细胞对抗原的有效反应所需的抗原受体或其配体以外的细胞表面分子。共刺激分子的实例是CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3。
CAR的胞质信号传导部分内的胞质信号传导序列可以以随机或特定的顺序彼此连接。长度优选为2至10个氨基酸的短的寡肽或多肽接头可以形成连接。突出的接头是甘氨酸-丝氨酸双体(doublet)。
作为实例,胞质结构域可包含CD3-ζ的信号传导结构域和CD28的信号传导结构域。在另一个实例中,胞质结构域可包含CD3-ζ的信号传导结构域和CD27的信号传导结构域。在另一个实例中,胞质结构域可以包含CD3-ζ的信号传导结构域、CD28的信号传导结构域和CD27的信号传导结构域。
本发明的CAR可以设计为包含如本文所述的上述结构域的任何部分或部件,特别是图2的A-D中所示的变体中。由抗原结合结构域介导的本发明CAR的特异性是对于抗原CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8中的一种或多种,构建功能性CAR所必需的所有其它结构域都可以选自上文提到的或者本领域技术人员众所周知的选项。
-表达配体的工程改造的细胞
在本发明的另一个实施方案中,所述配体是工程改造的细胞(或其群体),其表达对一种或多种抗原有特异性的至少一种抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
在一个优选实施方案中,工程改造的细胞的群体表达配体,如嵌合抗原受体(CAR),其包含对CLA以及一种或多种CAR和/或选自如下的抗原有特异性的抗原结合结构域:CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
工程改造的细胞的群体可以由T细胞、巨噬细胞或NK细胞组成。在所述免疫疗法中使用前,可以将工程改造的细胞的群体扩增为治疗有效量的细胞。
为了产生表达本发明的一种或多种CAR(包括变体)的细胞,编码本发明的CAR的DNA构建体可以通过本领域众所周知的方法(例如基于病毒的系统、物理方法、生物方法、化学方法)转染或转导至宿主细胞中。不管用于将编码本发明的CAR的核酸整合到宿主细胞中的方法,其结果是,宿主细胞表达对如公开的标志物有特异性的CAR。
在本发明的一个实施方案中,在用于产生工程改造的细胞的转染/转导过程后,通过本领域众所周知的方法,例如,基于荧光的分离技术(诸如)或磁性细胞分离方法(诸如),将此工程改造的细胞从未转染/未转导的细胞分离(富集或分开)。
在本发明的另一个实施方案中,免疫细胞(优先T细胞)的来源是获得自受试者。免疫细胞(优先T细胞)可获得自多种来源,诸如外周血单核细胞(PMBC)、骨髓、淋巴结组织、脐带血或胸腺组织。对于这些细胞的富集,可以使用本领域众所周知的方法,诸如通过FicollTM或PERCOLLTM梯度的离心,或者阳性/阴性选择技术,诸如荧光分选(例如FCASsort)或磁性分选(例如)。
例如,受试者的血液样品的T细胞被磁性标记(例如用与分别对CD4和CD8或可替代地CD62L有特异性的抗体偶联的磁珠)、洗涤、磁性富集和收集。然后可以将这些T细胞工程改造以在其细胞表面上表达如公开的抗原或优选的抗原组合。
在本发明的一个实施方案中,在遗传修饰之前或之后,通常可以使用本领域众所周知的方法(例如用抗CD3/抗CD28珠粒或者抗CD3/抗CD28纳米基质(如EP2711418A1中所公开)的多克隆刺激)活化和扩增表达如公开的抗原或优选的抗原组合的分离/富集的工程改造的T细胞以增加工程改造的T细胞的量。优先地,所述工程改造的T细胞的量增加至治疗有效量。
在本发明的一个实施方案中,产生表达本发明的CAR的细胞。编码本发明的CAR的RNA可以通过本领域众所周知的方法(例如基于病毒的系统、物理方法、生物方法、化学方法)转染或转导至宿主细胞中。通常,此“RNA工程改造的细胞”在WO2013/040557中详细公开。不管用于将编码本发明的CAR的RNA整合至宿主细胞中的方法,其结果是,宿主细胞表达对如公开的抗原或优选的抗原组合有特异性的CAR。使用“RNA工程改造的细胞”导致CAR在细胞中表达有限的时间(瞬时表达)的事实。
在本发明的一个实施方案中,工程改造的细胞在封闭的细胞培养系统中自动产生。此类方法包括以下步骤:
a)提供细胞样品;
b)通过离心制备所述细胞样品;
c)磁性分离所述细胞(优先T细胞、T细胞子集或T细胞祖细胞);
d)使用调节剂活化富集的细胞(优先T细胞、T细胞子集或T细胞祖细胞);
e)遗传修饰所述细胞(优先T细胞、T细胞子集或T细胞祖细胞)以表达如公开的一种或多种CAR或CAR/抗原的优选组合;
f)在培养室中扩增遗传修饰的T细胞、T细胞子集或T细胞祖细胞;
g)洗涤培养的细胞(优先T细胞、T细胞子集或T细胞祖细胞)。
所有这些步骤都可以在封闭且无菌的系统中进行。
该方法特别适用于制备基因修饰的细胞(优先T细胞、T细胞子集或T细胞祖细胞),其中富集的细胞(优先T细胞、T细胞子集或T细胞祖细胞)通过使用病毒和/或非病毒载体进行基因修饰。这些步骤中的任一个可以重复、省略或者可以以不同的顺序发生。在本发明的一个变体中,所述调节剂选自激动性抗体和/或细胞因子。
作为用于细胞修饰的封闭且无菌的系统,可以使用全自动细胞处理装置CliniMACS和相关的管道集合(Miltenyi Biotec GmbH,德国)(WO2009/072003)。该封闭系统满足几乎任何种类的细胞产品的GMP级处理的要求,并且可以允许降低洁净室要求、改善细胞制造过程的技术转移和协调。已经对于使细胞治疗剂的制造过程全自动化和标准化进行了开发。该仪器可以进行样品加载、细胞洗涤、基于密度的细胞分离(包括红细胞减少和血浆收获)、磁性分离、细胞活化、细胞修饰(转导)、细胞培养和最终产品配制。
因此使得过程模块(“步骤”)能够灵活地整合在封闭的、自动化和安全的GMP符合工作流程中,重现复杂的所需生物学过程。
在本发明的一个实施方案中,遗传修饰的细胞表达靶标之一。为了规避遗传修饰的细胞群体间的杀伤,该靶标在杀伤细胞上被暂时或永久地敲低或敲除。可以通过本领域众所周知的方法(诸如用于暂时敲低的siRNA或用于永久敲除的CRISPR系统)诱导表达的暂时或永久敲低或敲除。为了使用这些方法抑制靶标表达,这可以通过直接靶向编码靶标的整个基因、基因的部分,例如,特异性外显子、启动子区域或控制基因,诸如转录因子,来实现。在代表糖结构(诸如CLA)的靶结构的情况下,这也可以通过改变骨架蛋白上的糖基化位点或一种或多种催化糖基化的酶来实现。
使用方法
本发明的另一个实施方案是使癌细胞与配体结合的方法,所述配体包含对至少两种不同抗原有特异性的至少两种不同抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。换言之,所述癌细胞与包含至少两种不同抗原结合结构域的配体结合,其中第一抗原结合结构域对选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8的至少一种抗原是特异性的,且第二抗原结合结构域对选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8的至少一种其它抗原是特异性的。优先组合包含CLA与CD66c以及CLA与TSPAN8。
根据本发明的配体可以与试剂组合使用,所述试剂结合抗原并影响表达该抗原的癌细胞的活力,优先杀伤癌细胞。此类试剂的实例是溶瘤病毒、ADCC和免疫毒素。
溶瘤病毒是优先感染和杀伤癌细胞的病毒。随着被感染的癌细胞通过裂解被破坏,它们释放新的感染性病毒颗粒以帮助破坏剩余肿瘤。溶瘤病毒被认为不仅造成肿瘤细胞的直接破坏,而且还刺激宿主的抗肿瘤免疫反应。特异性靶向(例如,靶向/连接至如公开的抗原)涉及修饰病毒外壳蛋白以靶向肿瘤细胞(例如,利用对如公开的抗原有特异性的抗原结合结构域),同时减少进入非肿瘤细胞。
双特异性T细胞衔接体(engager)是经研究用作抗癌药物的一类人工双特异性单克隆抗体。它们针对癌细胞引导宿主的免疫系统(更具体地是T细胞的细胞毒性活性)。BiTE是在约55千道尔顿的单肽链上由不同抗体的两个单链可变片段(scFv),或者来自四个不同基因的氨基酸序列组成的融合蛋白。scFv之一经由CD3受体结合至T细胞,且其它经由肿瘤特异性分子结合至肿瘤细胞。与其它双特异性抗体相同,且不同于普通的单克隆抗体,在T细胞和肿瘤细胞之间形成连接。这引起T细胞通过产生蛋白如穿孔蛋白和颗粒酶对肿瘤细胞发挥细胞毒性活性,而不依赖于MHC I或共刺激分子的存在。这些蛋白进入肿瘤细胞并启动细胞的凋亡。这种作用模拟在T细胞攻击肿瘤细胞过程中观察到的生理过程。
抗体依赖性细胞介导的细胞毒性(ADCC)是需要存在与靶细胞表面结合的抗体的免疫系统攻击机制。抗体由结合靶抗原的结合区(Fab)和可由免疫细胞经由其表面上的Fc受体检测到的Fc区形成。这些Fc受体在许多免疫系统细胞(包括自然杀伤细胞)的表面上发现。当自然杀伤细胞遭遇用抗体包被的细胞时,Fc区与它们的Fc受体相互作用,导致穿孔蛋白和颗粒酶B的释放。这两种化学物质导致肿瘤细胞启动程序性细胞死亡(细胞凋亡)。已知诱导该细胞杀伤方法的抗体包括利妥昔单抗、奥法木单抗、曲妥珠单抗、西妥昔单抗和阿仑单抗。目前正在开发的第三代抗体具有改变的Fc区,其对特定类型的Fc受体(FcγRIIIA)具有更高的亲和性,这可以急剧增加ADCC率。
免疫毒素是由连接至毒素的靶向部分组成的人造蛋白。当该蛋白结合于细胞时,其通过胞吞作用被摄入,并且毒素杀伤该细胞。这些嵌合蛋白通常由连接至毒素片段的修饰抗体或抗体片段制成。“靶向部分”由抗体的Fv部分组成,所述抗体与通过细胞(优选特定细胞类型)表达的抗原特异性结合。毒素通常是源自细菌或植物蛋白(已经从其移除天然结合结构域,使得Fv将毒素引导到靶细胞上的抗原)的细胞毒性蛋白。
药物组合物
本发明的另一个目的是一种药物组合物,其包含表达如已经公开的CAR的工程改造的细胞的群体,任选地包含药学上可接受的载体如Composol或NaCl溶液。
用于治疗癌症的用途
如公开的工程改造的细胞的群体和/或包含工程改造的细胞的群体的药物组合物可用于用表达公开的靶分子的细胞治疗人类癌症、特别是人胰腺癌的方法。
所述药物组合物优选地包含表达根据权利要求1至7中任一项已经公开的CAR的工程改造的细胞的群体。在本发明的变体中,所述药物组合物与用于治疗癌症的化疗剂、放射试剂或免疫调节剂组合使用。
待治疗的癌症可包括造血癌、骨髓增生异常综合征、胰腺癌、头颈癌、皮肤肿瘤、急性淋巴细胞性白血病(ALL)中的微小残留疾病(MRD)、急性骨髓性白血病(AML)、肺癌、乳腺癌、卵巢癌、前列腺癌、结肠癌、黑色素瘤或其它血液癌症和实体瘤或其任何组合。在另一个实施方案中,所述癌症包括血液癌症诸如白血病(例如慢性淋巴细胞性白血病(CLL)、急性淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)或慢性骨髓性白血病(CML))、淋巴瘤(例如套细胞淋巴瘤、非霍奇金氏淋巴瘤或霍奇金氏淋巴瘤)或多发性骨髓瘤或其任何组合。此外,所述癌症可包括成年人肿瘤,包含口咽癌(舌、口、咽、头和颈),消化系统癌症(食管、胃、小肠、结肠、直肠、肛门、肝脏、肝内胆管、胆囊、胰腺),呼吸系统癌症(喉、肺和支气管),骨骼和关节癌,软组织癌,皮肤癌(黑色素瘤、基础和鳞状细胞癌),小儿肿瘤(神经母细胞瘤、横纹肌肉瘤、骨肉瘤、尤文氏肉瘤),中枢神经系统肿瘤(脑、星形细胞瘤、胶质母细胞瘤、胶质瘤)和乳腺癌,生殖器系统(子宫颈、子宫体、卵巢、阴户、阴道、前列腺、睾丸、阴茎、子宫内膜)的癌症,泌尿系统(膀胱、肾和肾盂、输尿管)的癌症,眼和眼眶的癌症,内分泌系统(甲状腺)的癌症,以及脑和其它神经系统的癌症,或其任何组合。
