CN113853205A - 表达FCγ受体的T细胞及其使用方法 - Google Patents
表达FCγ受体的T细胞及其使用方法 Download PDFInfo
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Abstract
提供了一种表达FCγ受体的T细胞。因此,提供了一种T细胞,被基因工程改造以表达:一第一多肽,包括一Fc受体共同γ链(FcRγ)的一氨基酸序列,所述氨基酸序列能够传递一激活信号;以及一第二多肽,包括能够结合一Fc配体的Fcγ受体的一胞外配体结合域,以及能够募集所述第一多肽的一氨基酸序列,使得在所述Fc配体与所述Fcγ受体的所述胞外配体结合域结合时,所述激活信号被传递。
Description
本申请要求于2019年3月19日提交的美国临时专利申请第62/820,357号的优先权,其内容通过引用整体并入本文。
序列表声明
于2020年3月19日建立的标题为81398SequenceListing.txt的ASCII文件(包括112,531个字节)与本申请同时提交,通过引用并入本文。
技术领域及背景技术
本发明在其一些实施方式中涉及一种表达Fcγ受体的T细胞及其使用方法。
癌症免疫疗法,包括基于细胞的疗法、抗体疗法和细胞因子疗法,在过去几年中已成为治疗各种类型癌症的一种有希望的策略,因为它具有规避耐药性的遗传和细胞机制,并且在保护健康组织的同时靶向肿瘤细胞。
基于抗体的癌症免疫疗法,例如单克隆抗体、抗体融合蛋白和抗体药物偶联物(antibody drug conjugates,ADC)依赖于识别癌细胞上相对于非癌细胞差异表达的细胞表面分子和/或免疫检查点阻断。基于抗体的免疫疗法与癌细胞的结合可通过各种机制导致癌细胞死亡,例如,抗体依赖性细胞介导的细胞毒性(antibody-dependent cell-mediated cytotoxicity,ADCC)、补体依赖性细胞毒性(complement-dependentcytotoxicity,CDC)、来自抗体-药物偶联物(antibody-drug conjugate,ADC)有效载荷的直接细胞毒性活性或抑制性检查点阻断。许多这些机制是通过细胞结合抗体的Fc结构域与造血细胞上的特殊细胞表面受体(Fc受体)结合启动的。
细胞治疗,例如使用具有T细胞受体(T cell receptor,TCR)的T细胞,其中所述T细胞特异于与癌细胞上(相对于非癌细胞)MHC第I类分子相关的差异表达的一抗原,显示出在几种类型的癌症中发挥抗肿瘤作用,例如血液恶性肿瘤。然而,抗原特异性效应淋巴细胞(antigen-specific effector lymphocytes)非常罕见,具有个体特异性,其识别谱有限,并且难以获得抗大多数恶性肿瘤获得。
已经揭示了结合基于抗体的癌症免疫治疗和基于细胞的治疗原理的策略,例如CAR T细胞以及与表达Fc受体的抗体和T细胞的联合治疗已被公开(例如,参见EP专利号:EP0340793;国际专利申请公开号:WO2017205254;美国专利申请公开号:US20150139943、US20180008638和US20160355566;以及Clemenceau等人;血液(Blood),2006,107:4669-4677)。然而,迄今为止利用这些细胞对抗实体瘤的尝试令人失望。因此,仍然迫切需要开发能够根除实体瘤的治疗方法,其具有更高的安全性,并且不完全依赖宿主T细胞库(T-cellrepertoire)。
其他背景技术包括美国专利号:US8313943和US611166;以及国际专利申请公开号:WO2015121454。
发明内容
根据本发明的一些实施方式的一方面,提供了一种T细胞,所述T细胞被基因工程改造以表达一第一多肽,包括一Fc受体共同γ链(Fc receptor commonγchain,FcRγ)的一氨基酸序列,所述氨基酸序列能够传递一激活信号;以及表达一第二多肽,包括能够结合一Fc配体的一Fcγ受体的一胞外配体结合域,以及能够募集所述第一多肽的一氨基酸序列,使得在所述Fc配体与所述Fcγ受体的所述胞外配体结合域结合时,所述激活信号被传递。
根据本发明的一些实施方式,所述第一多肽包含能够传递一激活信号的一CD3ζ链的一氨基酸序列。
根据本发明的一些实施方式,FcRγ位于CD3ζ链的N端。
根据本发明的一些实施方式,所述第二多肽包含能够传递一激活信号的一CD3ζ链的一氨基酸序列。
根据本发明的一些实施方式,能够募集所述第一多肽的所述氨基酸序列包含一Fc受体的跨膜结构域。
根据本发明的一些实施方式,能够募集所述第一多肽的所述氨基酸序列包含一Fc受体的细胞质域。
根据本发明的一些实施方式,所述Fc受体是Fcγ受体。
根据本发明的一些实施方式,所述Fcγ受体是CD64。
根据本发明的一些实施方式,所述第一多肽的分子量小于25千道尔顿。
根据本发明的一些实施方式,所述第一多肽不包括一靶点结合部位。
根据本发明的一些实施方式,所述第一多肽不包括scFv。
根据本发明的一些实施方式,所述第二多肽不包括scFv。
根据本发明的一些实施方式,所述T细胞不表达嵌合抗原受体(chimeric antigenreceptor,CAR)。
根据本发明的一些实施方式的一方面,提供了一种表达CD64的T细胞克隆,所述CD64包括:胞外域、跨膜结构域及细胞质域。
根据本发明的一些实施方式的一方面,提供了一种分离的T细胞群,所述T细胞群包括:表达内源CD64的至少80%的T细胞,所述CD64包括胞外域、跨膜结构域及细胞质域。
根据本发明的一些实施方式的一方面,提供了一种被基因工程改造以表达CD64的T细胞,所述CD64包括:胞外域、跨膜结构域及细胞质域。
根据本发明的一些实施方式,所述T细胞或所述T细胞群被基因工程改造以表达包括Fc受体共同γ链(FcRγ)的一氨基酸序列的一多肽,所述氨基酸序列能够传递一激活信号。
根据本发明的一些实施方式,所述多肽还包括CD3ζ链的一氨基酸序列,所述氨基酸序列能够传递一激活信号。
根据本发明的一些实施方式,所述T细胞或所述T细胞群内源性表达对一病理细胞具有特异性的一T细胞受体。
根据本发明的一些实施方式,所述T细胞或所述T细胞群被基因工程改造以表达一T细胞受体(T cell receptor,TCR)。
根据本发明的一些实施方式,所述T细胞或所述T细胞群被基因工程改造以表达一嵌合抗原受体。
根据本发明的一些实施方式的一方面,提供了一种在一受试者中治疗与一病理细胞相关的一疾病的方法,使用包括Fc结构域的一治疗组合物,所述治疗组合物对所述病理细胞具有特异性,所述方法包括:向所述受试者施用一治疗有效量的T细胞或是T细胞群,从而治疗所述受试者的所述疾病。
根据本发明的一些实施方式的一方面,提供了一种T细胞或T细胞群,在一受试者中治疗与一病理细胞相关的一疾病的用途,使用包括Fc结构域的一治疗组合物,所述治疗组合物对所述病理细胞具有特异性。
根据本发明的一些实施方式的一方面,提供了一种在一需要的受试者中治疗与一病理细胞相关的一疾病的方法,所述方法包括:向所述受试者施用一治疗有效量的T细胞或T细胞群;以及包括Fc结构域的一治疗组合物,所述治疗组合物对所述病理细胞具有特异性,从而治疗所述受试者的所述疾病。
根据本发明的一些实施方式的一方面,提供了一种T细胞或T细胞群;以及包括Fc结构域的一治疗组合物,在一需要的受试者中治疗与所述病理细胞相关的所述疾病的用途,所述治疗组合物对所述病理细胞具有特异性。
根据本发明的一些实施方式的一方面,提供了一种制品,所述制品包括:一包装材料,包装T细胞或T细胞群;以及包括Fc结构域的一治疗组合物。
根据本发明的一些实施方式,所述治疗组合物对一病理细胞具有特异性。
根据本发明的一些实施方式,所述治疗组合物是Fc融合蛋白。
根据本发明的一些实施方式,所述治疗组合物是一抗体(antibody,Ab)。
根据本发明的一些实施方式,所述抗体是IgG。
根据本发明的一些实施方式,所述疾病是癌症,并且其中所述病理细胞是癌细胞。
根据本发明的一些实施方式,所述癌症选自于由黑色素瘤、腺癌、乳腺癌、结肠癌、卵巢癌、肺癌及B细胞淋巴瘤所组成的群组。
根据本发明的一些实施方式,所述癌症选自于由黑色素瘤、腺癌及乳腺癌所组成的群组。
根据本发明的一些实施方式,所述抗体选自于由阿替利珠单抗(Atezolizumab)、西妥昔单抗(Cetuximab)、利妥昔单抗(Retuximab)、伽妥珠单抗(Gatipotuzumab)及静脉注射免疫球蛋白(Intravenous immunoglobulin,IVIG)所组成的群组。
根据本发明的一些实施方式,所述癌细胞表达选自于由PDL-1、CD19、E-钙粘蛋白(E-cadherin)、MUC1、TRP-1及TRP-2所组成的群组的一标记物。
根据本发明的一些实施方式,所述癌细胞表达PDL-1。
根据本发明的一些实施方式,所述抗体是抗PDL-1。
根据本发明的一些实施方式,所述抗体是阿替利珠单抗。
根据本发明的一些实施方式的一方面,提供了一种分离T细胞的方法,其特征在于,所述方法包括:使用结合CD64多肽或编码所述CD64多肽的一多核苷酸的一试剂从一受试者的一生物样品中分离CD64+T细胞。
根据本发明的一些实施方式,所述方法包括在所述分离后,培养、克隆、激活及基因工程改造所述CD64+T细胞的至少一个步骤。
根据本发明的一些实施方式,所述方法包括向有需要的一受试者施用多个所述CD64+T细胞。
根据本发明的一些实施方式,所述T细胞是CD4+T细胞。
根据本发明的一些实施方式,所述T细胞是CD8+T细胞。
根据本发明的一些实施方式,所述T细胞是增殖细胞。
根据本发明的一些实施方式,所述T细胞对于所述受试者是自体的。
除非另有定义,否则本文中使用的所有技术及/或科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。尽管与本文描述的那些类似或等同的方法及材料可以用于本发明的实施例的实践或测试中,但是下面描述了示例性的方法及/或材料。如有抵触,以专利说明书及其定义为准。另外,材料、方法及示例仅是说明性的,并非意图是限制性的。
附图说明
本文仅通过示例,参考附图描述了本发明的一些实施例。现在详细并具体地参考附图,要强调的是,示出的细节是作为示例,并且出于对本发明的实施例的说明性讨论的目的。就此而言,结合附图进行的描述对于本领域技术人员而言显而易见的是可以如何实践本发明的实施例。
附图中:
图1A至图1E证明CD4+T细胞连同肿瘤结合抗体(antibody,Ab)的过继转移诱导肿瘤细胞的直接杀伤;图1A是实验大纲的示意图;图1B显示了与未经治疗的对照组野生型(wild type,WT)小鼠相比,在注射从外周血(peripheral blood,PB)、肿瘤引流淋巴结(draining lymph node,DLN)或是肿瘤与抗黑色素瘤抗原TRP1(n=4)抗体结合所获得的CD4+T细胞后,WT小鼠中的B16F10肿瘤大小(mm2)的图表;图1C显示了与未经治疗的对照组小鼠(PBS)相比,在注射从外周血、肿瘤引流淋巴结或是肿瘤与抗TRP1抗体结合所获得的CD4+T细胞14天后,B16F10荷瘤(tumor-bearing)WT小鼠的显微照片;图1D显示了在过继转移CD4+T细胞后(有或没有抗TRP抗体(n=4)),RAG缺陷小鼠中的B16F10肿瘤大小(mm2)的图表;图1E显示了在过继转移指定的CD4+T克隆后(有或没有抗TRP1以及卵清蛋白抗体(n=4)),B16F10肿瘤大小(mm2)的图表;每个图表总结了至少3个经执行的代表性实验的结果;
图2A至图2C证明荷瘤小鼠中的CD4+T细胞亚群表达Fcγ受体;图2A显示了荷瘤小鼠(n=4)CD4+T细胞上所示Fcγ受体表达的代表性流式细胞术分析;图2B是显示B16F10荷瘤小鼠表达所示Fcγ受体(n=5)的CD4+T细胞百分比的图表;图2C是显示4T1荷瘤小鼠表达所示Fcγ受体(n=4)的CD4+T细胞百分比的图表;每个图表总结了三个典型实验的结果;
图3A至图3E证明,空白小鼠淋巴器官中的CD4+T细胞亚群表达Fcγ受体;图3A是图表,显示了在不同器官中表达所示Fcγ受体的空白小鼠的CD4+T细胞的百分比;图3B显示了表达FcγRI(CD64)的脾CD4+T细胞的代表性FACS分选(n=5);图3C显示了脾CD4+T细胞的共聚焦显微镜图像,所述脾CD4+T细胞按FcγRI的表达进行分选,并用指示标记物染色(n=3,放大倍数=x600);图3D显示了按FcγRI表达分选的脾CD4+T细胞中的CD3(左图)以及FcγRI(右图)的mRNA转录水平;将表达模式与分选脾CD11b+细胞进行比较;NGC=阴性对照;图3E显示了用指示标记物染色的空白小鼠的脾脏的组织切片的共焦显微镜图像;
图4A至图4D证明肿瘤特异性CD4+T细胞中FcγRI及其信号传导链的表达可诱导被抗体包裹的肿瘤细胞的有效溶解;图4A显示了从野生型小鼠(WT CD4)或OT-II小鼠(OT-IICD4)分离的脾脏FcγRI+/CD4+T细胞的代表性共聚焦显微镜图像,并且这些细胞与GFP标记的B16细胞在有或无指示抗体的情况下温育过夜(放大倍数=x800、n=5);图4B是图表,显示了与从WT小鼠分离的脾FcγRI+/CD4+(FcRI)或FcγRI neg/CD4+(FcRI(neg))T细胞(含或不含指示抗体)培养过夜的GFP标记B16细胞的Biotek H1M荧光读数;所述图表显示了3个实验的结果;图4C显示了感染抗肿瘤TCR、FcγRI和FcRγ的脾脏CD4+T细胞的代表性荧光显微镜图像,并与GFP标记B16细胞在有或无指示抗体的情况下培养过夜(放大倍数=x400、n=2);图4D显示了在过继转移模型中,感染抗肿瘤TCR、FcγRI和FcRγ的脾CD4+T细胞的体内抗肿瘤作用,其中具有或不具有抗TRP1抗体;
图5A至图5C证明FcγRI及其信号传导链在空白C57BL WT CD4+或CD8+T细胞中的表达诱导涂有抗体的肿瘤细胞的有效溶解;图5A显示了所使用的构建体的示意图:编码FcγRI T2A FcRγ的一构建体(SEQ ID NO:21、SEQ ID NO:22);编码FcγRI T2A Fcγ-CD3ζ的一构建体(SEQ ID NO:23、SEQ ID NO:24);编码FcγRI-CD3ζT2A FcRγ的一构建体(SEQ IDNO:27、SEQ ID NO:28,见图6A);编码FcγRI-CD3ζ的一构建体(SEQ ID NO:25、SEQ ID NO:26);以及编码FcγRIα胞外域TCRβ恒定区的一构建体(SEQ ID NO:41、SEQ ID NO:42);图5B显示了与感染图5A所示的构建体的CD4+和CD8+T细胞共培养的B16靶细胞的图像;在96孔盘中共培养的细胞,具有或不具有抗TRP1抗体48小时;以及在倒置光学显微镜下在X100放大倍数下拍摄的图像;图5C为图表,显示了与抗TRP1抗体以及使用上述不同构建体转导的CD8+T细胞共同培养的凋亡的B16细胞的annexin-V/PI染色的流式细胞术分析;
图6A至图6C是所设计构建体和所表达的结果受体的示意图;图6A显示了两种可选构建体的方案:在第一个(左图)中,CD3ζ链连接到FcγRIα链,Fc受体γ链(FcRγ)由T2A分离;在第二个(右图)中,CD3ζ链连接到FcRγ信号传导链,并且两者均通过T2A从FcγRIα链分离;图6B显示了表达的转导细胞和受体的图示:在左图中,CD3ζ链与FcγRIα融合;在右图中,FcγRIα与FcRγ-CD3ζ融合蛋白平行表示;图6C显示了治疗程序的方案;即,从荷瘤患者的外周血中分离T细胞,并用图6A、图6B所示的构建体之一进行感染;随后,数百万个转导的T细胞与临床批准的肿瘤结合抗体一起注回患者体内;
图7示出了编码FcγRIa及FcRγ作为单个肽的一构建体(SEQ ID NO:29、SEQ IDNO:30);以及编码FcγRIa、FcRγ及CD3ζ作为单一多肽的一构建体(SEQ ID No:31、SEQ IDNO:32);
图8显示了表达FcγRIα-2A-FcRγ构建体的细胞以及TCRβ、FcγRI和GFP染色的细胞的X200放大倍率的共聚焦显微镜图像;
图9是图表,说明了incuCyte成像仪在场中计数的细胞数与在96孔盘的孔中培养的B16-H2B-tdTomato细胞数之间的相关性;
图10A及图10B证明了不同比例的FcγRIα-2A-FcRγ感染细胞对B16靶细胞的杀伤;图10A显示了incuCyte成像仪在不同效应物(effector)共培养感染了FcγRIα-2A-FcRγ的CD8+T细胞与B16-H2B-tdTomato 2天后拍摄的代表性图像:目标比率范围从0.5:1到16:1,具有抗TRP-1抗体,x100放大倍率;图10B是图表,显示在不同效应物(effector)中,使用FcγRIα-2A-FcRγ感染的CD4+或CD8+T细胞与B16-H2B-tdTomato共培养2天后,incuCyte成像仪计数的靶细胞的数量:使用或不使用抗TRP-1抗体的目标比率;以及
图11A至图11C证明了与表达两个的单一多肽相比,表达两种不同多肽的优势,其中一种包含FcγRIα的配体结合域,而另一种包含FcRγ;图11A示出编码单一多肽的一构建体,包含FcγRIα胞外域-CD8a铰链以及跨膜结构域-FcRγ胞内域(SEQ ID NO:NO 43、SEQID NO:44);图11B显示了B16-H2B-tdTomato靶细胞的代表性图像,分别使用抗TRP-1抗体处理,或是使用结合共培养未感染的CD8+T细胞(假)或是使用FcγRIα胞外域-CD8a铰链以及跨膜结构域FcRγ胞内结构域构建体感染的CD8+T细胞的抗TRP-1抗体处理;在共培养48小时后,使用强光、红色及绿色滤光片,以x100放大倍率拍摄图像;图17C是图表,显示在如上文图11B中所述的共培养48小时后,由incuCyte成像仪计数的靶细胞的数量。
具体实施方式
本发明在其一些实施方式中涉及一种表达Fcγ受体的T细胞及其使用方法。
在详细解释本发明的至少一个实施方式之前,应当理解,本发明的应用不一定限于以下描述中阐述的或由实施例举例说明的细节。本发明能够有其他实施例或能够以各种方式实践或实施。
相对于非癌细胞及/或免疫检查点阻断,基于抗体(antibody,Ab)的癌症免疫疗法依赖于识别癌细胞上差异表达的细胞表面分子。基于抗体的免疫疗法与癌细胞的结合可通过多种机制导致癌细胞死亡,其中许多机制是通过细胞结合抗体的Fc结构域与造血细胞上的特化细胞表面受体(Fc受体)的结合而启动的。
另一方面,使用例如具有相对于非癌细胞,特异于与癌细胞上MHC I类分子相关的差异表达的抗原的T细胞受体(T cell receptor,TCR)的T细胞的细胞疗法,显示在几种类型的癌症中发挥抗肿瘤作用,例如血液系统恶性肿瘤。
在将本发明付诸实践的同时,本发明人现已发现表达高亲和力Fcγ受体FcγRI(CD64)的CD4+T的新型子集。这种肿瘤特异性FcγRI+CD4+T细胞能够结合涂有抗肿瘤抗体的肿瘤细胞,并且分泌裂解颗粒,导致显着的肿瘤裂解(示例1,图1A至图4B)。接下来,本发明人能够通过外源性表达FcγRI多肽以及Fcγ链多肽(示例2至3,图4C至图11C)来概括这种独特的CD4+T细胞群在常规CD4+以及CD8+T细胞中的细胞毒性能力。事实上,这些被基因工程改造的T细胞与抗肿瘤抗体结合发挥了显着的肿瘤杀伤能力。
因此,本教示的具体实施方式建议T细胞被基因工程改造以表达两种不同的多肽,一种包括Fcγ受体的配体结合域,而另一种包括Fc受体共同γ链;以及使用这些T细胞治疗与病理细胞相关的疾病(例如:癌症)的方法。
因此,根据本发明的一第一方面,提供了一种T细胞,所述T细胞被基因工程改造以表达一第一多肽,包括一Fc受体共同γ链(Fc receptor commonγchain,FcRγ)的一氨基酸序列,所述氨基酸序列能够传递一激活信号;以及表达一第二多肽,包括能够结合一Fc配体的一Fcγ受体的一胞外配体结合域以及能够募集所述第一多肽的一氨基酸序列,使得在所述Fc配体与所述Fcγ受体的所述胞外配体结合域结合时,所述激活信号被传递。
如本文所用,术语“T细胞”是指具有CD3+、具有CD4+或CD8+表型的T细胞受体(Tcell receptor,TCR)+的分化淋巴细胞。
根据具体实施方式,T细胞是效应细胞。
如本文所用,术语“效应T细胞”是指例如通过产生细胞因子或具有细胞毒活性来激活或指导其他免疫细胞的T细胞,例如CD4+、Th1/Th2、CD8+细胞毒性T淋巴细胞。
根据具体实施方式,T细胞是CD4+T细胞。
根据其他具体实施方式,T细胞是CD8+T细胞。
根据具体实施方式,T细胞是初始T细胞(naive T cell)。
根据具体实施方式,T细胞是记忆T细胞。记忆T细胞的非限制性示例包括具有CD3+/CD4+/CD45RA-/CCR7-表型的效应记忆CD4+T细胞、具有CD3+/CD4+/CD45RA-/CCR7+表型的中枢记忆CD4+T细胞、具有CD3+/CD8+CD45RA-/CCR7-表型的效应记忆CD8+T细胞;以及具有CD3+/CD8+CD45RA-/CCR7+表型的中枢记忆CD8+T细胞。
根据具体实施方式,T细胞是增殖细胞。
如本文所用,短语“增殖细胞”是指在刺激后增殖的T细胞,如细胞增殖试验所定义,例如但不限于CFSE染色、MTS、Alamar blue、BRDU、胸苷插入(thymidineincorporation)等试验。
根据具体实施方式,T细胞是增殖的CD4+T细胞。
根据具体实施方式,T细胞是增殖的CD8+T细胞。
根据具体实施方式,T细胞是人类T细胞。
从受试者获得T细胞的方法是本领域众所周知的,例如从受试者抽取全血并且收集在含有抗凝剂(例如,肝素或柠檬酸盐)的容器中;以及血液分离(apheresis),然后进行纯化。本领域技术人员已知多种从全血纯化T细胞的方法及试剂,例如,白细胞分离术(leukapheresis)、沉降(sedimentation,)、密度梯度离心(density gradientcentrifugation)(例如:ficoll)、离心淘析(centrifugal elutriation)、分提(fractionation)、化学裂解,例如红细胞(例如,通过ACK)、使用细胞表面标记物的选择(使用例如FACS分选器或磁性细胞分离技术,例如可从Invitrogen、Stemcell Technologies、Cellpro、Advanced Magnetics或是Miltenyi Biotec.商购获得),以及通过例如使用特异性抗体根除(eradication)(例如:杀死)或是通过基于阴性选择的基于亲和性的纯化(使用例如磁性细胞分离技术、FACS分选器及/或捕获ELISA标记)等方法去除特定的非T细胞类型。此类方法在例如实验免疫学手册(THE HANDBOOK OF EXPERIMENTAL IMMUNOLOGY),第1至第4卷(D.N.Weir,编辑)及FLOW CYTOMETRY AND CELL Sorting(A.Radbruch,编辑,Springer Verlag,2000)中有所描述。
根据具体实施方式,T细胞获自健康受试者。
根据具体实施方式,T细胞获自患有病理(例如:癌症)的受试者。
根据具体实施方式,T细胞表达对一病理(患病,例如:癌)细胞特异的一T细胞受体,即识别在主要组织相容性复合物(major histocompatibility complex,MHC)下呈现的一抗原,与非病理细胞相比,所述抗原由一病理细胞过度表达或单独表达。
根据具体实施方式,抗原是癌抗原,即与非癌细胞相比,癌细胞过度表达或单独表达的抗原。癌抗原可以是已知的癌抗原或在癌细胞中产生的新的特异性抗原(即:新抗原)。
已知癌症抗原的非限制性示例包括MAGE-AI、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-AS、MAGE-A6、MAGE-A7、MAGE-AS、MAGE-A9、MAGE-A10、MAGE-11、MAGE-A12、GAGE-I、GAGE-2、GAGE-3、GAGE-4、GAGE-5、GAGE-6、GAGE-7、GAGE-8、BAGE-1、RAGE-1、LB33/MUM-1、PRAME、NAG、MAGE-Xp2(MAGE-B2)、MAGE-Xp3(MAGE-B3)、MAGE-Xp4(MAGE-B4)、MAGE-Cl/CT7、MAGE-C2、NY-ES0-1、LAGE-1、SSX-1、SSX-2(HOM-MEL-40)、SSX-3、SSX-4、SSX-5、SCP-1及XAGE、黑素细胞分化抗原、p53、ras、CEA、MUCI、PMSA、PSA、酪氨酸酶、Melan-A、MART-I、gpl00、gp75、alphaactinin-4、BCR/ABL融合蛋白、Casp-8、Beta-catenin、cdc27、cdk4、cdkn2a、coa-1、dek-can融合蛋白、EF2、ETV6-AML1融合蛋白、LDLR-岩藻糖基转移酶AS融合蛋白(LDLR-fucosyltransferaseAS fusion protein)、HLA-A2、HLA-All、hsp70-2、KIAA0205、Mart2、Mum-2及3、neo-PAP、肌凝蛋白第I类、OS-9、pml-RARα融合蛋白、PTPRK、K-ras、N-ras、磷酸丙糖异构酶(Triosephosphate isomerase)、GnTV、Herv-K-mel、NA-88、SP17及TRP2-Int2、(MART-I)、E2A-PRL、H4-RET、IGH-IGK、MYL-RAR、Epstein Barr病毒抗原、EBNA、人类乳头瘤病毒(human papillomavirus,HPV)抗原E6及E7、TSP-180、MAGE-4、MAGE-5、MAGE-6、p185erbB2、plSOerbB-3、c-met、nm-23H1、PSA、TAG-72-4、CA 19-9、CA 72-4、CAM 17.1、NuMa、K-ras、α-胎儿蛋白(α-Fetoprotein)、13HCG、BCA225、BTAA、CA 125,CA 15-3(CA27.29\BCAA)、CA 195、CA 242、CA-50、CAM43、CD68\KP1、C0-029、FGF-5、0250、Ga733(EpCAM)、HTgp-175、M344、MA-50、MG7-Ag、MOV18、NB\170K、NYCO-I、RCASI、SDCCAG16、TA-90(Mac-2结合蛋白/亲环蛋白C相关蛋白(cyclophilin C-associated protein))、TAAL6、TAG72、TLP、TPS、酪氨酸酶相关蛋白、TRP-1或TRP-2。
根据具体实施方式,T细胞内源性表达对病理细胞(例如:癌细胞)特异的T细胞受体。
根据具体实施方式,T细胞是使用T细胞受体(TCR)转导的被工程化T细胞。
如本文所用,短语“使用TCR转导”或是“被基因工程改造以表达TCR”是指从T细胞克隆可变的α-及β-链,对MHC中呈现的所需抗原具有特异性。使用TCR进行转导的方法是本领域已知的,并且已公开,例如Nicholson等人,Adv Hematol,2012年,2012:404081;Wang及Rivière,癌症基因疗法(Cancer Gene Ther.);2015年3月;22(2):85-94);以及Lamers等人,癌症基因疗法(Cancer Gene Therapy),2002年,9,613-623。根据具体实施方式,TCR对病理细胞具有特异性。
根据具体实施方式,T细胞是使用嵌合抗原受体(chimeric antigen receptor,CAR)转导的被工程化的T细胞。
如本文所用,短语“使用CAR转导”或是“被基因工程改造以表达CAR”是指克隆编码嵌合抗原受体的核酸序列,其中CAR包括抗原识别部位及T细胞激活部位。嵌合抗原受体是一种人工构建的杂合蛋白或多肽,包括与T细胞信号或是T细胞激活域连接的抗体的抗原结合域(例如,单链可变片段(single chain variable fragment,scFv))。使用CAR转导的方法是本领域已知的,并且公开,例如Davila等人,肿瘤免疫学(Oncoimmunology),2012年12月1日;1(9):1577-1583;Wang及Rivière,癌症基因疗法(Cancer Gene Ther.),2015年3月;22(2):85-94);Maus等人,血液(Blood),2014年4月24日,123(17):2625-35;Porter DL,新英格兰医学杂志(The New England journal of medicine),2011年,365(8):725-733;Jackson HJ,自然综述:临床肿瘤学(Nat Rev Clin Oncol),2016年,13(6):370-383;以及Globerson-Levin等人,分子治疗(Mol Ther.),2014年,22(5):1029-1038。根据具体实施方式,抗原识别部位对病理细胞具有特异性。
根据其他具体实施方式,T细胞未转导(即:不表达)CAR。
本发明的一些实施方式的T细胞被基因工程改造以表达包括能够传递一激活信号的Fc受体共同γ链(FcRγ)的氨基酸序列的一第一多肽。
如本文所用,缩写为“FcRγ”的短语“Fc受体共同γ链”是指FCER1G基因(基因ID2207)的多肽表达产物。根据具体实施方式,FcRγ是人FcRγ。根据一具体的实施方式,FcRγ蛋白是指人蛋白,例如在以下GenBank Number NP_004097中提供的。
根据具体实施方式,本发明的一些实施方式的多肽包括全长FcRγ多肽。
根据具体实施方式,本发明的一些实施方式的多肽包括FcRγ多肽的功能片段。
如本文所用,短语“FcRγ多肽的功能片段”是指包括跨膜结构域及胞内结构域,并且在Fcγ受体与Fc配体结合后,至少保持在表达Fcγ受体的一细胞中传递一激活信号的能力的多肽部分。
根据具体实施方式,FcRγ多肽的功能片段能够形成同源二聚体。
根据具体实施方式,FcRγ多肽的功能片段包括ITAM基序。
如本文所用,术语“激活(activating)”或“激活(activation)”是指刺激T细胞的过程,其导致细胞增殖、成熟、细胞因子产生及/或效应功能(effector function)的诱导。
确定激活信号的信号传导的方法是本领域公知的,并且包括但不限于酶活性测定,例如激酶活性测定,以及使用例如聚合酶连锁反应(PCR)、Western印迹法(Westernblot)、免疫沉淀(immunoprecipitation)及免疫组织化学(immunohistochemistry)表达参与信号级联的分子。附加地或替代地,可以通过评估T细胞激活或功能来确定激活信号的传输。评估T细胞激活或功能的方法是本领域众所周知的,包括但不限于增殖试验,例如,CFSE染色、MTT、Alamar blue、BRDU及胸苷插入(thymidine incorporation);细胞毒性试验,例如,CFSE染色、铬释放、Calcin AM;细胞因子分泌试验,例如,细胞内细胞因子染色、ELISPOT及ELISA;使用流式细胞术来表达活化标记物,例如:CD25、CD69、CD137、CD107a、PD1及CD62L。
根据具体实施方式,本发明的一些实施方式的多肽包含包括SEQ ID NO:13的FcRγ多肽氨基酸序列。
根据具体实施方式,本发明的一些实施方式的多肽包含由SEQ ID NO:13组成的FcRγ多肽氨基酸序列。
根据具体实施方式,本发明的一些实施方式的多肽包含如SEQ ID NO:15中所示的氨基酸序列。
根据具体实施方式,本发明的一些实施方式的多肽包含由SEQ ID NO:15组成的FcRγ多肽氨基酸序列。
术语“FcRγ”还包括功能同源物(homologues)(天然存在的或合成/重组产生的),其表现出如上文所定义的所需活性(即,传递激活信号的能力,形成同源二聚体)。此类同源物可以与SEQ ID No:13或SEQ ID No:15的多肽例如至少70%、至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或是100%相同或同源;或是与编码相同的多核苷酸序列(例如:SEQ ID No:14或SEQ ID No:16)例如至少70%、至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或是100%相同。
可以使用任何蛋白质或是核酸序列比对算法(例如:Blast、ClustalW及MUSCLE)来确定序列同一性(identity)或是同源性(homology)。
同源物还可以指直系同源物(ortholog)、缺失、插入或置换变体,包括氨基酸置换,如下文进一步描述。
根据具体实施方式,FcRγ多肽可包括保守及非保守氨基酸取代。
根据具体实施方式,包括FcRγ的氨基酸序列的多肽的分子量小于100千道尔顿(kDa)、小于50kDa、小于25kDa或是小于20kDa,每种可能性代表本发明的单独的实施方式.
