CN105829349B - 肽嵌合抗原受体t细胞开关和其用途 - Google Patents
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Abstract
本文公开了嵌合抗原受体效应细胞(CAR‑EC)和CAR‑EC开关。可开关CAR‑EC一般是T细胞。一个或多个嵌合抗原受体可以识别CAR‑EC开关上的肽抗原。CAR‑EC和开关可以用于治疗有需要的受试者的病状。
Description
交叉引用
本申请要求2013年10月15日提交的美国临时申请序列号61/891,347、2013年10月25日提交的美国临时申请序列号61/895,704、2014年6月6日提交的美国临时申请序列号62/009,054、2014年7月29日提交的美国临时申请序列号62/030,526、以及2014年7月29日提交的美国临时申请序列号62/030,514的权益,其全部以全文引用的方式并入。
背景技术
免疫疗法成为化学疗法的有吸引力的替代物,包括使用遗传修饰的T细胞的过继转移“重教”免疫系统以识别并消除恶性肿瘤细胞的免疫疗法。遗传修饰的T细胞表达嵌合抗原受体,其一般由来源于对标靶恶性细胞上的肿瘤相关抗原产生受体特异性的单克隆抗体的信号传导内域、CD3-ζ跨膜域以及细胞外单链可变片段(scFv)组成。在经由嵌合抗原受体结合肿瘤相关抗原后,表达嵌合抗原受体的T细胞(CAR T细胞)设置对恶性细胞具细胞毒性的免疫反应。这类疗法可以避开化学疗法抗性并且已经显示对复发性/难治性疾病具活性,使得一些慢性淋巴细胞白血病(CLL)和急性成淋巴细胞白血病(ALL)患者持续缓解。然而,这些疗法需要进一步研究和优化,因为其引起不合需要的作用,诸如毒性淋巴细胞减少、血液学标靶的慢性低丙种球蛋白血症、实体肿瘤标靶的致命性脱靶细胞溶解、在使用表达抗CD19抗体的CAR T细胞的情况下持久的B细胞发育不全并且在一些情况下死亡。
控制CAR T细胞的活性的开关的引入将允许在消除赘生性细胞之后切断CAR T细胞活性和相关的免疫反应并且将允许B细胞再增殖。新近临床前研究已经展示CAR T细胞系统可以经由基于抗体的开关控制,其中这种抗体结合标靶细胞(例如,癌细胞),这阻断CART细胞结合标靶细胞并且“关闭”CAR-T活性。虽然这些系统在概念上允许使用CAR T细胞可开关地靶向肿瘤,但其可能受困于一系列限制。使用半胱氨酸或赖氨酸对抗体的非特异性标记产生包括可能是非功能性的,具有不可预测的药物动力学和/或免疫原性,并且可能难以优化的变体的异质产物。
发明内容
本文公开了嵌合抗原受体效应细胞开关,其包含:结合效应细胞上的嵌合抗原受体的肽抗原;以及结合标靶细胞上的细胞表面分子的靶向部分。肽抗原可以基于或来源于天然存在的肽。肽抗原可以基于或来源于非人类肽。肽抗原可以基于或来源于真核肽。肽抗原可以基于或来源于肽,其中这种肽由酵母表达。肽抗原可以基于或来源于酵母转录因子GCN4。肽抗原可以包含非天然存在的肽。肽抗原可以包含合成肽标签。肽抗原可以基于或来源于选自SEQ ID NO:2-7的序列。肽抗原可以包含与选自SEQ ID NO:2-7的肽序列至少约50%同源的序列。靶向部分可以包含靶向肽。靶向部分可以包含靶向抗体或抗体片段。靶向抗体或抗体片段可以选自由以下组成的群组:免疫球蛋白、无Fc的免疫球蛋白、和Fab,以及其片段。靶向部分可以选自由以下组成的群组:抗EGFR抗体、抗Her2抗体、抗EGFRvIII抗体、抗CD33抗体、抗CLL-1抗体、抗CEA抗体、抗CD19抗体、抗CD22抗体、抗BCMA抗体和抗CS1抗体,以及其片段。靶向抗体或抗体片段可以包含轻链和重链对,其中轻链和重链由基于或来源于选自由以下组成的群组的核酸序列对的核酸序列编码:SEQ ID NO:8和9;SEQ ID NO:8和10;SEQ ID NO:11和12;SEQ ID NO.13和14;SEQ ID NO:15和16;SEQ ID NO:17和18;以及SEQ ID NO:19和20。靶向抗体或抗体片段可以包含轻链和重链对,其中轻链和重链由基于或来源于选自由以下组成的群组的氨基酸序列对的氨基酸序列编码:SEQ ID NO:21和22;SEQ ID NO:23和24;SEQ ID NO.25和26;SEQ ID NO:27和28;以及SEQ ID NO:27和29。嵌合抗原受体效应细胞开关可以包含轻链和重链对,其中轻链和重链由基于或来源于选自由以下组成的群组的氨基酸序列对的氨基酸序列编码:SEQ ID NO:30和29;SEQ ID NO:36和29;SEQ ID NO:31和28;SEQ ID NO:27和32;SEQ ID NO:27和33;SEQ ID NO:27和34;以及SEQID NO:27和35。肽抗原可以融合至靶向抗体或抗体片段的末端。肽抗原可以融合至选自由以下组成的群组的靶向抗体或抗体片段的区域:轻链的N端、轻链的C端、重链的N端、Fab重链的C端以及恒定区重链的C端。肽抗原可以嫁接至靶向部分中。靶向部分可以包含靶向抗体或抗体片段。肽抗原可以嫁接至选自CH1域、CH2域、CH3域、CL域、VH域、VL域以及铰链区的靶向抗体或抗体片段的区域中。肽抗原可以嫁接于选自CH1域、CH2域、CH3域、CL域、VH域、VL域、重链、轻链以及铰链区的靶向抗体或抗体片段的两个区域之间,其中这两个区域是相邻的。肽抗原可以嫁接至靶向抗体或抗体片段的环中。肽抗原可以嫁接至靶向抗体或抗体片段的恒定域的环中。肽抗原可以嫁接于靶向抗体或抗体片段的铰链区与重链恒定域之间。肽抗原可以置换靶向抗体或抗体片段的一个或多个氨基酸。肽抗原可以嫁接至靶向抗体或抗体片段中而不置换氨基酸。嵌合抗原受体效应细胞可以进一步包含连接肽抗原和靶向部分的连接子。连接子可以是连接肽抗原和靶向部分的肽,其中靶向部分包含靶向多肽。连接子可以包含约1个至约20个氨基酸。连接子可以包含基于或来源于选自SEQ ID NO:38-42的序列的序列。肽抗原可以包含酵母转录因子GCN4或其同源物并且靶向部分选自由以下组成的群组:抗Her2抗体、抗BCMA抗体、抗CD19抗体、抗CEA抗体以及其片段。标靶细胞可以是癌细胞。细胞表面分子可以是肿瘤相关抗原。细胞表面分子可以选自由以下组成的群组:分化簇蛋白、受体、整合膜蛋白以及糖蛋白。嵌合抗原受体效应细胞开关的均质度可以为至少约90%。
本文进一步公开了医药组合物,其包含:包含以下的嵌合抗原受体效应细胞开关:结合效应细胞上的嵌合抗原受体的肽抗原,和结合标靶上的细胞表面分子的靶向部分;以及医药学上可接受的盐、赋形剂和/或媒剂。
本文公开了试剂盒,其包含:包含以下的嵌合抗原受体效应细胞开关:结合效应细胞上的嵌合抗原受体的肽抗原,和结合标靶细胞上的细胞表面分子的靶向部分;以及包含结合至嵌合抗原受体效应细胞开关的肽抗原的嵌合抗原受体的嵌合抗原受体效应细胞。靶向部分可以包含靶向肽。靶向部分包含靶向抗体或抗体片段。肽抗原嫁接于靶向部分内。试剂盒可以包含第一嵌合抗原受体效应细胞开关和第二嵌合抗原受体效应细胞开关,其中第一嵌合抗原受体效应细胞开关包含第一肽抗原和第一靶向部分并且第二嵌合抗原受体效应细胞开关包含第二肽抗原和第二靶向部分。第一肽抗原和第二肽抗原可以是相同的。第一靶向部分可以结合第一标靶细胞上的第一细胞表面分子并且第二靶向部分可以结合第二标靶细胞上的第二细胞表面分子,其中第一细胞表面分子和第二细胞表面分子是不同的。效应细胞可以选自T细胞、效应B细胞、自然杀伤细胞、巨噬细胞以及其祖细胞。效应细胞可以选自初始T细胞、记忆性干细胞T细胞、中枢记忆性T细胞、效应记忆性T细胞、辅助T细胞、CD4+T细胞、CD8+T细胞、CD8/CD4+T细胞、αβT细胞、γδT细胞、细胞毒性T细胞、自然杀伤T细胞、自然杀伤细胞、巨噬细胞。
本文进一步公开了结合嵌合抗原受体效应细胞开关的肽抗原的嵌合抗原受体。嵌合抗原受体可以包含结合嵌合抗原受体效应细胞开关的肽抗原的抗体或抗体片段。抗体片段或抗体片段可以结合真核抗原。抗体或抗体片段可以结合非天然存在的肽。抗体片段可以是scFv。抗体或抗体片段可以选自抗酵母转录因子GCN4抗体、抗抗体、抗HTP抗体以及其片段。嵌合抗原受体可以由基于或来源于SEQ ID NO:1的聚核苷酸编码。
本文公开了包含嵌合抗原受体的效应细胞,其中嵌合抗原受体结合嵌合抗原受体效应细胞开关的肽抗原。效应细胞可以是T细胞。效应细胞可以包含一个或多个基于或来源于SEQ ID NO:1的聚核苷酸。
本文进一步公开了包含具有编码嵌合抗原受体效应细胞开关的序列的聚核苷酸的载体,其中嵌合抗原受体效应细胞开关包含肽抗原和靶向部分,其中靶向部分包含肽并且结合标靶细胞上的细胞表面分子。
本文公开了包含以下的载体:具有编码靶向抗体或抗体片段的重链的第一序列的第一聚核苷酸;具有编码靶向抗体或抗体片段的轻链的第二序列的第二聚核苷酸;以及具有编码肽抗原的第三序列的第三聚核苷酸,其中载体的表达产生嵌合抗原受体效应细胞开关。第三序列可以与选自第一序列和第二序列的序列相邻。第三序列可以位于选自第一序列和第二序列的序列内。
本文进一步公开了产生嵌合抗原受体效应细胞开关的方法,其包括从一个或多个聚核苷酸载体表达:编码靶向抗体或抗体片段的重链的第一序列;编码靶向抗体或抗体片段的轻链的第二序列;以及编码肽抗原的第三序列,其中载体的表达产生嵌合抗原受体效应细胞开关。
附图说明
图1A图解了嵌合抗原受体T细胞(CAR T细胞)和使用本文所公开的开关的CAR T细胞开关疗法的一般概览。从受试者分离淋巴细胞并且随后将编码嵌合抗原受体的表达载体引入淋巴细胞中以产生嵌合抗原受体表达细胞。将所得工程改造的淋巴细胞连同CAR T细胞开关一起施用于受试者。
图1B图解了CAR T细胞开关,其包含由CAR T细胞的嵌合抗原受体结合的肽和对标靶细胞具选择性的靶向抗体。CAR T细胞开关与CAR T细胞的结合诱导将对也结合至CAR T细胞开关的恶性细胞具细胞毒性的免疫反应。
图2描绘了结合至来源于酵母转录因子GCN4(7P-14P)的肽(暗灰色代表GCN4肽)的亲和力成熟scFv(浅灰色和中灰色代表轻链和重链)的PDB 1P4B晶体结构。
图3示出了抗CD19-Fab-GCN4CL1CAR-EC开关的质谱分析。计算值:49533,实验值:49537.09。
图4示出了具有GCN4肽嫁接或融合至抗CD19抗体或抗体片段的各种区或域的各种抗CD19抗体或抗体片段的抗GCN4CAR T细胞的细胞毒性。
图5A示出了GCN4肽嫁接或融合至抗体或抗体片段的各种区或域的抗CD19抗体或抗体片段的非还原性SDS-PAGE凝胶。
图5B示出了GCN4肽嫁接或融合至抗体或抗体片段的各种区或域的抗CD19抗体或抗体片段的还原性SDS-PAGE凝胶。
图6描绘了抗CD19Fab(FMC63)中的酵母GCN4肽嫁接位置。
图7示出了异种移植肿瘤小鼠模型中抗CD19Fab-GCN4肽CAR T细胞开关和抗GCN4CAR T细胞的体内功效。图7A示出了未处理对比处理的小鼠中的肿瘤的定量。图7B描绘了未处理对比处理的小鼠中的肿瘤细胞的体内处理方案和显现。
图8示出了抗GCN4CAR T细胞和CAR T细胞开关(嫁接至轻链恒定域中的抗BCMA抗体-GCN4肽)对BCMA阳性细胞(OPM2)的细胞毒性。
具体实施方式
当前的嵌合抗原受体T细胞(CAR T细胞)疗法由于缺乏控制CAR T细胞活性的手段而可能是不可靠的。本文公开了选择性地活化和灭活嵌合抗原受体T细胞的组合物和方法,其可以提供比当前测试和施用的那些更安全并且更通用的免疫疗法。本文公开了可开关嵌合抗原受体效应细胞(CAR-EC)和嵌合抗原受体效应细胞(CAR-EC)开关,其中CAR-EC开关具有由CAR-EC上的嵌合抗原受体结合的第一区和结合标靶细胞上的细胞表面分子的第二区,从而从CAR-EC刺激对所结合的标靶细胞具细胞毒性的免疫反应。一般来说,CAR-EC是T细胞。以这种方式,CAR-EC开关可以充当CAR-EC活性的“开通开关”。可以通过减少或停止开关的施用来“切断”活性。这些CAR-EC开关可以与本文所公开的CAR-EC以及现有的CAR T细胞一起使用,用于治疗疾病或病状,诸如癌症,其中标靶细胞是恶性细胞。这种治疗在本文中可以称作可开关免疫疗法,其例示性示意概览描绘于图1中。
本文所公开的CAR-EC开关包含结合标靶细胞上的细胞表面分子的第一区和由嵌合抗原受体结合的第二区。一般来说,第一区是靶向多肽。靶向多肽可以是结合标靶细胞上的抗原的靶向抗体或抗体片段。替代地或另外,第一区可以包含非肽小分子(例如,维生素、代谢物)。第二区,在本文中称作嵌合抗原结合肽抗原(CAR-BP),包含肽。为简单起见,术语嵌合抗原结合肽抗原在本文中可以简单地称作肽抗原。一般来说,CAR-BP融合至靶向多肽的末端或嫁接于靶向多肽内。使CAR-BP融合或嫁接至靶向多肽可以通过将编码第一区和第二区的一个或多个聚核苷酸以所需的次序或组合克隆至聚核苷酸表达载体中来进行。
本文所公开的包括施用CAR-EC开关的治疗疾病或病状的方法可以通过减少或停止CAR-EC开关的施用提供可滴定的反应、改善的安全性和/或CAR-EC活性的终止。与通过与标靶细胞表面分子竞争结合CAR“切断”CAR-EC活性来控制CAR-EC活性的其它方法成对比,本文所公开的CAR-EC开关一般起到CAR-EC活化剂或“开通”开关的功能。