癌症的治疗可以涵盖涉及作为靶分子公开的至少一种抗原或作为靶分子公开的抗原的任何组合的任何方法。此类方法可以是例如用结合抗原并影响表达该抗原的癌细胞的活力、优先杀死癌细胞的试剂进行治疗。实例是如已经公开的溶瘤病毒、ADCC和免疫毒素。
为了治疗,可以分离受试者的免疫细胞,例如,T细胞。受试者可以患有所述癌症或者可以是健康受试者。这些细胞在体外或体内进行遗传修饰以表达一种或多种本发明的CAR。这些工程改造的细胞可以在体外或体内活化和扩增。在细胞疗法中,这些工程改造的细胞可以被输注到有需要的接受者中。这些细胞可以是药物组合物(所述细胞加上药学上可接受的载体)。输注的细胞能够杀伤接受者中表达公开的抗原中的一种或多种的癌细胞(或至少阻止其生长)。接受者可以是从其获得细胞的相同受试者(自体细胞疗法)或者可以来自相同物种的另一受试者(同种异基因细胞疗法)。
在本发明的一个实施方案中,患有胰腺癌的受试者可以用本发明的药物组合物连同免疫调节剂(诸如但不限于雷帕霉素或阻断PD-1/PD-L1或CTLA4信号传导的药剂)一起治疗。
在本发明的一个实施方案中,由于表达公开的抗原中的一种或多种的癌细胞可能仅仅是受试者的癌细胞的亚群的事实,受试者可以另外用化疗或放疗进行治疗。适于治疗癌症的化疗剂和放射试剂是本领域众所周知的。
在本发明的一个实施方案中,将表达CAR的细胞施用于患有癌症、特别是胰腺癌的受试者作为如上文公开的细胞疗法,但还与在相同工程改造的细胞上表达的第二活化性CAR组合施用,从而识别在表达公开的抗原中的一种或多种的癌细胞上的另外的表位以提高表达两种CAR的工程改造的细胞的特异性。该表位可以是膜结合的、细胞外基质的部分或者可溶性组分。
在本发明的一个实施方案中,将表达CAR的细胞施用于患有癌症的受试者作为如上文公开的细胞疗法,但还与在相同工程改造的细胞上表达的第二抑制性CAR组合施用,从而识别另外的表位以提高表达两种CAR的工程改造的细胞的特异性。该表位可以是膜结合的、细胞外基质的部分或者可溶性组分。
被工程改造以表达公开的抗原中的一种或多种的免疫细胞(优先T细胞)可以单独施用,或者与稀释剂和/或其它组分(诸如IL-2或其它细胞因子或细胞群体)组合作为药物组合物施用。简而言之,本发明的药物组合物可以包含与一种或多种药学上或生理学上可接受的载体、稀释剂或赋形剂组合的如本文所述的遗传修饰的细胞的细胞群体。此类组合物可以包含缓冲剂(诸如中性缓冲盐水、磷酸盐缓冲盐水等);碳水化合物(诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇);蛋白;多肽或氨基酸(诸如甘氨酸);抗氧化剂;螯合剂(诸如EDTA或谷胱甘肽);佐剂(诸如氢氧化铝);和防腐剂。
优先地,配制本发明的组合物用于静脉内施用。向受试者施用细胞组合物可以以本领域已知的任何方便的方式进行。
本发明的药物组合物可以以适合于待治疗的疾病的方式施用。适当的剂量可以通过临床试验确定。但是施用的量和频率也将由诸如患者的病况、患者疾病的类型和严重性的因素决定和影响。
包含本文公开的免疫细胞(优先T细胞)的药物组合物可以以104至109个细胞/kg体重,优选105至106个细胞/kg体重的剂量施用。细胞组合物也可以以这些剂量施用多次。细胞组合物可以直接注射到肿瘤、淋巴结或感染部位中。
实施例
以下实施例旨在更详细地解释本发明,但不将本发明限制于这些实施例。
实施例1:胰腺癌上的靶标的表达
异种移植的人胰腺癌细胞上的CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8的表达表明这些标志物在胰腺癌细胞上的强烈丰度,其与肿瘤微环境无关(图3)。此外,所有标志物也在原代人胰腺癌细胞(标记为Epcam+)上以高水平重现性表达,但在健康肿瘤浸润性白细胞(标记为CD45+)的细胞或其它健康组织驻留细胞类型(标记为双阴性)上不是如此(图4)。使用人胰腺癌中靶标表达的基于免疫组织化学的检测进一步验证这些结果(图5)。
实施例2:识别胰腺癌特异性靶标的CAR的结构
使用的接头可以包含允许检测CAR的表位/标签,如图1中所示。表位/标签的实例是YOL、cMYC或HIS。胰腺癌靶标特异性结合片段衍生自对CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和/或TSPAN8有特异性的一种或几种抗体。铰链区域可以衍生自例如IgG结构域、CD8α或CD28,并且可以包含允许检测CAR的表位/标签。跨膜结构域可以衍生自例如CD8α或CD28,随后为一至三个信号传导结构域。这些结构域可以衍生自例如CD28、4-1BB、OX40或CD3ζ。
实施例3:识别胰腺癌特异性靶标的双重CAR的结构
可以通过在一个CAR分子上组合多个抗原结合位点或通过使用在一个细胞中表达并且仅组合起作用的多个CAR分子,例如通过使用当单独使用时对细胞活化无效的每种CAR构建体的信号传导结构域,来解决两种或更多种靶标的识别(图2)。
实施例4:CLA特异性抗体的氨基酸序列
使用的特异性结合CLA的抗体的免疫球蛋白重链和轻链的可变部分的氨基酸序列分别如SEQ ID NO:1和SEQ ID NO:2中所给出。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。这些序列或对CLA具有特异性的其任何衍生序列可用于产生识别CLA的CAR。SEQ ID NO:1和SEQ ID NO:2中给出的序列仅仅是对抗原CLA有特异性的序列的示例(序列以氨基酸的单字母代码给出)。其它序列可用于产生也对抗原CLA有特异性的抗体的抗原结合结构域或CAR的抗原结合结构域。
实施例5:CD142特异性抗体的氨基酸序列
使用的特异性结合CD142的抗体的免疫球蛋白重链和轻链的可变部分的氨基酸序列分别如SEQ ID NO:3和SEQ ID NO:4中所给出。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。这些序列或对CD142具有特异性的其任何衍生序列可用于产生识别CD142的CAR。SEQID NO:3和SEQ ID NO:4中给出的序列仅仅是对抗原CD142有特异性的序列的示例(序列以氨基酸的单字母代码给出)。其它序列可用于产生也对抗原CD142有特异性的抗体的抗原结合结构域或CAR的抗原结合结构域。
实施例6:CD73特异性抗体的氨基酸序列
使用的特异性结合CD73的抗体的免疫球蛋白重链和轻链的可变部分的氨基酸序列分别如SEQ ID NO:5和SEQ ID NO:6中所给出。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。这些序列或对CD73具有特异性的其任何衍生序列可用于产生识别CD73的CAR。SEQ IDNO:5和SEQ ID NO:6中给出的序列仅仅是对抗原CD73有特异性的序列的示例(序列以氨基酸的单字母代码给出)。其它序列可用于产生也对抗原CD73有特异性的抗体的抗原结合结构域或CAR的抗原结合结构域。
实施例7:CD49c特异性抗体的氨基酸序列
使用的特异性结合CD49c的抗体的免疫球蛋白重链和轻链的可变部分的氨基酸序列分别如SEQ ID NO:7和SEQ ID NO:8中所给出。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。这些序列或对CD49c具有特异性的其任何衍生序列可用于产生识别CD49c的CAR。SEQID NO:7和SEQ ID NO:8中给出的序列仅仅是对抗原CD49c有特异性的序列的示例(序列以氨基酸的单字母代码给出)。其它序列可用于产生也对抗原CD49c有特异性的抗体的抗原结合结构域或CAR的抗原结合结构域。
实施例8:CD66c特异性抗体的氨基酸序列
使用的特异性结合CD66c的抗体的免疫球蛋白重链和轻链的可变部分的氨基酸序列分别如SEQ ID NO:9和SEQ ID NO:10中所给出。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。这些序列或对CD66c具有特异性的其任何衍生序列可用于产生识别CD66c的CAR。SEQID NO:9和SEQ ID NO:10中给出的序列仅仅是对抗原CD66c有特异性的序列的示例(序列以氨基酸的单字母代码给出)。其它序列可用于产生也对抗原CD66c有特异性的抗体的抗原结合结构域或CAR的抗原结合结构域。
实施例9:CD104特异性抗体的氨基酸序列
使用的特异性结合CD104的抗体的免疫球蛋白重链和轻链的可变部分的氨基酸序列分别如SEQ ID NO:11和SEQ ID NO:12中所给出。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。这些序列或对CD104具有特异性的其任何衍生序列可用于产生识别CD104的CAR。SEQID NO:11和SEQ ID NO:12中给出的序列仅仅是对抗原CD104有特异性的序列的示例(序列以氨基酸的单字母代码给出)。其它序列可用于产生也对抗原CD104有特异性的抗体的抗原结合结构域或CAR的抗原结合结构域。
实施例10:CD318特异性抗体的氨基酸序列
使用的特异性结合CD318的抗体的免疫球蛋白重链和轻链的可变部分的氨基酸序列分别如SEQ ID NO:13和SEQ ID NO:14中所给出。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。这些序列或对CD318具有特异性的其任何衍生序列可用于产生识别CD318的CAR。SEQID NO:13和SEQ ID NO:14中给出的序列仅仅是对抗原CD318有特异性的序列的示例(序列以氨基酸的单字母代码给出)。其它序列可用于产生也对抗原CD318有特异性的抗体的抗原结合结构域或CAR的抗原结合结构域。
实施例11:TSPAN8特异性抗体的氨基酸序列
使用的特异性结合TSPAN8的抗体的免疫球蛋白重链和轻链的可变部分的氨基酸序列分别如SEQ ID NO:15和SEQ ID NO:16中所给出。引起对抗原结合的特异性的相关位点是根据IMGT(免疫球蛋白或抗体的国际ImMunoGeneTics信息系统)定义的CDR,其在该序列中加下划线。这些序列或对TSPAN8具有特异性的其任何衍生序列可用于产生识别TSPAN8的CAR。SEQ ID NO:15和SEQ ID NO:16中给出的序列仅仅是对抗原TSPAN8有特异性的序列的示例(序列以氨基酸的单字母代码给出)。其它序列可用于产生也对抗原TSPAN8有特异性的抗体的抗原结合结构域或CAR的抗原结合结构域。
实施例12:CAR表达的验证
将75000个HEK 293T细胞接种在48孔中。24小时后使用MACSfectin转染方案用0.5μg质粒转染细胞。在转染后48小时,使用补充有1mM EDTA的PBS将细胞分离。遵循推荐的方案,用抗CD271抗体(Miltenyi Biotec GmbH)染色用一种质粒转染的细胞的三分之一。将另外三分之一在4℃下与山羊中产生的抗小鼠IgG(Fab特异性)抗体(Sigma Aldrich)以10μg/ml抗体浓度孵育30分钟。洗涤步骤后,将细胞在4℃下与鸡中产生的抗山羊IgG(H+L)交叉吸附的二抗(Thermo Fisher Scientific)以10μg/ml抗体浓度孵育30分钟。将最后三分之一仅仅如所述染色,以二抗作为背景对照。使用MACSQuant 10分析仪测量样品。图6中A显示作为转染效力和构建体表达的读数的在表面上表达LNGFR的细胞的百分比。图6中B显示在表面上表达CAR构建体的细胞的百分比。除了少数例外,所有CAR分子都可以成功表达。
实施例13:慢病毒表达载体的产生
将胰腺癌特异性CAR克隆到在人PGK启动子控制下的第三代SIN-慢病毒载体构建体中。用该表达质粒和编码结构蛋白gag-pol、rev和VSV-G包膜蛋白的其它质粒瞬时转染HEK293T细胞导致病毒载体颗粒释放到上清液中。随后通过低速离心富集病毒载体颗粒并在-70℃下储存。