根据具体实施方式,包括FcRγ的氨基酸序列的多肽的分子量小于25kDa。
根据具体实施方式,包括FcRγ的氨基酸序列的多肽不包括靶点结合部位(target-binding moiety)。
如本文所用,“靶点结合部位”是抗原结合部位,例如抗体,例如单链抗体(例如,scFv)。
因此,根据具体实施方式,包括FcRγ的氨基酸序列的多肽不包括scFv。
本发明的一些实施方式的T细胞被基因工程改造以表达一第二多肽,所述第二多肽包含能够结合一Fc配体的一Fcγ受体的一胞外配体结合域,以及能够募集所述第一多肽的一氨基酸序列(其包含一FcRγ的一氨基酸序列)。
如本文所用,短语“Fcγ受体的胞外配体结合域”是指包含能够结合一Fc配体的一胞外域的至少一Fcγ受体的一片段。
如本文所用,术语“Fc配体”是指例如一抗体的一Fc结构域。根据具体实施方式,Fc配体是IgG Fc结构域。
用于测试结合的测定是本领域众所周知的,包括但不限于流式细胞术、BiaCore、生物膜干涉技术测定、高效液相色谱法(high performance liquidchromatography,HPLC)、表面等离子体共振。
根据具体实施方式,Fcγ受体的胞外配体结合域以>10-6M、>10-7M、>10-8M或>10-9M的一Kd来结合Fc配体,每种可能性代表本发明的单独的实施方式。
根据具体实施方式,Fcγ受体的胞外配体结合域以>10-9M的一Kd来结合Fc配体。
如本文所用,术语“Fcγ受体”是指对IgG抗体的Fc结构域表现出结合特异性的一细胞表面受体。Fcγ受体的示例包括但不限于CD64A、CD64B、CD64C、CD32A、CD32B、CD16A及CD16B。术语“Fcγ受体”还包括功能同源物(天然存在的或合成/重组产生的)及/或包含保守及非保守氨基酸取代的Fc受体,其表现出所需活性(即,结合IgG Fc结合域的能力)。
根据具体实施方式,Fcγ受体是CD64。
如本文所用,术语“CD64”,也称为FcγRI,是指FCGR1A、FCGR1B或FCGR1C基因(基因ID分别为2209、2210、2211)的多肽表达产物,并且包括CD64A、CD64B及CD64C。全长CD64包含胞外、跨膜及胞内结构域,并且能够至少结合IgG(IgG1及IgG3)Fc结构域并募集FcRγ。确定FcRγ的结合及募集的方法是本领域众所周知的,并且也在上文及下文中进行描述。
根据具体实施方式,CD64是人CD64。根据一具体实施方式,CD64蛋白是指人CD64A蛋白,例如在以下UniProt编号P12314中所提供的。
根据一具体实施方式,CD64蛋白是指人CD64B蛋白,例如在以下UniProt编号Q92637中所提供的。
根据一具体实施方式,CD64蛋白是指人CD64C蛋白,例如在以下GenBank编号XM_001133198中所提供的。
根据具体实施方式,CD64氨基酸序列包含SEQ ID NO:5。
根据具体实施方式,CD64包含CD64多肽的功能片段。
如本文所用,短语“CD64多肽的功能片段”是指至少保持能够结合IgG(IgG1及IgG3)Fc结构域及/或募集FcRγ的多肽部分,如下文进一步描述。
术语“CD64”还包括功能同源物(天然存在的或合成/重组产生的),其表现出所需活性(即,结合IgG(IgG1及IgG3)Fc结构域及/或募集FcRγ)。此类同源物可以与多肽SEQ IDNo:5例如至少70%、至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%相同或同源;或与编码相同的多核苷酸序列例如SEQ ID No:6至少70%、至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%相同。
根据具体实施方式,CD64多肽可包含保守及非保守氨基酸取代。
因此,本发明的一些实施方式的多肽包含CD64的胞外配体结合域。
根据具体实施方式,多肽包含包括SEQ ID NO:7的CD64的胞外配体结合域。
根据具体实施方式,多肽包含由SEQ ID NO:7组成的CD64的胞外配体结合域。
本发明的一些实施方式的第二多肽包含能够募集第一多肽的一氨基酸序列(即,其包含FcRγ的一氨基酸序列),使得当Fc配体结合到Fcγ受体的细胞外配体结合域时,第一多肽传递激活信号。
根据具体实施方式,能够募集第一多肽的氨基酸序列直接募集第一多肽(即,没有中间多肽)。
此类氨基酸序列是本领域技术人员熟知的,并且包括例如几种Fc受体的跨膜及/或细胞质域,例如但不限于CD64、CD16A、CD16B、FcεRIβ、FcαRI(CD89)。
根据具体实施方式,能够募集第一多肽的氨基酸序列不属于Fcε受体(FcεR)。
确定第一多肽募集的方法是本领域众所周知的,并且包括但不限于酶活性测定,例如激酶活性测定,以及使用聚合酶连锁反应(PCR)、Western blot、免疫沉淀及免疫组织化学等方法表达参与信号级联的分子。另外或可选地,可以通过本领域众所周知的方法评估细胞活化或功能来实现确定第一多肽的募集,所述方法例如但不限于增殖测定,例如CFSE染色、MTT、Alamar blue、BRDU及胸苷插入、细胞毒性试验,例如CFSE染色、铬释放、Calcin AM等。用于确定FcRγ募集的示例性方法公开于例如在Kim,M.K.等人,2003年,血液(Blood)101(11):4479-4484;以及Harrison,P.T.等人,1995年,分子膜生物学(Mol MembrBiol)12(4):309-312,其内容通过引用完全并入本文。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含Fc受体的跨膜结构域。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含Fc受体的细胞质域。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含Fcγ受体的跨膜结构域。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含Fcγ受体的细胞质域。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含能够募集所述第一多肽的CD64氨基酸序列。
因此,根据具体实施方式,能够募集第一多肽的氨基酸序列包含CD64的跨膜结构域。
根据具体实施方式,能够募集第一多肽的氨基酸序列由CD64的跨膜结构域组成。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含SEQ ID NO:9。
根据具体实施方式,能够募集第一多肽的氨基酸序列由SEQ ID NO:9组成。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含CD64的胞内结构域。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含SEQ ID NO:11。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含CD64的跨膜结构域及胞内结构域。
根据具体实施方式,能够募集第一多肽的氨基酸序列包含SEQ ID NO:33。
根据具体实施方式,能够募集第一多肽的氨基酸序列由SEQ ID NO:33组成。
根据具体实施方式,第二多肽中的胞外配体结合域以及能够募集第一多肽的氨基酸序列均为CD64。
因此,根据具体实施方式,第二多肽包含CD64的胞外域及跨膜结构域。
根据具体实施方式,第二多肽包含SEQ ID NO:34。
根据具体实施方式,第二多肽包含CD64的胞外域、跨膜结构域及细胞质域。
根据具体实施方式,第二多肽包含SEQ ID NO:5。
根据具体实施方式,第二多肽包含CD64的细胞外配体结合域的氨基酸序列以及能够募集由SEQ ID NO:5组成的第一多肽的一氨基酸序列。
根据具体实施方式,第二多肽由SEQ ID NO:5组成。
根据具体实施方式,第二多肽不包含抗体。
根据一具体实施方式,第二多肽不包含scFv。
根据具体实施方式,第一以及第二多肽中的任一个包含能够传递一激活信号的CD3ζ链的一氨基酸序列。
根据具体实施方式,第一多肽包含CD3ζ链的一氨基酸序列。
根据具体实施方式,FcRγ位于CD3ζ链的N端。
根据具体实施方式,第二多肽包含CD3ζ链的一氨基酸序列。
根据具体实施方式,CD3ζ链位于能够募集第一多肽的氨基酸序列的C端。
如本文所用,术语“CD3ζ链”也称为TCRζ或是CD247是指CD247基因(基因ID 919)的多肽表达产物。根据具体实施方式,CD3ζ链是人CD3ζ链。根据一具体实施方式,CD3ζ链蛋白是指人蛋白,例如在以下GenBank编号NP_000725及/或NP_932170中提供的。
根据具体实施方式,本发明的一些实施方式的多肽包含全长CD3ζ链多肽。
根据具体实施方式,本发明的一些实施方式的多肽包含CD3ζ链多肽的功能片段。
如本文所用,短语“CD3z的功能片段”是指多肽的一部分,其包含至少一胞内结构域并且至少保持在T细胞中传递一激活信号的能力。通常,这样的氨基酸序列包含ITAM基序。
根据具体实施方式,CD3ζ链的氨基酸序列包含SEQ ID NO:17。
根据具体实施方式,CD3ζ链的氨基酸序列由SEQ ID NO:17组成。
根据具体实施方式,CD3ζ链的氨基酸序列包含SEQ ID NO:19。
根据具体实施方式,CD3ζ链的氨基酸序列由SEQ ID NO:19组成。
术语“CD3ζ链”还包括功能同源物(天然存在的或合成/重组产生的),其表现出所需的活性(即,传递激活信号的能力)。此类同源物可以与SEQ ID No:17或SEQ ID No:19的多肽例如至少70%、至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%相同或同源;或与编码相同的多核苷酸序列至少70%、至少75%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%或100%相同。
根据具体实施方式,CD3ζ链多肽可包含保守及非保守氨基酸取代。
根据具体实施方式,本文公开的任何多肽可包含共刺激信号传导域(co-stimulatory signaling domain)。
根据其他具体实施方式,本文公开的多肽不包含共刺激信号传导域。
根据具体实施方式,第一及第二多肽中的任一个包含共刺激信号传导域。
根据具体实施方式,第一多肽不包含共刺激信号传导域。
根据具体实施方式,第二多肽不包含共刺激信号传导域。
如本文所用,短语“共刺激信号传导域”是指共刺激分子的氨基酸序列,其能够传递导致T细胞活化的次级刺激信号。通常,共刺激信号传导域不包括ITAM结构域。
任何已知的共刺激信号传导域都可以与本发明的特定实施方式一起使用。共刺激信号传导域的非限制性示例包括4-1BB、CD28、OX40、ICOS、CD27、GITR、HVEM、TIM1、LFA1(CD11a)、CD2。
根据具体实施方式,共刺激信号传导域是4-1BB及/或OX40。
共刺激信号传导域的特定序列的非限制性示例在SEQ ID NO:45、SEQ ID NO:46(OX40)、SEQ ID NO:47、SEQ ID NO:48(4-1BB)中提供。
根据具体实施方式,本文公开的任何多肽可包含细胞因子受体信号传导域(cytokine receptor signaling domain)。
根据其他具体实施方式,本文公开的多肽不包含细胞因子受体信号传导域。
根据具体实施方式,第一及第二多肽中的任一个包含细胞因子受体信号传导域。
根据具体实施方式,第一多肽不包含细胞因子受体信号传导域。
根据具体实施方式,第二多肽不包含细胞因子受体信号传导域。
如本文所用,短语“细胞因子受体信号传导域”是指能够传递导致T细胞活化的刺激信号的细胞因子受体的氨基酸序列。
任何已知的细胞因子受体信号传导域均可用于本发明的特定的实施方式。细胞因子受体信号传导域的非限制性示例包括IL2rg,其是IL2受体共同γ链(例如,如在SEQ IDNO:63及SEQ ID NO:64中提供的)、Toll/IL1受体同源域(TIR),其是myd88受体的信号传导域、TNF受体胞内结构域(例如,如在SEQ ID NO:49及SEQ ID NO:50中提供的)、IL12-Rb1胞内结构域(例如,如在SEQ ID NO:51及SEQ ID NO:52中提供的)、IL12-Rb1胞内结构域(例如,如在SEQ ID NO:53及SEQ ID NO:54中提供的)、IL23受体胞内域(例如,如在SEQ ID NO:55及SEQ ID NO:56中提供的)、IFNγ受体1胞内域(例如,如在SEQ ID NO:57及SEQ ID NO:58中提供的)、IFNγ受体2胞内结构域(例如,如在SEQ ID NO:59及SEQ ID NO:60中提供的)、IL2Rb胞内结构域(例如,如在SEQ ID NO:61及SEQ ID NO:62中提供的)、IL1受体胞内结构域(例如,如在SEQ ID NO:65及SEQ ID NO:66中提供的)、IL1AcP受体胞内结构域(例如,如在SEQ ID NO:67及SEQ ID NO:68中提供的)。
包含在如本文所述的单个多肽中的任何组分可以直接或经由连接子彼此连接,每种可能性代表本发明的单独的实施方式。
根据具体实施方式,第二多肽不包含Fc受体的胞外配体结合结构域与能够募集第一多肽的氨基酸序列之间的连接子。
根据具体实施方式,第二多肽包含Fc受体的胞外配体结合结构域与能够募集第一多肽的氨基酸序列之间的连接子。
本领域已知的任何连接子均可用于本发明的特定实施方式。
根据具体实施方式,连接子可以是源自天然存在的多域蛋白质,或是经验连接子(empirical linker),例如如在Chichili等人,2013年,蛋白质科学(Protein Sci.),22(2):153-167;以及Chen等人,2013年,先进药物输送评论(Adv Drug Deliv Rev.)65(10):1357-1369中所述,其全部内容通过引用并入本文。在一些实施方式中,可以使用连接子设计数据库以及计算机程序设计连接子,例如如在Chen等人,2013年,先进药物输送评论(AdvDrug Deliv Rev.)65(10):1357-1369;以及Crasto等人,2000年,蛋白质工程(ProteinEng.),13(5):309-312中所述,其全部内容通过引用并入本文。
根据具体实施方式,连接子是合成的连接子。
根据具体实施方式,连接子是多肽。
本发明人发现表达具有肿瘤细胞根除功能的CD64的CD4+T细胞的新亚群(以下示例部分的示例1),本发明的具体实施方式考虑了表达CD64的T细胞以及获得及使用这类细胞的方法。
因此,根据本发明的一方面,提供了包含至少80%表达内源CD64的T细胞的分离的T细胞群,所述CD64包含胞外域、跨膜结构域以及细胞质域。
根据具体实施方式,分离的T细胞群包含至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%的表达内源性CD64的T细胞。
根据本发明的附加或替代方面,提供了一种分离T细胞的方法,所述方法包括使用结合CD64多肽或是编码CD64多肽的多核苷酸的试剂,来从受试者的生物样品中分离CD64+T细胞。
CD64+T细胞可以从任何生物样品中获得,例如外周血、骨髓(Bone marrow,BM)、组织例如脾脏、淋巴结、胸腺或肿瘤组织。生物样品的选择对于本领域技术人员来说是显而易见的。
根据具体实施方式,生物样品是外周血样品。
本领域技术人员已知多种从生物样品中纯化T细胞的方法及试剂。此类方法在例如实验免疫学手册(THE HANDBOOK OF EXPERIMENTAL IMMUNOLOGY),第1至第4卷(D.N.Weir,编辑)以及流式细胞术和细胞分选(FLOW CYTOMETRY AND CELL Sorting)(A.Radbruch,编辑,Springer Verlag,2000)中有所描述,并在上文中进一步描述。
为了分离CD64+T细胞,将生物样品与结合CD64多肽(例如,抗体)或编码所述CD64多肽的多核苷酸(例如,寡核苷酸探针或引物)的试剂接触,并使用例如FACS分选(FACSsorter)或磁性细胞分离技术来进一步选择细胞。
根据具体实施方式,试剂是抗CD64抗体。
根据具体实施方式,在分离CD64+T细胞后,细胞被培养、克隆、活化及/或基因工程改造。
根据具体实施方式,在分离CD64+T细胞后,将多个细胞施用于有需要的受试者。
因此,根据本发明的一方面,提供了表达CD64的T细胞克隆,所述CD64包含胞外域、跨膜结构域及细胞质域。
根据本发明的另一方面,提供了被基因工程改造以表达CD64的T细胞,所述CD64包含胞外域、跨膜结构域及细胞质域。
根据具体实施方式,T细胞被基因工程改造以表达全长CD64。
根据其他具体实施方式,T细胞被基因工程改造以表达CD64的功能片段。
根据其他具体实施方式,T细胞被基因工程改造以表达CD64的功能同源物。
根据具体实施方式,内源性或外源性表达CD64的T细胞可以被基因工程改造,以表达感兴趣的多肽。
根据具体实施方式,表达CD64的T细胞被基因工程改造,以表达包含能够传递一激活信号的FcRγ的一氨基酸序列的多肽。
根据具体实施方式,包含FcRγ氨基酸序列的多肽还包含能够传递一激活信号的CD3ζ链的一氨基酸序列。
为了在T细胞中表达任何公开的外源多肽,优选将编码所述多肽的一多核苷酸序列连接到适合T细胞表达的一核酸构建体(construct)中。这样的核酸构建体包括用于以组成型(constitutive)或诱导型方式指导细胞中多核苷酸序列转录的启动子序列。
本发明的一些实施方式的核酸构建体(在本文中也称为“表达载体”)包括使此载体适合复制及整合的附加序列(例如,穿梭载体(shuttle vectors))。此外,典型的克隆载体还可能包含转录以及转译起始序列、转录及转译终止子以及聚腺苷酸化信号。举例来说,此类构建体通常包括5'LTR、tRNA结合位点、包装信号、第二链DNA合成的起点及3'LTR或其一部分。
本发明的一些实施方式的核酸构建体通常包括或编码用于将多肽靶向细胞表面的一信号序列。根据一具体的实施方式,用于此目的的信号序列是一哺乳动物信号序列或是本发明的一些实施方式的多肽变体的信号序列。
真核启动子通常包含两种类型的识别序列,TATA盒(TATA box)及上游启动子元件。TATA盒,位于转录起始位点上游25至30个碱基对处,被认为参与指导RNA聚合酶开始RNA合成。其他上游启动子元件决定了转录启动的速率。
优选地,本发明的一些实施方式的核酸构建体所使用的启动子在转化的特定细胞群,即T细胞中具有活性。T细胞特异性启动子的示例包括淋巴特异性启动子(Calame等人,1988年,免疫学进展(Adv.Immunol.),43:235-275);特别是T细胞受体的启动子(Winoto等人,1989年,欧洲分子生物学学会会刊(EMBO J.)8:729-733)。
增强子元件可以从连接的同源或异源启动子刺激高达1,000倍的转录。当位于转录起始位点的下游或上游时,增强子是有活性的。许多源自病毒的增强子元件具有广泛的宿主范围,并且在多种组织中具有活性。例如,SV40早期基因增强子适用于多种细胞类型。适用于本发明的一些实施方式的其他增强子/启动子组合包括源自多瘤病毒、人或鼠巨细胞病毒(CMV)的那些,来自各种逆转录病毒,例如鼠白血病病毒、鼠或劳氏肉瘤病毒(Roussarcoma virus)及人类免疫缺陷病毒(human immunodeficiency virus,HIV)的长期重复。参见,增强子和真核表达(Enhancers and Eukaryotic Expression),冷泉港实验室出版社(Cold Spring Harbor Press),纽约州冷泉港(Cold Spring Harbor,N.Y.)1983年,在此引入作为参考。
在表达载体的构建中,启动子优选地位于距异源转录起始位点的距离与其距其自然环境中的转录起始位点的距离大致相同的位置。然而,如本领域中已知的,可以在不损失启动子功能的情况下调节此距离的一些变化。
也可以将多聚腺苷酸化序列添加到表达载体中,以提高mRNA转译的效率。准确有效的聚腺苷酸化需要两个不同的序列元件:位于聚腺苷酸化位点下游的富含GU或U的序列,以及位于11至30个核苷酸上游的高度保守的6个核苷酸序列AAUAAA。适用于本发明的一些实施方式的终止及聚腺苷酸化信号包括源自SV40的那些信号。
除了已经描述的元件之外,本发明的一些实施方式的表达载体通常可以包含旨在增加克隆核酸的表达水平或是促进携带重组DNA的细胞的鉴定的其他特定元件。例如,许多动物病毒含有促进病毒基因组在许可细胞类型中的染色体外复制的DNA序列。只要质粒上携带的基因或宿主细胞的基因组的基因提供适当的因子,带有这些病毒复制子的质粒就会被游离(episomally)复制。
载体可以包括或不包括真核复制子。如果存在真核复制子,则可以使用适当的选择标记在真核细胞中扩增载体。如果载体不包含真核复制子,则游离型扩增(episomalamplification)是不可能的。相反,重组DNA整合到被工程改造的细胞的基因组中,其中启动子指导所需核酸的表达。
本发明的一些实施方式的表达载体还可包括额外的多核苷酸序列,其允许例如从单个mRNA转译数种蛋白质,例如,内部核糖体进入位点(internal ribosome entry site,IRES)或是自剪切(self-cleavable)肽;以及启动子-嵌合多肽基因组整合的序列。
根据具体实施方式,本文所述的第一及第二多肽由不同的构建体表达。
根据其他具体实施方式,本文所述的第一及第二多肽以双顺反子(bicistronic)方式从单个构建体表达。这种表达可以通过本领域众所周知的方法实现,例如但不限于使用内部核糖体进入位点序列及/或编码自剪切肽的核酸序列,例如2A肽(例如:P2A、T2A、E2A)。
应当理解,包含在表达载体中的各个元件可以以多种构型排列。例如,增强子元件、启动子等,甚至编码多肽的多核苷酸序列可以以“头对尾(head-to-tail)”构型排列,可以作为反向互补物存在,或以互补构型存在,作为反平行链。尽管表达载体的非编码元件更可能出现这种多种构型,但也设想了表达载体内编码序列的替代构型。
哺乳动物表达载体的示例包括但不限于pcDNA3、pcDNA3.1(+/-)、pGL3、pZeoSV2(+/-)、pSecTag2、pDisplay、pEF/myc/cyto、pCMV/myc/cyto、pCR3.1、pSinRep5、DH26S、DHBB、pNMT1、pNMT41、pNMT81,其可从Invitrogen获得;pCI,其可从Promega获得;pMbac、pPbac、pBK-RSV及pBK-CMV,其可从Strategene获得;pTRES,其可从Clontech及其衍生产品获得。
也可以使用含有来自真核病毒如逆转录病毒的调控元件的表达载体。SV40载体包括pSVT7及pMT2。源于牛乳头瘤病毒的载体包括pBV-1MTHA,源于Epstein Bar病毒的载体包括pHEBO和p2O5。其他示例性载体包括pMSG、pAV009/A+、pMTO10/A+、pMAMneo-5、杆状病毒pDSVE,以及允许在SV-40早期启动子、SV-40晚期启动子、金属硫蛋白启动子、小鼠乳腺肿瘤病毒启动子、劳氏肉瘤病毒启动子、多角体启动子(polyhedrin promoter)或是其他被证明在真核细胞中有效表达的启动子的指导下表达蛋白质的任何其他载体。
如上所述,病毒是非常特殊的感染因子,在许多情况下,它们已经进化到可以躲避宿主防御机制。通常,病毒会在特定细胞类型中感染和繁殖。病毒载体的靶向特异性利用其天然特异性来特异性靶向预定细胞类型,从而将重组基因引入受感染细胞。选择合适的载体用于转化T细胞的能力完全在普通技术人员的能力范围内,因此本文不考虑选择提供一般描述。