本文进一步公开了包括CAR-EC开关和效应细胞的CAR-EC平台,这些效应细胞包含可以结合多个CAR-EC开关的通用嵌合抗原受体(CAR),从而提供一种或多种类型的标靶细胞的依序靶向(例如,异质性肿瘤的治疗)。CAR可以包含针对开关的超高亲和力抗体或抗体片段(例如,scFv)。产生本文所公开的CAR-EC开关的方法可以有利地通过亲和力、化合价、几何结构、长度和/或化学经由CAR-EC开关肽/抗体的位点特异性嫁接/融合来提供CAR-EC细胞活性的控制、脱靶反应性的滴定、肿瘤溶解综合症(TLS)的消除、细胞因子释放综合症(CRS)的衰减和/或CAR-EC开关结合的优化。
除非另有规定,否则如本文所用的术语“开关”和“CAR-EC开关”可互换使用并且可以指肽开关。肽抗体开关的抗体部分可以包含抗体的至少一部分或整个抗体。举例来说,肽抗体开关的抗体部分可以包含重链的至少一部分、轻链的一部分、可变区的一部分、恒定区的一部分、互补决定区(CDR)的一部分,或其组合。肽抗体开关和/或半抗原抗体开关的抗体部分可以包含Fc(可结晶片段)区的至少一部分。肽抗体开关的抗体部分可以包含互补决定区(例如,CDR1、CDR2、CDR3)的至少一部分。肽抗体开关的抗体部分可以包含Fab(抗原结合片段)区的至少一部分。肽开关可以是肽-Fab开关。
在更详细地描述本发明方法、试剂盒以及组合物之前,应了解,本发明并不限于所描述的特定方法、试剂盒或组合物,因为这些当然可以有变化。还应了解,本文所用的术语仅用于描述特定实施方案的目的,并且不意图具限制性,这是因为本发明的范围将仅受随附权利要求书限制。提出实施例以向本领域的一般技术人员提供如何制造和使用本发明的全面公开和描述,并且不意图限制本发明者视作其发明的范围,也不意图代表下文的实验是所进行的全部或唯一实验。已经努力确保关于所用数值(例如,量、温度等等)的精确度,但一些实验误差和偏差应考虑在内。除非另有指示,否则份数是重量份,分子量是平均分子量,温度是摄氏度,并且压力是大气压或近大气压。
在提供值的范围的情况下,应了解,除非上下文另有明确指示,否则还特别地公开介于那个范围的上限与下限之间的每个居中值,至下限单位的十分之一。介于规定范围内的任何规定值或居中值之间的每个较小范围和在那个规定范围内的任何其它规定或居中值涵盖于本发明内。这些较小范围的上限和下限可以独立地包括于范围内或排除在外,并且任一、无一或两个界限包括于较小范围内的每个范围也涵盖于本发明内,受制于在规定范围内任何特别排除的界限。在规定范围包括界限中的一者或两者的情况下,排除那些包括的界限中的任一者或两者的范围也包括于本发明中。
除非另有规定,否则本文所用的所有技术和科学术语具有与本发明所属领域的一般技术人员通常所理解的相同的含义。尽管类似或等效于本文所描述的那些的任何方法和材料可以用于本发明的实施或测试,但现在描述一些潜在和优选的方法和材料。本文所提及的所有公布以引用的方式并入本文中以结合所引用的公布公开和描述方法和/或材料。应了解,在存在矛盾的程度上本公开取代所并入的公布的任何公开内容。
如本领域的技术人员在阅读本公开后将显而易见,在不脱离本发明的范围或精神的情况下,本文描述和说明的个别实施方案中的每一者具有离散的组分和特征,其可以容易地与其它若干实施方案中的任一者的特征分离或组合。任何叙述的方法可以按所叙述的事件的顺序或按逻辑上可能的任何其它顺序进行。
必须注意,除非上下文另有明确指示,否则如本文和随附权利要求书中所用的单数形式“一个(a/an)”和“这个”包括复数个指示物。因此,举例来说,提及“一个细胞”包括多个这样的细胞并且提及“这个肽”包括提及本领域的技术人员所知的一个或多个肽和其等效物,例如多肽,等等。
仅仅提供本文所论述的公布在本申请的提交日期之前的公开内容。本文中无一事物被解释为承认本发明无权先于因现有发明所作的这类公布。此外,所提供的公布日期可以不同于可能需要独立确认的实际公布日期。
提供了产生用于使效应细胞与受试者中的标靶在一起的CAR-EC平台和CAR-EC开关的方法、试剂盒以及组合物。这些方法、试剂盒以及组合物在许多疾病中发现治疗用途。举例来说,异质性肿瘤和血细胞恶性病(例如,急性成淋巴细胞白血病和慢性淋巴细胞白血病)当CAR-EC开关键联以及CAR-EC开关细胞靶向部分的长度、化合价和定向得到优化时可以用CAR-EC平台更有效地治疗。异质性肿瘤可以用靶向多于一个肿瘤抗原的多个CAR-EC开关更有效地治疗。本发明的优点和特征对于本领域的技术人员在阅读如下文更全面描述的组合物和方法的细节后将变得显而易见。
虽然本文已经示出和描述本发明的优选实施方案,但本领域的技术人员将显而易见,这类实施方案仅作为实例而提供。在不脱离本发明的情况下众多变更、变化以及取代现在将为本领域的技术人员所想到。应了解,在实施本发明中可以采用本文所描述的本发明的实施方案的各种替代物。以上权利要求书意图界定本发明的范围并且从而涵盖在这些权利要求书的范围内的方法和结构以及其等效物。
IA.肽开关
本文公开了嵌合抗原受体效应细胞开关,其包含:结合效应细胞上的嵌合抗原受体的肽抗原;以及结合标靶上的细胞表面分子的靶向部分。靶向部分可以是靶向多肽,其包含结合细胞表面分子的靶向肽。靶向部分可以是包含靶向肽的靶向抗体或抗体片段,其中靶向肽是靶向抗体或抗体片段的抗原结合位点。靶向肽可以是抗体片段的至少一部分并且细胞表面分子可以是抗原。靶向部分可以包含识别和/或结合一个或多个抗原的一个或多个肽。靶向部分可以包含识别和/或结合仅一个抗原的一个或多个肽。肽抗原可能不包含识别和/或结合抗原的抗体或抗体片段。
本文进一步公开了CAR-EC开关,其包含:结合效应细胞上的CAR的肽抗原(CAR-BP),其中CAR-BP;以及结合标靶细胞上的细胞表面分子的靶向多肽。肽抗原可以融合至靶向多肽的末端。肽抗原可以嫁接至靶向多肽中(例如,靶向多肽的所选氨基酸之间)。靶向多肽可以融合至肽抗原的末端。靶向多肽可以嫁接至肽抗原中(例如,肽抗原的所选氨基酸之间)。
本文公开了CAR-EC开关,其包含:结合效应细胞上的CAR的肽抗原(CAR-BP);以及结合标靶上的抗原的靶向抗体或抗体片段。靶向抗体或抗体片段可以选自免疫球蛋白、Fab、Fab'、F(ab')2以及scFv。靶向抗体或抗体片段可以包含轻链。靶向抗体或抗体片段可以包含重链。
肽抗原可以融合至靶向抗体或抗体片段的轻链的N端。肽抗原可以融合至靶向抗体或抗体片段的轻链的C端。肽抗原可以融合至靶向抗体或抗体片段的重链的N端。肽抗原可以融合至靶向抗体或抗体片段的重链的C端。肽抗原可以融合至靶向抗体或抗体片段的VL域的N端。肽抗原可以融合至靶向抗体或抗体片段的VH域的N端。肽抗原可以融合至靶向抗体或抗体片段的CL域的C端。肽抗原可以融合至靶向抗体或抗体片段的Fc域的C端。肽抗原可以融合至IgG的VL域的N端。肽抗原可以融合至IgG的VH域的N端。肽抗原可以融合至IgG的CL域的C端。肽抗原可以融合至IgG的Fc域的C端。肽抗原可以融合至Fab的VL域的N端。肽抗原可以融合至Fab的VH域的N端。肽抗原可以融合至Fab的CL域的C端。肽抗原可以融合至Fab的CH1域的C端。
肽抗原可以嫁接至靶向抗体或抗体片段的内部位点中(例如,靶向抗体或抗体片段的所选氨基酸之间)。肽抗原可以嫁接至靶向抗体或抗体片段的重链中。肽抗原可以嫁接至靶向抗体或抗体片段的轻链中。肽抗原可以嫁接至靶向抗体或抗体片段的恒定域/区中。肽抗原可以嫁接至靶向抗体或抗体片段的可变域/区中。肽抗原可以嫁接至Fab的内部位点中。肽抗原可以嫁接至免疫球蛋白(例如,IgG)的内部位点中。肽抗原可以嫁接至选自CL域、CH1域、CH2域、CH3域、VL域、VH域以及铰链域的靶向抗体或其片段的域中。肽抗原可以嫁接于选自CL域、CH1域、CH2域、CH3域、VL域、VH域以及铰链域的抗体或其片段的两个域之间,其中这两个域是相邻的。肽抗原可以嫁接至抗体或其片段的CL域中。肽抗原可以嫁接至抗体或其片段的CH1域中。肽抗原可以嫁接至抗体或其片段的铰链域中。肽抗原可以嫁接至抗体或其片段的环中。肽抗原可以嫁接至抗体或其片段的CL域环中。
CAR-BP可以嫁接至抗体或抗体片段的C端中并且因此嵌合抗原受体与标靶之间的距离取决于CAR-EC开关的尺寸可能大不相同(大约是对于scFv对于Fab以及对于IgG)。虽然较大的距离可能负面影响体外功效,但全长抗体增加的停留时间可能在体内是较好的。
CAR-BP可以进一步包含连接子。连接子可以提供最佳的CAR-EC开关柔性、长度或几何结构用于促进CAR-EC对标靶细胞的相互作用或影响。CAR-BP可以进一步包含一个或多个连接子。CAR-BP可以包含两个连接子。连接子可以包含肽。连接子的长度可以为至少约1个、至少约2个、至少约3个、至少约4个、至少约5个、至少约6个、至少约7个、至少约8个、至少约9个或至少约10个氨基酸。一个或多个连接子可以包含约5个、约10个、约15个、约20个、约25个、约30个、约35个、约40个、约45个、约50个、约55个、约60个、约70个、约80个、约90个或约100个氨基酸。连接子可以位于CAR-BP的N端或C端处以使CAR-BP嫁接至靶向多肽。第一连接子可以融合至CAR-BP的N端并且第二连接子可以融合至CAR-BP的C端。连接子可以由序列(GGGGS)n(SEQ ID NO.40)组成,其中n可以为1、2、3、4、5或更大。连接子可以由序列(GGS)n(SEQ ID NO.40)组成,其中n可以为1、2、3、4、5或更大。CAR-BP可以用CAR-BP的任一端上的连接子嫁接至靶向多肽的内部位点中。连接子可以包含选自SEQ ID NO:40-44的序列。
肽抗原
肽抗原(CAR-BP)可以是由嵌合抗原受体(CAR)结合的肽。一般来说,肽抗原在人类中相对于肽可以具有高蛋白水解稳定性和低免疫原性。CAR-BP可以选自激素、细胞因子、趋化因子、生长因子、细胞粘着分子、信号传导肽、受体、细胞表面肽以及其片段。CAR-BP可以是类肽。CAR-BP可以是肽核酸(PNA)。CAR-BP可以是配体或其片段。配体可以是激素配体。配体可以是肽配体。CAR-BP可以是环肽。CAR-BP可以是线性肽。CAR-BP可以具有介于约2个与约10个、约10个与约20个、约20个与约30个、约30个与约40个、约40个与约50个、约50个与约60个、约60个与约70个、约70个与约80个、以及约80个与约90个氨基酸之间的长度。CAR-BP可以是抗原。CAR-BP可以是表位。CAR-BP可以是非线性表位。CAR-BP可以进一步包含第二肽。
肽抗原可能不包含抗体或抗体片段。肽抗原可以包含抗体或抗体片段的小于10个氨基酸。肽抗原可以包含抗体或抗体片段的小于12个氨基酸。肽抗原可以包含抗体或抗体片段的小于15个氨基酸。肽抗原可以包含抗体或抗体片段的小于20个氨基酸。肽抗原可以包含抗体或抗体片段的小于22个氨基酸。肽抗原可以包含抗体或抗体片段的小于30个氨基酸。肽抗原可能不包含抗体或抗体片段的互补位。
本文公开了包含靶向部分和肽抗原的嵌合抗原受体效应细胞开关,其中靶向部分是靶向多肽。靶向多肽可以包含靶向抗体或抗体片段。靶向抗体或抗体片段可以包含可变域。可变域可以选自VH域和VL域。肽抗原可能不位于VH域的N端处或附近。肽抗原可能不位于VL域的N端处或附近。
肽抗原可以包含非天然存在的肽。肽抗原可以包含合成肽。肽抗原可以包含非动物肽(例如,不在动物中表达的肽)。肽抗原可以包含非哺乳动物肽。肽抗原可以包含非人类肽。肽可以包含来源于植物、酵母、细菌、爬行动物、鸟或昆虫的肽。
肽抗原可以包含myc标签。肽抗原可以包含His标签。肽抗原可以包含HA标签。肽抗原可以包含多甲藻素叶绿素蛋白复合物。肽抗原可以包含绿色荧光蛋白(GFP)。肽抗原可以包含红色荧光蛋白(RFP)。肽抗原可以包含藻红蛋白(PE)。肽抗原可以包含抗生蛋白链菌素。肽抗原可以包含抗生物素蛋白。肽抗原可以包含辣根过氧化物酶(HRP)。肽抗原可以包含碱性磷酸酶。肽抗原可以包含葡萄糖氧化酶。肽抗原可以包含谷胱甘肽-S-转移酶(GST)。肽抗原可以包含麦芽糖结合蛋白。经由非限制性实例,肽抗原可以是c-myc标签、聚组氨酸标签、V5、VSVG、softag 1、softag 3、表达标签、S标签、棕榈酰化、亚硝基化、SUMO标签、硫氧还蛋白、聚(NANP)、聚Arg、钙调素结合蛋白、PurF片段、酮类固醇异构酶、PaP3.30、TAF12组蛋白折叠域、FKBP标签、SNAP标签、Halo标签、来自RNAse I的肽。肽抗原可以包含蛋白酶裂解位点。蛋白酶裂解位点可以由凝血酶、因子Xa、TEV蛋白酶或肠激酶识别。
肽抗原可以是小线性亲水肽。小线性亲水肽可以包含连接子。小线性亲水肽可以是亲水标靶肽(HTP)。小线性亲水肽可以包含序列GGGGSDYKDDDDK(SEQ ID NO:5)。小线性亲水肽可以包含序列GGGGSDYKDDDDKP(SEQ ID NO:6)。小线性亲水肽可以基本上由序列GGGGSDYKDDDDK(SEQ ID NO:5)组成。小线性亲水肽可以基本上由序列GGGGSDYKDDDDKP(SEQID NO:6)组成。小线性亲水肽可以与SEQ ID NO:5或6至少约50%同源。小线性亲水肽可以与SEQ ID NO:5或6至少约60%同源。小线性亲水肽可以与SEQ ID NO:5或6至少约70%同源。小线性亲水肽可以与SEQ ID NO:5或6至少约80%同源。小线性亲水肽可以与SEQ IDNO:5或6至少约85%同源。小线性亲水肽可以与SEQ ID NO:5或6至少约90%同源。小线性亲水肽相对于本领域中已知的其它肽可以具有减少的非特异性结合。小线性亲水肽相对于本文所公开的其它肽可以具有减少的非特异性结合和减少的融合蛋白不稳定性。肽抗原可以包含标签(SEQ ID NO:7)或其衍生物或同源物。