实施例14:T细胞分离和用胰腺癌特异性CAR的遗传修饰
使用MicroBeads和MACS(Miltenyi Biotec GmbH,德国)从供体机采血液成分(apheresis)或血沉棕黄层样品分离原代T细胞以达到超过90%的纯度(CD3+细胞)。将磁性富集的细胞洗涤并重悬浮于补充有200IU/mL人重组IL-2(Miltenyi Biotec GmbH,德国)的TexMACS培养基中。然后通过添加GMP TransAct CD3/CD28试剂(Miltenyi BiotecGmbH,德国)来刺激T细胞。
24小时后,通过用CD25和CD69抗体对T细胞染色并在MACSQuant分析仪(MiltenyiBiotec GmbH,德国)中通过流式细胞术分析来证实成功的T细胞刺激。然后通过添加编码胰腺癌特异性CAR的慢病毒载体以MOI=0.5-2转导经刺激的T细胞。静置培养4天后,洗涤细胞以除去过量的病毒载体和TransAct试剂,并再培养5-10天。通过使用抗人Fc荧光染料染色活CD3+细胞中的胰腺癌特异性CAR的表面表达和流式细胞术来测量病毒转导的效率。取决于所用的MOI,基因标记的T细胞的数量范围在10%和60%之间。
实施例15:胰腺癌特异性CAR功能性
将表达胰腺癌特异性靶标中的一种或多种的细胞或不表达这些靶标的细胞以不同的效应细胞与靶细胞的比率与扩增的表达胰腺癌特异性CAR的T细胞一起或者,作为对照,与非转导的T细胞一起孵育5或24小时。通过流式细胞术分析特异性靶细胞杀伤。或者,用靶标阳性或阴性的细胞系再刺激效应细胞。通过流式细胞术分析细胞因子产生(IFN-γ、IL-2、TNF-α)以及脱粒(CD107a)。只有携带胰腺癌特异性CAR的T细胞能够杀伤靶细胞,显示增加的细胞因子产生以及脱粒标志物上调。
此外,通过CAR T细胞和胰腺癌细胞的长期共培养分析杀伤效力和动力学。使用泛T细胞分离试剂盒(Miltenyi Biotec,德国)从健康供体的全血供应物分离T细胞。使用MACSGMP T细胞TransAct(Miltenyi Biotec,德国),在补充有40IU/ml IL-2(Miltenyi Biotec,德国)的TexMACSTM GMP培养基(Miltenyi Biotec,德国)中活化分离的T细胞。24小时后,将T细胞用含有CAR构建体的慢病毒载体以2的MOI转导。
随后,将T细胞在补充有40IU/ml IL-2的TexMACSTM GMP培养基中培养。
转导后第12天,经由报告蛋白LNGFR的流式细胞术测量评估CAR表达。将CAR阳性T细胞调节至相同数量,并接种于96孔板中,所述96孔板具有在200μl TexMACSTM GMP培养基中的胰腺腺癌细胞系BxPC3。在该测定前,用含有GFP的慢病毒载体转导BxPC3细胞。使用IncuCyte S3(Essen BioScience,德国)追踪和分析GFP阳性细胞。“绿色目标汇合度”被用作读出值,因为其与表达GFP的贴壁靶细胞的特异性裂解成反比。与模拟对照相比,所有CAR构建体介导肿瘤细胞的有效杀伤。结果显示于图7中。
实施例16:识别CLA的CAR结合结构域的氨基酸序列
对于特异性识别CLA的CAR的抗原结合结构域,使用scFv的抗原结合结构域,其具有SEQID NO:17或SEQ ID NO:18的氨基酸序列(该序列以氨基酸的单字母代码给出)。
实施例17:识别CD142的CAR结合结构域的氨基酸序列
对于特异性识别CD142的CAR的抗原结合结构域,使用scFv的抗原结合结构域,其具有SEQ ID NO:19或SEQ ID NO:20的氨基酸序列(该序列以氨基酸的单字母代码给出)。
实施例18:识别CD73的CAR结合结构域的氨基酸序列
对于特异性识别CD73的CAR的抗原结合结构域,使用scFv的抗原结合结构域,其具有SEQ ID NO:21或SEQ ID NO:22的氨基酸序列(该序列以氨基酸的单字母代码给出)。
实施例19:识别CD49c的CAR结合结构域的氨基酸序列
对于特异性识别CD49c的CAR的抗原结合结构域,使用scFv的抗原结合结构域,其具有SEQ ID NO:23或SEQ ID NO:24的氨基酸序列(该序列以氨基酸的单字母代码给出)。
实施例20:识别CD66c的CAR结合结构域的氨基酸序列
对于特异性识别CD66c的CAR的抗原结合结构域,使用scFv的抗原结合结构域,其具有SEQ ID NO:25或SEQ ID NO:26的氨基酸序列(该序列以氨基酸的单字母代码给出)。
实施例21:识别CD104的CAR结合结构域的氨基酸序列
对于特异性识别CD104的CAR的抗原结合结构域,使用scFv的抗原结合结构域,其具有SEQ ID NO:27或SEQ ID NO:28的氨基酸序列(该序列以氨基酸的单字母代码给出)。
实施例22:识别CD318的CAR结合结构域的氨基酸序列
对于特异性识别CD318的CAR的抗原结合结构域,使用scFv的抗原结合结构域,其具有SEQ ID NO:29或SEQ ID NO:30的氨基酸序列(该序列以氨基酸的单字母代码给出)。
实施例23:识别TSPAN8的CAR结合结构域的氨基酸序列
对于特异性识别TSPAN8的CAR的抗原结合结构域,使用scFv的抗原结合结构域,其具有SEQ ID NO:31或SEQ ID NO:32的氨基酸序列(该序列以氨基酸的单字母代码给出)。
实施例24:原代人胰腺癌细胞上的CLA和CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8的共表达
将人胰腺腺癌组织解离、染色和分析。图8a中的A)显示一般门控策略:在碎片排斥后,用碘化丙啶染色排除死细胞。通过对于前向散射针对面积与高度绘图排除不需要的双峰。将EpCAM+、CD45+以及CD45-/EpCAM-细胞区分,并进一步用对靶标特异性的PE或APC缀合的抗体进行分析。图8b中的B显示原代人胰腺癌细胞上的CLA与CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8的共表达。结果表明这些标志物之间的强烈共表达,其为双重靶向的先决条件(图8a中的A和图8b中的B)。
序列
SEQ ID NO:1
CLA VH
EVQLVESGGGLVQPGNSLKLSCSASGFTFSSYYGMHWIRQAPGEGLDWVAYISSSSGTVYADAVKARFTISRDNAKNTLYLQLNSLKSEDTAIYYCARAQNWDLFDYWGQGVM VTVSS
SEQ ID NO:2
CLA VL
QIMLTQQAESLWISPGERVSITCRASQSLLYTDGKHYLSWYQQKPGQTTKALIYHASVRTDGVPTRFIGSGSGTEFTLSIEHVQPEDFAIYYCLQTLKSPFTFGSGTKLEIK
SEQ ID NO:3
CD142 VH
QVQLKQSGPGLVQPSQSLSITCTVSGFSLSNYGVHWVRQSPGKGLEWLGVIWSGGSTDYNVAFISRLIITKDNSKSQVFLKMNSLQADDTAIYFCARTTGSVFNAMDHWGQGTSVTVSS
SEQ ID NO:4
CD142 VL
QIVLTQSPALMSASPGEKVTMTCSASSSVTYMYWYQQKPRSSPKPWIYLTSNLASGVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQWSSNPLTFGAGTKLELK
SEQ ID NO:5
CD73 VH
EVQLQQSGAELVKPGASVKLSCTASGFNIKDTYIHWVKQRPEQGLEWIGRIDPATGNTEYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCARGYYGSSYPPWFAYWGQGTLVTVSA
SEQ ID NO:6
CD73 VL
DIVMTQSHKFMSTSVGDRVSITCKASQDVGSAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSSYPLTFGAGTKLELK
SEQ ID NO:7
CD49c VH
EVQLQQSGAELVKPGASVKLSCTASGFNIKDTYMHWVKQRPEQGLEWIGRIDPANGHTKYDPKFQGKATITADTSSNAAYLQLNSLTSEDTAVYYCARRVAYAMDYWGQGTSVTVSS
SEQ ID NO:8
CD49c VL
ENVLTQSPAIMSASPGEKVTMTCSASSSVTYMHWYQQKSSTSPKLWIYDTSKLASGVPGRFSGSGSGNSYSLTISSMEAEDVATYCCFQGSGYPLTFGGGTKLEIK
SEQ ID NO:9
CD66c VH
QVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKSLEWLAHIWWNDERYYNPSLKNQLTISKDTSRNQVFLKITSVDTADTATYYCARSPRGYFDYWGHGTTLTVSS
SEQ ID NO:10
CD66c VL
DIVMTQSQKFMSTSVGDRVSVTCKASQNVVTNVAWYQQTPGQSPKALIYSASYRYSGVPDRFSGSGSGTDFTLTISNVQSGDLAEYFCQQYNSYPLTFGAGTKLELK
SEQ ID NO:11
CD104 VH
QVNLLQSGAALVKPGASVKLSCKASGYTFTDYYIFWVKQSHGKSLEWIGYINPNSGSTNYNEKFKRKATLSVDKSTNTAYMELSRLTSEDSATYYCTRRAYYGYNPFDYWGQGVMVTVSS
SEQ ID NO:12
CD104 VL
DIQMTQTPSSMPASLGERVTISCRASRGINNYLSWYQQNLDGTIKPLIYYTSNLQSGVPSRFSGSGSGTDYSLTISSLEPEDFAMYYCQQYDSSPWTFGGGTKLELK
SEQ ID NO:13
CD318 VH
EVQLQQSGAELVRPGALVKLSCKASGFNIKDYYIHWVKQRPEQGLEWIGWIDPENGHTIYDPKFQGKASITADTSSNTAYLQLSSLTSEDTAVYYCARLTGTTYAMDYWGQGTSVTVSS
SEQ ID NO:14
CD318 VL
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTTAVAWYQQKSGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTISSVQAEDLALYYCQQHYSTPYTFGGGTKLEIK
SEQ ID NO:15
TSPAN8 VH
EVKLLESGGGLVQPGGSMRLSCAASGFTFTDFYMNWIRQPAGKAPEWLGFIRNKASGYTTEYNPSVKGRFTISRDNTQNMLYLQMNTLRAEDTATYYCARAHSYYGYDYFDYWGQGVMVTVSS
SEQ ID NO:16
TSPAN8 VL
DIQMTQSPASLSASLEEIVTITCQASQDIGNWLSWYQQKPGKSPQLLIYGATSLADGVPSRFSGSRSGTQYSLKISRLQVEDIRIYYCLQAYSAPWTFGGGTKLELK
SEQ ID NO:17
CLA特异性scFv VH-接头-VL