重组病毒载体可用于多肽的体内表达,因为它们提供例如侧向感染及靶向特异性等优点。侧向感染是例如逆转录病毒生命周期中固有的,并且是单个受感染细胞产生许多子代病毒体的过程,这些子代病毒体萌芽并感染邻近细胞。结果是大面积被迅速感染,其中大部分最初并未被原始病毒颗粒感染。这与垂直型感染形成对比,在垂直型感染中,传染原仅通过子代传播。也可以产生不能侧向传播的病毒载体。如果所需的目的是将特定基因仅引入局部数量的靶细胞,则此特征可能很有用。
可以使用多种方法将本发明的一些实施方式的表达载体引入T细胞。此类方法通常描述在以下:Sambrook等人,分子克隆(Molecular Cloning):实验室手册(A LaboratoryManual),冷泉港实验室(Cold Springs Harbor Laboratory),纽约(1989,1992);Ausubel等人,分子生物学实验手册(Current Protocols in Molecular Biology),约翰威立(JohnWiley and Sons),Baltimore,Md.(1989);Chang等人,体细胞基因治疗(Somatic GeneTherapy),CRC出版社,Ann Arbor,Mich.(1995);Vega等人,基因靶向(Gene Targeting),CRC出版社,Ann Arbor Mich.(1995),载体:调查分子克隆载体及其用途(A Survey ofMolecular Cloning Vectors and Their Uses),Butterworths,马萨诸塞州波士顿(1988)以及Gilboa等人,Biotechniques 4(6):504-512,1986;并且包括例如稳定或瞬时转染、脂质转染、电穿孔及用重组病毒载体感染。此外,参见美国专利第5,464,764以及5,487,992号的正负选择方法(positive-negative selection methods)。
通过病毒感染引入核酸与其他方法(例如,脂质转染及电穿孔)相比具有多种优势,因为由于病毒的传染性,可以获得更高的转染效率。
目前优选的体内核酸转移技术包括使用病毒或非病毒构建体转染,例如腺病毒、慢病毒(lentivirus)、单纯疱疹病毒一型或是腺相关病毒(adeno-associated virus,AAV),以及脂质系统。可用于脂质介导的基因转移的脂质是,例如,DOTMA、DOPE及DC-Chol(Tonkinson等人,癌症调查(Cancer Investigation),14(1):54-65(1996))。用于基因治疗的最优选构建体是病毒,最优选腺病毒、AAV、慢病毒或是逆转录病毒。病毒构建体,例如逆转录病毒构建体包括至少一个转录启动子/增强子或基因座定义元件,或是通过其他方式控制基因表达的其他元件,例如交替剪接、核RNA输出或是转译后修饰信使。此类载体构建体还包括包装信号、长末端重复序列(Long terminal repeat,LTR)或是其部分,以及适用于所用病毒的正链及负链引物结合位点,除非它已经存在于病毒构建体中。此外,此类构建体通常包括用于将多肽靶向细胞中所需位点的信号序列。任选地,构建体还可以包括指导聚腺苷酸化的信号,以及一个或多个限制性位点及转译终止序列。举例来说,此类构建体通常包括5'LTR、tRNA结合位点、包装信号、第二链DNA合成的起点及3'LTR或其一部分。可以使用其他非病毒载体,例如阳离子脂质、聚赖氨酸及树枝状聚合物。
根据具体的实施方式,T细胞可以被新鲜分离、储存,例如,冷冻保存(即:冷冻(frozen))在例如长期(例如,数月、数年)任何阶段的液氮温度,以备将来使用;以及细胞系。
冷冻保存的方法是本领域普通技术人员公知的,并且公开于例如,国际专利申请公开第WO2007054160及WO 2001039594号;以及美国专利申请公开第US20120149108号中。
根据具体实施方式,T细胞可以储存在细胞库或储存库或储存设施中。
因此,本教示进一步建议使用本文公开的T细胞及方法作为但不限于过继性T细胞治疗疾病的来源,其可以从激活免疫细胞对抗病理细胞中受益,例如过度增殖疾病;与免疫抑制及感染有关的疾病。
因此,根据本发明的一方面,本文公开的T细胞用于过继性T细胞疗法。
根据本发明的具体实施方式使用的T细胞可以是自体的(autologous)或是非自体的(non-autologous);它们可以是同系的(syngeneic)或非同系的(non-syngeneic):与受试者同种异体(allogeneic)或是异种异体(xenogeneic);每种可能性代表本发明的单独的实施方式。
根据具体实施方式,细胞对于所述受试者是自体的(autologous)。
根据具体实施方式,细胞对于所述受试者是非自体的(non-autologous)。
根据具体实施方式,本文所述的T细胞在施用于受试者之前离体培养、扩增及/或活化。
培养、扩增及激活T细胞的方法是本领域技术人员众所周知的。例如,T细胞可以在一种或多种分子(例如但不限于抗CD3抗体、抗CD28抗体、抗CD3及抗CD28包被珠子(bead)(例如,从Miltenyi Biotec获得的CD3CD28 MACSiBeads)、IL-2、植物血凝素、抗原负载抗原递呈细胞(antigen-loaded antigen presenting cell,APC,例如:树突细胞)、肽组装(peptide loaded)重组MHC的存在下被体外激活。
由于本发明的具体实施方式的T细胞在FCγ受体的胞外配体结合域与Fc配体结合后被激活,它们可用于但不限于结合包含针对结合病理细胞的Fc结构域(例如:抗体)的治疗组合物来治疗与病理细胞相关的疾病。
因此,根据本发明的一方面,提供了一种在使用包含Fc结构域的治疗组合物治疗的受试者中治疗与病理细胞相关的疾病的方法,所述治疗组合物对所述病理细胞具有特异性,所述方法包括向受试者施用治疗有效量的本文公开的T细胞或T细胞群,从而治疗受试者的疾病。
根据本发明的另外的或替代的方面,提供了一种本文公开的T细胞或T细胞群在使用包含Fc结构域的治疗组合物治疗受试者中与病理细胞相关的疾病的用途,所述治疗组合物对所述病理细胞具有特异性。
根据本发明的另外的或替代的方面,提供了一种在需要的受试者中治疗与病理细胞相关的疾病的方法,所述方法包括向受试者施用一治疗有效量的本文公开的T细胞或T细胞群;以及包含Fc结构域的治疗组合物,所述治疗组合物对所述病理细胞具有特异性,从而治疗受试者的疾病。
根据本发明的另外的或替代的方面,提供了本文公开的T细胞或T细胞群;以及包含Fc结构域的治疗组合物,用于在需要的受试者中治疗与病理细胞相关的疾病,其中所述治疗组合物对所述病理细胞具有特异性。
如本文所用,术语“受试者”或是“需要的受试者”包括哺乳动物,优选任何年龄或性别的人类。受试者可能是健康的或显示出病理学的初步迹象,例如,癌症。此术语还包括有发展病理的风险的个体。
如本文所用,术语“治疗”是指治愈、逆转、减弱、减轻、最小化、抑制或停止疾病(disease)或病症(disorder)(例如,癌症)的有害影响。本领域技术人员将理解,可以使用各种方法和测定来评估病理的发展,并且类似地,可以使用各种方法和测定来评估病理(例如,恶性肿瘤)的减少、缓解或消退,如下所述。
如本文所用,术语“预防”是指防止在可能有患病风险但尚未被诊断为患有所述疾病的受试者中发生疾病、病症或症状。
如本文所用,短语“与病理细胞相关的疾病”是指病理细胞驱动疾病的发生和/或进展。
根据具体实施方式,疾病可受益于激活受试者的免疫细胞。
如本文所用,短语“可受益于激活免疫细胞的疾病”是指其中受试者的免疫应答活性可能足以至少改善疾病的症状或延迟症状发作的疾病,但是出于任何原因受试者在这样做时的免疫反应不是最佳的。
通过本发明的一些实施方式治疗的疾病的非限制性示例包括过度增殖性疾病、与免疫抑制相关的疾病、由药物(例如,mTOR抑制剂、钙调神经磷酸酶抑制剂、类固醇)和感染引起的免疫抑制。
根据具体实施方式,疾病包括感染。
如本文所用,术语“感染”或“传染病”是指由病原体诱发的疾病。病原体的具体实例包括病毒病原体、细菌病原体,例如细胞内分枝杆菌病原体(例如,结核分枝杆菌)、细胞内细菌病原体(例如,单核细胞增生李斯特菌(Listeria monocytogenes))或细胞内原生动物病原体(例如,利什曼原虫和锥虫(Leishmania and Trypanosoma))。
引起传染病的病毒病原体的具体类型包括但不限于逆转录病毒、圆环病毒、细小病毒(parvoviruses)、帕波病毒(papovaviruses)、腺病毒、疱疹病毒、虹彩病毒、痘病毒、肝炎病毒、小核糖核酸病毒、杯状病毒、披膜病毒(togaviruses)、黄病毒、呼肠孤病毒、粘液病毒(orthomyxoviruses)、副黏液病毒(paramyxoviruses)、枪弹型病毒(rhabdoviruses)、布尼亚病毒(bunyaviruses)、冠状病毒、沙粒病毒和丝状病毒。
可根据本发明的具体实施方式治疗的病毒感染的具体实例包括但不限于人类免疫缺陷病毒(HIV)诱导的获得性免疫缺陷综合征(AIDS)、流感、鼻病毒感染、病毒性脑膜炎、爱泼斯坦-巴尔病毒(EBV)感染、甲型、乙型或丙型肝炎病毒感染、麻疹、乳头状瘤病毒感染/疣、巨细胞病毒(CMV)感染、单纯疱疹病毒感染、黄热病、伊波拉(Ebola)病毒感染、狂犬病等。
根据具体实施方式,疾病包括过度增殖性疾病。
根据具体实施方式,过度增殖性疾病包括硬化、纤维化、特发性肺纤维化(Idiopathic pulmonary fibrosis)、银屑病(psoriasis)、系统性硬化/硬皮病、原发性胆汁性胆管炎、原发性硬化性胆管炎、肝纤维化、预防辐射诱导的肺纤维化、骨髓纤维化或腹膜后纤维化。
根据其他具体实施方式,过度增殖性疾病包括癌症。
因此,根据具体实施方式,病理细胞是癌细胞。
本发明的一些实施方式可以治疗的癌症可以是任何实体或非实体肿瘤、癌症转移及/或癌前病变。
根据具体实施方式,癌症是恶性癌症。
癌症的例子包括但不限于癌、母细胞瘤、肉瘤及淋巴瘤。此类癌症的更具体例子包括但不限于胃肠道肿瘤(结肠癌、直肠癌、结直肠癌(colorectal carcinoma)、结直肠癌(colorectal cancer)、大肠腺瘤、遗传性非息肉病一型、遗传性非息肉病二型、遗传性非息肉病三型、遗传性非息肉病六型、结直肠癌(colorectal cancer)、遗传性非息肉病7型、小肠癌及/或大肠癌、食道癌、伴有胼胝症(Tylosis)的食道癌、胃癌、胰腺癌、胰腺内分泌肿瘤)、子宫内膜癌、隆突性皮肤纤维肉瘤(dermatofibrosarcoma protuberans)、胆囊癌、胆道肿瘤、前列腺癌、前列腺腺癌、肾癌(例如Wilms’肿瘤二型或一型)、肝癌(例如,肝母细胞瘤、肝细胞癌、肝细胞癌)、膀胱癌、胚胎性横纹肌肉瘤(embryonal rhabdomyosarcoma)、生殖细胞肿瘤、滋养层肿瘤、睾丸生殖细胞肿瘤、卵巢、子宫、上皮性卵巢的未成熟畸胎瘤、骶尾部肿瘤、绒毛膜癌、胎盘部位滋养层肿瘤、上皮性成体肿瘤(epithelial adult tumor)、卵巢癌、浆液性卵巢癌、卵巢性索肿瘤(ovarian sex cord tumors)、子宫颈癌(cervicalcarcinoma)、子宫颈癌(uterine cervix carcinoma)、小细胞和非小细胞肺癌、鼻咽癌、乳腺癌(例如,导管内乳腺癌、浸润性导管内乳腺癌、散发性、乳腺癌、乳腺癌易感性(susceptibility to breast cancer)、乳腺癌4型、乳腺癌-1、乳腺癌-3、乳腺卵巢癌)、鳞状细胞癌(例如,头颈部)、神经源性肿瘤、星形细胞瘤、神经节母细胞瘤、神经母细胞瘤、淋巴瘤(例如,霍奇金氏病(Hodgkin's disease)、非霍奇金氏淋巴瘤、B细胞、伯基特(Burkitt)、皮肤T细胞、组织细胞、淋巴母细胞、T细胞、胸腺)、神经胶质瘤、腺癌、肾上腺肿瘤、遗传性肾上腺皮质癌、脑恶性肿瘤(肿瘤),各种其他癌(例如,支气管大细胞、导管癌、埃利希-勒特腹水(Ehrlich-Lettre ascites)、表皮样癌、大细胞癌、刘易斯肺(Lewis lung)癌、髓质癌、粘液表皮样癌(mucoepidermoid)、燕麦细胞癌、小细胞癌、梭形细胞癌、棘细胞癌、移行细胞癌、未分化癌、癌肉瘤、绒毛膜癌、囊腺癌)、室管膜母细胞瘤(ependimoblastoma)、上皮瘤、红白血病(例如,Friend、淋巴母细胞瘤)、纤维肉瘤、巨细胞瘤、神经胶质瘤、胶质母细胞瘤(例如,多形性、星形细胞瘤)、胶质瘤肝细胞瘤(gliomahepatoma)、异源杂交瘤(heterohybridoma)、异源骨髓瘤(heteromyeloma)、组织细胞瘤(histiocytoma)、杂交瘤(例如,B细胞)、肾肥大瘤(hypernephroma)、胰岛素瘤、胰岛瘤、角化瘤、平滑肌母细胞瘤、平滑肌肉瘤、白血病(例如,急性淋巴、急性淋巴细胞、急性淋巴母细胞前B细胞、急性淋巴细胞T细胞白血病、急性巨核细胞、单核细胞、急性髓细胞(acutemyelogenous)、急性髓细胞(acute myeloid)、急性髓细胞性伴嗜酸性粒细胞增多(acutemyeloid with eosinophilia)、B细胞、嗜碱性、慢性髓细胞性(chronic myeloid)、慢性、B细胞、嗜酸性粒细胞、Friend、粒细胞性(granulocytic)或粒细胞性(myelocytic)、毛细胞、淋巴细胞、巨核细胞、单核细胞、单核巨噬细胞、成髓细胞、髓细胞(myeloid)、髓单核细胞(myelomonocytic)、浆细胞、前B细胞、早幼粒细胞、亚急性、T细胞、淋巴肿瘤、易患髓系恶性肿瘤、急性非淋巴细胞白血病)、淋巴肉瘤、黑色素瘤、乳腺肿瘤、肥大细胞瘤、髓母细胞瘤、间皮瘤、转移性肿瘤、单核细胞瘤、多发性骨髓瘤、骨髓增生异常综合征、骨髓瘤、肾母细胞瘤、神经组织神经胶质瘤(nervous tissue glial tumor)、神经组织神经元瘤(nervoustissue neuronal tumor)、神经瘤(neurinoma)、神经母细胞瘤、寡树突胶质瘤(oligodendroglioma)、骨软骨瘤、骨髓瘤、骨肉瘤(例如,尤文氏(Ewing's))、乳头状瘤、移行细胞、嗜铬细胞瘤、垂体瘤(侵袭性)、浆细胞瘤、视网膜母细胞瘤、横纹肌肉瘤、肉瘤(例如,尤文氏、组织细胞、Jensen、成骨细胞、网状细胞)、神经鞘瘤、皮下肿瘤、畸胎瘤(例如,多能性)、畸胎瘤、睾丸肿瘤、胸腺瘤及毛上皮瘤(trichoepithelioma)、胃癌、纤维肉瘤、多形性胶质母细胞瘤、多发性血管球瘤、李-弗劳门尼综合征(Li-Fraumeni syndrome)、脂肪肉瘤、林奇氏癌症家族综合征II(lynch cancer family syndrome II)、男性生殖细胞瘤、肥大细胞白血病、甲状腺髓样癌(medullary thyroid)、多发性脑膜瘤、内分泌肿瘤粘液肉瘤(endocrine neoplasia myxosarcoma)、副神经节瘤、家族性非嗜铬细胞瘤(familial andsporadic)、毛母质瘤(pilomatricoma)、乳头状、家族性及散发性(familial andsporadic)、横纹肌样易感综合征(rhabdoid predisposition syndrome)、家族性(familial)、横纹肌样肿瘤(rhabdoid tumors)、软组织肉瘤以及伴有胶质母细胞瘤的Turcot综合征。
根据具体实施方式,癌症是癌前癌。
癌前病变在本领域中得到充分表征和已知(例如,参见Berman JJ.及Henson DE.,2003年,分类癌前病变:元数据方法(Classifying the pre-cancers:a metadataapproach),BMC Med Inform Decis Mak.3:8)。癌前病变的例子包括但不限于获得性(acquired)小癌前病变、具有核异型(nuclear atypia)性的获得性大病变、伴随发展为癌症的遗传性增生综合征发生的前体病变,以及获得性弥漫性增生(diffuse hyperplasias)及弥漫性化生(diffuse metaplasias)。小癌前病变的非限制性示例包括子宫颈的鳞状上皮内高阶上皮细胞病变(High grade squamous intraepithelial lesion of uterinecervix,HGSIL)、肛门上皮内瘤变(anal intraepithelial neoplasia,AIN)、声带发育不良、(结肠的)异常隐窝、前列腺上皮内瘤(prostatic intraepithelial neoplasia,PIN)。
具有核异型(nuclear atypia)性的获得性大病变的非限制性示例包括管状腺瘤、血管免疫母细胞性淋巴结病(angioimmunoblastic lymphadenopathy,AILD,是伴异常蛋白血症的血管免疫母细胞淋巴结病)、非典型脑膜瘤、胃息肉、大斑块副银屑病(large plaqueparapsoriasis)、骨髓增生异常、原位乳头状移行细胞癌(papillary transitional cellcarcinoma in-situ)、顽抗性贫血伴芽母细胞过多(refractory anemia with excessblasts),以及施奈德乳头状瘤(Schneiderian papilloma)。伴随发展为癌症的遗传性增生综合征发生的前体病变的非限制性示例包括非典型痣症候群(atypical mole syndrome)、C细胞腺瘤病(C cell adenomatosis)及MEA。获得性弥漫性增生及弥漫性化生的非限制性示例包括佩吉特氏骨病(Paget's disease of bone)及溃疡性结肠炎。
根据具体实施方式,癌症选自于由黑色素瘤、腺癌、乳腺癌(mammary carcinoma)、结肠癌、卵巢癌、肺癌及B细胞淋巴瘤所组成的群组。
根据具体实施方式,癌症选自于由黑色素瘤、腺癌及乳腺癌所组成的群组。
根据具体实施方式,癌症选自于由黑色素瘤、腺癌及乳腺癌所组成的群组。
根据具体实施方式,癌症或癌细胞表达选自于由PDL-1、E-钙粘蛋白(E-Cadherin)、CD19、MUC1、TRP-1及TRP-2所组成的群组的标记物。
根据具体实施方式,癌症或癌细胞表达PDL-1。
如上所述,根据具体实施方式,将T细胞与包含Fc结构域(例如:抗体)的治疗组合物组合施用于受试者。
T细胞的施用以及包含Fc结构域的治疗组合物的施用可以以相同的途径或以不同的途径进行。
T细胞的施用可以在包含Fc结构域的治疗组合物之后或伴随。
根据具体实施方式,在使用包含Fc结构域的治疗组合物治疗后,将本文公开的T细胞施用于受试者。
根据其他具体实施方式,本文公开的T细胞与包含Fc结构域的治疗组合物同时施用于受试者。
可以施用多轮T细胞及多剂量的包含Fc结构域的治疗组合物。因此,根据具体实施方式,在施用至少一次包含Fc结构域的治疗组合物之后,施用本文公开的T细胞。根据具体实施方式,按照使用包含Fc结构域的治疗组合物进行治疗的顺序实施本文所公开的细胞的施用。
根据具体实施方式,与非病理细胞相比,包含Fc结构域的治疗组合物对病理细胞具有特异性,即,结合病理(例如,癌)细胞过表达或单独表达的抗原。
包含对病理细胞具有特异性的Fc结构域的治疗组合物是本领域众所周知的并且包括但不限于Fc融合蛋白及抗体。
根据具体实施方式,Fc结构域属于IgG抗体。
如本文所用,术语“Fc融合蛋白”是指包含能够结合病理细胞(例如,在病理细胞上表达的一受体的一配体)与一抗体的Fc结构域组合的一氨基酸序列的一分子。
使用的Fc融合蛋白的选择完全在本领域技术人员的能力范围内,并且取决于疾病的类型,例如与病理相关的病理细胞表达的受体。
Weidle等人公开了可用于特定的实施方式的Fc融合蛋白的非限制性示例。癌症基因组学及蛋白质组学,2012年,9(6):357-372;以及Sioud等人,分子治疗-方法与临床进展(Molecular Therapy-Methods&Clinical Development)2015年,2,15043,其内容通过引用整体并入本文。
本发明中使用的术语“抗体”包括完整分子及其功能片段(能够结合抗原表位)。根据具体实施方式,抗体包含Fc结构域。
根据具体实施方式,抗体是IgG抗体(例如:IgGl、IgG2、IgG3、IgG4)。
根据一具体实施方式,抗体同种型是IgG1或IgG3。
所用抗体的选择完全在本领域技术人员的能力范围内,并且取决于疾病的类型以及与病理相关的病理细胞表达的抗原。
根据具体实施方式,抗体结合由肿瘤细胞过度表达或单独表达的抗原。
根据本发明的一些实施方式,抗体选自于由阿替利珠单抗(Atezolizumab)、阿维鲁单抗(Avelumab)、阿仑单抗(Alemtuzumab)、西妥昔单抗(Cetuximab)、帕尼单抗(Panitumumab)、尼妥珠单抗(Nimotuzumab)、利妥昔单抗(Rituximab)、加妥珠单抗(Gatipotuzumab)(以前称为加替坡单抗(PankoMab-)、曲妥珠单抗(Trastuzumab)、阿仑单抗(Alemtuzumab)、贝伐单抗(Bevacizumab)、奥法木单抗(Ofatumumab)、帕妥珠单抗(Pertuzumab)、奥法木单抗(Ofatumumab)、阿托珠单抗(Obinutuzumab)及静脉注射免疫球蛋白(Intravenous immunoglobulin,IVIG)所组成的群组。
根据具体实施方式,抗体选自于由阿替利珠单抗、利妥昔单抗、西妥昔单抗、加妥珠单抗及IVIG所组成的群组。
根据具体实施方式,抗体是抗PDL-1。
根据具体实施方式,癌细胞表达PDL-1,并且抗体是抗PDL-1。
根据具体实施方式,抗体是阿替利珠单抗。
根据具体实施方式,本文公开的T细胞和治疗组合物可以与其他已建立或实验性的治疗方案联合施用于受试者,以治疗与病理细胞相关的疾病(例如:癌症),包括但不限于镇痛药、化疗药药剂、放射治疗剂、细胞毒疗法(调理(conditioning))、激素疗法及本领域公知的其他治疗方案(例如手术)。
本文公开的T细胞和/或本文公开的治疗组合物可以本身或以药物组合物与合适的载体或赋形剂混合的形式施用于受试者。
如本文所用,“药物组合物”是指一种或多种本文所述的活性成分与其他化学成分例如生理上合适的载体和赋形剂的制剂。药物组合物的目的是促进将化合物施用于生物体。
在本文中,术语“活性成分”是指负责生物效应的T细胞和/或抗体。
因此,根据具体实施方式,T细胞是制剂中的活性成分。
在下文中,可以互换使用的短语“生理学上可接受的载体”以及“药学上可接受的载体”是指不会对生物体造成显着刺激,并且不会消除所施用化合物的生物活性和特性的载体或稀释剂。这些短语下包括佐剂(adjuvant)。
在本文中,术语“赋形剂(excipient)”是指加入到药物组合物中以进一步促进活性成分的给药的惰性物质。赋形剂的示例包括但不限于碳酸钙、磷酸钙、各种糖及淀粉、纤维素衍生物、明胶、植物油及聚乙二醇。
药物的配制以及给药技术可以在“Remington’s Pharmaceutical Sciences”,Mack Publishing Co.,Easton,PA,最新版本中找到,其通过引用并入本文。
合适的给药途径可以例如包括口服、直肠、经粘膜,尤其是经鼻、肠或肠胃外递送,包括肌内、皮内、皮下和髓内注射以及鞘内、直接心室内、心内,例如进入右侧或左侧心室腔,进入冠状动脉、静脉内、腹腔内、鼻内或眼内注射。