肽可以基于或来源于天然存在的肽。肽可以基于或来源于人类肽。肽可以基于或来源于在选自黑猩猩、猴、大鼠、小鼠、鸟、鱼、猪、马、母牛、山羊、鸡、兔以及天竺鼠的动物中表达的肽。肽可以基于或来源于哺乳动物肽。肽可以基于或来源于非哺乳动物肽。肽可以基于或来源于在植物中表达的肽。肽可以基于或来源于在细菌中表达的肽。肽可以基于或来源于原核肽。肽可以基于或来源于真核肽。肽可以基于或来源于由酵母表达的肽。肽抗原可以包含酵母转录因子GCN4肽或其衍生物或同源物。酵母转录因子GCN4肽可以包含序列RMKQLEPKVEELLPKNYHLENEVARLKKLVGER(SEQ ID NO:2)。酵母转录因子GCN4肽可以包含序列NYHLENEVARLKKL(SEQ ID NO:3)。酵母转录因子GCN4肽可以基本上由序列RMKQLEPKVEELLPKNYHLENEVARLKKLVGER(SEQ ID NO:2)组成。酵母转录因子GCN4肽可以基本上由序列NYHLENEVARLKKL(SEQ ID NO:3)组成。酵母转录因子GCN4肽可以包含SEQ ID NO.2的部分。SEQ ID NO.2的部分可以为至少4个氨基酸长。SEQ ID NO.2的部分可以为约4个、约5个、约6个、约7个、约8个、约9个、约10个、约11个、约12个或约13个氨基酸长。酵母转录因子GCN4肽可以与SEQ ID NO:2或3至少约50%同源。酵母转录因子GCN4肽可以与SEQ ID NO:2或3至少约60%同源。酵母转录因子GCN4肽可以与SEQ ID NO:2或3至少约70%同源。酵母转录因子GCN4肽可以与SEQ ID NO:2或3至少约80%同源。酵母转录因子GCN4肽可以与SEQ ID NO:2或3至少约85%同源。酵母转录因子GCN4肽可以与SEQ ID NO:2或3至少约90%同源。CAR-EC开关可以包含酵母GCN4肽和一个或多个连接子。CAR-EC开关可以包含SEQ ID NO.4。
靶向部分
靶向部分可以结合至标靶上的细胞表面分子。细胞表面分子可以包含抗原。细胞表面分子可以选自蛋白质、脂质部分、糖蛋白、糖脂、碳水化合物、多糖、核酸、MHC结合肽或其组合。细胞表面分子可以包含细菌、病毒以及其它微生物的部分(例如,包衣、被膜、细胞壁、鞭毛、纤毛以及毒素)。细胞表面分子可能由标靶细胞表达。细胞表面分子可能不由标靶细胞表达。经由非限制性实例,细胞表面分子可以是由并非标靶细胞的细胞表达并且结合至标靶细胞或标靶细胞的细胞表面分子的配体。而且,经由非限制性实例,细胞表面分子可以是结合至标靶细胞的细胞表面或细胞表面受体的毒素、外源性分子或病毒蛋白。
靶向多肽可以是靶向抗体或抗体片段。靶向抗体或抗体片段可以是免疫球蛋白(Ig)。免疫球蛋白可以选自IgG、IgA、IgD、IgE、IgM、其片段或其修饰。免疫球蛋白可以是IgG。IgG可以是IgG1。IgG可以是IgG2。IgG可以具有一个或多个Fc突变用于调节内源性T细胞FcR与CAR-EC开关的结合。IgG可以具有一个或多个Fc突变用于去除与FcR阳性细胞的FcR的Fc结合能力。Fc结合能力的去除可以减少CAR-EC与FcR阳性细胞交联的机会,其中CAR-EC与FcR阳性细胞的交联将在不存在标靶细胞的情况下活化CAR-EC。这样的话,调节内源性T细胞FcR与CAR-EC开关的结合可以减少无效或不合需要的免疫反应。一个或多个Fc突变可以去除糖基化位点。一个或多个Fc突变可以选自E233P、L234V、L235A、delG236、A327G、A330S、P331S、N297Q以及其任何组合。一个或多个Fc突变可以在IgG1中。IgG1中的一个或多个Fc突变可以是L234A、L235A或两者。替代地或另外,IgG1中的一个或多个Fc突变可以是L234A、L235E或两者。替代地或另外,IgG1中的一个或多个Fc突变可以是N297A。替代地或另外,一个或多个突变可以在IgG2中。IgG2中的一个或多个Fc突变可以是V234A、V237A或两者。
靶向抗体或抗体片段可以是无Fc的免疫球蛋白或其片段。
如本文所用的术语“抗体片段”指的是除全长形式以外的任何形式的抗体。本文中的抗体片段包括作为存在于全长抗体内的较小组分的抗体,以及已经工程改造的抗体。抗体片段包括(但不限于)Fv、Fc、Fab和(Fab')2、单链Fv(scFv)、双链抗体、三链抗体、四链抗体、双功能杂交抗体、CDR1、CDR2、CDR3、CDR的组合、可变区、构架区、恒定区、重链、轻链、替代性支架非抗体分子以及双特异性抗体。除非另有特别注明,否则使用术语“抗体”的声明和权利要求书可以特别地包括“抗体片段”。
靶向抗体片段可以是人类、完全人类、人源化、人类工程改造、非人类和/或嵌合抗体。可以使非人类抗体人源化以降低对人类的免疫原性,同时保留亲本非人类抗体的特异性和亲和力。嵌合抗体可以指经由原始地编码独立抗体的两个或更多个抗体基因的连接而形成的抗体。嵌合抗体可以包含至少一个来自第一抗体的氨基酸和至少一个来自第二抗体的氨基酸,其中第一和第二抗体是不同的。抗体或抗体片段的至少一部分可以来自牛物种、人类物种或鼠类物种。抗体或抗体片段的至少一部分可以来自大鼠、山羊、天竺鼠或兔。抗体或抗体片段的至少一部分可以来自人类。抗体或抗体片段抗体的至少一部分可以来自猕猴。
靶向抗体或抗体片段可以基于或来源于来自哺乳动物、鸟、鱼、两栖动物、爬行动物的抗体或抗体片段。哺乳动物包括(但不限于)食肉动物、啮齿动物、象、有袋动物、兔、蝙蝠、灵长类动物、海豹、食蚁动物、鲸类动物、奇蹄目动物以及偶蹄目动物。哺乳动物可以是人类、非人类灵长类动物、小鼠、绵羊、猫、犬、母牛、马、山羊或猪。
经由非限制性实例,靶向抗体或抗体片段可以靶向选自CD19、Her2、CLL-1、CD33、EGFRvIII、CD20、CD22、BCMA或其片段的抗原。抗原可以包含野生型抗原。抗原可以包含一个或多个突变。
靶向抗体或抗体片段可以是抗CD19抗体或其片段。靶向多肽可以是抗CD22抗体。靶向多肽可以是抗BCMA抗体或其片段。靶向多肽可以是抗CS1抗体或其片段。靶向多肽可以是抗EGFRvIII抗体或其片段。靶向多肽可以是抗Her2抗体或其片段。靶向多肽可以包含抗CD20抗体或抗体片段。靶向多肽可以包含利妥昔单抗(rituximab)。靶向多肽可以包含抗EGFR抗体或抗体片段。靶向多肽可以包含抗CEA抗体或抗体片段。靶向多肽可以包含抗CLL-1抗体或抗体片段。靶向多肽可以包含抗CD33抗体或抗体片段。靶向多肽可能不包含抗EpCAM抗体或其片段。
靶向抗体或抗体片段可以选自任何可商购的抗体。靶向抗体或抗体片段可以选自贺癌宁(ado-trastuzumab emtansine)、阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、布妥昔单抗(brentuximab)、维多汀(vedotin)、吉妥珠单抗(gemtuzumab)、奥唑米星(ozogamicin)、伊匹单抗(ipilimumab)、异贝莫单抗(ibritumomab)、替坦(tiuxetan)、帕尼单抗(panitumumab)、西妥昔单抗(cetuximab)、爱必妥(erbitux)、利妥昔单抗、曲妥珠单抗(trastuzumab)以及其片段。
靶向抗体或抗体片段可以包含抗CD19抗体或其片段。靶向抗体或其片段可以包含抗CD19抗体或其片段的轻链。抗CD19抗体或其片段的轻链可以由基于或来源于SEQ IDNO.8的核苷酸序列编码。核苷酸序列可以与SEQ ID NO.8约99%、约98%、约97%、约96%、约95%、约92%、约90%、约85%、约80%、约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%、约5%或约2%同源。靶向抗体或其片段可以包含抗CD19抗体或其片段的重链。抗CD19抗体或其片段的重链可以由基于或来源于SEQ ID NO.9的序列编码。核苷酸序列可以与SEQ ID NO.9约99%、约98%、约97%、约96%、约95%、约92%、约90%、约85%、约80%、约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%、约5%或约2%同源。
靶向抗体或抗体片段可以包含抗CD19抗体或其片段。靶向抗体或其片段可以包含抗CD19抗体或其片段的轻链。抗CD19抗体或片段的轻链可以包含基于或来源于SEQ IDNO.27的氨基酸序列。氨基酸序列可以与SEQ ID NO.27约99%、约98%、约97%、约96%、约95%、约92%、约90%、约85%、约80%、约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%、约5%或约2%同源。靶向抗体或其片段可以包含抗CD19或其片段的重链。靶向抗体或其片段可以包含抗CD19IgG的重链。抗CD19IgG的重链可以包含基于或来源于SEQ ID NO.28的序列。氨基酸序列可以与SEQID NO.28约99%、约98%、约97%、约96%、约95%、约92%、约90%、约85%、约80%、约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%、约5%或约2%同源。靶向抗体或其片段可以包含抗CD19Fab的重链。抗CD19Fab的重链可以包含基于或来源于SEQ ID NO.29的序列。氨基酸序列可以与SEQ IDNO.29约99%、约98%、约97%、约96%、约95%、约92%、约90%、约85%、约80%、约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%、约5%或约2%同源。
靶向抗体或抗体片段可以包含选自SEQ ID NO:8-20的核苷酸序列。靶向多肽可以基于或来源于选自SEQ ID NO:8-20的核苷酸。靶向抗体或抗体片段可以包含选自SEQ IDNO:21-29的氨基酸序列。靶向多肽可以基于或来源于选自SEQ ID NO:21-29的氨基酸序列。
本文公开了嵌合抗原受体效应细胞(CAR-EC)开关,其包含肽抗原和结合标靶细胞上的细胞表面分子的靶向部分。一般来说,效应细胞和标靶细胞与CAR-EC开关构建体的结合使得标靶细胞与效应细胞接近,这是足够靠近的以使效应细胞的活性对标靶细胞具有作用。举例来说,当T细胞和标靶细胞结合至CAR-EC开关时,T细胞可以产生对标靶细胞具有细胞毒性作用的免疫反应。
CAR-EC开关可以与多个标靶细胞相互作用。标靶细胞可以是感染的细胞。标靶细胞可以是病原感染的细胞。标靶细胞可以是患病的细胞。标靶细胞可以是遗传修饰的细胞。标靶细胞可能不是宿主细胞。标靶细胞可以来自侵入的生物体(例如,酵母、蠕虫、细菌、真菌)。本文进一步公开了与非细胞标靶上的分子相互作用的CAR-EC开关。非细胞标靶可以是病毒或其一部分。非细胞标靶可以是细胞的片段。非细胞标靶可以是细胞外基质组分或蛋白。
标靶细胞可以来源于组织。组织可以选自脑、食道、乳房、结肠、肺、神经胶质、卵巢、子宫、睾丸、前列腺、胃肠道、膀胱、肝、胸腺、骨以及皮肤。标靶细胞可以来源于一个或多个内分泌腺。替代地或另外,标靶细胞可以来源于一个或多个内分泌腺。内分泌腺可以是淋巴腺、垂体腺、甲状腺、甲状旁腺、胰腺、性腺或松果腺。
标靶细胞可以选自干细胞、多能细胞、造血干细胞或祖细胞。标靶细胞可以是循环细胞。标靶细胞可以是免疫细胞。
标靶细胞可以是癌症干细胞。标靶细胞可以是癌细胞。癌细胞可以来源于组织。经由非限制性实例,组织可以选自脑、食道、乳房、结肠、肺、神经胶质、卵巢、子宫、睾丸、前列腺、胃肠道、膀胱、肝、甲状腺以及皮肤。癌细胞可以来源于骨。癌细胞可以来源于血液。癌细胞可以来源于B细胞、T细胞、单核细胞、凝血细胞、白细胞、中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、淋巴细胞、造血干细胞或内皮祖细胞。癌细胞来源于CD19阳性B淋巴细胞。癌细胞可以来源于干细胞。癌细胞可以来源于多能细胞。癌细胞可以来源于一个或多个内分泌腺。内分泌腺可以是淋巴腺、垂体腺、甲状腺、甲状旁腺、胰腺、性腺或松果腺。
癌细胞可以是CD19阳性细胞。癌细胞可以是CD19阳性B淋巴细胞。癌细胞可以是Her2阳性细胞。Her2阳性细胞可以是Her2阳性乳癌细胞。标靶细胞可以是BCMA阳性细胞。癌细胞可以是BCMA阳性多发性骨髓瘤细胞。癌细胞可以是CS1阳性细胞。CS1阳性细胞可以是多发性骨髓瘤细胞。癌细胞可以是EGFRvIII阳性细胞。癌细胞可以是EGFRvIII阳性成胶质细胞瘤细胞。癌细胞可以是CD20阳性细胞。癌细胞可以是CD22阳性细胞。