EVQLVESGGGLVQPGNSLKLSCSASGFTFSSYGMHWIRQAPGEGLDWVAYISSSSGTVYADAVKARFTISRDNAKNTLYLQLNSLKSEDTAIYYCARAQNWDLFDYWGQGVMVTVSSGGGGSGGGGSGGGGSQIMLTQQAESLWISPGERVSITCRASQSLLYTDGKHYLSWYQQKPGQTTKALIYHASVRTDGVPTRFIGSGSGTEFTLSIEHVQPEDFAIYYCLQTLKSPFTFGSGTKLEIK
SEQ ID NO:18
CLA特异性scFv VL-接头-VH
QIMLTQQAESLWISPGERVSITCRASQSLLYTDGKHYLSWYQQKPGQTTKALIYHASVRTDGVPTRFIGSGSGTEFTLSIEHVQPEDFAIYYCLQTLKSPFTFGSGTKLEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGNSLKLSCSASGFTFSSYGMHWIRQAPGEGLDWVAYISSSSGTVYADAVKARFTISRDNAKNTLYLQLNSLKSEDTAIYYCARAQNWDLFDYWGQGVMVTVSS
SEQ ID NO:19
CD142特异性 CAR 序列 VH-接头-VL
QVQLKQSGPGLVQPSQSLSITCTVSGFSLSNYGVHWVRQSPGKGLEWLGVIWSGGSTDYNVAFISRLIITKDNSKSQVFLKMNSLQADDTAIYFCARTTGSVFNAMDHWGQGTSVTVSSGGGGSGGGGSGGGGSQIVLTQSPALMSASPGEKVTMTCSASSSVTYMYWYQQKPRSSPKPWIYLTSNLASGVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQWSSNPLTFGAGTKLELK
SEQ ID NO:20
CD142 特异性 CAR 序列 VL-接头-VH
QIVLTQSPALMSASPGEKVTMTCSASSSVTYMYWYQQKPRSSPKPWIYLTSNLASGVPARFSGSGSGTSYSLTISSVEAEDAATYYCQQWSSNPLTFGAGTKLELKGGGGSGGGGSGGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLSNYGVHWVRQSPGKGLEWLGVIWSGGSTDYNVAFISRLIITKDNSKSQVFLKMNSLQADDTAIYFCARTTGSVFNAMDHWGQGTSVTVSS
SEQ ID NO:21
CD73 特异性 CAR 序列 :VH-接头 -VL
EVQLQQSGAELVKPGASVKLSCTASGFNIKDTYIHWVKQRPEQGLEWIGRIDPATGNTEYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCARGYYGSSYPPWFAYWGQGTLVTVSAGGGGSGGGGSGGGGSDIVMTQSHKFMSTSVGDRVSITCKASQDVGSAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSSYPLTFGAGTKLELK
SEQ ID NO:22
CD73 特异性 CAR,序列 VL-接头-VH
DIVMTQSHKFMSTSVGDRVSITCKASQDVGSAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSSYPLTFGAGTKLELKGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKLSCTASGFNIKDTYIHWVKQRPEQGLEWIGRIDPATGNTEYDPKFQGKATITADTSSNTAYLHLSSLTSEDTAVYYCARGYYGSSYPPWFAYWGQGTLVTVSA
SEQ ID NO:23
CD49c 特异性 CAR 序列 VH-接头-VL
EVQLQQSGAELVKPGASVKLSCTASGFNIKDTYMHWVKQRPEQGLEWIGRIDPANGHTKYDPKFQGKATITADTSSNAAYLQLNSLTSEDTAVYYCARRVAYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSENVLTQSPAIMSASPGEKVTMTCSASSSVTYMHWYQQKSSTSPKLWIYDTSKLASGVPGRFSGSGSGNSYSLTISSMEAEDVATYCCFQGSGYPLTFGGGTKLEIK
SEQ ID NO:24
CD49c 特异性 CAR 序列 VL-接头-VH
ENVLTQSPAIMSASPGEKVTMTCSASSSVTYMHWYQQKSSTSPKLWIYDTSKLASGVPGRFSGSGSGNSYSLTISSMEAEDVATYCCFQGSGYPLTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKLSCTASGFNIKDTYMHWVKQRPEQGLEWIGRIDPANGHTKYDPKFQGKATITADTSSNAAYLQLNSLTSEDTAVYYCARRVAYAMDYWGQGTSVTVSS
SEQ ID NO:25
CD66c 特异性 CAR 序列 VH-接头-VL
QVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKSLEWLAHIWWNDERYYNPSLKNQLTISKDTSRNQVFLKITSVDTADTATYYCARSPRGYFDYWGHGTTLTVSSGGGGSGGGGSGGGGSDIVMTQSQKFMSTSVGDRVSVTCKASQNVVTNVAWYQQTPGQSPKALIYSASYRYSGVPDRFSGSGSGTDFTLTISNVQSGDLAEYFCQQYNSYPLTFGAGTKLELK
SEQ ID NO:26
CD66c 特异性 CAR 序列 VL-接头-VH
DIVMTQSQKFMSTSVGDRVSVTCKASQNVVTNVAWYQQTPGQSPKALIYSASYRYSGVPDRFSGSGSGTDFTLTISNVQSGDLAEYFCQQYNSYPLTFGAGTKLELKGGGGSGGGGSGGGGSQVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKSLEWLAHIWWNDERYYNPSLKNQLTISKDTSRNQVFLKITSVDTADTATYYCARSPRGYFDYWGHGTTLTVSS
SEQ ID NO:27
CD104 特异性 CAR 序列 VH-接头-VL
QVNLLQSGAALVKPGASVKLSCKASGYTFTDYYIFWVKQSHGKSLEWIGYINPNSGSTNYNEKFKRKATLSVDKSTNTAYMELSRLTSEDSATYYCTRRAYYGYNPFDYWGQGVMVTVSSGGGGSGGGGSGGGGSDIQMTQTPSSMPASLGERVTISCRASRGINNYLSWYQQNLDGTIKPLlYYTSNLQSGVPSRFSGSGSGTDYSLTISSLEPEDFAMYYCQQYDSSPWTFGGGTKLELK
SEQ ID NO:28
CD104 特异性 CAR 序列 VL-接头-VH
DIQMTQTPSSMPASLGERVTISCRASRGINNYLSWYQQNLDGTIKPLIYYTSNLQSGVPSRFSGSGSGTDYSLTISSLEPEDFAMYYCQQYDSSPWTFGGGTKLELKGGGGSGGGGSGGGGSQVNLLQSGAALVKPGASVKLSCKASGYTFTDYYIFWVKQSHGKSLEWIGYINPNSGSTNYNEKFKRKATLSVDKSTNTAYMELSRLTSEDSATYYCTRRAYYGYNPFDYWGQGVMVTVSS
SEQ ID NO:29
CD318 特异性 CAR 序列VH-接头-VL
EVQLQQSGAELVRPGALVKLSCKASGFNIKDYYIHWVKQRPEQGLEWIGWIDPENGHTIYDPKFQGKASITADTSSNTAYLQLSSLTSEDTAVYYCARLTGTTYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSDIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKSGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTISSVQAEDLALYYCQQHYSTPYTFGGGTKLEIK
SEQ ID NO:30
CD318 特异性 CAR 序列 VL-接头-VH
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKSGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTISSVQAEDLALYYCQQHYSTPYTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLQQSGAELVRPGALVKLSCKASGFNIKDYYIHWVKQRPEQGLEWIGWIDPENGHTIYDPKFQGKASITADTSSNTAYLQLSSLTSEDTAVYYCARLTGTTYAMDYWGQGTSVTVSS
SEQ ID NO:31
TSPAN8 特异性 CAR 序列 VH-接头-VL
EVKLLESGGGLVQPGGSMRLSCAASGFTFTDFYMNWIRQPAGKAPEWLGFIRNKASGYTTEYNPSVKGRFTISRDNTQNMLYLQMNTLRAEDTATYYCARAHSYYGYDYFDYWGQGVMVTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASLEEIVTITCQASQDIGNWLSWYQQKPGKSPQLLIYGATSLADGVPSRFSGSRSGTQYSLKISRLQVEDTRIYYCLQAYSAPWTFGGGTKLELK
SEQ ID NO:32
TSPAN8特异性CAR序列VL-接头-VH
DTQMTQSPASLSASLEEIVTITCQASQDIGNWLSWYQQKPGKSPQLLIYGATSLADGVPSRFSGSRSGTQYSLKISRLQVEDIRIYYCLQAYSAPWTFGGGTKLELKGGGGSGGGGSGGGGSEVKLLESGGGLVQPGGSMRLSCAASGFTFTDFYMNWIRQPAGKAPEWLGFIRNKASGYTTEYNPSVKGRFTISRDNTQNMLYLQMNTLRAEDTATYYCARAHSYYGYDYFDYWGQGVMVTVSS
序列表
<110> 美天施生物科技有限责任公司
<120> 对肿瘤细胞有特异性的嵌合抗原受体
<130> MIL_098
<160> 32
<170> BiSSAP 1.3.6
<210> 1
<211> 117
<212> PRT
<213> 智人
<220>
<223> CLA VH
<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Lys Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Ile Arg Gln Ala Pro Gly Glu Gly Leu Asp Trp Val
35 40 45
Ala Tyr Ile Ser Ser Ser Ser Gly Thr Val Tyr Ala Asp Ala Val Lys