将药物递送至中枢神经系统的常规方法包括:神经外科策略(例如,脑内注射或脑室内输注);试剂的分子操作(例如,产生嵌合融合蛋白,其包含对内皮细胞表面分子具有亲和力的转运肽与自身不能穿过脑血管障壁(blood-brain barrier,BBB)的试剂的组合),以试图利用其中之一BBB的内源性转运途径;旨在增加药物脂溶性的药理学策略(例如,水溶性药物与脂质或胆固醇载体的结合);以及通过高渗破坏(由于将甘露醇溶液注入颈动脉或使用生物活性剂,如血管紧张素肽)导致BBB完整性的暂时破坏。然而,这些策略中的每一个都有局限性,例如与侵入性外科手术相关的固有风险、由内源性运输系统固有的限制强加的尺寸限制、与系统给药嵌合分子相关的潜在不良生物副作用,嵌合分子由可能在中枢神经系统外活跃的载体基序组成,以及在BBB被破坏的大脑区域内可能存在脑损伤的风险,这使其成为次优的递送方法。
或者,可以以局部而非全身方式施用药物组合物,例如,通过将药物组合物直接注射到患者的组织区域中。
根据一具体实施方式,本发明的T细胞或包含T细胞的药物组合物通过静脉注射(IV)途径给药。
本发明的一些实施方式的药物组合物可以通过本领域公知的方法制造,例如通过常规混合、溶解、制粒、糖衣丸制造、研磨、乳化、包封、包埋或冻干方法。
根据本发明的一些实施方式使用的药物组合物因此可以使用一种或多种生理学可接受的载体以常规方式配制,所述载体包括赋形剂及助剂,其促进将活性成分加工成可药用的制剂。适当的配方取决于所选择的给药途径。
对于注射剂,药物组合物的活性成分可以配制在水溶液中,优选在生理相容的缓冲液中,例如汉克氏溶液(Hank’s solution)、林格氏溶液(Ringer’ssolution)或生理盐缓冲液。对于透粘膜给药,在制剂中使用适合要渗透的屏障的渗透剂。这种渗透剂是本领域公知的。
对于口服给药,可以通过将活性化合物与本领域公知的药学上可接受的载体组合来容易地配制药物组合物。此类载体能够将药物组合物配制成片剂、丸剂、糖衣锭(dragees)、胶囊、液体、凝胶、糖浆、浆液、悬浮液等,供患者口服摄取。可使用固体赋形剂制备用于口服使用的药理学制剂,任选研磨所得混合物,并在需要时加入合适的助剂后处理颗粒混合物,以获得片剂或糖衣丸芯。合适的赋形剂特别是例如糖类的填充剂,包括乳糖、蔗糖、甘露醇或山梨糖醇;纤维素制剂,例如玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍胶(gum tragacanth)、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠;及/或生理上可接受的聚合物,例如聚乙烯吡咯烷酮(PVP)。如果需要,可以加入崩解剂(disintegrating agent),如交联聚乙烯吡咯烷酮、琼脂或海藻酸或其盐,例如海藻酸钠。
糖衣丸芯(Dragee cores)具有合适的涂层。为此,可使用浓缩糖溶液,其可任选地包含阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波姆凝胶(carbopol gel)、聚乙二醇、二氧化钛、漆溶液(lacquer solutions)及合适的有机溶剂或溶剂混合物。可以将染料或颜料添加到片剂或糖衣丸包衣中,用于识别或表征活性化合物剂量的不同组合。
可口服使用的药物组合物包括由明胶制成的推入式(push-fit)胶囊以及由明胶及增塑剂如甘油或山梨糖醇制成的软密封胶囊。推入式胶囊可包含与填充剂,例如乳糖、粘合剂,例如淀粉、润滑剂例如滑石或硬脂酸镁以及任选的稳定剂混合的活性成分。在软胶囊中,活性成分可以溶解或悬浮在合适的液体中,例如脂肪油、液体石蜡或液体聚乙二醇。此外,可以添加稳定剂。用于口服给药的所有制剂的剂量应适合于所选择的给药途径。
对于口腔给药,组合物可以采用以常规方式配制的片剂或锭剂的形式。
对于通过鼻吸入给药,根据本发明的一些实施方式使用的活性成分以气雾剂喷雾形式从加压包或雾化器使用合适的推进剂方便地递送,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷或二氧化碳。在加压气雾剂的情况下,剂量单位可通过提供阀门以输送计量的量来确定。可以配制用于分配器的例如明胶的胶囊和药筒,其含有化合物和合适的粉末基质,例如乳糖或淀粉的粉末混合物。
本文所述的药物组合物可以配制用于肠胃外给药,例如通过推注或连续输注。注射用制剂可以单位剂型存在,例如安瓿(ampoules)或多剂量容器,任选添加防腐剂。组合物可以是在油性或水性载体中的悬浮液、溶液或乳液,并且可以包含配制剂,例如悬浮剂、稳定剂及/或分散剂。
肠胃外给药的药物组合物包括水溶性形式的活性制剂的水溶液。此外,活性成分的悬浮液可以制备成合适的油性或水基注射悬浮液。合适的亲脂性溶剂或载体包括脂肪油如芝麻油,或合成脂肪酸酯如油酸乙酯、甘油三酯或脂质体。水性注射悬浮液可能含有增加悬浮液粘度的物质,例如羧甲基纤维素钠、山梨糖醇或葡聚糖。任选地,悬浮液还可以包含合适的稳定剂或增加活性成分溶解度,以允许制备高浓度溶液的试剂。
或者,活性成分可以是粉末形式,以便在使用前用合适的载体例如无菌、无热原的水基溶液配制。
本发明的一些实施方式的药物组合物也可以使用例如可可脂或其他甘油酯等常规栓剂基质,在例如栓剂或保留灌肠剂的直肠组合物中配制。
替代实施方式包括在受试者中提供活性成分的持续释放或延长的活性持续时间的注射剂(depots),如本领域公知的。
适用于本发明的一些实施方式的上下文中的药物组合物包括其中以有效实现预期目的的量包含活性成分的组合物。更具体地,治疗有效量是指有效预防、减轻或改善病症(例如,癌症)的症状或是延长被治疗的受试者的存活的活性成分的量。
确定治疗有效量完全在本领域技术人员的能力范围内,尤其是根据本文提供的详细公开内容。
对于本发明方法中使用的任何制剂,治疗有效量或剂量可以从体外和细胞培养试验中初步估计。例如,可以在动物模型中配制剂量以达到所需的浓度或效价。此类信息可用于更准确地确定人体的有用剂量。
本文所述的活性成分的毒性和治疗功效可以通过体外、细胞培养物或实验动物中的标准药学程序来确定。从这些体外和细胞培养试验以及动物研究中获得的数据可用于制定一系列用于人类的剂量。剂量可根据所采用的剂型和所采用的给药途径而变化。确切的配方、给药途径和剂量可由个体医师根据患者的状况选择(参见例如,Fingl等人,1975年,《治疗学的药理学基础(The Pharmacological Basis of Therapeutics)》,第1章第1页)。
剂量和间隔可以单独调整,以提供足以诱导或抑制生物效应的活性成分水平(最小有效浓度,MEC)。每种制剂的MEC会有所不同,但可以根据体外数据进行估计。达到MEC所需的剂量将取决于个体特征及给药途径。检测分析可用于确定血浆浓度。
根据待治疗病症的严重性和反应性,给药可以是单次或多次给药,治疗过程持续数天至数周,或是直至治愈或实现疾病状态的减轻。
当然,要施用的组合物的量将取决于所治疗的对象、病痛的严重程度、施用方式、处方医师的判断等。
如果需要,本发明的一些实施方式的组合物可存在于包装或分配器装置中,例如美国食品药品监督管理局(FDA)批准的试剂盒,其可含有一种或多种含有活性成分的单位剂型。例如,包装可以包括金属或塑料箔,例如泡罩包装(blister pack)。包装或分配器装置可附有使用说明。包装或分配器也可以通过与容器相关联的通知来调整,通知的格式由管制药品制造、使用或销售的政府机构规定,所述通知反映了机构对成分或人类或兽医的施用形式的批准。例如,此类通知可能是美国食品和药物管理局批准的处方药标签或批准的产品说明书。还可以制备包含在兼容药物载体中配制的本发明制剂的组合物,将其放置在适当的容器中,并对其进行标记以处理指示的状况,如上所述。
根据本发明的另一方面,提供了包含包装本文公开的T细胞或T细胞群的包装材料以及包含Fc结构域的治疗组合物的制品。
根据具体实施方式,制品被鉴定用于治疗与病理细胞相关的疾病(例如,癌症)。
根据具体实施方式,本文公开的T细胞或T细胞群;以及包含Fc结构域的治疗组合物被包装在单独的容器中。
根据具体实施方式,本文公开的T细胞或T细胞群;以及包含Fc结构域的治疗组合物被包装在复合制剂中。
如本文所用,术语“约”是指约±10%。
术语“包含”(comprises)、“包含”(comprising)、“包括”(includes)、“包括”(including)、“具有”(having)及其词形变化是指“包括但不限于”。
术语“由...组成”(consisting of)意指“包括并且限于”。
术语“基本上由...组成”(consisting essentially of)是指组合物、方法或结构可包括另外的成分、步骤及/或部件,但前提是另外的成分、步骤及/或部件实质上不改变所要求保护的组合物、方法或结构的基本特征及新特征。
本文所使用的单数形式“一(a)”、“一(an)”及“所述(the)”包括复数引用,除非上下文另外明确指出。例如,术语“一化合物”或“至少一化合物”可以包括多个化合物,包括其混合物。
在整个申请中,本发明的各种实施方式可以以一范围形式呈现。但应当理解是,范围形式的描述仅仅是为了方便及简洁,不应被解释为对本发明的范围的强行限制。因此,范围的描述应当被认为已经具体公开了所有可能的子范围以及范围内的单个数值。例如,对从1到6的一范围的描述应视为已明确公开了例如从1至3、从1至4、从1至5、从2至4、从2至6、从3至6等子范围,以及在所述范围内的单个数值,例如1、2、3、4、5及6。无论范围的宽度皆适用。
每当在本文中指示一数值范围时,其意在包括在指示的范围内的任何引用数字(分数或整数)。短语“在一第一指示数字与一第二指示数字之间的范围”以及“自一第一指示数字至一第二指示数字的范围”在本文中可互换使用,并且意在包括第一及第二指示数字以及它们之间的所有分数及整数。
如本文所用,术语“方法”是指用于完成给定任务的方式、手段、技术和程序,包括但不限于化学、药理学、生物学、生物化学和医学领域的从业者已知的或从已知的方式、手段、技术和程序发展而来的那些方式、手段、技术和程序。
当提及特定序列表时,此类提及应理解为还包括与其互补序列基本对应的序列,包括微小的序列变异,例如由测序错误、克隆错误或导致碱基替换的其他改变导致,碱基缺失或碱基添加,前提是此类变异的频率小于50个核苷酸中的1个,或者,小于100个核苷酸中的1个,或者,小于200个核苷酸中的1个,或者,小于500个核苷酸中的1个,或者,小于1000个核苷酸中的1个,或者,小于5,000个核苷酸中的1个,或者,小于10,000个核苷酸中的1个。
应当理解,为了清楚起见,在分开的实施方式的上下文中描述的本发明的某些特征也可以在单个实施方式中组合提供。相反地,为了简洁起见,在单个实施方式的上下文中描述的本发明的各种特征也可以单独地、或以任何合适的子组合、或适当地在本发明的任何其他描述的实施方式中提供。在各种实施方式的上下文中描述的某些特征不被认为是那些实施方式的必要特征,除非所述实施方式在没有那些元素的情况下不起作用。
如上文所述以及如以下权利要求书所述,本发明的各种实施方式及方面在以下示例中得到实验支持。
示例
现在参考以下示例,这些示例与以上描述一起以非限制性方式说明了本发明的一些实施方式。
通常,本文使用的命名和本发明使用的实验室程序包括分子、生化、微生物和重组DNA技术。这些技术在文献中有详尽的解释。参见,例如,“分子克隆:实验室手册(MolecularCloning:A laboratory Manual)”Sambrook等人,(1989);“分子生物学中的当前协议(Current Protocols in Molecular Biology)”第I-III卷,Ausubel,R.M.,编辑,(1994);Ausubel等人,“分子生物学的当前协议(Current Protocols in Molecular Biology)”,John Wiley and Sons,巴尔的摩(Baltimore),马里兰州(Maryland)(1989);Perbal,“分子克隆实用指南(A Practical Guide to Molecular Cloning)”,John Wiley&Sons,纽约(New York)(1988);Watson等人,“重组DNA(Recombinant DNA)”,《科学美国人》,纽约;Birren等人,(编辑)“基因组分析:实验室手册系列(Genome Analysis:A LaboratoryManual Series")”,第1-4卷,冷泉港实验室出版社(Cold Spring Harbor LaboratoryPress),纽约(1998);美国专利中阐述的方法:第4,666,828号;第4,683,202号;第4,801,531号;第5,192,659号和第5,272,057号;“细胞生物学:实验室手册(Cell Biology:ALaboratory Handbook)”,第I-III卷,Cellis,J.E.,编辑,(1994);“动物细胞培养-基本技术手册(Culture of Animal Cells-A Manual of Basic Technique)”,Freshney,Wiley-Liss,纽约(1994),第三版;“免疫学的当前协议(Current Protocols in Immunology)”第I-III卷,Coligan J.E.,编辑,(1994);Stites等人,(编辑),“基础和临床免疫学(Basicand Clinical Immunology)”(第8版),Appleton&Lange,诺沃克(Norwalk),康涅狄格州(CT)(1994);Mishell及Shiigi(编辑),“细胞免疫学的选择方法(Selected Methods inCellular Immunology)”,W.H.Freeman and Co.,纽约(1980);可用的免疫测定法在专利和科学文献中有广泛的描述,参见,例如美国专利第3,791,932号;第3,839,153号;第3,850,752号;第3,850,578号;第3,853,987号;第3,867,517号;第3,879,262号;第3,901,654号;第3,935,074号;第3,984,533号;第3,996,345号;第4,034,074号;第4,098,876号;第4,879,219号;第5,011,771号和第5,281,521号;“寡核苷酸合成(OligonucleotideSynthesis)”Gait,M.J.,编辑,(1984);“核酸杂交(Nucleic Acid Hybridization)”Hames,BD及Higgins SJ,编辑(1985);“转录和转译(Transcription and Translation)”Hames,BD及Higgins SJ编辑(1984);“动物细胞培养(Animal Cell Culture)”Freshney,RI,编辑(1986);“固定化细胞和酶(Immobilized Cells and Enzymes)”IRL出版社(1986);“分子克隆实用指南(A Practical Guide to Molecular Cloning)”Perbal,B.(1984)和“酶学方法(Methods in Enzymology)”第1-317卷,学术出版社(Academic Press);“PCR方案:方法和应用指南(PCR Protocols:A Guide To Methods And Applications)”,学术出版社,圣地亚哥(San Diego),加利福尼亚州(CA)(1990);Marshak等人,“蛋白质纯化和表征的策略-实验室课程手册(Strategies for Protein Purification and Characterization-ALaboratory Course Manual)”CSHL出版社(1996);所有这些都以引用方式并入,就像在此完全阐述一样。本文件中提供了其他一般参考。其中的程序被认为是本领域公知的,并且是为了读者的方便而提供的。其中包含的所有信息通过引用并入本文。
示例1
与抗癌抗体联合表达Fcγ受体的CD4+T细胞亚群在诱导直接肿瘤裂解中发挥作用:
材料和方法:
小鼠:野生型(Wild-type,WT)C57BL/6和Balb/cOlaHsd小鼠获自Envigo(耶路撒冷(Jerusalem),以色列(Israel))和Jackson Laboratories(Bar-Harbor,ME,美国)。T细胞缺陷小鼠B6.Cg-Rag1tm1Mom和TCR基因转殖小鼠Tyrp1B-w Tg(Tcrα、Tcrβ)9Rest/J购自Jackson实验室。B6.Cg-Tg(Tcrα、Tcrβ)425Cbn/J购自Jackson实验室,或由Weizmann研究所RonenAlon教授友情提供。所有小鼠都饲养在美国实验动物护理认证协会(AmericanAssociation for the Accreditation of Laboratory Animal Care)认可的动物设施中,并保持在无特定病原体的条件下。在所有实验中使用雄性和雌性8至12周龄小鼠。所有动物实验均获得特拉维夫(Tel-Aviv)大学或斯坦福(Stanford)大学机构动物护理和使用委员会的批准。
细胞系:B16F10细胞(CRL-6475)和4T1(CRL-2539)细胞购自ATCC,HEK-293FT购自ThermoFisher Scientific(沃尔瑟姆(Waltham),麻萨诸塞州(MA))。在标准条件下,细胞在补充有10%热灭活FBS(以色列生物工业公司(Biological Industries,Israel))、2mM L-谷氨酰胺和100μg/mL青霉素/链霉素(GIBCO)的DMEM(GIBCO)中培养。根据制造商的说明,使用EZ-PCRMycoplasma检测试剂盒(以色列生物工业公司)对细胞进行常规支原体检测。
T细胞分离:通过吸入CO2安乐死后,从每只小鼠身上同时进行所有组织制备。从淋巴器官中分离T细胞:从安乐死的小鼠身上取出脾脏、淋巴结和胸腺,并通过70μM细胞过滤器(strainer)(Gibco,Thermo Fisher Scientific,Waltham,MA)捣碎。随后,通过在2,000rpm、5分钟、4-8℃下离心来洗涤细胞。分离肿瘤浸润性T细胞:在HBSS中使用2,000U/mlDNase I和2mg/mL胶原酶IV(均来自Sigma Aldrich,Merck,Israel)在37℃下将肿瘤酶解30分钟,且搭配磁力搅拌器(400转)。随后,通过在4至8℃下以2,000rpm离心5分钟来洗涤细胞。为了从外周血中分离T细胞:在灌注动物之前通过后腔静脉收集外周血,并在以1:1稀释于FACS缓冲液之前转移到肝素包被的真空管中(Hanks平衡盐溶液,2%FSC、0.05mM EDTA)。淋巴细胞在-Paque Premium(Sigma-Aldrich)梯度上富集,收集的PBMC使用FACS缓冲液洗涤两次。对于所有组织,根据制造商的说明,将细胞与抗CD4或抗CD8磁珠(MojoSortTM Nanobeads,BioLegend,Carlsbad,CA)一起温育,并通过FACSAriaII进一步分选为FCSlo/SSClo/TCRβ+/MHCIIneg细胞。
T细胞培养和扩增:在RPMI-1640中培养T细胞,其中补充有1%Pen-Strep、10%热灭活FBS、1%丙酮酸钠、1%MEM-Eagle非必需氨基酸、1%胰岛素转铁蛋白-硒和50μMβ-巯基乙醇。对于T细胞扩增,培养皿在PBS中预涂有0.5μg/ml抗CD3(17A2)和0.5μg/ml抗CD28(3751)LEAF抗体(均购自BioLegend),并补充有1,000IU/mL重组鼠IL-2(PeproTech,RockyHill,NJ)。
流式细胞术:使用流式细胞术(CytoFLEX,Beckman Coulter,LakeviewIndianapolis,IA)分析纯化的T细胞,并通过FACS(BD FACSAriaTM III,BD Biosciences,Franklin Lakes,NJ)进行分类。使用FlowJo软件(Tree Star)分析数据集。使用了与FITC结合或对以下小鼠抗原具有特异性的抗TRP1单克隆抗体:(Alexa Fluor 647或BrilliantViolet 421)CD3(克隆17A2)、(藻红蛋白)CD4(克隆RM 4-4)、(Brilliant Violet 605)CD8(克隆53-6.7)、(Alexa Fluor 488)CD11b(克隆M1/70)、(APC/Cy7)CD44(IM7)、(藻红蛋白/Cy7)CD62L(MEL-14)、(Alexa Fluor 647)FcRIV(克隆9E9)、(Brilliant Violet 421)TCRb(H57-597)、(别藻蓝蛋白(Allophycocyanin))MHCII(M5/114.15.2)、(荧光素)FcRI(克隆X54-5/7.1)、(藻红蛋白/Cy7)FcRII/III 93)。对于人类特定的抗原,使用了:(Alexa Fluor488)CD3(HIT3a)、(Alexa Fluor 594)CD4(RPA-T4)、(别藻蓝蛋白)CD19(HIB19)、(AlexaFluor 647)CD8(HIT8a)、(Brilliant Violet 650)CD11c(3.9)、(Alexa Fluor 647)CD16(3G8)、(PerCp/Cy5.5)CD32(FUN-2)、(Brilliant Violet 421)CD64(10.1)、(别藻蓝蛋白/Cy7)CD45RO(UCHL1)、(藻红蛋白/Cy7)CD45RA(HI100)。所有抗体均购自BioLegend。将细胞悬浮在由含2%FCS和0.05mM EDTA的HBSS组成的FACS缓冲液中。
CD3和FcγRI的PCR扩增:使用RNeasy Micro Kit(Qiagen,Valencia,CA)从CD11b+、FcγRI+和FcγRIneg CD4+分选的细胞中纯化总RNA,并使用NanoDrop One(Thermo FisherScientific,Pittsburgh,PA)进行定量。根据制造商的方案,使用qScript cDNA合成试剂盒(Quanta biosciences,Beverly,MA)进行逆转录。使用AGACACCGCTACACATCTGC(SEQ ID NO:1)和GGGAAGTTTGTGCCCCAGTA(SEQ ID NO:2)引物通过PCR分析cDNA样品,以检测FcγRI序列,并且CD3ε多肽序列使用GCATTCTGAGAGGATGCGGT(SEQ ID NO:3)和TGGCCTTGGCCTTCCTATTC(SEQ ID NO:4)引物,并通过琼脂糖凝胶电泳进行分析。
体内肿瘤模型:对于黑色素瘤研究,将悬浮在50μL DMEM中的2x105B16F10细胞皮下注射至C57BL/6小鼠右胁上方,每周使用卡尺测量生长肿瘤的大小两次。当肿瘤达到120mm2时,出于伦理考虑将小鼠处死。在注射后第8天和第12天,或当肿瘤达到20mm2时(第0天和第4天)进行治疗。对于三阴性乳腺癌模型,将30μL DMEM中的2x105 4T1细胞注射到12周龄雌性Balb/c小鼠的5号脂肪垫中。在第12天,处死小鼠并分析来自DLN、肿瘤和非DLN的CD4+T细胞。
肿瘤免疫疗法:给动物瘤内注射80微克的抗CD40(克隆FGK4.5;BioXCell)和10微克的TNFα(BioLegend),并注射或不注射100微克/小鼠抗人/小鼠TRP1 IgG抗体(克隆TA99;BioXCell)。100微克/小鼠的抗鸡卵清蛋白(克隆TOSGAA1;BioLegend)用作对照。