细胞表面分子可以是抗原。抗原可以是细胞上的表面抗原或细胞表面标志物的至少一部分。抗原可以是细胞上的受体或辅受体。抗原可以指可以由主要组织相容性复合物(MHC)结合并且呈递至T细胞受体的分子或分子片段。术语“抗原”也可以指免疫原。免疫原如果单独注射至受试者中,可以激发适应性免疫反应。免疫原可以独立诱导免疫反应。抗原可以是超抗原、T依赖性抗原或T非依赖性抗原。抗原可以是外源性抗原。外源性抗原通常是已经例如通过吸入、摄入或注射从外部进入体内的抗原。一些抗原可能开始是外源性抗原,并且稍后变成内源性的(例如,细胞内病毒)。抗原可以是内源性抗原。内源性抗原可以是已经在细胞内作为正常细胞代谢的结果,或由于病原体感染(例如,病毒、细菌、真菌、寄生虫)而产生的抗原。抗原可以是自体抗原。自体抗原可以是由罹患特定自体免疫疾病的患者的免疫系统识别的正常蛋白质或蛋白质复合物(并且有时是DNA或RNA)。这些抗原在正常条件下不应是免疫系统的标靶,但归因于遗传和/或环境因素,对这种抗原的正常免疫耐受性不存在于这些患者中。抗原可能由于病状或疾病而存在或过度表达。病状或疾病可以是癌症或白血病。病状可以是发炎性疾病或病状。病状或疾病可以是代谢疾病。病状可以是遗传病症。
细胞表面分子可以是已经指定为肿瘤抗原的抗原。肿瘤抗原或新抗原可以是由MHC I或MHC II分子呈递于肿瘤细胞的表面上的抗原。这些抗原有时可以由肿瘤细胞呈递并且从不由正常细胞呈递。在这种情况下,这些抗原被称为肿瘤特异性抗原(TSA),并且一般由肿瘤特异性突变产生。更常见的是由肿瘤细胞和正常细胞呈递的抗原,并且其被称为肿瘤相关抗原(TAA)。识别这些抗原的细胞毒性T淋巴细胞可以能够破坏在增殖或转移之前的肿瘤细胞。肿瘤抗原还可以在肿瘤的表面上呈例如突变的受体形式,在这种情况下其可以由B细胞识别。除非另有规定,否则术语“肿瘤抗原”、“肿瘤特异性抗原”以及“肿瘤相关抗原”在本文中可互换使用。
细胞表面分子可以是受体。受体可以是细胞外受体。受体可以是细胞表面受体。经由非限制性实例,受体可以结合激素、神经递质、细胞因子、生长因子或细胞识别分子。受体可以是跨膜受体。受体可以是酶联受体。受体可以是G蛋白偶合受体(GPCR)。受体可以是生长因子受体。经由非限制性实例,生长因子受体可以选自表皮生长因子受体、成纤维细胞生长因子受体、血小板源性生长因子受体、神经生长因子受体、转化生长因子受体、骨形态发生蛋白生长因子受体、肝细胞生长因子受体、血管内皮生长因子受体、干细胞因子受体、胰岛素生长因子受体、生长调节素受体、促红细胞生成素受体以及其同源物和片段。受体可以是激素受体。受体可以是胰岛素受体。经由非限制性实例,受体可以选自类花生酸受体、前列腺素受体、雌激素受体、促卵泡激素受体、孕酮受体、生长激素受体、促性腺激素释放激素受体、其同源物以及其片段。受体可以是肾上腺素能受体。受体可以是整合素。受体可以是Eph受体。受体可以是促黄体激素受体。细胞表面分子可以与促黄体激素受体至少约50%同源。受体可以是免疫受体。经由非限制性实例,免疫受体可以选自模式识别受体、钟样受体、NOD样受体、杀伤活化受体、杀伤抑制受体、Fc受体、B细胞受体、补体受体、趋化因子受体以及细胞因子受体。经由非限制性实例,细胞因子受体可以选自白介素受体、干扰素受体、转化生长因子受体、肿瘤坏死因子受体、集落刺激因子受体、其同源物以及其片段。受体可以是受体激酶。受体激酶可以是酪氨酸激酶受体。受体激酶可以是丝氨酸激酶受体。受体激酶可以是苏氨酸激酶受体。经由非限制性实例,受体激酶可以活化选自Ras、Raf、PI3K、蛋白激酶A、蛋白激酶B、蛋白激酶C、AKT、AMPK、磷脂酶、其同源物以及其片段的信号传导蛋白。受体激酶可以活化MAPK/ERK信号传导路径。受体激酶可以活化Jak、Stat或Smad。
细胞表面分子可以是非受体细胞表面蛋白。细胞表面分子可以是分化簇蛋白。经由非限制性实例,细胞表面分子可以选自CD34、CD31、CD117、CD45、CD11b、CD15、CD24、CD114、CD182、CD14、CD11a、CD91、CD16、CD3、CD4、CD25、CD8、CD38、CD22、CD61、CD56、CD30、CD13、CD33、其片段以及其同源物。
细胞表面分子可以是不包含肽的分子。细胞表面分子可以包含脂质。细胞表面分子可以包含脂质部分或脂质基团。脂质部分可以包含固醇。脂质部分可以包含脂肪酸。抗原可以包含糖脂。细胞表面分子可以包含碳水化合物。
本文公开了CAR-EC开关,其包含(a)包含来自酵母转录因子肽的肽的嵌合抗原受体结合肽抗原;以及(b)靶向多肽。酵母转录因子肽可以是GCN4肽。靶向多肽可以包含靶向抗体或抗体片段。靶向抗体或抗体片段可以包含抗体的重链。靶向抗体或抗体片段可以包含抗体的轻链。靶向抗体或抗体片段可以包含抗体的Fab。靶向抗体或抗体片段可以包含抗CD19抗体或其片段。靶向抗体或抗体片段可以包含抗Her2抗体或其片段。靶向抗体或抗体片段可以选自抗CS1抗体、抗BCMA抗体、抗EGFRvIII抗体、抗CD20抗体、抗EGFR抗体、抗CEA抗体、抗CLL-1抗体、抗CD33抗体以及其片段。
本文进一步公开了CAR-EC开关,其包含(a)包含亲水标靶肽(HTP)标签的CAR结合区;以及(b)靶向多肽。靶向多肽可以包含靶向抗体或抗体片段。靶向抗体或抗体片段可以包含抗体的重链。靶向抗体或抗体片段可以包含抗体的轻链。靶向抗体或抗体片段可以包含抗体的Fab。靶向抗体或抗体片段可以包含抗CD19抗体或其片段。靶向抗体或抗体片段可以包含抗Her2抗体或其片段。靶向抗体或抗体片段可以选自抗CS1抗体、抗BCMA抗体、抗EGFRvIII抗体、抗CD20抗体、抗EGFR抗体、抗CEA抗体、抗CLL-1抗体、抗CD33抗体以及其片段。
嵌合抗原受体效应细胞开关可以包含选自SEQ ID NO.32、SEQ ID NO.33、SEQ IDNO.34、SEQ ID NO.35以及SEQ ID NO.38的重链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.34、SEQ ID NO.35以及SEQ ID NO.38的序列至少50%同源的重链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.32、SEQ IDNO.33、SEQ ID NO.34、SEQ ID NO.35以及SEQ ID NO.38的序列至少60%同源的重链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.34、SEQID NO.35以及SEQ ID NO.38的序列至少70%同源的重链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.34、SEQ ID NO.35以及SEQ ID NO.38的序列至少80%同源的重链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.34、SEQ ID NO.35以及SEQ ID NO.38的序列至少90%同源的重链。
嵌合抗原受体效应细胞开关可以包含选自SEQ ID NO.30、SEQ ID NO.31、SEQ IDNO.36以及SEQ ID NO.37的轻链。嵌合抗原受体效应细胞开关可以包含与选自SEQ IDNO.30、SEQ ID NO.31、SEQ ID NO.36以及SEQ ID NO.37的序列至少50%同源的轻链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.30、SEQ ID NO.31、SEQ ID NO.36以及SEQ ID NO.37的序列至少60%同源的轻链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.30、SEQ ID NO.31、SEQ ID NO.36以及SEQ ID NO.37的序列至少70%同源的轻链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.30、SEQ ID NO.31、SEQ IDNO.36以及SEQ ID NO.37的序列至少80%同源的轻链。嵌合抗原受体效应细胞开关可以包含与选自SEQ ID NO.30、SEQ ID NO.31、SEQ ID NO.36以及SEQ ID NO.37的序列至少90%同源的轻链。
嵌合抗原受体效应细胞开关可以包含SEQ ID NO.29的重链和SEQ ID NO.30的轻链。嵌合抗原受体效应细胞开关可以包含SEQ ID NO.29的重链和SEQ ID NO.36的轻链。嵌合抗原受体效应细胞开关可以包含SEQ ID NO.28的重链和SEQ ID NO.31的轻链。嵌合抗原受体效应细胞开关可以包含SEQ ID NO.32的重链和SEQ ID NO.27的轻链。嵌合抗原受体效应细胞开关可以包含SEQ ID NO.33的重链和SEQ ID NO.27的轻链。嵌合抗原受体效应细胞开关可以包含SEQ ID NO.34的重链和SEQ ID NO.27的轻链。嵌合抗原受体效应细胞开关可以包含SEQ ID NO.35的重链和SEQ ID NO.27的轻链。嵌合抗原受体效应细胞开关可以包含SEQ ID NO.38的重链和SEQ ID NO.37的轻链。
多价CAR-EC开关
本文例示了包含嵌合抗原受体结合肽抗原(CAR-BP)和靶向多肽的CAR-EC开关。然而,本领域的技术人员应了解,这些开关可以进一步包含额外的靶向多肽和/或额外的CAR-BP。一个或多个CAR-BP可以嫁接至靶向多肽的一个或多个嫁接位点中。一个或多个CAR-BP可以融合至靶向多肽的一个或多个末端。这可能是有利的,因为可以预测若干嫁接/融合位点提供CAR-BP与CAR的最佳结合。举例来说,第一CAR-BP可以嫁接至靶向多肽的第一域中并且第二CAR-BP可以嫁接至靶向多肽的第二域中。第一域和第二域可以是相同的。第一域和第二域可以是不同的。经由非限制性实例,第一CAR-BP可以嫁接至靶向抗体或抗体片段的轻链中并且第二CAR-BP可以嫁接至靶向抗体或抗体片段的重链中。第一CAR-BP可以融合至靶向多肽的第一末端并且第二CAR-BP可以融合至靶向多肽的第二末端。经由非限制性实例,第一CAR-BP可以融合至靶向抗体或抗体片段的轻链的C端并且第二CAR-BP可以融合至靶向抗体或抗体片段的重链的N端。第一CAR-BP可以融合至靶向多肽的末端并且第二CAR-BP可以嫁接于靶向多肽的域内。第一CAR-BP和第二CAR-BP可以是相同或相似的,以使得CAR-EC开关可以与表达一个CAR的CAR-EC细胞一起使用。第一CAR-BP和第二CAR-BP可以是不同的,以使得CAR-EC开关可以与表达一个或多个CAR的CAR-EC细胞或表达不同CAR的多个CAR-EC细胞一起使用。
本文所公开的肽开关可以包含一个或多个CAR-BP。本文所公开的肽开关可以包含两个或更多个CAR-BP。本文所公开的肽开关可以包含三个或更多个CAR-BP。本文所公开的肽开关可以包含1个、2个、3个、4个、5个、6个、7个或更多个CAR-BP。一个或多个CAR-BP可以经由一个或多个连接子融合或嫁接至靶向多肽。因此,本文所公开的肽开关可以包含一个或多个连接子(例如,L1、L2)。本文所公开的肽开关可以包含两个或更多个连接子。本文所公开的肽开关可以包含三个或更多个连接子。本文所公开的肽开关可以包含1个、2个、3个、4个、5个、6个、7个或更多个连接子。
IB.肽-小分子开关
本文进一步公开了包含CAR结合区和靶向部分的CAR-EC开关,其中CAR结合区是CAR结合肽抗原并且靶向部分是非肽小分子。非肽小分子可以是细胞靶向分子、化学配体、核酸、维生素、底物或底物类似物。非肽小分子可能不包含两个氨基酸,其中这两个氨基酸由酰胺键连接。CAR-EC开关可以进一步包含连接子。CAR结合肽抗原(CAR-BP)和小分子可以位点特异性地连接。CAR结合肽抗原可以包含非天然氨基酸。CAR结合肽抗原和小分子可以由非天然氨基酸位点特异性地连接。小分子可以结合标靶细胞上的细胞表面分子。细胞表面分子可以选自抗原、蛋白质、肽、脂质、固醇、糖脂以及细胞表面标志物。CAR结合肽抗原可以选自标签、酵母转录因子GCN4以及亲水标靶肽(HTP)。小分子可以是2-[3-(1,3-二羧丙基)脲基]戊二酸。小分子可以是盐酸盐。CAR-EC开关可以进一步包含连接子。
本文公开了产生CAR-EC开关的方法,其包括使CAR结合区偶联至靶向部分,其中CAR-EC开关包含CAR结合区和靶向部分,其中CAR结合区是CAR结合肽抗原并且靶向部分是小分子。这种方法可以进一步包括使小分子偶联至连接子以形成小分子-连接子中间物。小分子或小分子-连接子中间物可以包含一个或多个反应性官能团,其可以与并入CAR-EC开关中之前的CAR-BP上的互补反应性官能团反应。连接子或小分子-连接子中间物可以是双功能的。连接子或小分子-连接子中间物可以是异双功能的。