50 55 60
Ala Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Leu Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Gln Asn Trp Asp Leu Phe Asp Tyr Trp Gly Gln Gly Val Met
100 105 110
Val Thr Val Ser Ser
115
<210> 2
<211> 112
<212> PRT
<213> 智人
<220>
<223> CLA VL
<400> 2
Gln Ile Met Leu Thr Gln Gln Ala Glu Ser Leu Trp Ile Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Ile Thr Cys Arg Ala Ser Gln Ser Leu Leu Tyr Thr
20 25 30
Asp Gly Lys His Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Thr
35 40 45
Thr Lys Ala Leu Ile Tyr His Ala Ser Val Arg Thr Asp Gly Val Pro
50 55 60
Thr Arg Phe Ile Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile
65 70 75 80
Glu His Val Gln Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Leu Gln Thr
85 90 95
Leu Lys Ser Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 3
<211> 119
<212> PRT
<213> 智人
<220>
<223> CD142 VH
<400> 3
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Val Ala Phe Ile
50 55 60
Ser Arg Leu Ile Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Phe Cys Ala
85 90 95
Arg Thr Thr Gly Ser Val Phe Asn Ala Met Asp His Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 4
<211> 106
<212> PRT
<213> 智人
<220>
<223> CD142 VL
<400> 4
Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 5
<211> 122
<212> PRT
<213> 智人
<220>
<223> CD73 VH
<400> 5
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Thr Gly Asn Thr Glu Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Tyr Gly Ser Ser Tyr Pro Pro Trp Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 6
<211> 107
<212> PRT
<213> 智人
<220>
<223> CD73 VL
<400> 6
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 7
<211> 117
<212> PRT
<213> 智人
<220>
<223> CD49C VH
<400> 7
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Ala Ala Tyr
65 70 75 80
Leu Gln Leu Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Ala Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 8
<211> 106
<212> PRT
<213> 智人
<220>
<223> CD49C VL
<400> 8
Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Ser Thr Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Val Ala Thr Tyr Cys Cys Phe Gln Gly Ser Gly Tyr Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 9
<211> 118
<212> PRT
<213> 智人
<220>
<223> CD66C VH
<400> 9
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Ser Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asn Asp Glu Arg Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Asn Gln Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ser Pro Arg Gly Tyr Phe Asp Tyr Trp Gly His Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 10
<211> 107
<212> PRT
<213> 智人
<220>
<223> CD66C VL
<400> 10
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Val Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Thr Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Gly Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 11
<211> 120
<212> PRT
<213> 智人
<220>
<223> CD104 VH
<400> 11
Gln Val Asn Leu Leu Gln Ser Gly Ala Ala Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Ile Phe Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Arg Lys Ala Thr Leu Ser Val Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Thr Tyr Tyr Cys
85 90 95
Thr Arg Arg Ala Tyr Tyr Gly Tyr Asn Pro Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Val Met Val Thr Val Ser Ser
115 120
<210> 12
<211> 107
<212> PRT
<213> 智人
<220>
<223> CD104 VL
<400> 12
Asp Ile Gln Met Thr Gln Thr Pro Ser Ser Met Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Arg Ala Ser Arg Gly Ile Asn Asn Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Asn Leu Asp Gly Thr Ile Lys Pro Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr Asp Ser Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 13
<211> 119
<212> PRT
<213> 智人
<220>
<223> CD318 VH
<400> 13
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Leu Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly His Thr Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Ser Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Thr Gly Thr Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 14
<211> 107
<212> PRT
<213> 智人
<220>
<223> CD318 VL
<400> 14
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Ser Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 15
<211> 123
<212> PRT
<213> 智人
<220>
<223> TSPAN8 VH
<400> 15
Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Phe
20 25 30
Tyr Met Asn Trp Ile Arg Gln Pro Ala Gly Lys Ala Pro Glu Trp Leu
35 40 45
Gly Phe Ile Arg Asn Lys Ala Ser Gly Tyr Thr Thr Glu Tyr Asn Pro
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Gln Asn Met
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Ala His Ser Tyr Tyr Gly Tyr Asp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Val Met Val Thr Val Ser Ser
115 120
<210> 16
<211> 107
<212> PRT
<213> 智人
<220>
<223> TSPAN8 VL
<400> 16
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Glu
1 5 10 15
Glu Ile Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Gly Asn Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Arg Leu Gln Val
65 70 75 80