过继T细胞转移:C57Bl/6小鼠皮下注射2x105 B16F10肿瘤细胞。在第12天和第14天,给小鼠瘤内注射80微克的抗CD40(克隆FGK4.5;BioXCell)、1微克的IFNγ(Biolegend)及/或200微克的抗TRP1。在第7天,对小鼠实施安乐死,切除肿瘤和引流淋巴结,并分离以获得单细胞悬液。随后,使用磁珠(EasySep,StemCell technologies)富集T细胞,并通过FACSAriaII进一步分选为FCSlo/SSClo/TCRβ+/MHCIIneg细胞。T细胞在含有1,000IU/mL IL-2(Peprotech)的T细胞培养基中,在涂有0.5μg/mL抗CD3的培养盘上培养。9至12天后,轻轻收集T细胞,并将总共1x106细胞静脉注射到携带平均大小为30至50平方毫米的肿瘤的小鼠中。
免疫组织化学:对于冷冻切片,组织在4%多聚甲醛中固定1小时,然后在20%蔗糖溶液中平衡过夜。随后,将组织包埋在冷冻组织基质(Scigen O.C.T.Compound CryostatEmbedding Medium,Thermo Fisher Scientific)中,并在-80℃下冷冻。使用5%BSA封闭5μm厚的切片,并用1:100稀释的一抗染色。使用抗CD3(克隆17A2)、抗CD4(RM4-4)、抗TCRβ(H57-597)、抗FcRI(X54-5/7.1)、抗FcRII/III(93)、抗FcRIV(9E9)进行染色。细胞核用Hoechst 33342(Fluka)复染。使用ZEISS LSM 800共焦显微镜进行显微镜检查,并使用ZEN软件(ZEISS,德国)进行分析。
共聚焦显微镜检查:B16-Wassabi和CD4+T细胞在玻璃底共聚焦板(Cellvis,Mountain View,CA)上在不含IL-2的T细胞培养基中共培养,并在标准条件下温育过夜。细胞进一步与BV421结合抗CD107(BioLegend)以1:100稀释度温育1小时。使用Zeiss LSM800共聚焦激光扫描显微镜收集图像,并使用ZEN软件(Carl Zeiss Microscopy)进行分析。
Fab2'片段的制备:抗TRP1 Ab(克隆TA99;BioXCell)在在pH值为4.5的20mM醋酸钠进行透析,并在37℃旋转培养箱中使用琼脂糖胃蛋白酶珠(Goldbio,St.Louis,MO)消化16小时。接下来,将样品离心并收集上清液,针对PBS pH 7.4进行透析,并与蛋白A琼脂糖珠(Santa Cruz Biotechnology,Dallas,TX)一起旋转温育2小时。离心后收集Fab2'部分,并通过PAGE进行分析。
杀伤试验:CD4+T细胞与B16靶细胞(每孔30,000个细胞)以1:2(T:E)的比例在圆底96孔盘中共培养,有或没有以下抗体:抗鸡卵清蛋白(克隆TOSGAA1;BioLegend)、抗TRP-1(克隆TA99;BioXCell)或抗TRP-1 Fab2'。24小时和48小时后,用PBS替换培养培养基,并通过Synergy H1M读板器(BioTek,Winooski,VT)测量wasabi的荧光强度(激发485nm发射528nm)。48小时后,细胞使用膜联蛋白V(Biolegend)染色15分钟,碘化丙啶在冰上染色2分钟,并通过流式细胞术分析染色水平。
统计分析:每个实验进行3次。每个实验组由至少三只小鼠组成。当分析多个组时,使用非参数单因子变异数分析(one-way ANOVA)或非参数学生t检验(Student’s t-test)确定结果的显着性。
结果:
CD4+T细胞和肿瘤结合抗体的过继转移诱导直接肿瘤溶解:在之前的一项研究中,对自发性黑色素瘤小鼠模型以及接受GM-CSF和CTLA-4治疗的黑色素瘤患者中进行有效免疫治疗后发生的变化进行了分析。分析表明,有效的免疫疗法与各种解剖器官19中大量存在抗原的CD4+T细胞群的大量扩增密切相关。在后续研究中,本发明人表征了哪个器官含有最有效的肿瘤反应性CD4+T细胞。为此,从血液、引流淋巴结(DLN)和WT C57BL/6小鼠的B16黑色素瘤肿瘤中分离出效应CD4+T细胞,并通过静脉注射转移到携带B16黑色素瘤细胞的WTC57BL/6小鼠体内,结合抗黑色素瘤抗原TRP1的抗体(gp75,图1A)。虽然从血液中注射效应CD4+T细胞对肿瘤消退的影响很小,但从肿瘤和DLN中注射CD4+T细胞诱导了显着、持久的肿瘤消退(图1B至图1C)。在下一步中,本发明人评估了转移的CD4+细胞是否直接杀死肿瘤细胞,或者更确切地说是通过激活其他效应T细胞来介导它们的杀伤。因此,使用B16细胞攻击RAG缺陷小鼠(RAG-/-),让肿瘤生长10天。随后,RAG-/-小鼠被注射了来自WT C57BL/6荷瘤小鼠的1x106效应子CD4+,具有或不具有抗TRP1抗体。有趣的是,这种治疗在RAG-/-小鼠中的疗效与免疫活性小鼠的疗效相当,这表明肿瘤溶解是由转移的抗体和CD4+T细胞直接诱导的(图1D)。接下来,评估抗体和T细胞受体(TCR)的特异性是否在诱导肿瘤消退中起作用。为此,从识别无关卵清蛋白(Ova)表位的OT-II或识别源自TRP1的肽的RAG1-BW TRP-1TCR小鼠中分离出携带单个TCR的CD4+T细胞。随后,将效应T细胞注射到携带B16黑色素瘤细胞的WTC57BL/6小鼠中,并结合抗Ova的抗体(在B16上不表达)或抗肿瘤抗原TRP1的抗体。单独的效应T细胞的过继转移几乎是惰性的,这些群组中的肿瘤生长与未治疗小鼠的肿瘤生长相当。同样,使用抗体注射Ova反应性T细胞对肿瘤生长的影响很小。与此形成鲜明对比的是,注射TRP1反应性CD4+T细胞和抗TRP1抗体,而不是抗Ova抗体,诱导了完全持久的肿瘤根除(图1E)。
总之,这些结果表明CD4+的细胞毒活性需要TCR,以及抗体都靶向肿瘤细胞。
淋巴和癌性器官中的CD4+T细胞亚群表达Fcγ受体:尽管人们普遍认为T细胞不表达Fcγ受体(FcγR),但鉴于上文所述的结果,本发明人决定重新审视这一概念。为此,从携带B16黑色素瘤细胞的WT C57BL/6小鼠中收集肿瘤、DLN和PB,并通过FACS分析CD4+T细胞上FcγR的表达模式。分析表明,大约5%的肿瘤浸润性CD4+T细胞表达所有三种类型的FcγR(FcγRI(CD64,在本文中也称为FcγRIα)、FcγRII/III和FcγRIV),其水平与已知表达这些受体的抗原呈递细胞的水平相当(图2A)。
在DLN中也观察到表达FcγR的CD4+T细胞的百分比较低(但可检测),但在外周血中未观察到(图2B)。接下来,评估了此子集是否存在于另一个肿瘤模型中,或者更确切地说仅限于B16黑色素瘤。事实上,所有三种FcγR均在携带4T1乳腺癌细胞的Balb/c小鼠的肿瘤和DLN中的CD4+T细胞上表达,但具有不同的表达模式(图2C)。
发明人还测试了此群体是否存在于空白小鼠中,或者更确切地说是仅在肿瘤进展期间被诱导。为此,从空白小鼠中收获了各种器官,并分析了T细胞上的FcγR表达。在淋巴结、脾脏和骨髓(BM)中发现了表达FcγR的T细胞,但在血液或胸腺中未发现(图3A)。这些T细胞在RAG-/-小鼠中完全不存在,表明它们的成熟依赖于TCR重排(数据未显示)。为确保这些确实是T细胞,将脾细胞应用于Ficoll梯度,在CD4磁珠上富集,并对FcγRI+和FcγRIneg/CD3+/MHCIIneg/dull进行分类(图3B)。共聚焦分析表明,这两个亚群具有相似的形态和大小,并且具有相同的细胞膜TCRβ染色。额外染色进一步表明FcγRI在靠近CD4分子的细胞膜上表达(图3C)。这些结果通过PCR扩增FcγRI转录物得到了进一步验证。与FACS和共聚焦结果一致,发现FcγRI基因转录物在FcγRI+/CD3+/MHCIIneg/dull CD4+T细胞中表达,而不是在传统的FcγRI阴性CD4+T细胞中表达(图3D)。此外,空白脾脏和肿瘤的组织切片染色进一步表明,这些细胞仅位于T细胞区的边缘(图3E)。
表达FcγRI的肿瘤特异性CD4+T细胞诱导有效的肿瘤细胞裂解:在下一步中,测试FcγR在T细胞上的表达是否具有功能性,或者仅仅是表面标记物。为此,从WT C57BL/6对照小鼠中分离表达或不表达FcγRI的脾CD4+T细胞,并与B16肿瘤细胞一起温育过夜。FcγRI+/CD4+T细胞,而不是FcγRIneg/CD4+T细胞,与B16与抗TRP1抗体组合的温育诱导了显着的肿瘤细胞裂解。当FcγRI+/CD4+T细胞与抗卵清蛋白抗体或抗TRP1 Fab2'一起温育时,肿瘤细胞裂解被完全消除。此外,从OT-II小鼠中分离的FcγRI+/CD4+与B16和抗TRP1的温育不会诱导肿瘤杀伤,表明TCR必须靶向肿瘤抗原(图4A至图4B)。
示例2
CD4+和CD8+T细胞中FcγRI和FcRγ的外源表达诱导有效的肿瘤细胞裂解
材料和方法:
小鼠和细胞系:如上文示例1中所述。此外,通过使用含有pLVX-H2B-tdTomato的慢病毒感染B16F10细胞,获得tdTomato B16F10细胞,然后通过FACS(BD FACSAriaTM III,BDBiosciences,Franklin Lakes,NJ)对高表达tdTomato群体进行分选。
T细胞分离:从WT C57BL/6小鼠中取出脾脏,并通过70μM细胞过滤器(strainer)捣碎。随后,根据制造商的说明,收集脾细胞并与抗CD4或抗CD8磁珠(MojoSortTM Nanobeads,BioLegend,Carlsbad,CA)一起温育。
T细胞转导:生成了三种逆转录病毒包装质粒:TRP1反应性TCR(SEQ ID NO:35、SEQID NO:36)、FcγRI(SEQ ID NO:5、SEQ ID NO:6)和Fc受体信号传导γ链(FcRγ,SEQ IDNO:15、SEQ ID NO:16)。此外,还产生了几种构建体来表达FcγRI、FcRγ及/或TCR CD3ζ链;FcγRI胞外域和TCRβ恒定区;和FcγRI胞外域、CD8铰链+跨膜域以及单质粒中的FcRγ(参见图5A、图6A、图7和图11A,SEQ ID No:21-28和41-44)。具体来说,融合序列的插入由GeneART(Thermo Fisher Scientific)合成到pMK载体中,并且使用IRES-GFP序列上游的EcoRI/XhoI位点进一步克隆到pMIGII中。通过pBABE5'和IRES-Rev引物测序(HyLabsIsrael)来验证克隆。组蛋白H2B序列使用AATAACACTAGTGCCACCATGCCTGAACCGGCAAAAT(SEQID NO:45)and AACAACCCCGGGACTTGTCGTCATCGTCTTTGT(SEQ ID NO:46)引物扩增,并克隆到含有EF1启动子的pLVX载体(Clontech)中,与tdTomato符合读框的SpeI/XmaI位点。序列通过MSC\v正向和tdTomato反向引物(HyLabs Israel)进行验证。
逆转录病毒感染:从小鼠血液中分离小鼠CD4+和CD8+T细胞,并且使用上述构建体感染如下:将铂E细胞接种(plated)在10cm培养盘上,并使用Polyplus试剂(Polyplus转染),用2:1摩尔比(molar ratio)的pMIGII45和PCL-Eco质粒共转染。24小时后,将培养基更换为补充有0.075%碳酸氢钠的完全DMEM。24小时和48小时后收集含有培养基的病毒,并以100,000g离心1小时。将沉淀轻轻重悬在1mL培养基中,并使其在4℃下过夜恢复。在感染之前,将脾CD4+T细胞或脾CD8+T细胞在含有高剂量IL-2(1,000IU/ml)的T细胞培养基中,在预先涂有抗CD3(0.5μg/mL)的盘中进行培养。接下来,将0.3mL浓缩逆转录病毒添加到每2x106 CD4+或CD8+T细胞中,其中含有10μg/mL聚凝胺(polybrene)。细胞在37℃、5%CO2中温育30分钟,然后在37℃、1,200rpm下离心1小时。随后,更换80%的培养基,并将T细胞在含有高剂量IL-2的T细胞培养基中再培养3天。
慢病毒感染:在EF1启动子下,将含有H2B-tdTomato的pLVX质粒与psPAX2(Addgene质粒#12260)以及pCMV-VSV-G(Addgene质粒#8454)一起转染HEK-293FT细胞。在24和48小时后收集含有培养基的病毒。对于感染,将B16F10细胞与病毒和100μg/mL聚凝胺(SigmaAldrich,Merck,以色列)一起温育30分钟,然后在更换培养基之前离心30分钟。3天后,表达tdTomato的细胞通过FACSAriaII进行分类。
体内肿瘤模型:如上文示例1中所述。
过继T细胞转移:C57Bl/6小鼠皮下注射2x105 B16F10肿瘤细胞。9至12天后,将总共1x106转导的T细胞静脉注射到携带平均大小为30至50mm2的肿瘤的小鼠中,其中具有或不具有200微克的抗TRP1。
杀伤试验(Killing assay):CD4+或CD8+T细胞与B16靶细胞(每孔30,000个细胞)以1:2(T:E)的比例在具有或不具有抗TRP-1(克隆TA99;BioXCell)的圆底96孔盘中共培养。在倒置光学显微镜下,在X100放大倍率下,拍摄温育48小时后的图像。此外,48小时后,细胞使用膜联蛋白V(Biolegend)染色15分钟,以及使用碘化丙啶在冰上染色2分钟,并且通过流式细胞术分析染色水平。IncuCyte成像仪杀伤测定通过在96孔盘中培养104个H2B-tdTomatoB16F10靶细胞进行。2小时后,在200微升的培养基中加入2x104 T细胞,其中具有或不具有15微克的抗TRP-1抗体,并且通过incuCyte S3成像仪(Sartorius)成像至少24小时。然后,通过incuCyte软件使用图像计算靶细胞数。
共聚焦显微镜:将CD4+以及CD8+T细胞接种在玻璃底共聚焦板上,并使用抗CD3(克隆17A2)、抗TCRβ(H57-597)、抗FcRI(X54-5/7.1)染色。使用Zeiss LSM800共聚焦激光扫描显微镜收集图像,并使用ZEN软件(Carl Zeiss Microscopy)进行分析。
统计分析:如上文示例1中所述。
结果:
在下一步中,发明人测试了上文示例1中描述的杀伤机制是否可以在FcγRIneg/CD4+T细胞中模拟。为此,脾CD4+T细胞使用三种逆转录病毒包装质粒进行感染:TRP1-反应性TCR、FcγRI及/或Fc受体信号传导γ链(FcRγ),并且接种B16肿瘤细胞(图4C)。重要的是,感染了肿瘤特异性TCR、FcγRI及γ链的CD4+T细胞诱导了最显着的杀伤反应,这可以从T细胞膜上的CD107a以及涂有抗体的肿瘤细胞的细胞死亡中看出。抗体介导的B16被TCR-FcγRI-TcRγ感染的CD4+杀伤的代表性显微镜图像显示在右图上(图4C)。感染后的CD4+T细胞在过继转移模型中进行测试,其中具有或不具有抗TRP1抗体,以评估体内细胞的杀伤活性。如图4D所示,与体外相同,在体内模型中,TRP1的TCR与FcγRI以及信号传导γ链的表达,结合抗TRP1抗体,介导了肿瘤的根除。
随后,克隆了以下构建体(图5A、图6A及图7):FcγRIα和FcRγ由T2A序列(SEQ IDNo:21、SEQ ID No:22)、FcγRIαT2A FcRγ-CD3ζ(ζ链ITAMS)融合(SEQ ID No:23、SEQ IDNo:24)、FcγRIα-CD3ζ融合(SEQ ID No:25、SEQ ID No:26)、FcγRIα-CD3ζT2A FcRγ(SEQID No:27、SEQ ID No:28)以及FcγRIα-TCRβ恒定区(SEQ ID No:41、SEQ ID No:42)分隔。这些质粒被装入逆转录病毒中,用于感染CD4+和CD8+T细胞。进一步将转导的T细胞与抗TRP1抗体共同培养,并且测试B16杀伤活性(图5B)。为了比较不同受体设置介导的杀伤水平,与转导的CD8+T细胞共培养的B16细胞使用膜联蛋白-V/PI(annexin-V/PI)进行染色,并通过流式细胞术进行分析(图5C)。
综上所述,这些结果表明,当靶细胞被抗体包被时,通过FcγRI和FcRγ信号传导链的伴随信号可以在常规CD4+和CD8+T细胞中发挥杀伤能力。此外,比较表明分离FcγR信号分子的优势比将CD3ζ信号传导的ITAMS或TCRβ与FcγRI受体融合更有效。
为了验证FcγRIα-2A-FcRγ构建体的膜定位,对细胞进行TCRβ及CD3以及FcγRIα染色。共聚焦分析表明FcγRIα均匀地位在T细胞膜上(图8)。随后,使用表达组蛋白H2B-tdTomato的B16细胞评估感染了FcγRIα-2A-FcRγ构建体的T细胞的杀伤能力。最初,B16-H2B-tdTomato以每孔24个细胞到50,000个细胞的连续浓度进行培养,在incuCyte中成像,并且通过incuCyte分析工具进行计数,其检测以及计数由相机捕获的场中的红色荧光核。图9中的图表显示了培养的细胞数量与场中计数的细胞数量之间的直接相关性。因此,incuCyte成像系统被用于评估抗TRP-1抗体和表达FcγRIα-2A-FcRγ的T细胞对B16-H2B-tdTomato的杀伤,其中这些T细胞以不同的效应物(effector)与靶标物的比率进行培养,范围为0.5:1至16:1。48小时后的代表性图像(图10A)以及靶细胞数量(图10B)显示,当效应物:靶标比率为8比1或更高时,CD8+和CD4+T细胞均杀死了肿瘤细胞。
随后,克隆了另外的构建体(图11A):FcγRIα胞外域-CD8铰链(hinge)及跨膜域-FcRγ-(SEQ ID NO:43、SEQ ID NO:44)。此构建体在CD8+T细胞中表达,并使用表达组蛋白H2B-tdTomato的B16细胞评估其杀伤能力(图11B至图11C)。结果表明,与表达两者的单一多肽相比,表达两种不同多肽的优势,一种包含FcγRIα的配体结合域,另一种包含FcRγ。
示例3
外源表达FcγRI及FcRγ的小鼠以及人类CD4+及CD8+T细胞具有抗肿瘤效果:
材料及方法:
T细胞转导:如上文示例2中所述产生若干构建体。此外,产生了用于将FcγRI、FcRγ及TCR CD3ζ链表达为单一多肽的额外构建体(参见图7,SEQ ID No:29-32)。从小鼠血液中分离小鼠CD4+和CD8+T细胞,并使用上文示例2的构建体进行感染。人类CD4+和CD8+T细胞是从健康供体的血液中或是从对阿替利珠(Atezolizumab)治疗无效并且被上述构建体感染的黑色素瘤患者的血液中分离出来的。
体外测量转导的小鼠T细胞的细胞毒活性:转导的T细胞与B16、4T1或MC38肿瘤细胞共培养,这些肿瘤细胞表达高水平的PDL1,其中具有或不具有抗PDL1抗体(BioXCell)。在几个时间点,使用由Biotek H1M盘判读器(plate reader)创建的荧光活细胞测定来测量肿瘤细胞裂解。
体外测量转导的患者来源T细胞的细胞毒活性:从健康供体分离的转导T细胞与表达PDL1的SK-Mel-5及A375肿瘤细胞系一起温育,其中具有或不具有阿替利珠(Atezolizumab)。在几个时间点,测量肿瘤细胞裂解。此外,从对阿替利珠(Atezolizumab)治疗无效的黑色素瘤患者的血液中分离的转导T细胞与自体(autologous)黑色素瘤肿瘤细胞共培养,其中具有或不具有阿替利珠(Atezolizumab)。在几个时间点,使用Biotek H1M盘判读器(plate reader)通过荧光活细胞测定来测量肿瘤细胞裂解。
体外测试转导的T细胞的特异性:由于T细胞也可以表达PDL1,尽管通常水平较低,因此测试了引发靶细胞杀伤的抗原浓度。为此,巨噬细胞、B细胞及内皮细胞从空白小鼠(naive mice)以及健康人类供体中分离出来,并使用IFNγ激活,以诱导PDL1表达。细胞与转导的T细胞一起温育(incubated)过夜,其中具有或是不具有抗PDL1抗体,细胞死亡率由膜联蛋白V(annexin V)及碘化丙啶(PI)染色确定。
测试转导的小鼠T细胞根除被建立的实体瘤的能力:对小鼠注射B16细胞、MC38或4T1,所有这些细胞都表达高水平的PDL1,但对阻断抗体无效。一旦肿瘤形成,小鼠通过静脉注射转导的小鼠T细胞(具有或是不具有抗小鼠PDL1抗体)来进行治疗,并监测肿瘤负荷。此外,通过流式细胞术分析肿瘤的T细胞浸润、扩增及IFNγ分泌。在共聚焦显微镜下通过tunnel染色确定肿瘤细胞凋亡。
测试转导的人类T细胞根除人类肿瘤的能力:将表达PDL1的肿瘤细胞系SK-Mel-5及A375移植到裸(nude)-scid-IL2Rγ-/-小鼠(NSG)中,并使其生长至可触及的大小。随后,小鼠被注射具有或不具有阿替利珠(Atezolizumab)的转导人T细胞,并监测肿瘤生长。此外,通过流式细胞术分析肿瘤的T细胞浸润、扩增及IFNγ分泌。在共聚焦显微镜下通过tunnel染色确定肿瘤细胞凋亡。
测试转导的肿瘤T细胞杀死难治性人类肿瘤的能力:从患者身上获取新鲜肿瘤样本及PBMC,这些患者的肿瘤表达高水平的PDL1,并且正在接受切除手术。从癌症患者中建立转导的细胞系,并且注射到NSG小鼠中。一旦肿瘤达到可触及的大小,小鼠就会被注射有或没有阿替利珠(Atezolizumab)的转导自体(autologous)T细胞,并监测肿瘤的生长。
评估小鼠的健康状况、细胞激素风暴(cytokine storm)的迹象及肿瘤溶解综合征:除了监测同系(syngeneic)小鼠及NSG小鼠的肿瘤生长外,还定期检查小鼠在治疗后的健康状况。为此,每隔一天对小鼠称重,并且评估它们的活动水平,以及皮炎、腹泻和急性疼痛的迹象。此外,小鼠每周从视网膜撕裂处取血两次,并测试CRP、MCP-1、IL-6、TNFα、IFNγ及IL-1的血清水平。还检测了血清样本的代谢异常,包括钾、磷酸盐、钙、尿酸、葡萄糖、肌酐及白蛋白的水平,以及肝酶ALT、AST、ALP。
测试脱靶肿瘤细胞毒性和自身免疫的迹象:
一旦实验结束,使用或没有使用阿替利珠(Atezolizumab)的转导T细胞处理的小鼠通过染色连续组织切片进行分析。通过Ki67染色测试淋巴器官中的过度淋巴细胞增殖,并通过对T细胞、B细胞及髓细胞染色来测试肝脏、肾上腺皮质、唾液腺、肾脏、心脏、皮肤及结肠的免疫浸润。
尽管已经结合其特定实施例描述了本发明,但很明显,对于本领域技术人员而言,许多替代、修改及变化会是显而易见的。因此,其旨在包括落入所附权利要求的精神及广泛范围内的所有此类替代、修改及变化。
本说明书中提及的所有出版物、专利及专利申请均在本文中通过引用整体并入本说明书中,达到如同每个单独的出版物、专利或专利申请被具体及单独地指出通过引用并入本文的相同程度。另外,本申请中任何参考文献的引用或识别不应被解释为承认这样的参考文献可作为本发明的现有技术。在使用章节标题的范围内,不应将其解释为必然的限制。
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(在整个申请中引用了其他参考文献)
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18.Joyce,J.A.&Fearon,D.T.T;细胞排斥、免疫特权和肿瘤微环境(T cellexclusion,immune privilege,and the tumor microenvironment);Science;348,74-80,doi:10.1126/science.aaa6204 348/6230/74[pii](2015);以及
19.Spitzer,M.H.等人;有效的癌症免疫治疗需要全身免疫(Systemic ImmunityIs Required for Effective Cancer Immunotherapy);Cell;168,487-502 e415,doi:S0092-8674(16)31738-X[pii]10.1016/j.cell.2016.12.022(2017)。
序列表
<110> 拉莫特特拉维夫大学有限公司 (RAMOT AT TEL-AVIV UNIVERSITY LTD.)