小分子-连接子中间物或CAR-EC开关可以是生物正交反应的产物,其非限制性实例在Kim等,《化学生物学新观点(Curr Opin Chem Bio)》17:412-419(2013)中评述。小分子-连接子中间物、连接子或CAR-EC开关可以包含肟、四唑、狄尔斯-阿尔德加合物(DielsAlder adduct)、杂狄尔斯-阿尔德加合物、芳香族取代反应产物、亲核取代反应产物、酯、酰胺、氨基甲酸酯、醚、硫醚或迈克尔反应产物(Michael reaction product)。小分子-连接子中间物、连接子或CAR-EC开关是环加成产物、复分解反应产物、金属介导的交叉偶合反应产物、自由基聚合产物、氧化偶合产物、酰基转移反应产物或光点击反应产物。环加成可以是胡伊斯根环加成(Huisgen-cycloaddition)。环加成可以是无铜[3+2]胡伊斯根环加成。环加成可以是狄尔斯-阿尔德反应。环加成可以是杂狄尔斯-阿尔德反应。小分子-连接子中间物可以是酶介导的反应的产物。小分子-连接子中间物可以是转谷氨酰胺酶介导的反应的产物,其非限制性实例描述于Lin等,《美国化学会志(J.Am.Chem.Soc.)》128:4542-4543(2006)和WO 2013/093809中。小分子-连接子中间物、连接子或CAR-EC开关可以包含连接两个半胱氨酸残基的二硫桥,诸如PolyTherics的ThioBridgeTM技术。小分子-连接子中间物、连接子或CAR-EC开关可以包含连接两个氨基酸残基的马来酰亚胺桥。小分子-连接子中间物、连接子或CAR-EC开关可以包含连接两个半胱氨酸残基的马来酰亚胺桥。
小分子-连接子中间物或连接子可以在一个或多个末端处包含烷氧基-胺(或氨氧基)基团、叠氮基和/或环辛炔基。小分子-连接子中间物或连接子可以在一个末端处包含烷氧基-胺并且在另一个末端处包含叠氮基。小分子-连接子中间物或连接子可以在一个末端处包含烷氧基-胺并且在另一个末端处包含环辛炔基。烷氧基-胺可以与氨基酸上的酮基形成稳定的肟。烷氧基-胺可以与非天然氨基酸上的酮基形成稳定的肟。酮基可以在对乙酰基苯丙氨酸(pAcF)上。
II.嵌合抗原受体(CAR)
本文公开了调控表达嵌合抗原受体(CAR)的细胞的活性的CAR-EC开关。嵌合抗原受体可以包含胞外域、跨膜域以及胞内域。胞外域可以结合至CAR-EC开关的肽抗原(例如,CAR-BP)。胞外域可以包含结合至CAR-EC开关的CAR-BP的抗体或抗体片段(CAR抗体)。CAR抗体可以包含抗体的至少一部分。在一些情况下,CAR抗体不是全长抗体。CAR抗体可以包含免疫球蛋白或其片段的至少一部分。免疫球蛋白或其片段可以选自由scFv、二-scFv、双-scFv、Fab、Fc、F(ab')2、pFc'、纳米抗体、亲和体、DARPin、双链抗体、骆驼抗体、工程改造的T细胞受体、以及单抗体(monobody)组成的群组。免疫球蛋白可以选自由IgA1、IgA2、IgD、IgM、IgE、IgG1、IgG2、IgG3以及IgG4组成的群组。CAR抗体可以包含单链可变片段(scFv)的至少一部分。CAR抗体可以是人类、完全人类、人源化、人类工程改造、非人类和/或嵌合抗体。
CAR抗体可以具有小于约0.01pM、约0.02pM、约0.03pM、约0.04pM、0.05pM、约0.06pM、约0.07pM、约0.08pM、约0.09pM、约0.1pM、约0.2pM、0.3pM、约0.4pM、约0.5pM、约0.6pM、约0.7pM、约0.8pM、约0.9pM或约1pM、约2pM、约3pM、约4pM、约5pM、约6pM、约7pM、约8pM、约9pM、约10pM、约0.01nM、约0.02nM、约0.03nM、约0.04nM、约0.05nM、约0.06nM、约0.07nM、约0.08nM、约0.09nM、约0.1nM、约0.2nM、约0.3nM、约0.4nM、约0.5nM、约0.6nM、约0.7nM、约0.8nM、约0.9nM、约1nM、约2nM、约2.5nM、约3nM、约4nM、约5nM、约6nM、约7nM、约8nM、约9nM、约10nM、约12nM、约14nM、约16nM、约18nM、约20nM、约22nM、约24nM、约26nM、约28nM或约30nM的对CAR-BP的结合亲和力。
CAR抗体可以识别合成(非天然存在的)肽。CAR抗体可以包含识别标签或其片段的抗体或抗体片段。CAR抗体可以包含识别酵母转录因子GCN4或其片段的抗体或抗体片段。CAR抗体可以包含抗HTP抗体或其片段。
CAR的跨膜域和/或胞内域可以包含细胞质信号传导域的至少一部分。胞内域可以包含选自包含CD3ζ、CD28以及4-1BB的群组的信号传导分子的至少一部分。胞内域可以包含Fc受体或其一部分。Fc受体或其部分可以是CD16或其一部分。信号传导分子可以包含CD3ζ。信号传导分子可以包含CD28。信号传导分子可以包含4-1BB。胞内域可以包含CD3ζ的至少一部分。胞内域可以包含CD28的至少一部分。胞内域可以包含4-1BB的至少一部分。胞内域可以包含OX-40的至少一部分。胞内域可以包含CD30的至少一部分。胞内域可以包含CD40的至少一部分。胞内域可以包含CD2的至少一部分。胞内域可以包含CD27的至少一部分。胞内域可以包含PD-1的至少一部分。胞内域可以包含ICOS的至少一部分。胞内域可以包含淋巴细胞功能相关抗原1(LFA-1)的至少一部分。胞内域可以包含CD7的至少一部分。胞内域可以包含LIGHT的至少一部分。胞内域可以包含NKG2C的至少一部分。胞内域可以包含B7-H3的至少一部分。胞内域可以包含来自一个或多个信号传导分子的细胞质信号传导域的至少一部分。胞内域可以包含两个或更多个细胞质信号传导域的至少一部分。两个或更多个细胞质信号传导域可以来自两个或更多个不同信号传导分子。胞内域可以包含三个或更多个细胞质信号传导域的至少一部分。胞内域可以包含四个或更多个细胞质信号传导域的至少一部分。胞内域可以包含结合至一个或多个信号传导分子的配体的至少一部分。胞内域可以包含结合至CD83的配体的至少一部分。
III.嵌合抗原受体效应细胞(CAR-EC)
本文所公开的方法、平台以及试剂盒可以包含一个或多个嵌合抗原受体效应细胞(CAR-EC)或其用途。本文所公开的嵌合抗原受体效应细胞表达嵌合抗原受体。嵌合抗原受体(CAR)可以是本文所公开的任何CAR。在方法、平台或试剂盒包含两个或更多个效应细胞的情况下,这两个或更多个效应细胞可以属于相同细胞类型。两个或更多个效应细胞可以属于不同细胞类型。两个或更多个效应细胞可以属于相同细胞谱系。两个或更多个效应细胞可以属于不同细胞谱系。两个或更多个效应细胞可以包含两个或更多个相同的CAR。两个或更多个效应细胞可以包含两个或更多个不同的CAR。两个或更多个效应细胞可以包含两个或更多个相似的CAR。
效应细胞可以是T细胞。效应细胞可以是T细胞谱系的细胞。效应细胞可以是成熟T细胞。效应细胞可以是前体T细胞。效应细胞可以是细胞毒性T细胞。效应细胞可以是初始T细胞。效应细胞可以是记忆性干细胞T细胞(TMSC)。效应细胞可以是中枢记忆性T细胞(TCM)。效应细胞可以是效应T细胞(TE)。效应细胞可以是CD4+T细胞。T细胞可以是CD8+T细胞。效应细胞可以是CD4+和CD8+细胞。效应细胞可以是αβT细胞。效应细胞可以是γβT细胞。效应细胞可以是自然杀伤T细胞。效应细胞可以是辅助T细胞。
虽然本公开的优选实施方案描述了包含T细胞的方法、试剂盒以及平台,但本领域的技术人员还可以了解,可以使用其它细胞类型替代T细胞。效应细胞可以是当接近标靶或标靶细胞时对标靶或标靶细胞具有作用的效应细胞。效应细胞可以是当接近标靶或标靶细胞时对标靶或标靶细胞具有细胞毒性作用的细胞。效应细胞可以是免疫细胞。效应细胞可以选自B细胞、单核细胞、凝血细胞、白细胞、中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞或淋巴细胞。效应细胞可以是淋巴细胞。效应细胞可以是巨噬细胞。效应细胞可以是吞噬细胞。效应细胞可以是效应B细胞。效应细胞可以是自然杀伤细胞。效应细胞可以分离自或来源于罹患疾病或病状的受试者。效应细胞可以是来源于将要用本文所公开的CAR-EC开关或CAR-EC平台治疗的受试者的细胞。
T细胞可以表达由一个或多个基于或来源于SEQ ID NO:1的聚核苷酸编码的嵌合抗原受体。聚核苷酸可以与一个或多个基于或来源于SEQ ID NO:1的聚核苷酸至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或95%一致。聚核苷酸可以与一个或多个基于或来源于SEQ ID NO:1的聚核苷酸至少约70%一致。由一个或多个聚核苷酸编码的多肽可以基于或来源于SEQ ID NO:1。多肽可以由与一个或多个基于或来源于SEQ ID NO:1的聚核苷酸至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或95%一致的聚核苷酸编码。聚核苷酸可以组成性地表达。聚核苷酸可以条件性地表达。
本文公开了产生嵌合抗原受体效应细胞(CAR-EC)的方法,这些方法包括将一个或多个编码嵌合抗原受体或嵌合抗原受体复合物的聚核苷酸引入效应细胞中。效应细胞可以是T细胞。将一个或多个编码嵌合抗原受体或嵌合抗原受体复合物的聚核苷酸引入效应细胞中可以包括用一个或多个聚核苷酸转染效应细胞。将一个或多个编码嵌合抗原受体或嵌合抗原受体复合物的聚核苷酸引入效应细胞中可以包括用包含一个或多个编码本文所公开的嵌合抗原受体的聚核苷酸的一个或多个病毒病毒性地感染效应细胞。病毒可以是慢病毒。病毒可以是腺病毒。病毒可以是逆转录病毒。病毒可以是腺相关病毒。病毒可以是自身互补型腺相关病毒(scAAV)。病毒可以是修饰的人类免疫缺陷(HIV)病毒。病毒可以是修饰的单纯疱疹病毒(HSV)病毒。产生CAR-EC的其它方法可以包括将一个或多个编码嵌合抗原受体的聚核苷酸转移至细胞中的方法,其中这些方法包括将转座子、锌指核酸酶、TALEN或CRISPR添加至细胞中。转座子可以是睡美人转座子。一个或多个聚核苷酸可以基于或来源于SEQ ID NO:1。
IV.CAR-EC平台
本文公开了包含效应细胞的嵌合抗原受体效应细胞(CAR-EC)平台,其中效应细胞包含编码嵌合抗原受体(CAR)的聚核苷酸;以及嵌合抗原受体效应细胞(CAR-EC)开关,其中CAR-EC开关包含CAR结合肽抗原和靶向多肽并且其中CAR-EC开关结合标靶细胞上的细胞表面分子。CAR-EC开关可以选自本文所公开的任何CAR-EC开关。
CAR-EC平台可以包含两个或更多个CAR-EC开关。CAR-EC平台可以包含3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个或更多个CAR-EC开关。CAR-EC平台可以包含多于20个、多于25个、多于30个、多于35个、多于40个、多于45个或多于50个CAR-EC开关。两个或更多个开关可以选自本文所公开的一个或多个CAR-EC开关或其组合。
本文所公开的CAR-EC平台可以进一步包含第一CAR-EC开关和第二CAR-EC开关,其中第一CAR-EC开关包含第一CAR-BP和第一靶向多肽并且第二CAR-EC开关包含第二CAR-BP和第二靶向多肽。第一CAR-BP和第二CAR-BP可以是相同的。第一CAR-BP和第二CAR-BP可以是不同的。第一CAR-BP和第二CAR-BP可以约99%、约98%、约97%、约96%、约95%、约92%、约90%、约85%、约80%、约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%、约5%或约2%同源。第一靶向多肽和第二靶向多肽可以是相同的。第一靶向多肽和第二靶向多肽可以是不同的。第一靶向多肽和第二靶向多肽可以约99%、约98%、约97%、约96%、约95%、约92%、约90%、约85%、约80%、约75%、约70%、约65%、约60%、约55%、约50%、约45%、约40%、约35%、约30%、约25%、约20%、约15%、约10%、约5%或约2%同源。
V.试剂盒、载体以及聚核苷酸
本文公开了包含本文所公开的一个或多个CAR-EC开关的试剂盒。试剂盒可以进一步包含两个或更多个CAR-EC开关。试剂盒可以包含三个CAR-EC开关。试剂盒可以包含约3个、4个、5个、6个、7个、8个、9个、10个、12个、15个、20个、24个、30个、35个、48个、50个、55个、60个、65个、70个、75个、80个、85个、90个、96个、100个、120个、150个、200个、300个、384个、400个、500个、600个、700个、800个、900个或1000个CAR-EC开关。试剂盒可以用于生物研究。试剂盒可以用于诊断疾病或病状。试剂盒可以用于治疗疾病或病状。试剂盒的CAR-EC开关可以与本文所公开的CAR-EC细胞或临床上使用或测试的现有CAR T细胞一起使用。试剂盒可以进一步包含一个或多个效应细胞。试剂盒可以进一步包含一个或多个CAR-EC细胞。CAR-EC细胞可以是T细胞。T细胞可以表达一个或多个CAR。试剂盒可以进一步包含编码一个或多个CAR的聚核苷酸。试剂盒可以进一步包含有包含编码一个或多个CAR的聚核苷酸的载体。CAR可以选自本文所公开的CAR中的任一者。试剂盒可以包含一个或多个编码本文所公开的CAR-EC开关或其一部分的聚核苷酸(例如,抗体、抗体片段、肽)。