Glu Asp Ile Arg Ile Tyr Tyr Cys Leu Gln Ala Tyr Ser Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 17
<211> 244
<212> PRT
<213> 智人
<220>
<223> CLA特异性SCFV VH-接头-VL
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Lys Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Ile Arg Gln Ala Pro Gly Glu Gly Leu Asp Trp Val
35 40 45
Ala Tyr Ile Ser Ser Ser Ser Gly Thr Val Tyr Ala Asp Ala Val Lys
50 55 60
Ala Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Leu Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Gln Asn Trp Asp Leu Phe Asp Tyr Trp Gly Gln Gly Val Met
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gln Ile Met Leu Thr Gln Gln Ala Glu Ser Leu Trp
130 135 140
Ile Ser Pro Gly Glu Arg Val Ser Ile Thr Cys Arg Ala Ser Gln Ser
145 150 155 160
Leu Leu Tyr Thr Asp Gly Lys His Tyr Leu Ser Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Thr Thr Lys Ala Leu Ile Tyr His Ala Ser Val Arg Thr
180 185 190
Asp Gly Val Pro Thr Arg Phe Ile Gly Ser Gly Ser Gly Thr Glu Phe
195 200 205
Thr Leu Ser Ile Glu His Val Gln Pro Glu Asp Phe Ala Ile Tyr Tyr
210 215 220
Cys Leu Gln Thr Leu Lys Ser Pro Phe Thr Phe Gly Ser Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
<210> 18
<211> 244
<212> PRT
<213> 智人
<220>
<223> CLA特异性SCFV VL-接头-VH
<400> 18
Gln Ile Met Leu Thr Gln Gln Ala Glu Ser Leu Trp Ile Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Ile Thr Cys Arg Ala Ser Gln Ser Leu Leu Tyr Thr
20 25 30
Asp Gly Lys His Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Thr
35 40 45
Thr Lys Ala Leu Ile Tyr His Ala Ser Val Arg Thr Asp Gly Val Pro
50 55 60
Thr Arg Phe Ile Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile
65 70 75 80
Glu His Val Gln Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Leu Gln Thr
85 90 95
Leu Lys Ser Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
130 135 140
Leu Lys Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly
145 150 155 160
Met His Trp Ile Arg Gln Ala Pro Gly Glu Gly Leu Asp Trp Val Ala
165 170 175
Tyr Ile Ser Ser Ser Ser Gly Thr Val Tyr Ala Asp Ala Val Lys Ala
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
195 200 205
Leu Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Arg
210 215 220
Ala Gln Asn Trp Asp Leu Phe Asp Tyr Trp Gly Gln Gly Val Met Val
225 230 235 240
Thr Val Ser Ser
<210> 19
<211> 240
<212> PRT
<213> 智人
<220>
<223> CD142特异性CAR序列VH-接头-VL
<400> 19
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Val Ala Phe Ile
50 55 60
Ser Arg Leu Ile Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Phe Cys Ala
85 90 95
Arg Thr Thr Gly Ser Val Phe Asn Ala Met Asp His Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Leu
130 135 140
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser
145 150 155 160
Ser Ser Val Thr Tyr Met Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser
165 170 175
Pro Lys Pro Trp Ile Tyr Leu Thr Ser Asn Leu Ala Ser Gly Val Pro
180 185 190
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
195 200 205
Ser Ser Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
210 215 220
Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
225 230 235 240
<210> 20
<211> 240
<212> PRT
<213> 智人
<220>
<223> CD142特异性CAR序列VL-接头-VH
<400> 20
Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln Ser
115 120 125
Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr
130 135 140
Val Ser Gly Phe Ser Leu Ser Asn Tyr Gly Val His Trp Val Arg Gln
145 150 155 160
Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly
165 170 175
Ser Thr Asp Tyr Asn Val Ala Phe Ile Ser Arg Leu Ile Ile Thr Lys
180 185 190
Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Ala
195 200 205
Asp Asp Thr Ala Ile Tyr Phe Cys Ala Arg Thr Thr Gly Ser Val Phe
210 215 220
Asn Ala Met Asp His Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
225 230 235 240
<210> 21
<211> 244
<212> PRT
<213> 智人
<220>
<223> CD73特异性CAR序列VH-接头-VL
<400> 21
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Thr Gly Asn Thr Glu Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Tyr Gly Ser Ser Tyr Pro Pro Trp Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys
145 150 155 160
Lys Ala Ser Gln Asp Val Gly Ser Ala Val Ala Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His
180 185 190
Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr Phe
210 215 220
Cys Gln Gln Tyr Ser Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys
225 230 235 240
Leu Glu Leu Lys
<210> 22
<211> 244
<212> PRT
<213> 智人
<220>
<223> CD73特异性CAR序列VL-接头-VH
<400> 22
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln
115 120 125
Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys
130 135 140
Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Lys
145 150 155 160
Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala
165 170 175
Thr Gly Asn Thr Glu Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile
180 185 190
Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu His Leu Ser Ser Leu
195 200 205
Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Tyr Gly
210 215 220
Ser Ser Tyr Pro Pro Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ala
<210> 23
<211> 238