亚龙·卡米 (CARMI, Yaron)
皮勒·里德 (RIDER, Peleg)
戴安娜·拉苏鲁尼里亚娜 (RASOULOUNIRIANA, Diana)
<120> 表达FCγ受体的T细胞及其使用方法
<130> 81398
<150> US 62/820,357
<151> 2019-03-19
<160> 68
<170> PatentIn version 3.5
<210> 1
<211> 20
<212> DNA
<213> Artificial sequence
<220>
<223> 单链DNA寡核苷酸
<400> 1
agacaccgct acacatctgc 20
<210> 2
<211> 20
<212> DNA
<213> Artificial sequence
<220>
<223> 单链DNA寡核苷酸
<400> 2
gggaagtttg tgccccagta 20
<210> 3
<211> 20
<212> DNA
<213> Artificial sequence
<220>
<223> 单链DNA寡核苷酸
<400> 3
gcattctgag aggatgcggt 20
<210> 4
<211> 20
<212> DNA
<213> Artificial sequence
<220>
<223> 单链DNA寡核苷酸
<400> 4
tggccttggc cttcctattc 20
<210> 5
<211> 404
<212> PRT
<213> Artificial sequence
<220>
<223> Fcγ受体1 (CD64) AA序列
<400> 5
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
195 200 205
Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
210 215 220
Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
225 230 235 240
Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
245 250 255
Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
260 265 270
Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
275 280 285
Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe
290 295 300
Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val
305 310 315 320
Lys Ile His Arg Leu Gln Arg Glu Lys Lys Tyr Asn Leu Glu Val Pro
325 330 335
Leu Val Ser Glu Gln Gly Lys Lys Ala Asn Ser Phe Gln Gln Val Arg
340 345 350
Ser Asp Gly Val Tyr Glu Glu Val Thr Ala Thr Ala Ser Gln Thr Thr
355 360 365
Pro Lys Glu Ala Pro Asp Gly Pro Arg Ser Ser Val Gly Asp Cys Gly
370 375 380
Pro Glu Gln Pro Glu Pro Leu Pro Pro Ser Asp Ser Thr Gly Ala Gln
385 390 395 400
Thr Ser Gln Ser
<210> 6
<211> 1215
<212> DNA
<213> Artificial sequence
<220>
<223> Fcγ受体1 (CD64) NA序列
<400> 6
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gagcatccgt gtcatctccc ttcccggagg ggagtctggt caccctgaac 660
tgtgagacga atttgctcct gcagagaccc ggcttacagc ttcacttctc cttctacgtg 720
ggcagcaaga tcctggagta caggaacaca tcctcagagt accatatagc aagggcggaa 780
agagaagatg ctggattcta ctggtgtgag gtagccacgg aggacagcag tgtccttaag 840
cgcagccctg agttggagct ccaagtgctt ggtccccagt catcagctcc tgtctggttt 900
cacatcctgt tttatctgtc agtgggaata atgttttcgt tgaacacggt tctctatgtg 960
aaaatacaca ggctgcagag agagaagaaa tacaacttag aagtcccttt ggtttctgag 1020
cagggaaaga aagcaaattc ctttcagcaa gttagaagcg atggcgtgta tgaagaagta 1080
acagccactg cgagccagac cacaccaaaa gaagcgcccg atggacctcg aagctcagtg 1140
ggtgactgtg gacccgagca gcctgaaccc cttcctccca gtgacagtac tggggcacaa 1200
acttcccaaa gttga 1215
<210> 7
<211> 273
<212> PRT
<213> Artificial sequence
<220>
<223> CD64-AA序列的胞外结构域
<400> 7
Glu Val Val Asn Ala Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp
1 5 10 15
Val Ser Ile Phe Gln Lys Glu Asn Val Thr Leu Trp Cys Glu Gly Pro
20 25 30
His Leu Pro Gly Asp Ser Ser Thr Gln Trp Phe Ile Asn Gly Thr Ala
35 40 45
Val Gln Ile Ser Thr Pro Ser Tyr Ser Ile Pro Glu Ala Ser Phe Gln
50 55 60
Asp Ser Gly Glu Tyr Arg Cys Gln Ile Gly Ser Ser Met Pro Ser Asp
65 70 75 80
Pro Val Gln Leu Gln Ile His Asn Asp Trp Leu Leu Leu Gln Ala Ser
85 90 95
Arg Arg Val Leu Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Gly
100 105 110
Trp Lys Asn Lys Leu Val Tyr Asn Val Val Phe Tyr Arg Asn Gly Lys
115 120 125
Ser Phe Gln Phe Ser Ser Asp Ser Glu Val Ala Ile Leu Lys Thr Asn
130 135 140
Leu Ser His Ser Gly Ile Tyr His Cys Ser Gly Thr Gly Arg His Arg
145 150 155 160
Tyr Thr Ser Ala Gly Val Ser Ile Thr Val Lys Glu Leu Phe Thr Thr
165 170 175
Pro Val Leu Arg Ala Ser Val Ser Ser Pro Phe Pro Glu Gly Ser Leu
180 185 190
Val Thr Leu Asn Cys Glu Thr Asn Leu Leu Leu Gln Arg Pro Gly Leu
195 200 205
Gln Leu His Phe Ser Phe Tyr Val Gly Ser Lys Ile Leu Glu Tyr Arg
210 215 220
Asn Thr Ser Ser Glu Tyr His Ile Ala Arg Ala Glu Arg Glu Asp Ala
225 230 235 240
Gly Phe Tyr Trp Cys Glu Val Ala Thr Glu Asp Ser Ser Val Leu Lys
245 250 255
Arg Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Pro Gln Ser Ser Ala
260 265 270
Pro
<210> 8
<211> 819
<212> DNA
<213> Artificial sequence
<220>
<223> CD64-NA序列的胞外结构域
<400> 8
gaagtggtta atgccaccaa ggctgtgatc accttgcagc ctccatgggt cagtattttc 60
cagaaggaaa atgtcacttt atggtgtgag gggcctcacc tgcctggaga cagttccaca 120
caatggttta tcaacggaac agccgttcag atctccacgc ctagttatag catcccagag 180
gccagttttc aggacagtgg cgaatacagg tgtcagatag gttcctcaat gccaagtgac 240
cctgtgcagt tgcaaatcca caatgattgg ctgctactcc aggcctcccg cagagtcctc 300
acagaaggag aacccctggc cttgaggtgt cacggatgga agaataaact ggtgtacaat 360
gtggttttct atagaaatgg aaaatccttt cagttttctt cagattcgga ggtcgccatt 420
ctgaaaacca acctgagtca cagcggcatc taccactgct caggcacggg aagacaccgc 480
tacacatctg caggagtgtc catcacggtg aaagagctgt ttaccacgcc agtgctgaga 540
gcatccgtgt catctccctt cccggagggg agtctggtca ccctgaactg tgagacgaat 600
ttgctcctgc agagacccgg cttacagctt cacttctcct tctacgtggg cagcaagatc 660
ctggagtaca ggaacacatc ctcagagtac catatagcaa gggcggaaag agaagatgct 720
ggattctact ggtgtgaggt agccacggag gacagcagtg tccttaagcg cagccctgag 780
ttggagctcc aagtgcttgg tccccagtca tcagctcct 819
<210> 9
<211> 23
<212> PRT
<213> Artificial sequence
<220>
<223> CD64 AA序列的跨膜结构域
<400> 9
Val Trp Phe His Ile Leu Phe Tyr Leu Ser Val Gly Ile Met Phe Ser
1 5 10 15
Leu Asn Thr Val Leu Tyr Val
20
<210> 10
<211> 69
<212> DNA
<213> Artificial sequence
<220>
<223> CD64 NA序列的跨膜结构域
<400> 10
gtctggtttc acatcctgtt ttatctgtca gtgggaataa tgttttcgtt gaacacggtt 60
ctctatgtg 69
<210> 11
<211> 84
<212> PRT
<213> Artificial sequence
<220>
<223> CD64 AA序列的胞内结构域
<400> 11
Lys Ile His Arg Leu Gln Arg Glu Lys Lys Tyr Asn Leu Glu Val Pro
1 5 10 15
Leu Val Ser Glu Gln Gly Lys Lys Ala Asn Ser Phe Gln Gln Val Arg
20 25 30
Ser Asp Gly Val Tyr Glu Glu Val Thr Ala Thr Ala Ser Gln Thr Thr
35 40 45
Pro Lys Glu Ala Pro Asp Gly Pro Arg Ser Ser Val Gly Asp Cys Gly
50 55 60
Pro Glu Gln Pro Glu Pro Leu Pro Pro Ser Asp Ser Thr Gly Ala Gln
65 70 75 80
Thr Ser Gln Ser
<210> 12
<211> 255
<212> DNA
<213> Artificial sequence
<220>
<223> CD64 NA序列的胞内结构域
<400> 12
aaaatacaca ggctgcagag agagaagaaa tacaacttag aagtcccttt ggtttctgag 60
cagggaaaga aagcaaattc ctttcagcaa gttagaagcg atggcgtgta tgaagaagta 120
acagccactg cgagccagac cacaccaaaa gaagcgcccg atggacctcg aagctcagtg 180
ggtgactgtg gacccgagca gcctgaaccc cttcctccca gtgacagtac tggggcacaa 240
acttcccaaa gttga 255
<210> 13
<211> 86
<212> PRT
<213> Artificial sequence
<220>
<223> Fc受体共同γ链AA序列
<400> 13
Met Ile Ser Ala Val Ile Leu Phe Leu Leu Leu Leu Val Glu Gln Ala
1 5 10 15
Ala Ala Leu Gly Glu Pro Gln Leu Cys Tyr Ile Leu Asp Ala Val Leu
20 25 30
Phe Leu Tyr Gly Ile Val Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile
35 40 45
Gln Val Arg Lys Ala Ala Ile Ala Ser Arg Glu Lys Ala Asp Ala Val
50 55 60
Tyr Thr Gly Leu Asn Thr Arg Ser Gln Glu Thr Tyr Glu Thr Leu Lys
65 70 75 80
His Glu Lys Pro Pro Gln
85
<210> 14
<211> 261
<212> DNA
<213> Artificial sequence
<220>
<223> Fc受体共同γ链NA序列
<400> 14
atgatctcag ccgtgatctt gttcttgctc cttttggtgg aacaagcagc cgccctggga 60
gagccgcagc tctgctatat cctggatgct gtcctgtttt tgtatggtat tgtccttacc 120
ctactctact gtcgactcaa gatccaggtc cgaaaggcag ctatagccag ccgtgagaaa 180
gcagatgctg tctacacggg cctgaacacc cggagccagg agacatatga gactctgaag 240
catgagaaac caccccagta g 261
<210> 15
<211> 86
<212> PRT
<213> Artificial sequence
<220>
<223> Fc受体共同γ链AA序列(构建体中)
<400> 15
Met Ile Ser Ala Val Ile Leu Phe Leu Leu Leu Leu Val Glu Gln Ala
1 5 10 15
Ala Ala Leu Gly Glu Pro Gln Leu Cys Tyr Ile Leu Asp Ala Val Leu
20 25 30
Phe Leu Tyr Gly Ile Val Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile
35 40 45
Gln Val Arg Lys Ala Ala Ile Ala Ser Arg Glu Lys Ala Asp Ala Val
50 55 60
Tyr Thr Gly Leu Asn Thr Arg Ser Gln Glu Thr Tyr Glu Thr Leu Lys
65 70 75 80
His Glu Lys Pro Pro Gln
85
<210> 16
<211> 261
<212> DNA
<213> Artificial sequence
<220>
<223> Fc受体共同γ链NA序列(构建体中)
<400> 16
atgatctcag ccgtgatctt gttcttgctc cttttggtgg aacaagcagc cgccctggga 60
gagccgcagc tctgctatat cctggatgct gtcctgtttt tgtatggtat tgtccttacc 120
ctactctact gtcgactcaa gatccaggtc cgaaaggcag ctatagccag ccgtgagaaa 180
gcagatgctg tctacacggg cctgaacacc cggagccagg agacatatga gactctgaag 240
catgagaaac caccccagta g 261
<210> 17
<211> 164
<212> PRT
<213> Artificial sequence
<220>
<223> CD3 ζ AA序列
<400> 17
Met Lys Trp Lys Val Ser Val Leu Ala Cys Ile Leu His Val Arg Phe
1 5 10 15
Pro Gly Ala Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Ile Thr Ala
35 40 45
Leu Tyr Leu Arg Ala Lys Phe Ser Arg Ser Ala Glu Thr Ala Ala Asn
50 55 60
Leu Gln Asp Pro Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
65 70 75 80
Glu Glu Tyr Asp Val Leu Glu Lys Lys Arg Ala Arg Asp Pro Glu Met
85 90 95
Gly Gly Lys Gln Gln Arg Arg Arg Asn Pro Gln Glu Gly Val Tyr Asn
100 105 110
Ala Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Thr
115 120 125
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
130 135 140
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Thr
145 150 155 160
Leu Ala Pro Arg
<210> 18
<211> 495
<212> DNA
<213> Artificial sequence
<220>
<223> CD3 ζ NA序列
<400> 18
atgaagtgga aagtgtctgt tctcgcctgc atcctccacg tgcggttccc aggagcagag 60
gcacagagct ttggtctgct ggatcccaaa ctctgctact tgctagatgg aatcctcttc 120
atctacggag tcatcatcac agccctgtac ctgagagcaa aattcagcag gagtgcagag 180
actgctgcca acctgcagga ccccaaccag ctctacaatg agctcaatct agggcgaaga 240
gaggaatatg acgtcttgga gaagaagcgg gctcgggatc cagagatggg aggcaaacag 300
cagaggagga ggaaccccca ggaaggcgta tacaatgcac tgcagaaaga caagatggca 360
gaagcctaca gtgagatcgg cacaaaaggc gagaggcgga gaggcaaggg gcacgatggc 420
ctttaccagg gtctcagcac tgccaccaag gacacctatg atgccctgca tatgcagacc 480
ctggcccctc gctaa 495
<210> 19
<211> 113
<212> PRT
<213> Artificial sequence
<220>
<223> CD3 ζ胞内ITAM结构域AA序列
<400> 19
Arg Ala Lys Phe Ser Arg Ser Ala Glu Thr Ala Ala Asn Leu Gln Asp
1 5 10 15
Pro Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Glu Lys Lys Arg Ala Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Gln Gln Arg Arg Arg Asn Pro Gln Glu Gly Val Tyr Asn Ala Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Thr Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Thr Leu Ala Pro
100 105 110
Arg
<210> 20
<211> 339
<212> DNA
<213> Artificial sequence
<220>
<223> CD3 ζ胞内ITAM结构域NA序列
<400> 20
agagcaaaat tcagcaggag tgcagagact gctgccaacc tgcaggaccc caaccagctc 60
tacaatgagc tcaatctagg gcgaagagag gaatatgacg tcttggagaa gaagcgggct 120
cgggatccag agatgggagg caaacagcag aggaggagga acccccagga aggcgtatac 180
aatgcactgc agaaagacaa gatggcagaa gcctacagtg agatcggcac aaaaggcgag 240
aggcggagag gcaaggggca cgatggcctt taccagggtc tcagcactgc caccaaggac 300
acctatgatg ccctgcatat gcagaccctg gcccctcgc 339
<210> 21
<211> 508
<212> PRT
<213> Artificial sequence
<220>
<223> FcgRI-T2A-γ构建体AA序列
<400> 21
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
195 200 205
Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
210 215 220
Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
225 230 235 240
Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
245 250 255
Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
260 265 270
Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
275 280 285
Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe
290 295 300
Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val
305 310 315 320
Lys Ile His Arg Leu Gln Arg Glu Lys Lys Tyr Asn Leu Glu Val Pro
325 330 335
Leu Val Ser Glu Gln Gly Lys Lys Ala Asn Ser Phe Gln Gln Val Arg
340 345 350
Ser Asp Gly Val Tyr Glu Glu Val Thr Ala Thr Ala Ser Gln Thr Thr
355 360 365
Pro Lys Glu Ala Pro Asp Gly Pro Arg Ser Ser Val Gly Asp Cys Gly
370 375 380
Pro Glu Gln Pro Glu Pro Leu Pro Pro Ser Asp Ser Thr Gly Ala Gln
385 390 395 400
Thr Ser Gln Ser Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val
405 410 415
Glu Glu Asn Pro Gly Pro Met Ile Ser Ala Val Ile Leu Phe Leu Leu
420 425 430
Leu Leu Val Glu Gln Ala Ala Ala Leu Gly Glu Pro Gln Leu Cys Tyr
435 440 445
Ile Leu Asp Ala Val Leu Phe Leu Tyr Gly Ile Val Leu Thr Leu Leu
450 455 460
Tyr Cys Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Ala Ser Arg
465 470 475 480
Glu Lys Ala Asp Ala Val Tyr Thr Gly Leu Asn Thr Arg Ser Gln Glu
485 490 495
Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
500 505
<210> 22
<211> 1527
<212> DNA
<213> Artificial sequence
<220>
<223> FcgRI-T2A-γ构建体NA序列
<400> 22
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gagcatccgt gtcatctccc ttcccggagg ggagtctggt caccctgaac 660
tgtgagacga atttgctcct gcagagaccc ggcttacagc ttcacttctc cttctacgtg 720
ggcagcaaga tcctggagta caggaacaca tcctcagagt accatatagc aagggcggaa 780
agagaagatg ctggattcta ctggtgtgag gtagccacgg aggacagcag tgtccttaag 840
cgcagccctg agttggagct ccaagtgctt ggtccccagt catcagctcc tgtctggttt 900
cacatcctgt tttatctgtc agtgggaata atgttttcgt tgaacacggt tctctatgtg 960
aaaatacaca ggctgcagag agagaagaaa tacaacttag aagtcccttt ggtttctgag 1020
cagggaaaga aagcaaattc ctttcagcaa gttagaagcg atggcgtgta tgaagaagta 1080
acagccactg cgagccagac cacaccaaaa gaagcgcccg atggacctcg aagctcagtg 1140
ggtgactgtg gacccgagca gcctgaaccc cttcctccca gtgacagtac tggggcacaa 1200
acttcccaaa gtgagggcag aggaagtctg ctaacatgcg gtgacgtcga ggagaatcct 1260
ggcccaatga tctcagccgt gatcttgttc ttgctccttt tggtggaaca agcagccgcc 1320
ctgggagagc cgcagctctg ctatatcctg gatgctgtcc tgtttttgta tggtattgtc 1380
cttaccctac tctactgtcg actcaagatc caggtccgaa aggcagctat agccagccgt 1440
gagaaagcag atgctgtcta cacgggcctg aacacccgga gccaggagac atatgagact 1500
ctgaagcatg agaaaccacc ccagtag 1527
<210> 23
<211> 621
<212> PRT
<213> Artificial sequence
<220>
<223> FcgRI-T2A-FcRg-CD3ζ构建体AA序列
<400> 23
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
195 200 205
Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
210 215 220
Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
225 230 235 240
Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
245 250 255
Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
260 265 270
Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
275 280 285
Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe
290 295 300
Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val
305 310 315 320
Lys Ile His Arg Leu Gln Arg Glu Lys Lys Tyr Asn Leu Glu Val Pro
325 330 335
Leu Val Ser Glu Gln Gly Lys Lys Ala Asn Ser Phe Gln Gln Val Arg
340 345 350
Ser Asp Gly Val Tyr Glu Glu Val Thr Ala Thr Ala Ser Gln Thr Thr
355 360 365
Pro Lys Glu Ala Pro Asp Gly Pro Arg Ser Ser Val Gly Asp Cys Gly
370 375 380
Pro Glu Gln Pro Glu Pro Leu Pro Pro Ser Asp Ser Thr Gly Ala Gln
385 390 395 400
Thr Ser Gln Ser Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val
405 410 415
Glu Glu Asn Pro Gly Pro Met Ile Ser Ala Val Ile Leu Phe Leu Leu
420 425 430
Leu Leu Val Glu Gln Ala Ala Ala Leu Gly Glu Pro Gln Leu Cys Tyr
435 440 445
Ile Leu Asp Ala Val Leu Phe Leu Tyr Gly Ile Val Leu Thr Leu Leu
450 455 460
Tyr Cys Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Ala Ser Arg
465 470 475 480
Glu Lys Ala Asp Ala Val Tyr Thr Gly Leu Asn Thr Arg Ser Gln Glu
485 490 495
Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln Arg Ala Lys Phe
500 505 510
Ser Arg Ser Ala Glu Thr Ala Ala Asn Leu Gln Asp Pro Asn Gln Leu
515 520 525
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Glu
530 535 540
Lys Lys Arg Ala Arg Asp Pro Glu Met Gly Gly Lys Gln Gln Arg Arg
545 550 555 560
Arg Asn Pro Gln Glu Gly Val Tyr Asn Ala Leu Gln Lys Asp Lys Met
565 570 575
Ala Glu Ala Tyr Ser Glu Ile Gly Thr Lys Gly Glu Arg Arg Arg Gly
580 585 590
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
595 600 605
Thr Tyr Asp Ala Leu His Met Gln Thr Leu Ala Pro Arg
610 615 620
<210> 24
<211> 1866
<212> DNA
<213> Artificial sequence
<220>
<223> FcgRI-T2A-FcRg-CD3ζ构建体NA序列
<400> 24
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gagcatccgt gtcatctccc ttcccggagg ggagtctggt caccctgaac 660
tgtgagacga atttgctcct gcagagaccc ggcttacagc ttcacttctc cttctacgtg 720
ggcagcaaga tcctggagta caggaacaca tcctcagagt accatatagc aagggcggaa 780
agagaagatg ctggattcta ctggtgtgag gtagccacgg aggacagcag tgtccttaag 840
cgcagccctg agttggagct ccaagtgctt ggtccccagt catcagctcc tgtctggttt 900
cacatcctgt tttatctgtc agtgggaata atgttttcgt tgaacacggt tctctatgtg 960
aaaatacaca ggctgcagag agagaagaaa tacaacttag aagtcccttt ggtttctgag 1020
cagggaaaga aagcaaattc ctttcagcaa gttagaagcg atggcgtgta tgaagaagta 1080
acagccactg cgagccagac cacaccaaaa gaagcgcccg atggacctcg aagctcagtg 1140
ggtgactgtg gacccgagca gcctgaaccc cttcctccca gtgacagtac tggggcacaa 1200
acttcccaaa gtgagggcag aggaagtctg ctaacatgcg gtgacgtcga ggagaatcct 1260
ggcccaatga tctcagccgt gatcttgttc ttgctccttt tggtggaaca agcagccgcc 1320
ctgggagagc cgcagctctg ctatatcctg gatgctgtcc tgtttttgta tggtattgtc 1380
cttaccctac tctactgtcg actcaagatc caggtccgaa aggcagctat agccagccgt 1440
gagaaagcag atgctgtcta cacgggcctg aacacccgga gccaggagac atatgagact 1500
ctgaagcatg agaaaccacc ccagagagca aaattcagca ggagtgcaga gactgctgcc 1560
aacctgcagg accccaacca gctctacaat gagctcaatc tagggcgaag agaggaatat 1620
gacgtcttgg agaagaagcg ggctcgggat ccagagatgg gaggcaaaca gcagaggagg 1680
aggaaccccc aggaaggcgt atacaatgca ctgcagaaag acaagatggc agaagcctac 1740
agtgagatcg gcacaaaagg cgagaggcgg agaggcaagg ggcacgatgg cctttaccag 1800
ggtctcagca ctgccaccaa ggacacctat gatgccctgc atatgcagac cctggcccct 1860
cgctaa 1866
<210> 25
<211> 517
<212> PRT
<213> Artificial sequence
<220>
<223> FcgRI-CD3ζ构建体AA序列
<400> 25
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
195 200 205
Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
210 215 220
Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
225 230 235 240
Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
245 250 255
Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
260 265 270
Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
275 280 285
Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe
290 295 300
Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val
305 310 315 320
Lys Ile His Arg Leu Gln Arg Glu Lys Lys Tyr Asn Leu Glu Val Pro
325 330 335
Leu Val Ser Glu Gln Gly Lys Lys Ala Asn Ser Phe Gln Gln Val Arg
340 345 350
Ser Asp Gly Val Tyr Glu Glu Val Thr Ala Thr Ala Ser Gln Thr Thr
355 360 365
Pro Lys Glu Ala Pro Asp Gly Pro Arg Ser Ser Val Gly Asp Cys Gly
370 375 380
Pro Glu Gln Pro Glu Pro Leu Pro Pro Ser Asp Ser Thr Gly Ala Gln
385 390 395 400
Thr Ser Gln Ser Arg Ala Lys Phe Ser Arg Ser Ala Glu Thr Ala Ala
405 410 415
Asn Leu Gln Asp Pro Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
420 425 430
Arg Glu Glu Tyr Asp Val Leu Glu Lys Lys Arg Ala Arg Asp Pro Glu
435 440 445
Met Gly Gly Lys Gln Gln Arg Arg Arg Asn Pro Gln Glu Gly Val Tyr
450 455 460
Asn Ala Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
465 470 475 480
Thr Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
485 490 495
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
500 505 510
Thr Leu Ala Pro Arg
515
<210> 26
<211> 1554
<212> DNA
<213> Artificial sequence
<220>
<223> FcgRI-CD3ζ构建体NA序列
<400> 26
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gagcatccgt gtcatctccc ttcccggagg ggagtctggt caccctgaac 660
tgtgagacga atttgctcct gcagagaccc ggcttacagc ttcacttctc cttctacgtg 720
ggcagcaaga tcctggagta caggaacaca tcctcagagt accatatagc aagggcggaa 780
agagaagatg ctggattcta ctggtgtgag gtagccacgg aggacagcag tgtccttaag 840
cgcagccctg agttggagct ccaagtgctt ggtccccagt catcagctcc tgtctggttt 900
cacatcctgt tttatctgtc agtgggaata atgttttcgt tgaacacggt tctctatgtg 960
aaaatacaca ggctgcagag agagaagaaa tacaacttag aagtcccttt ggtttctgag 1020
cagggaaaga aagcaaattc ctttcagcaa gttagaagcg atggcgtgta tgaagaagta 1080
acagccactg cgagccagac cacaccaaaa gaagcgcccg atggacctcg aagctcagtg 1140
ggtgactgtg gacccgagca gcctgaaccc cttcctccca gtgacagtac tggggcacaa 1200
acttcccaaa gtagagcaaa attcagcagg agtgcagaga ctgctgccaa cctgcaggac 1260
cccaaccagc tctacaatga gctcaatcta gggcgaagag aggaatatga cgtcttggag 1320
aagaagcggg ctcgggatcc agagatggga ggcaaacagc agaggaggag gaacccccag 1380
gaaggcgtat acaatgcact gcagaaagac aagatggcag aagcctacag tgagatcggc 1440
acaaaaggcg agaggcggag aggcaagggg cacgatggcc tttaccaggg tctcagcact 1500
gccaccaagg acacctatga tgccctgcat atgcagaccc tggcccctcg ctaa 1554
<210> 27
<211> 621
<212> PRT
<213> Artificial sequence
<220>
<223> FcgRI-CD3ζ-T2A-FcRg构建体AA序列
<400> 27
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
195 200 205
Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
210 215 220
Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
225 230 235 240
Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
245 250 255
Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
260 265 270
Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
275 280 285
Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe
290 295 300
Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val
305 310 315 320
Lys Ile His Arg Leu Gln Arg Glu Lys Lys Tyr Asn Leu Glu Val Pro
325 330 335
Leu Val Ser Glu Gln Gly Lys Lys Ala Asn Ser Phe Gln Gln Val Arg
340 345 350
Ser Asp Gly Val Tyr Glu Glu Val Thr Ala Thr Ala Ser Gln Thr Thr
355 360 365
Pro Lys Glu Ala Pro Asp Gly Pro Arg Ser Ser Val Gly Asp Cys Gly
370 375 380
Pro Glu Gln Pro Glu Pro Leu Pro Pro Ser Asp Ser Thr Gly Ala Gln
385 390 395 400
Thr Ser Gln Ser Arg Ala Lys Phe Ser Arg Ser Ala Glu Thr Ala Ala
405 410 415
Asn Leu Gln Asp Pro Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
420 425 430
Arg Glu Glu Tyr Asp Val Leu Glu Lys Lys Arg Ala Arg Asp Pro Glu
435 440 445