本文进一步公开了编码CAR-EC开关或其部分的载体和聚核苷酸,其中CAR-EC开关包含嵌合抗原受体结合肽抗原和靶向多肽,其中靶向肽结合标靶细胞上的细胞表面分子。聚核苷酸可以是DNA。聚核苷酸可以是RNA。除非另有规定,否则如本文所用的术语“聚核苷酸”和“载体”可互换使用。靶向多肽可以是抗体或抗体片段。载体可以包含编码抗体或抗体片段的重链的序列。载体可以包含编码抗体或抗体片段的轻链的序列。载体可以包含编码抗体或抗体片段的轻链的序列和编码抗体或抗体片段的重链的序列。轻链和重链可以从相同载体表达。轻链和重链可以从两个独立载体表达。
本文公开了编码嵌合抗原受体的载体和聚核苷酸,其中嵌合抗原受体包含结合至嵌合抗原受体效应细胞开关的肽的胞外域。胞外域可以包含抗体或抗体片段。抗体或抗体片段可以结合嵌合抗原受体效应细胞开关的肽抗原。肽抗原可以是酵母肽。酵母肽可以是GCN4。f a或其部分可以由一个或多个基于或来源于SEQ ID NO:1的聚核苷酸编码。CAR或其部分可以由与一个或多个基于或来源于SEQ ID NO:1的聚核苷酸至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或95%一致的聚核苷酸编码。由聚核苷酸编码的CAR或其部分可以与一个或多个基于或来源于SEQ ID NO:1的聚核苷酸至少约70%一致。本文公开了包含一个或多个基于或来源于SEQID NO:1的聚核苷酸的载体。
包含编码本文所公开的嵌合抗原受体和/或嵌合抗原受体效应细胞开关以及其部分的序列的载体可以选自任何可商购的表达载体。表达载体可以是原核表达载体。表达载体可以是真核表达载体。表达载体可以是哺乳动物表达载体。表达载体可以是病毒表达载体。表达载体可以具有用于CAR和/或CAR-EC开关编码序列的组成性表达的组成性启动子。表达载体可以具有用于CAR和/或CAR-EC开关编码序列的条件性表达的诱导性启动子。
VI.治疗用途
本文公开了用于治疗有需要的受试者的疾病或病状的方法、平台以及试剂盒,这种方法包括将嵌合抗原受体效应细胞(CAR-EC)开关施用于受试者,其中CAR-EC开关包含:CAR结合肽抗原;以及靶向部分。本文公开了治疗有需要的受试者的疾病或病状的方法,这种方法包括施用本文所公开的CAR-EC开关中的任一者。
这些方法可以包括施用CAR-EC细胞和一个或多个CAR-EC开关。这些方法可以包括施用约1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、12个、15个、20个、24个、30个、35个、48个、50个、55个、60个、65个、70个、75个、80个、85个、90个、96个、100个、120个、150个、200个、300个、384个、400个、500个、600个、700个、800个、900个、1000个或更多个CAR-EC开关。这些方法可以包括施用两个或更多个CAR-EC开关。两个或更多个CAR-EC开关可以包含相同的CAR结合肽抗原。多于两个CAR-EC开关可以包含相同的细胞靶向多肽。两个或更多个CAR-EC开关可以包含一个或多个不同的CAR结合肽抗原。多于两个CAR-EC开关可以包含一个或多个不同的细胞靶向多肽。这些方法可以包括多个CAR-EC细胞和一个或多个CAR-EC开关。
本文公开了治疗有需要的受试者的疾病或病状的方法,这种方法包括将嵌合抗原受体效应细胞(CAR-EC)开关施用于受试者,其中CAR-EC开关包含:嵌合抗原受体结合肽抗原(CAR-BP);以及结合标靶上的抗原的靶向部分。经由非限制性实例,CAR-BP可以选自标签、酵母转录因子GCN4以及亲水标靶肽(HTP)。经由非限制性实例,靶向部分可以选自抗CD19抗体、抗CD20抗体、抗CD22抗体、抗EGFR抗体、抗EGFRvIII抗体、抗Her2抗体、抗CS1抗体、抗BCMA抗体、抗CEA抗体、抗CLL-1抗体以及抗CD33抗体。
这些方法可以包括施用一个或多个嵌合抗原受体效应细胞。这些方法可以包括施用一个或多个T细胞。一个或多个效应细胞可以选自T细胞,其选自初始T细胞、记忆性干细胞T细胞、中枢记忆性T细胞、效应记忆性T细胞、辅助T细胞、CD4+T细胞、CD8+T细胞、CD8/CD4+T细胞、αβT细胞、γδT细胞、细胞毒性T细胞、自然杀伤T细胞、自然杀伤细胞、巨噬细胞。
CAR-EC开关可以具有治疗作用,这至少部分依赖于使效应细胞接近标靶细胞。对CAR-EC开关的预期适应症的治疗作用可以至少部分归因于CAR-EC开关使效应细胞募集至标靶细胞。对CAR-EC开关的预期适应症的治疗作用可以主要归因于CAR-EC开关使效应细胞募集至标靶细胞。CAR-EC开关的治疗作用可以至少部分依赖于刺激CAR-EC细胞中的免疫反应。
施用CAR-EC开关在未进一步施用效应细胞的情况下可能不具有任何治疗作用。CAR-EC开关在未进一步施用效应细胞的情况下可能不具有显著、所需和/或预期的治疗作用。CAR-EC开关在未进一步施用效应细胞的情况下对CAR-EC平台的预期适应症可能不具有任何治疗作用。CAR-EC开关的部分或组分(例如,CAR-BP或靶向部分)在未偶联至CAR-EC开关的第二部分或组分(例如,CAR-BP或靶向部分)的情况下对CAR-EC开关的预期适应症可能不具有治疗作用。CAR-EC开关的部分或组分(例如,CAR-BP或靶向部分)当作为CAR-EC平台的一部分施用以提供治疗作用时的剂量在CAR-EC开关的部分或组分单独以那个剂量施用时可能不具有治疗作用。CAR-EC开关的部分或组分可能并不预期具有除了使T细胞募集至标靶细胞以外的任何治疗作用。单独施用CAR-EC开关的部分或组分可能对标靶细胞具有治疗作用,其中这种治疗作用相对于施用CAR-EC开关和CAR-EC细胞的治疗作用是可忽略的。施用CAR-EC开关的部分或组分可能对标靶细胞具有治疗作用,其中这种治疗作用小于施用CAR-EC开关和CAR-EC细胞的治疗作用。
本文公开了本文所公开的CAR-EC开关治疗有需要的受试者的疾病或病状的用途。本文进一步公开了本文所公开的CAR-EC开关制造用于治疗疾病的药物的用途。
本文公开了开关的用途,这种开关包含结合效应细胞上的CAR的肽抗原(CAR-BP);以及结合标靶上的抗原的靶向多肽,以治疗有需要的受试者的疾病或病状。本文进一步公开了开关的用途,这种开关包含结合效应细胞上的CAR的肽抗原(CAR-BP),其中CAR-BP;以及结合标靶上的抗原的靶向多肽,以制造用于治疗疾病的药物。
本文公开了CAR-EC开关的用途,这种CAR-EC开关包含CAR-BP,其中CAR-BP包含亲水标靶肽(HTP)或其衍生物和靶向多肽,其中靶向多肽包含抗CD19抗体或其片段;以及包含CAR的效应细胞,其中CAR包含抗HTP抗体,其中抗CD19抗体或其片段结合B细胞上的CD19,以治疗多发性骨髓瘤。
本文公开了CAR-EC开关的用途,这种CAR-EC开关包含CAR-BP,其中CAR-BP包含酵母转录因子GCN4或其衍生物和靶向多肽,其中靶向多肽包含抗CD19抗体或其片段;以及包含CAR的效应细胞,其中CAR包含抗GCN4抗体,其中抗CD19抗体或其片段结合成淋巴细胞、淋巴细胞或B细胞上的CD19,以治疗急性成淋巴细胞白血病、慢性淋巴细胞白血病或B细胞淋巴瘤。
疾病或病状可以是细胞增殖性病症。细胞增殖性病症可以选自实体肿瘤、淋巴瘤、白血病以及脂肉瘤。细胞增殖性病症可以是急性、慢性、复发性、难治性、加速的、缓解期、I期、II期、III期、IV期、青少年或成人的。细胞增殖性病症可以选自骨髓性白血病、成淋巴细胞白血病、髓系白血病、急性髓系白血病、骨髓单核细胞白血病、中性粒细胞白血病、骨髓增生异常综合症、B细胞淋巴瘤、伯基特淋巴瘤(burkitt lymphoma)、大细胞淋巴瘤、混合细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、霍奇金淋巴瘤(hodgkin lymphoma)、复发性小淋巴细胞淋巴瘤、毛细胞白血病、多发性骨髓瘤、嗜碱性粒细胞白血病、嗜酸性粒细胞白血病、成巨核细胞白血病、成单核细胞白血病、单核细胞白血病、红白血病、红系白血病以及肝细胞癌。细胞增殖性病症可以包括血液恶性病。血液恶性病可以包括B细胞恶性病。细胞增殖性病症可以包括慢性淋巴细胞白血病。细胞增殖性病症可以包括急性成淋巴细胞白血病。细胞增殖性病症可以包括CD19阳性伯基特氏淋巴瘤。
疾病或病状可以是癌症、病原体感染、自体免疫疾病、发炎性疾病或遗传病症。
在一些情况下,一种或多种疾病包括癌症。癌症可以包括复发性和/或难治性癌症。癌症的实例包括(但不限于)肉瘤、癌瘤、淋巴瘤或白血病。
癌症可以包括神经内分泌癌。癌症可以包括胰腺癌。癌症可以包括外分泌胰腺癌。癌症可以包括甲状腺癌。甲状腺癌可以包括髓样甲状腺癌。癌症可以包括前列腺癌。
癌症可以包括上皮癌。癌症可以包括乳癌。癌症可以包括子宫内膜癌。癌症可以包括卵巢癌。卵巢癌可以包括间质卵巢癌。癌症可以包括子宫颈癌。
癌症可以包括皮肤癌。皮肤癌可以包括新生血管皮肤癌。皮肤癌可以包括黑素瘤。
癌症可以包括肾癌。
癌症可以包括肺癌。肺癌可以包括小细胞肺癌。肺癌可以包括非小细胞肺癌。
癌症可以包括结肠直肠癌。癌症可以包括胃癌。癌症可以包括结肠癌。
癌症可以包括脑癌。脑癌可以包括脑肿瘤。癌症可以包括成胶质细胞瘤。癌症可以包括星形细胞瘤。
癌症可以包括血癌。血癌可以包括白血病。白血病可以包括髓系白血病。癌症可以包括淋巴瘤。淋巴瘤可以包含非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)。
癌症可以包括肉瘤。肉瘤可以包括尤文氏肉瘤(Ewing's sarcoma)。
肉瘤是骨、软骨、脂肪、肌肉、血管或者其它结缔或支持组织的癌症。肉瘤包括(但不限于)骨癌、纤维肉瘤、软骨肉瘤、尤文氏肉瘤、恶性血管内皮瘤、恶性神经鞘瘤、双侧前庭神经鞘瘤、骨肉瘤、软组织肉瘤(例如,泡状软部肉瘤、血管肉瘤、叶状囊肉瘤、皮肤纤维肉瘤、硬纤维瘤、上皮样肉瘤、骨外骨肉瘤、纤维肉瘤、血管外皮细胞瘤、血管肉瘤、卡波西氏肉瘤(Kaposi's sarcoma)、平滑肌肉瘤、脂肉瘤、淋巴管肉瘤、淋巴肉瘤、恶性纤维组织细胞瘤、神经纤维肉瘤、横纹肌肉瘤以及滑膜肉瘤)。
癌瘤是始于上皮细胞的癌症,上皮细胞是覆盖体表,产生激素,并且构成腺体的细胞。经由非限制性实例,癌瘤包括乳癌、胰腺癌、肺癌、结肠癌、结肠直肠癌、直肠癌、肾癌、膀胱癌、胃癌、前列腺癌、肝癌、卵巢癌、脑癌、阴道癌、外阴癌、子宫癌、口腔癌、阴茎癌、睾丸癌、食道癌、皮肤癌、输卵管癌、头颈癌、胃肠间质癌、腺癌、皮肤或眼内黑素瘤、肛门区癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、尿道癌、肾盂癌、输尿管癌、子宫内膜癌、子宫颈癌、垂体腺癌、中枢神经系统(CNS)赘瘤、原发性CNS淋巴瘤、脑干胶质瘤以及脊椎轴肿瘤。在一些情况下,癌症是皮肤癌,诸如基底细胞癌、鳞状、黑素瘤、非黑素瘤或光化性(日光性)角化病。
在一些情况下,癌症是肺癌。肺癌可以始于从气管分支以支持肺(支气管)或肺的小气囊(肺泡)的气道。肺癌包括非小细胞肺癌(NSCLC)、小细胞肺癌以及间皮瘤。NSCLC的实例包括鳞状细胞癌、腺癌以及大细胞癌。间皮瘤可以是肺和胸腔的内衬(胸膜)或腹部的内衬(腹膜)的癌性肿瘤。间皮瘤可以归因于石棉暴露。癌症可以是脑癌,诸如成胶质细胞瘤。
或者,癌症可以是中枢神经系统(CNS)肿瘤。CNS肿瘤可以归类为胶质瘤或非胶质瘤。胶质瘤可以是恶性胶质瘤、高级别胶质瘤、弥漫性内生性脑桥胶质瘤。胶质瘤的实例包括星形细胞瘤、少枝胶质瘤(或少枝胶质瘤和星形细胞瘤元素的混合物)以及室管膜瘤。星形细胞瘤包括(但不限于)低级别星形细胞瘤、间变性星形细胞瘤、多形性成胶质细胞瘤、毛细胞性星形细胞瘤、多形性黄色星形细胞瘤以及室管膜下巨细胞星形细胞瘤。少枝胶质瘤包括低级别少枝胶质瘤(或少枝星形细胞瘤)和间变性少枝胶质瘤。非胶质瘤包括脑膜瘤、垂体腺瘤、原发性CNS淋巴瘤以及成神经管细胞瘤。在一些情况下,癌症是脑膜瘤。
白血病可以是急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病或慢性髓细胞白血病。白血病的额外类型包括毛细胞白血病、慢性骨髓单核细胞白血病以及青少年骨髓单核细胞白血病。
淋巴瘤是淋巴细胞的癌症并且可以从B或T淋巴细胞发展。淋巴瘤的两种主要类型是霍奇金氏淋巴瘤,先前称为霍奇金氏病(Hodgkin's disease),和非霍奇金氏淋巴瘤。霍奇金氏淋巴瘤的特点是李-斯细胞(Reed-Sternberg cell)的存在。非霍奇金氏淋巴瘤是并非霍奇金氏淋巴瘤的所有淋巴瘤。非霍奇金淋巴瘤可以是惰性淋巴瘤和侵袭性淋巴瘤。非霍奇金氏淋巴瘤包括(但不限于)弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、粘膜相关的淋巴组织淋巴瘤(MALT)、小细胞淋巴细胞淋巴瘤、套细胞淋巴瘤、伯基特氏淋巴瘤、纵隔大B细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症(macroglobulinemia)、结节边缘区B细胞淋巴瘤(NMZL)、脾边缘区淋巴瘤(SMZL)、结外边缘区B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤以及淋巴瘤样肉芽肿病。