<212> PRT
<213> 智人
<220>
<223> CD49C特异性CAR序列VH-接头-VL
<400> 23
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Ala Ala Tyr
65 70 75 80
Leu Gln Leu Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Val Ala Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser
130 135 140
Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser
145 150 155 160
Val Thr Tyr Met His Trp Tyr Gln Gln Lys Ser Ser Thr Ser Pro Lys
165 170 175
Leu Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg
180 185 190
Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser
195 200 205
Met Glu Ala Glu Asp Val Ala Thr Tyr Cys Cys Phe Gln Gly Ser Gly
210 215 220
Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 24
<211> 238
<212> PRT
<213> 智人
<220>
<223> CD49C特异性CAR序列VL-接头-VH
<400> 24
Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Ser Thr Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Val Ala Thr Tyr Cys Cys Phe Gln Gly Ser Gly Tyr Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser
115 120 125
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Thr
130 135 140
Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Met His Trp Val Lys Gln
145 150 155 160
Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asn
165 170 175
Gly His Thr Lys Tyr Asp Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr
180 185 190
Ala Asp Thr Ser Ser Asn Ala Ala Tyr Leu Gln Leu Asn Ser Leu Thr
195 200 205
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Val Ala Tyr Ala
210 215 220
Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
225 230 235
<210> 25
<211> 240
<212> PRT
<213> 智人
<220>
<223> CD66C特异性CAR序列VH-接头-VL
<400> 25
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Ser Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asn Asp Glu Arg Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Asn Gln Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ser Pro Arg Gly Tyr Phe Asp Tyr Trp Gly His Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met
130 135 140
Ser Thr Ser Val Gly Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln
145 150 155 160
Asn Val Val Thr Asn Val Ala Trp Tyr Gln Gln Thr Pro Gly Gln Ser
165 170 175
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
180 185 190
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
195 200 205
Ser Asn Val Gln Ser Gly Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr
210 215 220
Asn Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
225 230 235 240
<210> 26
<211> 240
<212> PRT
<213> 智人
<220>
<223> CD66C特异性CAR序列VL-接头-VH
<400> 26
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Val Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Thr Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Gly Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu
115 120 125
Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys
130 135 140
Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Gly Trp
145 150 155 160
Ile Arg Gln Pro Ser Gly Lys Ser Leu Glu Trp Leu Ala His Ile Trp
165 170 175
Trp Asn Asp Glu Arg Tyr Tyr Asn Pro Ser Leu Lys Asn Gln Leu Thr
180 185 190
Ile Ser Lys Asp Thr Ser Arg Asn Gln Val Phe Leu Lys Ile Thr Ser
195 200 205
Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ser Pro Arg
210 215 220
Gly Tyr Phe Asp Tyr Trp Gly His Gly Thr Thr Leu Thr Val Ser Ser
225 230 235 240
<210> 27
<211> 242
<212> PRT
<213> 智人
<220>
<223> CD104特异性CAR序列VH-接头-VL
<400> 27
Gln Val Asn Leu Leu Gln Ser Gly Ala Ala Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Ile Phe Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Asn Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Arg Lys Ala Thr Leu Ser Val Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Thr Tyr Tyr Cys
85 90 95
Thr Arg Arg Ala Tyr Tyr Gly Tyr Asn Pro Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Val Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Pro Ser
130 135 140
Ser Met Pro Ala Ser Leu Gly Glu Arg Val Thr Ile Ser Cys Arg Ala
145 150 155 160
Ser Arg Gly Ile Asn Asn Tyr Leu Ser Trp Tyr Gln Gln Asn Leu Asp
165 170 175
Gly Thr Ile Lys Pro Leu Ile Tyr Tyr Thr Ser Asn Leu Gln Ser Gly
180 185 190
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu
195 200 205
Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Met Tyr Tyr Cys Gln
210 215 220
Gln Tyr Asp Ser Ser Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu
225 230 235 240
Leu Lys
<210> 28
<211> 242
<212> PRT
<213> 智人
<220>
<223> CD104特异性CAR序列VL-接头-VH
<400> 28
Asp Ile Gln Met Thr Gln Thr Pro Ser Ser Met Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Arg Ala Ser Arg Gly Ile Asn Asn Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Asn Leu Asp Gly Thr Ile Lys Pro Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr Asp Ser Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Asn Leu Leu Gln
115 120 125
Ser Gly Ala Ala Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys
130 135 140
Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Ile Phe Trp Val Lys
145 150 155 160
Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Tyr Ile Asn Pro Asn
165 170 175
Ser Gly Ser Thr Asn Tyr Asn Glu Lys Phe Lys Arg Lys Ala Thr Leu