Met Gly Gly Lys Gln Gln Arg Arg Arg Asn Pro Gln Glu Gly Val Tyr
450 455 460
Asn Ala Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
465 470 475 480
Thr Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
485 490 495
Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
500 505 510
Thr Leu Ala Pro Arg Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp
515 520 525
Val Glu Glu Asn Pro Gly Pro Met Ile Ser Ala Val Ile Leu Phe Leu
530 535 540
Leu Leu Leu Val Glu Gln Ala Ala Ala Leu Gly Glu Pro Gln Leu Cys
545 550 555 560
Tyr Ile Leu Asp Ala Val Leu Phe Leu Tyr Gly Ile Val Leu Thr Leu
565 570 575
Leu Tyr Cys Arg Leu Lys Ile Gln Val Arg Lys Ala Ala Ile Ala Ser
580 585 590
Arg Glu Lys Ala Asp Ala Val Tyr Thr Gly Leu Asn Thr Arg Ser Gln
595 600 605
Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
610 615 620
<210> 28
<211> 1866
<212> DNA
<213> Artificial sequence
<220>
<223> FcgRI-CD3ζ-T2A-FcRg构建体NA序列
<400> 28
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gagcatccgt gtcatctccc ttcccggagg ggagtctggt caccctgaac 660
tgtgagacga atttgctcct gcagagaccc ggcttacagc ttcacttctc cttctacgtg 720
ggcagcaaga tcctggagta caggaacaca tcctcagagt accatatagc aagggcggaa 780
agagaagatg ctggattcta ctggtgtgag gtagccacgg aggacagcag tgtccttaag 840
cgcagccctg agttggagct ccaagtgctt ggtccccagt catcagctcc tgtctggttt 900
cacatcctgt tttatctgtc agtgggaata atgttttcgt tgaacacggt tctctatgtg 960
aaaatacaca ggctgcagag agagaagaaa tacaacttag aagtcccttt ggtttctgag 1020
cagggaaaga aagcaaattc ctttcagcaa gttagaagcg atggcgtgta tgaagaagta 1080
acagccactg cgagccagac cacaccaaaa gaagcgcccg atggacctcg aagctcagtg 1140
ggtgactgtg gacccgagca gcctgaaccc cttcctccca gtgacagtac tggggcacaa 1200
acttcccaaa gtagagcaaa attcagcagg agtgcagaga ctgctgccaa cctgcaggac 1260
cccaaccagc tctacaatga gctcaatcta gggcgaagag aggaatatga cgtcttggag 1320
aagaagcggg ctcgggatcc agagatggga ggcaaacagc agaggaggag gaacccccag 1380
gaaggcgtat acaatgcact gcagaaagac aagatggcag aagcctacag tgagatcggc 1440
acaaaaggcg agaggcggag aggcaagggg cacgatggcc tttaccaggg tctcagcact 1500
gccaccaagg acacctatga tgccctgcat atgcagaccc tggcccctcg cgagggcaga 1560
ggaagtctgc taacatgcgg tgacgtcgag gagaatcctg gcccaatgat ctcagccgtg 1620
atcttgttct tgctcctttt ggtggaacaa gcagccgccc tgggagagcc gcagctctgc 1680
tatatcctgg atgctgtcct gtttttgtat ggtattgtcc ttaccctact ctactgtcga 1740
ctcaagatcc aggtccgaaa ggcagctata gccagccgtg agaaagcaga tgctgtctac 1800
acgggcctga acacccggag ccaggagaca tatgagactc tgaagcatga gaaaccaccc 1860
cagtag 1866
<210> 29
<211> 388
<212> PRT
<213> Artificial sequence
<220>
<223> FcgRI-FcRg构建体AA序列
<400> 29
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
195 200 205
Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
210 215 220
Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
225 230 235 240
Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
245 250 255
Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
260 265 270
Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
275 280 285
Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe
290 295 300
Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val
305 310 315 320
Leu Gly Glu Pro Gln Leu Cys Tyr Ile Leu Asp Ala Val Leu Phe Leu
325 330 335
Tyr Gly Ile Val Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile Gln Val
340 345 350
Arg Lys Ala Ala Ile Ala Ser Arg Glu Lys Ala Asp Ala Val Tyr Thr
355 360 365
Gly Leu Asn Thr Arg Ser Gln Glu Thr Tyr Glu Thr Leu Lys His Glu
370 375 380
Lys Pro Pro Gln
385
<210> 30
<211> 1167
<212> DNA
<213> Artificial sequence
<220>
<223> FcgRI-FcRg构建体NA序列
<400> 30
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gagcatccgt gtcatctccc ttcccggagg ggagtctggt caccctgaac 660
tgtgagacga atttgctcct gcagagaccc ggcttacagc ttcacttctc cttctacgtg 720
ggcagcaaga tcctggagta caggaacaca tcctcagagt accatatagc aagggcggaa 780
agagaagatg ctggattcta ctggtgtgag gtagccacgg aggacagcag tgtccttaag 840
cgcagccctg agttggagct ccaagtgctt ggtccccagt catcagctcc tgtctggttt 900
cacatcctgt tttatctgtc agtgggaata atgttttcgt tgaacacggt tctctatgtg 960
ctgggagagc cgcagctctg ctatatcctg gatgctgtcc tgtttttgta tggtattgtc 1020
cttaccctac tctactgtcg actcaagatc caggtccgaa aggcagctat agccagccgt 1080
gagaaagcag atgctgtcta cacgggcctg aacacccgga gccaggagac atatgagact 1140
ctgaagcatg agaaaccacc ccagtaa 1167
<210> 31
<211> 519
<212> PRT
<213> Artificial sequence
<220>
<223> FcgRI-FcRg-CD3ζ构建体AA序列
<400> 31
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
195 200 205
Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
210 215 220
Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
225 230 235 240
Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
245 250 255
Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
260 265 270
Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
275 280 285
Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe
290 295 300
Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val
305 310 315 320
Met Ile Ser Ala Val Ile Leu Phe Leu Leu Leu Leu Val Glu Gln Ala
325 330 335
Ala Ala Leu Gly Glu Pro Gln Leu Cys Tyr Ile Leu Asp Ala Val Leu
340 345 350
Phe Leu Tyr Gly Ile Val Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile
355 360 365
Gln Val Arg Lys Ala Ala Ile Ala Ser Arg Glu Lys Ala Asp Ala Val
370 375 380
Tyr Thr Gly Leu Asn Thr Arg Ser Gln Glu Thr Tyr Glu Thr Leu Lys
385 390 395 400
His Glu Lys Pro Pro Gln Arg Ala Lys Phe Ser Arg Ser Ala Glu Thr
405 410 415
Ala Ala Asn Leu Gln Asp Pro Asn Gln Leu Tyr Asn Glu Leu Asn Leu
420 425 430
Gly Arg Arg Glu Glu Tyr Asp Val Leu Glu Lys Lys Arg Ala Arg Asp
435 440 445
Pro Glu Met Gly Gly Lys Gln Gln Arg Arg Arg Asn Pro Gln Glu Gly
450 455 460
Val Tyr Asn Ala Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu
465 470 475 480
Ile Gly Thr Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu
485 490 495
Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His
500 505 510
Met Gln Thr Leu Ala Pro Arg
515
<210> 32
<211> 1560
<212> DNA
<213> Artificial sequence
<220>
<223> FcgRI-FcRg-CD3ζ构建体NA序列
<400> 32
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gagcatccgt gtcatctccc ttcccggagg ggagtctggt caccctgaac 660
tgtgagacga atttgctcct gcagagaccc ggcttacagc ttcacttctc cttctacgtg 720
ggcagcaaga tcctggagta caggaacaca tcctcagagt accatatagc aagggcggaa 780
agagaagatg ctggattcta ctggtgtgag gtagccacgg aggacagcag tgtccttaag 840
cgcagccctg agttggagct ccaagtgctt ggtccccagt catcagctcc tgtctggttt 900
cacatcctgt tttatctgtc agtgggaata atgttttcgt tgaacacggt tctctatgtg 960
atgatctcag ccgtgatctt gttcttgctc cttttggtgg aacaagcagc cgccctggga 1020
gagccgcagc tctgctatat cctggatgct gtcctgtttt tgtatggtat tgtccttacc 1080
ctactctact gtcgactcaa gatccaggtc cgaaaggcag ctatagccag ccgtgagaaa 1140
gcagatgctg tctacacggg cctgaacacc cggagccagg agacatatga gactctgaag 1200
catgagaaac caccccagag agcaaaattc agcaggagtg cagagactgc tgccaacctg 1260
caggacccca accagctcta caatgagctc aatctagggc gaagagagga atatgacgtc 1320
ttggagaaga agcgggctcg ggatccagag atgggaggca aacagcagag gaggaggaac 1380
ccccaggaag gcgtatacaa tgcactgcag aaagacaaga tggcagaagc ctacagtgag 1440
atcggcacaa aaggcgagag gcggagaggc aaggggcacg atggccttta ccagggtctc 1500
agcactgcca ccaaggacac ctatgatgcc ctgcatatgc agaccctggc ccctcgctaa 1560
<210> 33
<211> 23
<212> PRT
<213> Artificial sequence
<220>
<223> CD64 AA序列的跨膜+胞内结构域
<400> 33
Val Trp Phe His Ile Leu Phe Tyr Leu Ser Val Gly Ile Met Phe Ser
1 5 10 15
Leu Asn Thr Val Leu Tyr Val
20
<210> 34
<211> 296
<212> PRT
<213> Artificial sequence
<220>
<223> CD64 AA序列的胞外+跨膜结构域
<400> 34
Glu Val Val Asn Ala Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp
1 5 10 15
Val Ser Ile Phe Gln Lys Glu Asn Val Thr Leu Trp Cys Glu Gly Pro
20 25 30
His Leu Pro Gly Asp Ser Ser Thr Gln Trp Phe Ile Asn Gly Thr Ala
35 40 45
Val Gln Ile Ser Thr Pro Ser Tyr Ser Ile Pro Glu Ala Ser Phe Gln
50 55 60
Asp Ser Gly Glu Tyr Arg Cys Gln Ile Gly Ser Ser Met Pro Ser Asp
65 70 75 80
Pro Val Gln Leu Gln Ile His Asn Asp Trp Leu Leu Leu Gln Ala Ser
85 90 95
Arg Arg Val Leu Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Gly
100 105 110
Trp Lys Asn Lys Leu Val Tyr Asn Val Val Phe Tyr Arg Asn Gly Lys
115 120 125
Ser Phe Gln Phe Ser Ser Asp Ser Glu Val Ala Ile Leu Lys Thr Asn
130 135 140
Leu Ser His Ser Gly Ile Tyr His Cys Ser Gly Thr Gly Arg His Arg
145 150 155 160
Tyr Thr Ser Ala Gly Val Ser Ile Thr Val Lys Glu Leu Phe Thr Thr
165 170 175
Pro Val Leu Arg Ala Ser Val Ser Ser Pro Phe Pro Glu Gly Ser Leu
180 185 190
Val Thr Leu Asn Cys Glu Thr Asn Leu Leu Leu Gln Arg Pro Gly Leu
195 200 205
Gln Leu His Phe Ser Phe Tyr Val Gly Ser Lys Ile Leu Glu Tyr Arg
210 215 220
Asn Thr Ser Ser Glu Tyr His Ile Ala Arg Ala Glu Arg Glu Asp Ala
225 230 235 240
Gly Phe Tyr Trp Cys Glu Val Ala Thr Glu Asp Ser Ser Val Leu Lys
245 250 255
Arg Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Pro Gln Ser Ser Ala
260 265 270
Pro Val Trp Phe His Ile Leu Phe Tyr Leu Ser Val Gly Ile Met Phe
275 280 285
Ser Leu Asn Thr Val Leu Tyr Val
290 295
<210> 35
<211> 591
<212> PRT
<213> Artificial sequence
<220>
<223> TRP-1 CD4 TCR(α链,P2A,β链)构建体,AA序列
<400> 35
Met Val Leu Ala Leu Leu Pro Val Leu Gly Ile His Phe Leu Leu Arg
1 5 10 15
Asp Ala Gln Ala Gln Ser Val Thr Gln Pro Asp Ala Arg Val Thr Val
20 25 30
Ser Glu Gly Ala Ser Leu Gln Leu Arg Cys Lys Tyr Ser Ser Ser Val
35 40 45
Thr Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Arg Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Tyr Ser Gly Asp Pro Val Val Gln Gly Val Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Ser Lys Ser Asn Ser Ser Phe His Leu Arg
85 90 95
Lys Ala Ser Val His Trp Ser Asp Ser Ala Val Tyr Phe Cys Ala Val
100 105 110
Ser Ser Asn Asn Asn Arg Ile Phe Phe Gly Asp Gly Thr Gln Leu Val
115 120 125
Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys
130 135 140
Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr
165 170 175
Asp Lys Thr Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly
180 185 190
Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe
195 200 205
Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
210 215 220
Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Gly Ser Gly Ala
260 265 270
Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Gln Glu Asn Pro
275 280 285
Gly Pro Leu Tyr Ser Leu Leu Ala Phe Leu Leu Gly Met Phe Leu Gly
290 295 300
Val Ser Ala Gln Thr Ile His Gln Trp Pro Val Ala Glu Ile Lys Ala
305 310 315 320
Val Gly Ser Pro Leu Ser Leu Gly Cys Thr Ile Lys Gly Lys Ser Ser
325 330 335
Pro Asn Leu Tyr Trp Tyr Trp Gln Ala Thr Gly Gly Thr Leu Gln Gln
340 345 350
Leu Phe Tyr Ser Ile Thr Val Gly Gln Val Glu Ser Val Val Gln Leu
355 360 365
Asn Leu Ser Ala Ser Arg Pro Lys Asp Asp Gln Phe Ile Leu Ser Thr
370 375 380
Glu Lys Leu Leu Leu Ser His Ser Gly Phe Tyr Leu Cys Ala Trp Ser
385 390 395 400
Pro Gly His Gln Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu
405 410 415
Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
420 425 430
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
435 440 445
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
450 455 460
Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Ala
465 470 475 480
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
485 490 495
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
500 505 510
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
515 520 525
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
530 535 540
Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
545 550 555 560
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
565 570 575
Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
580 585 590
<210> 36
<211> 1776
<212> DNA
<213> Artificial sequence
<220>
<223> TRP-1 CD4 TCR(α链,P2A,β链)构建体,NA序列
<400> 36
atggtcctgg cgctcctccc agtgctgggg atacactttc tcctgagaga tgcccaagct 60
cagtcagtga cgcagcccga tgctcgtgtc actgtctctg aaggagcctc tctgcagctg 120
agatgcaagt attcctcctc tgtgacacct tatctgttct ggtatgtcca gtacccgcgg 180
caggggctgc agctgctcct caagtactat tccggagacc cagtggttca aggagtgaat 240
ggctttgagg ctgagttcag caagagtaac tcttccttcc acctgcggaa agcctccgtg 300
cactggagcg actcggctgt gtacttctgt gctgtgagct cgaacaataa cagaatcttc 360
tttggtgatg ggacgcagct ggtggtgaag cccaacatcc agaacccaga acctgctgtg 420
taccagttaa aagatcctcg gtctcaggac agcaccctct gcctgttcac cgactttgac 480
tcccaaatca atgtgccgaa aactatggaa tctggaacgt tcatcactga caaaactgtg 540
ctggacatga aagctatgga ttccaagagc aatggggcca ttgcctggag caaccagaca 600
agcttcacct gccaagatat cttcaaagag accaacgcca cctaccccag ttcagacgtt 660
ccctgtgatg ccacgttgac tgagaaaagc tttgaaacag atatgaacct aaactttcaa 720
aacctgtcag ttatgggact ccgaatcctc ctgctgaaag tagccggatt taacctgctc 780
atgacgctga ggctgtggtc cagtggctct ggcgccacga acttctctct gttaaagcaa 840
gcaggagacg tgcaagaaaa ccccggtccc ctgtactctc tccttgcctt tctcctgggc 900
atgttcttgg gtgttagtgc tcagactatc catcaatggc cagttgccga gatcaaggct 960
gtgggcagcc cactgtctct ggggtgtacc ataaagggga aatcaagccc taacctctac 1020
tggtactggc aggccacagg aggcaccctc cagcaactct tctactctat tactgttggc 1080
caggtagagt cggtggtgca actgaacctc tcagcttcca ggccgaagga cgaccaattc 1140
atcctaagca cggagaagct gcttctcagc cactctggct tctacctctg tgcctggagt 1200
ccgggacatc aagacaccca gtactttggg ccaggcactc ggctcctcgt gttagaggat 1260
ctgagaaatg tgactccacc caaggtctcc ttgtttgagc catcaaaagc agagattgca 1320
aacaaacaaa aggctaccct cgtgtgcttg gccaggggct tcttccctga ccacgtggag 1380
ctgagctggt gggtgaatgg caaggaggtc cacagtgggg tcagcacgga ccctcaggcc 1440
tacaaggaga gcaattatag ctactgcctg agcagccgcc tgagggtctc tgctaccttc 1500
tggcacaatc ctcgcaacca cttccgctgc caagtgcagt tccacgggct ttcagaggag 1560
gacaagtggc cagagggctc acccaaacct gtcacacaga acatcagtgc agaggcctgg 1620
ggccgagcag actgtgggat tacctcagca tcctatcaac aaggggtctt gtctgccacc 1680
atcctctatg agatcctgct agggaaagcc accctgtatg ctgtgcttgt cagtacactg 1740
gtggtgatgg ctatggtcaa aagaaagaat tcatga 1776
<210> 37
<211> 172
<212> PRT
<213> Artificial sequence
<220>
<223> TCRβ恒定区aa序列
<400> 37
Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser
1 5 10 15
Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala
20 25 30
Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
35 40 45
Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr Lys Glu
50 55 60
Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr
65 70 75 80
Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His
85 90 95
Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val
100 105 110
Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile
115 120 125
Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr
130 135 140
Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Gly
145 150 155 160
Leu Val Leu Met Ala Met Val Lys Arg Lys Asn Ser
165 170
<210> 38
<211> 516
<212> DNA
<213> Artificial sequence
<220>
<223> TCRβ恒定区NA序列
<400> 38
gatctgagaa atgtgactcc acccaaggtc tccttgtttg agccatcaaa agcagagatt 60
gcaaacaaac aaaaggctac cctcgtgtgc ttggccaggg gcttcttccc tgaccacgtg 120
gagctgagct ggtgggtgaa tggcaaggag gtccacagtg gggtcagcac ggaccctcag 180
gcctacaagg agagcaatta tagctactgc ctgagcagcc gcctgagggt ctctgctacc 240
ttctggcaca atcctcgaaa ccacttccgc tgccaagtgc agttccatgg gctttcggag 300
gaggacaagt ggccagaggg ctcacccaaa cctgtcacac agaacatcag tgcagaggcc 360
tggggccgag cagactgtgg aatcacttca gcatcctatc atcagggggt tctgtctgca 420
accatcctct atgagatcct actggggaag gccaccctat atgctgtgct ggtcagtggc 480
ctggtgctga tggccatggt caagagaaaa aattcc 516
<210> 39
<211> 66
<212> PRT
<213> Artificial sequence
<220>
<223> CD8铰链+TM aa序列
<400> 39
Thr Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val His Pro Thr
1 5 10 15
Gly Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly Ser
20 25 30
Val Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
35 40 45
Pro Leu Ala Gly Ile Cys Val Ala Leu Leu Leu Ser Leu Ile Ile Thr
50 55 60
Leu Ile
65
<210> 40
<211> 198
<212> DNA
<213> Artificial sequence
<220>
<223> CD8铰链+TM NA序列
<400> 40
actactacca agccagtgct gcgaactccc tcacctgtgc accctaccgg gacatctcag 60
ccccagagac cagaagattg tcggccccgt ggctcagtga aggggaccgg attggacttc 120
gcctgtgata tttacatctg ggcacccttg gccggaatct gcgtggccct tctgctgtcc 180
ttgatcatca ctctcatc 198
<210> 41
<211> 382
<212> PRT
<213> Artificial sequence
<220>
<223> FcgRI胞外TCRβ恒定区构建体aa序列
<400> 41
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Gly Ser Thr Arg
195 200 205
Pro Arg Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu
210 215 220
Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys
225 230 235 240
Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val
245 250 255
Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr
260 265 270
Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser
275 280 285
Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln
290 295 300
Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys
305 310 315 320
Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys
325 330 335
Gly Ile Thr Ser Ala Ser Tyr His Gln Gly Val Leu Ser Ala Thr Ile
340 345 350
Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val
355 360 365
Ser Gly Leu Val Leu Met Ala Met Val Lys Arg Lys Asn Ser
370 375 380
<210> 42
<211> 1146
<212> DNA
<213> Artificial sequence
<220>
<223> FcgRI胞外TCRβ恒定区构建体NA序列
<400> 42
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gaggatccac gcgtccgcgg gatctgagaa atgtgactcc acccaaggtc 660
tccttgtttg agccatcaaa agcagagatt gcaaacaaac aaaaggctac cctcgtgtgc 720
ttggccaggg gcttcttccc tgaccacgtg gagctgagct ggtgggtgaa tggcaaggag 780
gtccacagtg gggtcagcac ggaccctcag gcctacaagg agagcaatta tagctactgc 840
ctgagcagcc gcctgagggt ctctgctacc ttctggcaca atcctcgaaa ccacttccgc 900
tgccaagtgc agttccatgg gctttcggag gaggacaagt ggccagaggg ctcacccaaa 960
cctgtcacac agaacatcag tgcagaggcc tggggccgag cagactgtgg aatcacttca 1020
gcatcctatc atcagggggt tctgtctgca accatcctct atgagatcct actggggaag 1080
gccaccctat atgctgtgct ggtcagtggc ctggtgctga tggccatggt caagagaaaa 1140
aattcc 1146
<210> 43
<211> 405
<212> PRT
<213> Artificial sequence
<220>
<223> FcgRI胞外-CD8-铰链+TM-Fcrg构建体aa序列
<400> 43
Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu
1 5 10 15
Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala
20 25 30
Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn
35 40 45
Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr
50 55 60
Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr
65 70 75 80
Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln
85 90 95
Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn
100 105 110
Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu
115 120 125
Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn
130 135 140
Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser
145 150 155 160
Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His
165 170 175
Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile
180 185 190
Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser
195 200 205
Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn
210 215 220
Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val
225 230 235 240
Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile
245 250 255
Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala
260 265 270
Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln
275 280 285
Val Leu Gly Pro Gln Ser Ser Ala Pro Thr Thr Thr Lys Pro Val Leu
290 295 300
Arg Thr Pro Ser Pro Val His Pro Thr Gly Thr Ser Gln Pro Gln Arg
305 310 315 320
Pro Glu Asp Cys Arg Pro Arg Gly Ser Val Lys Gly Thr Gly Leu Asp
325 330 335
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Ile Cys Val
340 345 350
Ala Leu Leu Leu Ser Leu Ile Ile Thr Leu Ile Arg Leu Lys Ile Gln
355 360 365
Val Arg Lys Ala Ala Ile Ala Ser Arg Glu Lys Ala Asp Ala Val Tyr
370 375 380
Thr Gly Leu Asn Thr Arg Ser Gln Glu Thr Tyr Glu Thr Leu Lys His
385 390 395 400
Glu Lys Pro Pro Gln
405
<210> 44
<211> 1218
<212> DNA
<213> Artificial sequence
<220>
<223> FcgRI胞外-CD8-铰链+TM-Fcrg构建体NA序列
<400> 44
atgattctta ccagctttgg agatgacatg tggcttctaa caactctgct actttgggtt 60
ccagtcggtg gggaagtggt taatgccacc aaggctgtga tcaccttgca gcctccatgg 120
gtcagtattt tccagaagga aaatgtcact ttatggtgtg aggggcctca cctgcctgga 180
gacagttcca cacaatggtt tatcaacgga acagccgttc agatctccac gcctagttat 240
agcatcccag aggccagttt tcaggacagt ggcgaataca ggtgtcagat aggttcctca 300
atgccaagtg accctgtgca gttgcaaatc cacaatgatt ggctgctact ccaggcctcc 360
cgcagagtcc tcacagaagg agaacccctg gccttgaggt gtcacggatg gaagaataaa 420
ctggtgtaca atgtggtttt ctatagaaat ggaaaatcct ttcagttttc ttcagattcg 480
gaggtcgcca ttctgaaaac caacctgagt cacagcggca tctaccactg ctcaggcacg 540
ggaagacacc gctacacatc tgcaggagtg tccatcacgg tgaaagagct gtttaccacg 600
ccagtgctga gagcatccgt gtcatctccc ttcccggagg ggagtctggt caccctgaac 660
tgtgagacga atttgctcct gcagagaccc ggcttacagc ttcacttctc cttctacgtg 720
ggcagcaaga tcctggagta caggaacaca tcctcagagt accatatagc aagggcggaa 780
agagaagatg ctggattcta ctggtgtgag gtagccacgg aggacagcag tgtccttaag 840
cgcagccctg agttggagct ccaagtgctt ggtccccagt catcagctcc tactactacc 900
aagccagtgc tgcgaactcc ctcacctgtg caccctaccg ggacatctca gccccagaga 960
ccagaagatt gtcggccccg tggctcagtg aaggggaccg gattggactt cgcctgtgat 1020
atttacatct gggcaccctt ggccggaatc tgcgtggccc ttctgctgtc cttgatcatc 1080
actctcatcc gactcaagat ccaggtccga aaggcagcta tagccagccg tgagaaagca 1140
gatgctgtct acacgggcct gaacacccgg agccaggaga catatgagac tctgaagcat 1200
gagaaaccac cccagtag 1218
<210> 45
<211> 36
<212> PRT