癌症可以包括实体肿瘤。癌症可以包括肉瘤。癌症可以选自由膀胱癌、乳癌、结肠癌、直肠癌、子宫内膜癌、肾癌、肺癌、黑素瘤、骨髓瘤、甲状腺癌、胰腺癌、胶质瘤、脑恶性胶质瘤、成胶质细胞瘤、卵巢癌以及前列腺癌组成的群组。癌症可以具有不均匀的抗原表达。癌症可以具有调节的抗原表达。抗原可以是表面抗原。癌症可以不包括骨髓瘤。癌症可以不包括黑素瘤。癌症可以不包括结肠癌。癌症可以是急性成淋巴细胞白血病(ALL)。癌症可以是复发性ALL。癌症可以是难治性ALL。癌症可以是复发性、难治性ALL。癌症可以是慢性淋巴细胞白血病(CLL)。癌症可以是复发性CLL。癌症可以是难治性CLL。癌症可以是复发性、难治性CLL。
癌症可以包括乳癌。乳癌可以是三阳性乳癌(雌激素受体、孕酮受体以及Her2阳性)。乳癌可以是三阴性乳癌(雌激素受体、孕酮受体以及Her2阴性)。乳癌可以是雌激素受体阳性。乳癌可以是雌激素受体阴性。乳癌可以是孕酮受体阳性。乳癌可以是孕酮受体阴性。乳癌可以包括Her2阴性乳癌。乳癌可以包括低表达Her2乳癌。乳癌可以包括Her2阳性乳癌。表达Her2的细胞系已经针对抗原密度充分表征,这反映了临床免疫组织化学表征,其将恶性病分类为0(<20,000个Her2抗原/细胞)、1+(100,000个Her2抗原/细胞)、2+(500,000个Her2抗原/细胞)以及3+(>2,000,000个Her2抗原/细胞)。本发明提供了治疗这类类别的乳癌的方法。乳癌可以包括归类为Her2 0的乳癌。乳癌可以包括归类为Her2 1+的乳癌。乳癌可以包括归类为Her2 2+的乳癌。乳癌可以包括归类为Her2 3+的乳癌。
疾病或病状可以是病原体感染。病原体感染可以由一个或多个病原体引起。在一些情况下,病原体是细菌、真菌、病毒或原生动物。
例示性病原体包括(但不限于):博德特氏菌(Bordetella)、疏螺旋体(Borrelia)、布鲁氏菌(Brucella)、弯曲杆菌(Campylobacter)、衣原体(Chlamydia)、嗜衣原体(Chlamydophila)、梭菌(Clostridium)、棒状杆菌(Corynebacterium)、肠球菌(Enterococcus)、埃希氏菌(Escherichia)、弗朗西斯氏菌(Francisella)、嗜血杆菌(Haemophilus)、螺杆菌(Helicobacter)、军团菌(Legionella)、钩端螺旋体(Leptospira)、李斯特氏菌(Listeria)、分枝杆菌(Mycobacterium)、支原体(Mycoplasma)、奈瑟氏菌(Neisseria)、假单胞菌(Pseudomonas)、立克次氏体(Rickettsia)、沙门氏菌(Salmonella)、志贺氏菌(Shigella)、葡萄球菌(Staphylococcus)、链球菌(Streptococcus)、密螺旋体(Treponema)、弧菌(Vibrio)或耶尔森氏菌(Yersinia)。在一些情况下,由病原体引起的疾病或病状是结核病并且异质性样品包含来源于细菌结核分枝杆菌(Mycobacterium tuberculosis)的外来分子和来源于受试者的分子。在一些情况下,由细菌引起的疾病或病状是结核病;肺炎,其可以由诸如链球菌和假单胞菌的细菌引起;食源性疾病,其可以由诸如志贺氏菌、弯曲杆菌以及沙门氏菌的细菌引起;以及感染,诸如破伤风、伤寒、白喉、梅毒以及麻疯。疾病或病状可以是细菌性阴道病,由天然存在的细菌丛的失衡引起的阴道疾病。或者,疾病或病状是细菌性脑膜炎,脑膜(例如,覆盖脑和脊髓的保护膜)的细菌性发炎。由细菌引起的其它疾病或病状包括(但不限于)细菌性肺炎、尿路感染、细菌性胃肠炎以及细菌性皮肤感染。细菌性皮肤感染的实例包括(但不限于)脓疱病,其可以由金黄色葡萄球菌(Staphylococcus aureus)或化脓性链球菌(Streptococcuspyogenes)引起;丹毒,其可以由具有淋巴道扩散的深层表皮的链球菌细菌性感染引起;以及蜂窝组织炎,其可以由正常皮肤菌丛或由外源性细菌引起。
病原体可以是真菌,诸如假丝酵母(Candida)、曲霉(Aspergillus)、隐球菌(Cryptococcus)、组织浆菌(Histoplasma)、肺囊虫(Pneumocystis)以及葡萄穗霉(Stachybotrys)。由真菌引起的疾病或病状的实例包括(但不限于)股癣、酵母感染、环癣以及脚癣(athlete's foot)。
病原体可以是病毒。病毒的实例包括(但不限于)腺病毒、柯萨奇病毒(coxsackievirus)、爱泼斯坦-巴尔病毒(Epstein-Barr virus)、肝炎病毒(例如,A型、B型以及C型肝炎)、单纯疱疹病毒(1型和2型)、巨细胞病毒、疱疹病毒、HIV、流感病毒、麻疹病毒、腮腺炎病毒、乳头状瘤病毒、副流感病毒、脊髓灰质炎病毒、呼吸道合胞病毒、风疹病毒以及水痘-带状疱疹病毒。由病毒引起的疾病或病状的实例包括(但不限于)伤风、流感、肝炎、AIDS、水痘、风疹、腮腺炎、麻疹、疣以及脊髓灰质炎。
病原体可以是原生动物,诸如棘阿米巴(Acanthamoeba)(例如,阿斯特罗尼棘阿米巴(A.astronyxis)、卡氏棘阿米巴(A.castellanii)、柯氏棘阿米巴(A.culbertsoni)、哈氏棘阿米巴(A.hatchetti)、多噬棘阿米巴(A.polyphaga)、皱棘阿米巴(A.rhysodes)、赫氏棘阿米巴(A.healyi)、迪维勒斯棘阿米巴(A.divionensis))、短粒虫(Brachiola)(例如,康氏短粒虫(B connori)、小泡短粒虫(B.vesicularum))、隐孢子虫(Cryptosporidium)(例如,微小隐孢子虫(C.parvum))、环孢子虫(Cyclospora)(例如,卡耶塔环孢子虫(C.cayetanensis))、脑胞内原虫(Encephalitozoon)(例如,家兔脑胞内原虫(E.cuniculi)、贺伦脑胞内原虫(E.hellem)、肠道脑胞内原虫(E.intestinalis))、内阿米巴(Entamoeba)(例如,溶组织内阿米巴(E.histolytica))、肠微孢子虫(Enterocytozoon)(例如,毕氏肠微孢子虫(E.bieneusi))、贾第鞭毛虫(Giardia)(例如,蓝氏贾第鞭毛虫(G.lamblia))、等孢子球虫(Isospora)(例如,贝氏等孢子球虫(I.belli))、微孢子虫(Microsporidium)(例如,非洲微孢子虫(M.africanum)、锡兰微孢子虫(M.ceylonensis))、耐格里原虫(Naegleria)(例如,福氏耐格里原虫(N.fowleri))、微粒子虫(Nosema)(例如,按蚊微粒子虫(N.algerae)、眼微粒子虫(N.ocularum))、匹里虫(Pleistophora)、气管普孢虫(Trachipleistophora)(例如,害人气管普孢虫(T.anthropophthera)、人气管普孢虫(T.hominis))以及条纹微孢子虫(Vittaforma)(例如,角膜条纹微孢子虫(V.corneae))。
疾病或病状可以是自体免疫疾病或自体免疫相关疾病。自体免疫病症可以是身体免疫系统的功能障碍,这导致身体攻击其自身的组织。自体免疫疾病和自体免疫相关疾病的实例包括(但不限于)阿狄森氏病(Addison's disease)、斑秃、强直性脊柱炎、抗磷脂综合症(APS)、自体免疫再生障碍性贫血、自体免疫溶血性贫血、自体免疫肝炎、自体免疫心肌炎、白塞氏病(Behcet's disease)、口炎性腹泻、克罗恩氏病(Crohn's disease)、皮肌炎、嗜酸性粒细胞筋膜炎、结节性红斑、巨细胞动脉炎(颞动脉炎)、古德帕斯彻氏综合症(Goodpasture's syndrome)、格雷夫斯氏病(Graves'disease)、桥本氏病(Hashimoto'sdisease)、特发性血小板减少性紫癜(ITP)、IgA肾病、青少年关节炎、糖尿病、青少年糖尿病、川崎综合症(Kawasaki syndrome)、兰伯特-伊顿综合症(Lambert-Eaton syndrome)、狼疮(SLE)、混合结缔组织病(MCTD)、多发性硬化、重症肌无力、天疱疮、结节性多动脉炎、I型、II型以及III型自体免疫多腺综合症、风湿性多肌痛、多肌炎、牛皮癣、牛皮癣关节炎、赖特尔氏综合症(Reiter's syndrome)、复发性多软骨炎、类风湿性关节炎、肉状瘤病、硬皮病、修格兰氏综合症(Sjogren's syndrome)、精子和睾丸自体免疫、僵人综合症、高安氏动脉炎(Takayasu's arteritis)、颞动脉炎/巨细胞动脉炎、溃疡性结肠炎、葡萄膜炎、血管炎、白癜风以及韦格纳氏肉芽肿病(Wegener's granulomatosis)。
疾病或病状可以是发炎性疾病。发炎性疾病的实例包括(但不限于)牙槽炎、淀粉样变性、脉管炎、强直性脊柱炎、无血管性坏死、巴塞多氏病(Basedow's disease)、贝尔氏麻痹(Bell's palsy)、滑囊炎、腕管综合症、乳糜泻、胆管炎、髌骨软骨软化症、慢性活动性肝炎、慢性疲劳综合症、科根氏综合症(Cogan's syndrome)、先天性髋关节发育不良、肋软骨炎、克罗恩氏病、囊性纤维化、狄克凡氏肌腱炎(De Quervain's tendinitis)、糖尿病相关的关节炎、弥漫性特发性骨肥厚、盘状狼疮、埃勒斯-当洛斯综合症(Ehlers-Danlossyndrome)、家族性地中海热、筋膜炎、纤维组织炎/纤维肌痛、冰冻肩、腱鞘囊肿、巨细胞动脉炎、痛风、格雷夫斯氏病、HIV相关的风湿病综合症、甲状旁腺功能亢进相关的关节炎、感染性关节炎、发炎性肠道综合症/肠易激综合症、青少年类风湿性关节炎、莱姆病(lymedisease)、马凡氏综合症(Marfan's Syndrome)、米古利兹氏病(Mikulicz's Disease)、混合结缔组织病、多发性硬化、肌筋膜疼痛综合症、骨关节炎、骨软化症、骨质疏松症和皮质类固醇诱发的骨质疏松症、佩吉特氏病(Paget's Disease)、回纹型风湿病、帕金森氏病(Parkinson's Disease)、普鲁默氏病(Plummer's Disease)、风湿性多肌痛、多肌炎、假性痛风、牛皮癣关节炎、雷诺氏现象/综合症(Raynaud's Phenomenon/Syndrome)、赖特尔氏综合症、风湿热、类风湿性关节炎、肉状瘤病、坐骨神经痛(腰椎神经根病)、硬皮病、坏血病、镰状细胞关节炎、修格兰氏综合症、椎管狭窄、脊椎滑脱、斯提耳氏病(Still's Disease)、全身性红斑狼疮、高安氏(无脉)病、肌腱炎、网球肘/高尔夫肘、甲状腺相关的关节炎、扳机指、溃疡性结肠炎、韦格纳氏肉芽肿病以及惠普耳氏病(Whipple's Disease)。
本文所公开的治疗方法可以包括如由细胞因子水平测量的脱靶活性。这种方法当与其它CAR-EC疗法相比时可以降低如由细胞因子水平测量的脱靶活性。这种方法可以降低如由干扰素γ水平测量的脱靶活性。可以降低的其它脱靶活性包括毒性淋巴细胞减少症、实体肿瘤标靶的致命性细胞溶解以及血液标靶的慢性低丙种球蛋白血症。本文所公开的治疗方法和组合物可以用于治疗包含CD19介导的B细胞发育不全的癌症。方法和组合物可以使CD19介导的B细胞发育不全减至最低。这种方法可以避免长期B细胞发育不全。
本文所公开的CAR-EC平台、方法以及组合物可以用于治疗有需要的受试者的异质性肿瘤或异质性血细胞恶性病。“泛B细胞”标志物CD20是B细胞赘瘤的最普遍靶向的抗原并且FDA批准的抗体利妥昔单抗是许多白血病和淋巴瘤治疗中至关重要的组分。然而,与CD20抗原表达的调节相关的抗性机制在相当数量的患者中出现。显然,用单独的CD19或CD20抗原靶向对于治愈性疗法是不足够的。本文所公开的方法提供了具有不同特异性的两个或更多个开关(例如,抗CD19抗体CAR-EC开关和抗CD20抗体CAR-EC开关)的构建和施用。本文所公开的方法提供了具有不同特异性的两个或更多个开关(例如,抗CD19抗体CAR-EC开关和抗CD22抗体CAR-EC开关)的构建和施用。这种方法可以提供在临床中对抗复发倾向的显著优点,同时避免B细胞的持久损失。异质性肿瘤或异质性血细胞恶性病也可以用抗CD19抗体CAR-EC开关和抗CD22抗体CAR-EC开关治疗。一个或多个CAR-EC开关可以依序或同时施用。