180 185 190
Ser Val Asp Lys Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu
195 200 205
Thr Ser Glu Asp Ser Ala Thr Tyr Tyr Cys Thr Arg Arg Ala Tyr Tyr
210 215 220
Gly Tyr Asn Pro Phe Asp Tyr Trp Gly Gln Gly Val Met Val Thr Val
225 230 235 240
Ser Ser
<210> 29
<211> 241
<212> PRT
<213> 智人
<220>
<223> CD318特异性CAR序列VH-接头-VL
<400> 29
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Leu Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly His Thr Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Ser Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Thr Gly Thr Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser His Lys Phe
130 135 140
Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser
145 150 155 160
Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln Lys Ser Gly Gln
165 170 175
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Val
180 185 190
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr
195 200 205
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln
210 215 220
His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys
<210> 30
<211> 241
<212> PRT
<213> 智人
<220>
<223> CD318特异性CAR序列VL-接头-VH
<400> 30
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Ser Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln
115 120 125
Ser Gly Ala Glu Leu Val Arg Pro Gly Ala Leu Val Lys Leu Ser Cys
130 135 140
Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr Tyr Ile His Trp Val Lys
145 150 155 160
Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly Trp Ile Asp Pro Glu
165 170 175
Asn Gly His Thr Ile Tyr Asp Pro Lys Phe Gln Gly Lys Ala Ser Ile
180 185 190
Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu Gln Leu Ser Ser Leu
195 200 205
Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Leu Thr Gly Thr
210 215 220
Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser
225 230 235 240
Ser
<210> 31
<211> 245
<212> PRT
<213> 智人
<220>
<223> TSPAN8特异性CAR序列VH-接头-VL
<400> 31
Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Phe
20 25 30
Tyr Met Asn Trp Ile Arg Gln Pro Ala Gly Lys Ala Pro Glu Trp Leu
35 40 45
Gly Phe Ile Arg Asn Lys Ala Ser Gly Tyr Thr Thr Glu Tyr Asn Pro
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Gln Asn Met
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Ala His Ser Tyr Tyr Gly Tyr Asp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Val Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ala Ser Leu Ser Ala Ser Leu Glu Glu Ile Val Thr Ile Thr
145 150 155 160
Cys Gln Ala Ser Gln Asp Ile Gly Asn Trp Leu Ser Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile Tyr Gly Ala Thr Ser Leu
180 185 190
Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Gln
195 200 205
Tyr Ser Leu Lys Ile Ser Arg Leu Gln Val Glu Asp Ile Arg Ile Tyr
210 215 220
Tyr Cys Leu Gln Ala Tyr Ser Ala Pro Trp Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Leu Lys
245
<210> 32
<211> 245
<212> PRT
<213> 智人
<220>
<223> TSPAN8特异性CAR序列VL-接头-VH
<400> 32
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Glu
1 5 10 15
Glu Ile Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Gly Asn Trp
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Arg Leu Gln Val
65 70 75 80
Glu Asp Ile Arg Ile Tyr Tyr Cys Leu Gln Ala Tyr Ser Ala Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Leu Glu
115 120 125
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Met Arg Leu Ser Cys
130 135 140
Ala Ala Ser Gly Phe Thr Phe Thr Asp Phe Tyr Met Asn Trp Ile Arg
145 150 155 160
Gln Pro Ala Gly Lys Ala Pro Glu Trp Leu Gly Phe Ile Arg Asn Lys
165 170 175
Ala Ser Gly Tyr Thr Thr Glu Tyr Asn Pro Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Thr Gln Asn Met Leu Tyr Leu Gln Met Asn
195 200 205
Thr Leu Arg Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Ala His
210 215 220
Ser Tyr Tyr Gly Tyr Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Val Met
225 230 235 240
Val Thr Val Ser Ser
245
Claims (13)
1.配体,其包含对一种或多种抗原有特异性的抗原结合结构域,其特征在于所述配体是嵌合抗原受体(CAR),其包含对一种或多种抗原有特异性的抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
2.根据权利要求1所述的配体,其特征在于所述配体包含对至少两种不同抗原有特异性的至少两种不同的抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
3.根据权利要求1或2所述的配体,其特征在于所述CAR包含对CLA以及一种或多种抗原有特异性的抗原结合结构域,所述抗原选自CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
4.根据权利要求1或2所述的配体,其特征在于所述CAR包含抗原结合结构域、跨膜结构域和/或细胞内信号传导结构域,并且包含与相同或不同的跨膜结构域和/或细胞内信号传导结构域缀合的对两种不同抗原有特异性的至少两种抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
5.根据权利要求1-4中任一项所述的配体,其特征在于所述跨膜结构域包含4-1BB、CD8和/或CD28的跨膜结构域的序列;且所述细胞内信号传导结构域包含CD28、CD137和CD3ζ中的一种或多种的细胞内信号传导结构域的序列。
6.根据权利要求1-5中任一项所述的配体,其特征在于所述配体是工程改造的细胞,其表达对一种或多种抗原有特异性的至少一种抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
7.使癌细胞与根据权利要求1-6中任一项所述的配体结合的方法。
8.根据权利要求7所述的结合癌细胞的方法,其特征在于所述配体包含对至少两种不同抗原有特异性的至少两种不同抗原结合结构域,所述抗原选自CLA、CD142、CD73、CD49c、CD66c、CD104、CD318和TSPAN8。
9.工程改造的细胞的群体,其表达至少一种根据权利要求1-6中任一项所述的配体。
10.根据权利要求9所述的工程改造的细胞的群体用于治疗人类癌症的用途。
11.药物组合物,其包含表达根据权利要求1-6中任一项所述的CAR的工程改造的细胞的群体。
12.根据权利要求11所述的药物组合物用于治疗人类癌症的用途。
13.根据权利要求11所述的药物组合物结合化疗剂、放射试剂或免疫调节剂用于治疗癌症的用途。
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