<213> Artificial sequence
<220>
<223> OX40胞内结构域AA序列
<400> 45
Arg Lys Ala Trp Arg Leu Pro Asn Thr Pro Lys Pro Cys Trp Gly Asn
1 5 10 15
Ser Phe Arg Thr Pro Ile Gln Glu Glu His Thr Asp Ala His Phe Thr
20 25 30
Leu Ala Lys Ile
35
<210> 46
<211> 108
<212> DNA
<213> Artificial sequence
<220>
<223> OX40胞内结构域NA序列
<400> 46
cggaaggctt ggagattgcc taacactccc aaaccttgtt ggggaaacag cttcaggacc 60
ccgatccagg aggaacacac agacgcacac tttactctgg ccaagatc 108
<210> 47
<211> 48
<212> PRT
<213> Artificial sequence
<220>
<223> 41BB胞内结构域AA序列
<400> 47
Ser Val Leu Lys Trp Ile Arg Lys Lys Phe Pro His Ile Phe Lys Gln
1 5 10 15
Pro Phe Lys Lys Thr Thr Gly Ala Ala Gln Glu Glu Asp Ala Cys Ser
20 25 30
Cys Arg Cys Pro Gln Glu Glu Glu Gly Gly Gly Gly Gly Tyr Glu Leu
35 40 45
<210> 48
<211> 144
<212> DNA
<213> Artificial sequence
<220>
<223> 41BB细胞内结构域NA序列
<400> 48
tctgtgctca aatggatcag gaaaaaattc ccccacatat tcaagcaacc atttaagaag 60
accactggag cagctcaaga ggaagatgct tgtagctgcc gatgtccaca ggaagaagaa 120
ggaggaggag gaggctatga gctg 144
<210> 49
<211> 186
<212> PRT
<213> Artificial sequence
<220>
<223> TNFR2胞内信号传导域AA序列
<400> 49
Lys Lys Lys Pro Ser Cys Leu Gln Arg Asp Ala Lys Val Pro His Val
1 5 10 15
Pro Asp Glu Lys Ser Gln Asp Ala Val Gly Leu Glu Gln Gln His Leu
20 25 30
Leu Thr Thr Ala Pro Ser Ser Ser Ser Ser Ser Leu Glu Ser Ser Ala
35 40 45
Ser Ala Gly Asp Arg Arg Ala Pro Pro Gly Gly His Pro Gln Ala Arg
50 55 60
Val Met Ala Glu Ala Gln Gly Phe Gln Glu Ala Arg Ala Ser Ser Arg
65 70 75 80
Ile Ser Asp Ser Ser His Gly Ser His Gly Thr His Val Asn Val Thr
85 90 95
Cys Ile Val Asn Val Cys Ser Ser Ser Asp His Ser Ser Gln Cys Ser
100 105 110
Ser Gln Ala Ser Ala Thr Val Gly Asp Pro Asp Ala Lys Pro Ser Ala
115 120 125
Ser Pro Lys Asp Glu Gln Val Pro Phe Ser Gln Glu Glu Cys Pro Ser
130 135 140
Gln Ser Pro Cys Glu Thr Thr Glu Thr Leu Gln Ser His Glu Lys Pro
145 150 155 160
Leu Pro Leu Gly Val Pro Asp Met Gly Met Lys Pro Ser Gln Ala Gly
165 170 175
Trp Phe Asp Gln Ile Ala Val Lys Val Ala
180 185
<210> 50
<211> 558
<212> DNA
<213> Artificial sequence
<220>
<223> TNFR2胞内信号传导域NA序列
<400> 50
aaaaagaagc cctcctgcct acaaagagat gccaaggtgc ctcatgtgcc tgatgagaaa 60
tcccaggatg cagtaggcct tgagcagcag cacctgttga ccacagcacc cagttccagc 120
agcagctccc tagagagctc agccagcgct ggggaccgaa gggcgccccc tgggggccat 180
ccccaagcaa gagtcatggc ggaggcccaa gggtttcagg aggcccgtgc cagctccagg 240
atttcagatt cttcccacgg aagccacggg acccacgtca acgtcacctg catcgtgaac 300
gtctgtagca gctctgacca cagttctcag tgctcttccc aagccagcgc cacagtggga 360
gacccagatg ccaagccctc agcgtcccca aaggatgagc aggtcccctt ctctcaggag 420
gagtgtccgt ctcagtcccc gtgtgagact acagagacac tgcagagcca tgagaagccc 480
ttgccccttg gtgtgccgga tatgggcatg aagcccagcc aagctggctg gtttgatcag 540
attgcagtca aagtggcc 558
<210> 51
<211> 147
<212> PRT
<213> Artificial sequence
<220>
<223> IL-12Rb1胞内AA序列
<400> 51
Asn Arg Ala Ala Trp His Leu Cys Pro Pro Leu Pro Thr Pro Cys Gly
1 5 10 15
Ser Thr Ala Val Glu Phe Pro Gly Ser Gln Gly Lys Gln Ala Trp Gln
20 25 30
Trp Cys Asn Pro Glu Asp Phe Pro Glu Val Leu Tyr Pro Arg Asp Ala
35 40 45
Leu Val Val Glu Met Pro Gly Asp Arg Gly Asp Gly Thr Glu Ser Pro
50 55 60
Gln Ala Ala Pro Glu Cys Ala Leu Asp Thr Arg Arg Pro Leu Glu Thr
65 70 75 80
Gln Arg Gln Arg Gln Val Gln Ala Leu Ser Glu Ala Arg Arg Leu Gly
85 90 95
Leu Ala Arg Glu Asp Cys Pro Arg Gly Asp Leu Ala His Val Thr Leu
100 105 110
Pro Leu Leu Leu Gly Gly Val Thr Gln Gly Ala Ser Val Leu Asp Asp
115 120 125
Leu Trp Arg Thr His Lys Thr Ala Glu Pro Gly Pro Pro Thr Leu Gly
130 135 140
Gln Glu Ala
145
<210> 52
<211> 441
<212> DNA
<213> Artificial sequence
<220>
<223> IL-12Rb1胞内NA序列
<400> 52
aacagggccg cctggcactt gtgcccaccc ctgcctacac cctgtggcag cactgccgtg 60
gagttccctg gcagccaggg caagcaggct tggcagtggt gcaaccctga ggacttcccg 120
gaggtgttgt acccgcgaga tgcgctggtg gtcgagatgc ccggagacag aggcgacggg 180
acagagtcgc cccaggccgc ccctgagtgc gccctggaca caaggcggcc cttggagact 240
cagaggcaga ggcaggtgca ggcactgtca gaggccaggc gcctgggcct ggctagggag 300
gactgtcccc gtggtgacct ggcccacgtg acactcccgc tgctcctggg aggtgtgacc 360
cagggagcct ctgtacttga cgatctttgg aggacccata agactgcgga gccgggaccg 420
cccactttgg ggcaagaggc c 441
<210> 53
<211> 216
<212> PRT
<213> Artificial sequence
<220>
<223> IL-12Rb2胞内AA序列
<400> 53
Arg Tyr Phe Arg Gln Lys Ala Phe Thr Leu Leu Ser Thr Leu Lys Pro
1 5 10 15
Gln Trp Tyr Ser Arg Thr Ile Pro Asp Pro Ala Asn Ser Thr Trp Val
20 25 30
Lys Lys Tyr Pro Ile Leu Glu Glu Lys Ile Gln Leu Pro Thr Asp Asn
35 40 45
Leu Leu Met Ala Trp Pro Thr Pro Glu Glu Pro Glu Pro Leu Ile Ile
50 55 60
His Glu Val Leu Tyr His Met Ile Pro Val Val Arg Gln Pro Tyr Tyr
65 70 75 80
Phe Lys Arg Gly Gln Gly Phe Gln Gly Tyr Ser Thr Ser Lys Gln Asp
85 90 95
Ala Met Tyr Ile Ala Asn Pro Gln Ala Thr Gly Thr Leu Thr Ala Glu
100 105 110
Thr Arg Gln Leu Val Asn Leu Tyr Lys Val Leu Glu Ser Arg Asp Pro
115 120 125
Asp Ser Lys Leu Ala Asn Leu Thr Ser Pro Leu Thr Val Thr Pro Val
130 135 140
Asn Tyr Leu Pro Ser His Glu Gly Tyr Leu Pro Ser Asn Ile Glu Asp
145 150 155 160
Leu Ser Pro His Glu Ala Asp Pro Thr Asp Ser Phe Asp Leu Glu His
165 170 175
Gln His Ile Ser Leu Ser Ile Phe Ala Ser Ser Ser Leu Arg Pro Leu
180 185 190
Ile Phe Gly Gly Glu Arg Leu Thr Leu Asp Arg Leu Lys Met Gly Tyr
195 200 205
Asp Ser Leu Met Ser Asn Glu Ala
210 215
<210> 54
<211> 648
<212> DNA
<213> Artificial sequence
<220>
<223> IL-12Rb2胞内NA序列
<400> 54
cgttacttcc ggcaaaaggc atttactctc ctgtctactc tcaaacctca atggtatagc 60
agaaccattc cagatccagc aaacagcact tgggtaaaga agtatcccat tctggaggag 120
aagatccagc tacctacgga taatctcctg atggcatggc ccactcctga agagcctgag 180
cccctgatca tccatgaagt cctctaccac atgatcccag ttgtcagaca accatattac 240
ttcaaaagag gccaaggatt ccaaggctac tctacctcca agcaagatgc aatgtatatt 300
gccaatccac aagctacagg aactctcaca gctgagacca gacagctagt gaacctatac 360
aaggtgctag aaagcagaga ccctgactca aaactggcca acctgaccag ccccttgaca 420
gtcaccccag tgaactacct tcctagccat gaaggctatt taccctccaa catagaagat 480
ctgtcaccac atgaggctga cccaactgat tcttttgacc tggagcatca acatatttct 540
ctttccattt ttgcatcaag ttctctccgc ccactcatct tcggtggtga gcggctgact 600
ctagatcggt taaagatggg ctatgactcc ctcatgagta atgaggct 648
<210> 55
<211> 249
<212> PRT
<213> Artificial sequence
<220>
<223> IL-23R胞内AA序列
<400> 55
Asn Arg Ser Leu Arg Ile Gly Ile Lys Arg Lys Val Leu Leu Met Ile
1 5 10 15
Pro Lys Trp Leu Tyr Glu Asp Ile Pro Asn Met Glu Asn Ser Asn Val
20 25 30
Ala Lys Leu Leu Gln Glu Lys Ser Val Phe Glu Asn Asp Asn Ala Ser
35 40 45
Glu Gln Ala Leu Tyr Val Asp Pro Val Leu Thr Glu Ile Ser Glu Ile
50 55 60
Ser Pro Leu Glu His Lys Pro Thr Asp Tyr Lys Glu Glu Arg Leu Thr
65 70 75 80
Gly Leu Leu Glu Thr Arg Asp Cys Pro Leu Gly Met Leu Ser Thr Ser
85 90 95
Ser Ser Val Val Tyr Ile Pro Asp Leu Asn Thr Gly Tyr Lys Pro Gln
100 105 110
Val Ser Asn Val Pro Pro Gly Gly Asn Leu Phe Ile Asn Arg Asp Glu
115 120 125
Arg Asp Pro Thr Ser Leu Glu Thr Thr Asp Asp His Phe Ala Arg Leu
130 135 140
Lys Thr Tyr Pro Asn Phe Gln Phe Ser Ala Ser Ser Met Ala Leu Leu
145 150 155 160
Asn Lys Thr Leu Ile Leu Asp Glu Leu Cys Leu Val Leu Asn Gln Gly
165 170 175
Glu Phe Asn Ser Leu Asp Ile Lys Asn Ser Arg Gln Glu Glu Thr Ser
180 185 190
Ile Val Leu Gln Ser Asp Ser Pro Ser Glu Thr Ile Pro Ala Gln Thr
195 200 205
Leu Leu Ser Asp Glu Phe Val Ser Cys Leu Ala Ile Gly Asn Glu Asp
210 215 220
Leu Pro Ser Ile Asn Ser Tyr Phe Pro Gln Asn Val Leu Glu Ser His
225 230 235 240
Phe Ser Arg Ile Ser Leu Phe Gln Lys
245
<210> 56
<211> 747
<212> DNA
<213> Artificial sequence
<220>
<223> IL-23R胞内NA序列
<400> 56
aacagatcac ttcgaatagg aattaaaaga aaagttttac tgatgatccc aaagtggctt 60
tatgaagata ttcctaatat ggaaaatagc aatgttgcaa aattattaca ggaaaaaagt 120
gtatttgaga atgataatgc cagtgagcag gccctgtatg tggatcctgt ccttacagag 180
ataagtgaaa tctctcccct ggaacacaaa cccacagatt acaaagaaga aaggctcaca 240
ggactccttg agacaagaga ctgtcctcta ggaatgttgt ctaccagttc ttctgttgtg 300
tatattcctg acctcaacac tggatacaaa ccccaggttt caaatgttcc tcctggagga 360
aaccttttca ttaacagaga tgaaagagac cctacatccc ttgagaccac agatgaccac 420
tttgccagat tgaaaacata tcccaacttc caattttctg cttcaagtat ggctttacta 480
aacaaaacac taattcttga tgaattgtgc ctcgttttaa atcaaggaga gttcaattct 540
cttgacataa aaaactcaag acaggaggaa accagcatcg ttttgcaaag tgactcaccc 600
agtgaaacta tcccagcgca gactctgttg tctgatgaat ttgtctcctg tttggcaatt 660
gggaatgaag acttgccatc tattaattct tactttccac agaacgtttt ggaaagccat 720
ttcagtagaa tttcactctt ccaaaag 747
<210> 57
<211> 202
<212> PRT
<213> Artificial sequence
<220>
<223> IFNgR1胞内AA序列
<400> 57
Trp Tyr Thr Lys Asn Asn Ser Phe Lys Arg Lys Ser Ile Met Leu Pro
1 5 10 15
Lys Ser Leu Leu Ser Val Val Lys Ser Ala Thr Leu Glu Thr Lys Pro
20 25 30
Glu Ser Lys Tyr Ser Leu Val Thr Pro His Gln Pro Ala Val Leu Glu
35 40 45
Ser Glu Thr Val Ile Cys Glu Glu Pro Leu Ser Thr Val Thr Ala Pro
50 55 60
Asp Ser Pro Glu Ala Ala Glu Gln Glu Glu Leu Ser Lys Glu Thr Lys
65 70 75 80
Ala Leu Glu Ala Gly Gly Ser Thr Ser Ala Met Thr Pro Asp Ser Pro
85 90 95
Pro Thr Pro Thr Gln Arg Arg Ser Phe Ser Leu Leu Ser Ser Asn Gln
100 105 110
Ser Gly Pro Cys Ser Leu Thr Ala Tyr His Ser Arg Asn Gly Ser Asp
115 120 125
Ser Gly Leu Val Gly Ser Gly Ser Ser Ile Ser Asp Leu Glu Ser Leu
130 135 140
Pro Asn Asn Asn Ser Glu Thr Lys Met Ala Glu His Asp Pro Pro Pro
145 150 155 160
Val Arg Lys Ala Pro Met Ala Ser Gly Tyr Asp Lys Pro His Met Leu
165 170 175
Val Asp Val Leu Val Asp Val Gly Gly Lys Glu Ser Leu Met Gly Tyr
180 185 190
Arg Leu Thr Gly Glu Ala Gln Glu Leu Ser
195 200
<210> 58
<211> 606
<212> DNA
<213> Artificial sequence
<220>
<223> IFNgR1胞内NA序列
<400> 58
tggtatacta agaacaattc attcaagaga aaaagcataa tgttacctaa gtccttgctc 60
tctgtggtaa aaagtgccac gttagagaca aaacctgaat cgaagtattc acttgtcaca 120
ccgcaccagc cagctgtcct agagagtgag acggtgatct gtgaagagcc cctgtccaca 180
gtgacagctc cagacagccc cgaagcagca gaacaggaag aactttcaaa agaaacaaag 240
gctctggagg ctggaggaag cacgtctgcc atgaccccag acagccctcc aactccgaca 300
caaagacgca gcttttccct gttaagtagt aaccagtcag gcccttgtag cctcaccgcc 360
tatcactccc gaaacggctc tgacagtggc ctcgtgggat cgggcagctc catatcggac 420
ttggaatctc tcccaaacaa caactcagaa acaaagatgg cagagcacga ccctccaccc 480
gtgagaaagg cccccatggc ctccggttat gacaaaccgc acatgttggt ggacgtgctt 540
gtggatgttg gggggaagga gtctctcatg gggtatagac tcacaggaga ggcccaggag 600
ctgtcc 606
<210> 59
<211> 67
<212> PRT
<213> Artificial sequence
<220>
<223> IFNgR2胞内AA序列
<400> 59
Leu Lys Tyr Gln Ser Arg Val Lys Tyr Trp Phe Gln Ala Pro Pro Asn
1 5 10 15
Ile Pro Glu Gln Ile Glu Glu Tyr Leu Lys Asp Pro Asp Gln Phe Ile
20 25 30
Leu Glu Val Leu Asp Lys Asp Gly Ser Pro Lys Glu Asp Ser Trp Asp
35 40 45
Ser Val Ser Ile Ile Ser Ser Pro Glu Lys Glu Arg Asp Asp Val Leu
50 55 60
Gln Thr Pro
65
<210> 60
<211> 201
<212> DNA
<213> Artificial sequence
<220>
<223> IFNgR2胞内NA序列
<400> 60
ctcaaatacc aaagccgagt gaagtactgg tttcaggctc cgccaaacat cccggaacaa 60
atcgaagagt atctaaagga cccagaccaa ttcatcttag aggtcttgga caaggacggt 120
tcaccgaagg aggactcctg ggactccgtg tcaattattt cttctccaga aaaggagcga 180
gatgatgtgc tccaaacacc g 201
<210> 61
<211> 271
<212> PRT
<213> Artificial sequence
<220>
<223> IL-2Rb胞内AA序列
<400> 61
Lys Cys Arg Tyr Leu Gly Pro Trp Leu Lys Thr Val Leu Lys Cys His
1 5 10 15
Ile Pro Asp Pro Ser Glu Phe Phe Ser Gln Leu Ser Ser Gln His Gly
20 25 30
Gly Asp Leu Gln Lys Trp Leu Ser Ser Pro Val Pro Leu Ser Phe Phe
35 40 45
Ser Pro Ser Gly Pro Ala Pro Glu Ile Ser Pro Leu Glu Val Leu Asp
50 55 60
Gly Asp Ser Lys Ala Val Gln Leu Leu Leu Leu Gln Lys Asp Ser Ala
65 70 75 80
Pro Leu Pro Ser Pro Ser Gly His Ser Gln Ala Ser Cys Phe Thr Asn
85 90 95
Gln Gly Tyr Phe Phe Phe His Leu Pro Asn Ala Leu Glu Ile Glu Ser
100 105 110
Cys Gln Val Tyr Phe Thr Tyr Asp Pro Cys Val Glu Glu Glu Val Glu
115 120 125
Glu Asp Gly Ser Arg Leu Pro Glu Gly Ser Pro His Pro Pro Leu Leu
130 135 140
Pro Leu Ala Gly Glu Gln Asp Asp Tyr Cys Ala Phe Pro Pro Arg Asp
145 150 155 160
Asp Leu Leu Leu Phe Ser Pro Ser Leu Ser Thr Pro Asn Thr Ala Tyr
165 170 175
Gly Gly Ser Arg Ala Pro Glu Glu Arg Ser Pro Leu Ser Leu His Glu
180 185 190
Gly Leu Pro Ser Leu Ala Ser Arg Asp Leu Met Gly Leu Gln Arg Pro
195 200 205
Leu Glu Arg Met Pro Glu Gly Asp Gly Glu Gly Leu Ser Ala Asn Ser
210 215 220
Ser Gly Glu Gln Ala Ser Val Pro Glu Gly Asn Leu His Gly Gln Asp
225 230 235 240
Gln Asp Arg Gly Gln Gly Pro Ile Leu Thr Leu Asn Thr Asp Ala Tyr
245 250 255
Leu Ser Leu Gln Glu Leu Gln Ala Gln Asp Ser Val His Leu Ile
260 265 270
<210> 62
<211> 813
<212> DNA
<213> Artificial sequence
<220>
<223> IL-2Rb胞内NA序列
<400> 62
aagtgccggt accttgggcc atggctgaag acagttctca agtgccacat cccagatcct 60
tctgagttct tctcccagct gagctcccag catgggggag accttcagaa atggctctcc 120
tcgcctgtcc ccttgtcctt cttcagcccc agtggccctg cccctgagat ctctccgctg 180
gaagtgctcg acggagattc caaggccgtg cagctgctcc tgttacagaa ggactctgcc 240
cctttaccct cgcccagcgg ccactcacag gccagctgct tcaccaacca gggctacttc 300
ttcttccatc tgcccaatgc cttggagatc gaatcctgcc aggtgtactt cacctatgac 360
ccctgtgtgg aagaggaggt ggaggaggat gggtcaaggc tgcccgaggg atctccccac 420
ccacctctgc tgcctctggc tggagaacag gatgactact gtgccttccc gcccagggat 480
gacctgctgc tcttctcccc gagcctcagc acccccaaca ctgcctatgg gggcagcaga 540
gcccctgaag aaagatctcc actctccctg catgagggac ttccctccct agcatcccgt 600
gacctgatgg gcttacagcg ccctctggag cggatgccgg aaggtgatgg agaggggctg 660
tctgccaata gctctgggga gcaggccagt gtcccagaag gcaaccttca tgggcaagat 720
caggacagag gccagggccc catcctgacc ctgaacaccg atgcctatct gtctcttcaa 780
gaactacagg cccaagattc agtccaccta ata 813
<210> 63
<211> 85
<212> PRT
<213> Artificial sequence
<220>
<223> IL-2R共同γ胞内AA序列
<400> 63
Glu Arg Met Pro Pro Ile Pro Pro Ile Lys Asn Leu Glu Asp Leu Val
1 5 10 15
Thr Glu Tyr Gln Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly
20 25 30
Leu Thr Glu Ser Leu Gln Pro Asp Tyr Ser Glu Arg Phe Cys His Val
35 40 45
Ser Glu Ile Pro Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Gly
50 55 60
Ser Pro Cys Ser Leu His Ser Pro Tyr Trp Pro Pro Pro Cys Tyr Ser
65 70 75 80
Leu Lys Pro Glu Ala
85
<210> 64
<211> 255
<212> DNA
<213> Artificial sequence
<220>
<223> IL-2R共同γ胞内NA序列
<400> 64
gaacgaatgc ctccaattcc ccccatcaag aatctagagg atctggttac tgaataccaa 60
gggaactttt cggcctggag tggtgtgtct aaagggctga ctgagagtct gcagccagac 120
tacagtgaac ggttctgcca cgtcagcgag attcccccca aaggaggggc cctaggagag 180
gggcctggag gttctccttg cagcctgcat agcccttact ggcctccccc atgttattct 240
ctgaagccgg aagcc 255
<210> 65
<211> 217
<212> PRT
<213> Artificial sequence
<220>
<223> IL-1R1胞内AA序列
<400> 65
Lys Val Phe Lys Val Asp Ile Val Leu Trp Tyr Arg Asp Ser Cys Ser
1 5 10 15
Gly Phe Leu Pro Ser Lys Ala Ser Asp Gly Lys Thr Tyr Asp Ala Tyr
20 25 30
Ile Leu Tyr Pro Lys Thr Leu Gly Glu Gly Ser Phe Ser Asp Leu Asp
35 40 45
Thr Phe Val Phe Lys Leu Leu Pro Glu Val Leu Glu Gly Gln Phe Gly
50 55 60
Tyr Lys Leu Phe Ile Tyr Gly Arg Asp Asp Tyr Val Gly Glu Asp Thr
65 70 75 80
Ile Glu Val Thr Asn Glu Asn Val Lys Lys Ser Arg Arg Leu Ile Ile
85 90 95
Ile Leu Val Arg Asp Met Gly Gly Phe Ser Trp Leu Gly Gln Ser Ser
100 105 110
Glu Glu Gln Ile Ala Ile Tyr Asn Ala Leu Ile Gln Glu Gly Ile Lys
115 120 125
Ile Val Leu Leu Glu Leu Glu Lys Ile Gln Asp Tyr Glu Lys Met Pro
130 135 140
Asp Ser Ile Gln Phe Ile Lys Gln Lys His Gly Val Ile Cys Trp Ser
145 150 155 160
Gly Asp Phe Gln Glu Arg Pro Gln Ser Ala Lys Thr Arg Phe Trp Lys
165 170 175
Asn Leu Arg Tyr Gln Met Pro Ala Gln Arg Arg Ser Pro Leu Ser Lys
180 185 190
His Arg Leu Leu Thr Leu Asp Pro Val Arg Asp Thr Lys Glu Lys Leu
195 200 205
Pro Ala Ala Thr His Leu Pro Leu Gly
210 215
<210> 66
<211> 651
<212> DNA
<213> Artificial sequence
<220>
<223> IL-1R1胞内NA序列
<400> 66
aaagtcttca aggttgacat agtgctttgg tacagggact cctgctctgg ttttcttcct 60
tcaaaagctt cagatggaaa gacatacgat gcctatattc tttatcccaa gaccctggga 120
gaggggtcct tctcagactt agatactttt gtttttaaac tgttgcctga ggtcttggag 180
ggacagtttg gatacaagct gttcatttat ggaagggatg actatgttgg agaagatacc 240
atcgaggtta ctaatgaaaa tgtaaagaaa agcaggaggc tgattatcat tctagtgaga 300
gatatgggag gcttcagctg gctgggccag tcatctgaag agcaaatagc catatacaat 360
gctctcatcc aggaaggaat taaaatcgtc ctgcttgagt tggagaaaat ccaagactat 420
gagaaaatgc cagattctat tcagttcatt aagcagaaac acggagtcat ttgctggtca 480
ggagactttc aagaaagacc acagtctgca aagaccaggt tctggaaaaa cttaagatac 540
cagatgccag cccaacggag atcaccattg tctaaacacc gcttactaac cctggatcct 600
gtgcgggaca ctaaggagaa actgccggca gcaacacact taccactcgg c 651
<210> 67
<211> 182
<212> PRT
<213> Artificial sequence
<220>
<223> IL-1AcP胞内AA序列
<400> 67
Tyr Arg Ala His Phe Gly Thr Asp Glu Thr Ile Leu Asp Gly Lys Glu
1 5 10 15
Tyr Asp Ile Tyr Val Ser Tyr Ala Arg Asn Val Glu Glu Glu Glu Phe
20 25 30
Val Leu Leu Thr Leu Arg Gly Val Leu Glu Asn Glu Phe Gly Tyr Lys
35 40 45
Leu Cys Ile Phe Asp Arg Asp Ser Leu Pro Gly Gly Ile Val Thr Asp
50 55 60
Glu Thr Leu Ser Phe Ile Gln Lys Ser Arg Arg Leu Leu Val Val Leu
65 70 75 80
Ser Pro Asn Tyr Val Leu Gln Gly Thr Gln Ala Leu Leu Glu Leu Lys
85 90 95
Ala Gly Leu Glu Asn Met Ala Ser Arg Gly Asn Ile Asn Val Ile Leu
100 105 110
Val Gln Tyr Lys Ala Val Lys Asp Met Lys Val Lys Glu Leu Lys Arg
115 120 125
Ala Lys Thr Val Leu Thr Val Ile Lys Trp Lys Gly Glu Lys Ser Lys
130 135 140
Tyr Pro Gln Gly Arg Phe Trp Lys Gln Leu Gln Val Ala Met Pro Val
145 150 155 160
Lys Lys Ser Pro Arg Trp Ser Ser Asn Asp Lys Gln Gly Leu Ser Tyr
165 170 175
Ser Ser Leu Lys Asn Val
180
<210> 68
<211> 546
<212> DNA
<213> Artificial sequence
<220>
<223> IL-1AcP胞内NA序列
<400> 68
taccgagctc actttggaac agatgaaaca attcttgatg gaaaggagta tgatatttat 60
gtttcctatg caagaaatgt ggaagaagag gaatttgtgc tgctgacgct gcgtggagtt 120
ttggagaatg agtttggata caagctgtgc atcttcgaca gagacagcct gcctggggga 180
attgtcacag atgagaccct gagcttcatt cagaaaagca gacgactcct ggttgtccta 240
agtcccaact acgtgctcca gggaacacaa gccctcctgg agctcaaggc tggcctagaa 300
aatatggcct cacggggcaa catcaacgtc attttagtgc agtacaaagc tgtgaaggac 360
atgaaggtga aagagctgaa gcgggctaag acggtgctca cggtcattaa atggaaagga 420
gagaaatcca agtatcctca gggcaggttc tggaagcagt tgcaggtggc catgccagtg 480
aagaagagtc ccaggtggtc tagcaatgac aagcagggtc tctcctactc atccctgaaa 540
aacgta 546
Claims (42)
1.一种T细胞,其特征在于:所述T细胞被基因工程改造以表达一第一多肽,包括一Fc受体共同γ链FcRγ的一氨基酸序列,所述氨基酸序列能够传递一激活信号;以及表达一第二多肽,包括能够结合一Fc配体的一Fcγ受体的一胞外配体结合域,以及能够募集所述第一多肽的一氨基酸序列,使得在所述Fc配体与所述Fcγ受体的所述胞外配体结合域结合时,所述激活信号被传递。
2.如权利要求1所述的T细胞,其特征在于:能够募集所述第一多肽的所述氨基酸序列包括一Fc受体的跨膜结构域。
3.如权利要求1至2中任一项所述的T细胞,其特征在于:能够募集所述第一多肽的所述氨基酸序列包括一Fc受体的细胞质域。
4.如权利要求2至3中任一项所述的T细胞,其特征在于:所述Fc受体是Fcγ受体。
5.如权利要求1及4中任一项所述的T细胞,其特征在于:所述Fcγ受体是CD64。
6.如权利要求1至5中任一项所述的T细胞,其特征在于:所述第一多肽的分子量小于25千道尔顿。
7.如权利要求1至6中任一项所述的T细胞,其特征在于:所述第一多肽不包括一靶点结合部位。
8.如权利要求1至7中任一项所述的T细胞,其特征在于:所述第一多肽不包括scFv。
9.如权利要求1至8中任一项所述的T细胞,其特征在于:所述第二多肽不包括scFv。
10.如权利要求1至9中任一项所述的T细胞,其特征在于:所述T细胞不表达嵌合抗原受体。
11.一种表达CD64的T细胞克隆,其特征在于:所述CD64包括:胞外域、跨膜结构域及细胞质域。
12.一种分离的T细胞群,其特征在于,所述T细胞群包括:表达内源CD64的至少80%的T细胞,所述CD64包括胞外域、跨膜结构域及细胞质域。
13.一种被基因工程改造以表达CD64的T细胞,其特征在于:所述CD64包括:胞外域、跨膜结构域及细胞质域。
14.如权利要求11至13中任一项所述的T细胞或T细胞群,其特征在于:所述T细胞或所述T细胞群被基因工程改造以表达包括Fc受体共同γ链的一氨基酸序列的一多肽,所述氨基酸序列能够传递一激活信号。
15.如权利要求14所述的T细胞或T细胞群,其特征在于:所述多肽还包括CD3ζ链的一氨基酸序列,所述氨基酸序列能够传递一激活信号。
16.如权利要求1至15中任一项所述的T细胞或T细胞群,其特征在于:所述T细胞或所述T细胞群内源性表达对一病理细胞具有特异性的一T细胞受体。
17.如权利要求1至15中任一项所述的T细胞或T细胞群,其特征在于:所述T细胞或所述T细胞群被基因工程改造以表达一T细胞受体。
18.如权利要求1至7以及11至15中任一项所述的T细胞或T细胞群,其特征在于:所述T细胞或所述T细胞群被基因工程改造以表达一嵌合抗原受体。
19.一种在一受试者中治疗与一病理细胞相关的一疾病的方法,其特征在于,使用包括Fc结构域的一治疗组合物,所述治疗组合物对所述病理细胞具有特异性,所述方法包括:向所述受试者施用如权利要求1至9以及14至18中任一项所述的一治疗有效量的T细胞或是T细胞群,从而治疗所述受试者的所述疾病。
20.如权利要求1至10以及14至18中任一项所述的T细胞或T细胞群,在一受试者中治疗与一病理细胞相关的一疾病的用途,使用包括Fc结构域的一治疗组合物,所述治疗组合物对所述病理细胞具有特异性。
21.一种在一需要的受试者中治疗与一病理细胞相关的一疾病的方法,其特征在于,所述方法包括:向所述受试者施用如权利要求1至10以及14至18中任一项所述的一治疗有效量的T细胞或T细胞群;以及包括Fc结构域的一治疗组合物,所述治疗组合物对所述病理细胞具有特异性,从而治疗所述受试者的所述疾病。
22.如权利要求1至10以及14至18中任一项所述的T细胞或T细胞群;以及包括Fc结构域的一治疗组合物,在一需要的受试者中治疗与所述病理细胞相关的所述疾病的用途,所述治疗组合物对所述病理细胞具有特异性。
23.一种制品,其特征在于,所述制品包括:一包装材料,包装如权利要求1至18中任一项所述的T细胞或T细胞群;以及包括Fc结构域的一治疗组合物。
24.如权利要求23所述的制品,其特征在于:所述治疗组合物对一病理细胞具有特异性。
25.如权利要求19至24中任一项所述的T方法、T细胞或T细胞群的用途或是制品,其特征在于:所述治疗组合物是Fc融合蛋白。
26.如权利要求19至24中任一项所述的T方法、T细胞或T细胞群的用途或是制品,其特征在于:所述治疗组合物是一抗体。
27.如权利要求26所述的T方法、T细胞或T细胞群的用途或是制品,其特征在于:所述抗体是IgG。
28.如权利要求16以及19至27中任一项所述的T细胞、T细胞群、方法或是T细胞或T细胞群的用途,其特征在于:所述疾病是癌症,并且其中所述病理细胞是癌细胞。
29.如权利要求28所述的T细胞、T细胞群、方法或是T细胞或T细胞群的用途,其特征在于:所述癌症选自于由黑色素瘤、腺癌、乳腺癌、结肠癌、卵巢癌、肺癌及B细胞淋巴瘤所组成的群组。
30.如权利要求28所述的T细胞、T细胞群、方法或是T细胞或T细胞群的用途,其特征在于:所述癌症选自于由黑色素瘤、腺癌及乳腺癌所组成的群组。
31.如权利要求26至30中任一项所述的方法、T细胞或T细胞群的用途或是制品,其特征在于:所述抗体选自于由阿替利珠单抗、西妥昔单抗、利妥昔单抗、伽妥珠单抗及静脉注射免疫球蛋白所组成的群组。
32.如权利要求28至30中任一项所述的T细胞、T细胞群、方法或是T细胞或T细胞群的用途,其特征在于:所述癌细胞表达选自于由PDL-1、CD19、E-钙粘蛋白、MUC1、TRP-1及TRP-2所组成的群组的一标记物。
33.如权利要求28至30中任一项所述的T细胞、T细胞群、方法或是T细胞或T细胞群的用途,其特征在于:所述癌细胞表达PDL-1。
34.如权利要求26至30以及32至33中任一项所述的T细胞、T细胞群、方法、T细胞或T细胞群的用途或是制品,其特征在于:所述抗体是抗PDL-1。
35.如权利要求26至30以及32至34中任一项所述的T细胞、T细胞群、方法、T细胞或T细胞群的用途或是制品,其特征在于:所述抗体是阿替利珠单抗。
36.一种分离T细胞的方法,其特征在于,所述方法包括:使用结合CD64多肽或编码所述CD64多肽的一多核苷酸的一试剂从一受试者的一生物样品中分离CD64+T细胞。
37.如权利要求36所述的方法,其特征在于:所述方法包括在所述分离后,培养、克隆、激活及基因工程改造所述CD64+T细胞的至少一个步骤。
38.如权利要求36至37中任一项所述的方法,其特征在于:所述方法包括向有需要的一受试者施用多个所述CD64+T细胞。
39.如权利要求1至38中任一项所述的T细胞、T细胞群、方法、T细胞或T细胞群的用途或是制品,其特征在于:所述T细胞是CD4+T细胞。
40.如权利要求1至38中任一项所述的T细胞、T细胞群、方法、T细胞或T细胞群的用途或是制品,其特征在于:所述T细胞是CD8+T细胞。
41.如权利要求1至40中任一项所述的T细胞、T细胞群、方法、T细胞或T细胞群的用途或是制品,其特征在于:所述T细胞是增殖细胞。
42.如权利要求19至22、27至35以及38至41中任一项所述的方法或是T细胞或T细胞群的用途,其特征在于:所述T细胞对于所述受试者是自体的。
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US20170151283A1 (en) * | 2014-05-23 | 2017-06-01 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treating antibody resistance |
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