CAR-EC开关可以与一种或多种额外的治疗剂一起施用。一种或多种额外的治疗剂可以选自由免疫疗法、化学疗法以及类固醇组成的群组。一种或多种额外的治疗剂可以是化学疗法药物。化学疗法药物可以是烷化剂、抗代谢物、蒽环霉素(anthracycline)、拓扑异构酶抑制剂、有丝分裂抑制剂、皮质类固醇或分化剂。化学疗法药物可以选自放线菌素D(actinomycin-D)、博莱霉素(bleomycin)、六甲蜜胺(altretamine)、硼替佐米(bortezomib)、白消安(busulfan)、卡铂(carboplatin)、卡培他滨(capecitabine)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)、顺铂(cisplatin)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、环磷酰胺(cyclophosphamide)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、道诺霉素(daunorubicin)、多烯紫杉醇(docetaxel)、阿霉素、表柔比星(epirubicin)、依托泊苷(etoposide)、雌莫司汀(estramustine)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、氟尿嘧啶(fluorouracil)、吉西他滨(gemcitbine)(Gemzar)、羟基脲(hydroxyurea)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊立替康(irinotecan)(Camptosar)、伊沙匹隆(ixabepilone)、L-天冬酰胺酶、洛莫司汀(lomustine)、二氯甲基二乙胺(mechlorethamine)、美法仑(melphalan)、6-巯基嘌呤(6-mercaptopurine)、甲氨蝶呤(methotrexate)、丝裂霉素C(mitomycin-C)、太平洋紫杉醇(paclitaxel)(Taxol)、培美曲塞(pemetrexed)、喷司他丁(pentostatin)、链脲菌素(streptozocin)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、硫鸟嘌呤(thioguanine)、塞替派(thiotepa)、拓扑替康(topotecan)(Hycamtin)、长春新碱(vincristine)、长春碱(vinblastine)、长春瑞滨(vinorelbine)、类视色素(retinoid)、维甲酸(tretinoin)(ATRA或)、蓓萨罗丁(bexarotene)以及三氧化二砷化学疗法可以作为供吞咽的丸剂、作为至肌肉或脂肪组织中的注射剂静脉内、局部或直接施用于体腔中。
一种或多种额外的治疗剂可以包括血管生成抑制剂。血管生成抑制剂可以选自贝伐单抗(bevacizumab)、伊曲康唑(itraconazole)、羧胺三唑(carboxyamidotriazole)、TNP-470、CM101、IFNα、IL-12、血小板因子4、苏拉明(suramin)、SU5416、血小板反应蛋白(thrombospondin)、VEGFR拮抗剂、具有肝素的血管抑制类固醇、源自CAR-ECilage的血管生成抑制因子、基质金属蛋白酶抑制剂、血管抑素(angiostatin)、内皮抑素(endostatin)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、帕唑帕尼(pazopanib)、依维莫司(everolimus)、2-甲氧基雌二醇(2-methoxyestradiol)、替可加兰(tecogalan)、四硫钼酸盐(tetrathiomolybdate)、沙利度胺(thalidomide)、催乳素(prolactin)、αvβ3抑制剂、利诺胺(linomide)、他喹莫德(tasquinimod)、可溶性VEGFR-1、可溶性NRP-1、血管生成素2(angiopoietin 2)、血管抑制因子(vasostatin)、钙网蛋白(calreticulin)、TIMP、CDAI、Meth-1、Meth-2、干扰素-α、干扰素-β、干扰素-γ、CXCL10、IL-4、IL-12、IL-18、凝血酶原(prothrombin)、抗凝血酶III片段、催乳素、VEGI、SPARC、骨桥蛋白(osteopontin)、乳腺丝抑蛋白(maspin)、血管能抑素(canstatin)、增殖蛋白相关蛋白(proliferin-relatedprotein)以及休眠蛋白(restin)。
一种或多种额外的治疗剂可以包括激素疗法。激素疗法可以选自抗雌激素(例如,氟维司群(fulvestrant)他莫昔芬(tamoxifen)、托瑞米芬(toremifene));芳香酶抑制剂(例如,阿那曲唑(anastrozole)依西美坦(exemestane)来曲唑(letrozole));孕酮(例如,醋酸甲地孕酮(megestrol acetate));雌激素;抗雄激素(例如,比卡鲁胺(bicalutamide)氟他胺(flutamide)尼鲁米特(nilutamide));促性腺激素释放激素(GnRH)或促黄体激素释放激素(LHRH)激动剂或类似物(例如,亮丙瑞林(leuprolide)戈舍瑞林(goserelin))。
一种或多种额外的治疗剂可以包括类固醇。类固醇可以是皮质类固醇。类固醇可以是皮质醇或其衍生物。类固醇可以选自强的松(prednisone)、甲基强的松龙(methylprednisolone)或地塞米松(dexamethasone)。
CAR-EC开关可以与一种或多种额外的疗法一起施用。一种或多种额外的疗法可以包括激光疗法。一种或多种额外的疗法可以包括放射疗法。一种或多种额外的疗法可以包括手术。
本文公开了用于治疗受试者的疾病或病状的平台、试剂盒以及方法。受试者可以是健康受试者。受试者可以罹患疾病或病状。受试者可以罹患多于一种疾病或病状。受试者可以罹患慢性淋巴细胞白血病。受试者可以罹患急性成淋巴细胞白血病。受试者可以是动物。受试者可以是哺乳动物。哺乳动物可以是人类、黑猩猩、大猩猩、猴、牛、马、驴、骡、犬、猫、猪、兔、山羊、绵羊、大鼠、仓鼠、天竺鼠或小鼠。受试者可以是鸟或鸡。受试者可以是人类。受试者可以是儿童。儿童可以罹患急性成淋巴细胞白血病。受试者可以小于6月龄。受试者可以约1岁、约2岁、约3岁、约4岁、约5岁、约6岁、约7岁、约8岁、约9岁、约10岁、约11岁、约12岁、约13岁、约14岁、约15岁、约18岁、约20岁、约25岁、约30岁、约35岁、约40岁、约45岁、约50岁、约55岁、约60岁、约65岁、约70岁、约75岁、约80岁、约85岁、约90岁、约95岁、约100岁或约105岁。
VII.清除效应细胞的方法
本文进一步公开了清除受试者中的CAR-EC细胞的方法,其包括施用CAR-EC切断开关。CAR-EC切断开关可以包含靶向效应细胞上的细胞表面标志物的抗体或抗体片段。CAR-EC切断开关可以包含由CAR-EC的CAR结合的肽。CAR-EC切断开关可以包含由CAR-EC的CAR结合的CAR-BP。
CAR-EC切断开关的抗体、抗体片段或肽可以偶联至药物或毒素。药物或毒素可以选自美登素(maytasine)(例如,DM1、DM4)、单甲基澳瑞他汀E(monomethylauristatin E)、单甲基澳瑞他汀F(monomethylauristatin F)、Ki-4.dgA、尾海兔素10(dolastatin 10)、加利车霉素(calicheamicin)、SN-38、倍癌霉素(duocarmycin)、伊立替康、蓖麻毒素(ricin)、皂草素(saporin)、白树毒素(gelonin)、美洲商陆抗病毒蛋白、绿脓假单胞菌(pseudomonasaeruginosa)外毒素A或白喉毒素。毒素可以包含毒药、细菌毒素(例如,引起破伤风的细菌毒素,白喉)、植物毒素或动物毒素。毒素可以是蛇毒。毒素可以包含长春碱。毒素可以包含澳瑞他汀(auristatin)。毒素可以含于脂质体膜包覆的囊泡中。在毒素含于脂质体膜包覆的囊泡中的情况下,抗体附接至囊泡。
细胞表面标志物可以是病毒蛋白或其片段。替代地或另外,效应细胞表达并非细胞表面标志物的病毒蛋白或其片段。表达病毒蛋白或其片段的效应细胞可以用药物靶向。在效应细胞包含病毒蛋白或其片段的情况下,药物可以选自包含以下的群组:阿巴卡韦(abacavir)、阿昔洛韦(acyclovir)、阿昔洛韦(acyclovir)、阿德福韦(adefovir)、金刚烷胺(amantadine)、安普那韦(amprenavir)、安普利近(ampligen)、阿比朵尔(arbidol)、阿扎那韦(atazanavir)、立普妥(atripla)、巴拉弗(balavir)、波普瑞韦尔特(boceprevirertet)、西多福韦(cidofovir)、可比韦(combivir)、地瑞纳韦(darunavir)、地拉韦定(delavirdine)、地达诺新(didanosine)、二十二醇、依度尿苷(edoxudine)、依法韦仑(efavirenz)、恩曲他滨(emtricitabine)、恩夫韦地(enfuvirtide)、恩替卡韦(entecavir)、进入抑制剂、泛昔洛韦(famciclovir)、固定剂量组合抗逆转录病毒药物、福米韦生(fomivirsen)、福沙那韦(fosamprenavir)、膦甲酸(foscarnet)、膦乙酸(fosfonet)、融合抑制剂、更昔洛韦(ganciclovir)、伊巴他滨(ibacitabine)、伊木那韦(imunovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韦(indinavir)、肌苷、整合酶抑制剂、III型干扰素、II型干扰素、I型干扰素、干扰素、拉米夫定(lamivudine)、洛匹那韦(lopinavir)、洛韦胺(loviride)、马拉韦罗(maraviroc)、吗啉胍(moroxydine)、甲吲噻腙(methisazone)、奈非那韦(nelfinavir)、奈韦拉平(nevirapine)、奈克沙韦(nexavir)、核苷类似物、奥司他韦(oseltamivir)、聚乙二醇干扰素α-2a(peginterferonalfa-2a)、喷昔洛韦(penciclovir)、帕拉米韦(peramivir)、普拉康纳利(pleconaril)、鬼臼毒素(podophyllotoxin)、蛋白酶抑制剂、雷特格韦(raltegravir)、逆转录酶抑制剂、利巴韦林(ribavirin)、金刚乙胺(rimantadine)、利托那韦(ritonavir)、普拉咪定(pyramidine)、沙奎那韦(saquinavir)、索非布韦(sofosbuvir)、司他夫定(stavudine)、协同增强剂逆转录病毒药物、茶树油、特拉匹韦(telaprevir)、替诺福韦(tenofovir)、替诺福韦二吡呋酯(tenofovir disoproxil)、替拉那韦(tipranavir)、三氟尿苷(trifluridine)、三协唯(trizivir)、曲金刚胺(tromantadine)、特鲁瓦达(truvada)、伐昔洛韦(valaciclovir)、维克韦罗(vicriviroc)、阿糖腺苷(vidarabine)、韦拉米啶(viramidine)、扎西他滨(zacitabine)、扎那米韦(zanamivir)或齐多夫定(zidovudine)。药物可以是更昔洛韦。药物可以是阿昔洛韦。
VIII.医药组合物
本文公开了一种医药组合物,其包含本文所公开的CAR-EC开关中的一者或多者。组合物可以进一步包含一种或多种医药学上可接受的盐、赋形剂或媒剂。用于本发明医药组合物中的医药学上可接受的盐、赋形剂或媒剂包括载剂、赋形剂、稀释液、抗氧化剂、防腐剂、着色剂、调味剂和稀释剂、乳化剂、悬浮剂、溶剂、填充剂、膨胀剂、缓冲液、递送媒剂、张度剂、共溶剂、湿润剂、复合剂、缓冲剂、抗微生物剂以及表面活性剂。
中性缓冲盐水或与血清白蛋白混合的盐水是例示性的适当载剂。医药组合物可以包括抗氧化剂,诸如抗坏血酸;低分子量多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、二糖以及其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖醇,诸如甘露糖醇或山梨糖醇;成盐平衡离子,诸如钠;和/或非离子表面活性剂,诸如吐温(Tween)、普朗尼克(pluronic)或聚乙二醇(PEG)。同样经由实例,适合的张度增强剂包括碱金属卤化物(优选氯化钠或氯化钾)、甘露糖醇、山梨糖醇等等。适合的防腐剂包括苯扎氯铵(benzalkonium chloride)、硫柳汞(thimerosal)、苯乙醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯己定(chlorhexidine)、山梨酸等等。过氧化氢也可以用作防腐剂。适合的共溶剂包括甘油、丙二醇以及PEG。适合的复合剂包括咖啡碱、聚乙烯吡咯烷酮、β-环糊精或羟基-丙基-β-环糊精。适合的表面活性剂或湿润剂包括脱水山梨糖醇酯、聚山梨醇酯(诸如聚山梨醇酯80)、缓血酸胺、卵磷脂、胆固醇、泰洛沙泊(tyloxapal)等等。缓冲液可以是常规缓冲液,诸如乙酸盐、硼酸盐、柠檬酸盐、磷酸盐、碳酸氢盐或Tris-HCl。乙酸盐缓冲液可以为约pH 4-5.5,并且Tris缓冲液可以为约pH 7-8.5。额外的医药剂阐述于《雷明顿氏制药科学(Remington's Pharmaceutical Sciences)》,第18版,A.R.Gennaro编,Mack PublishingCompany,1990中。
组合物可以呈液体形式或呈冻干或冷冻干燥形式,并且可以包括一种或多种冻干保护剂、赋形剂、表面活性剂、高分子量结构添加剂和/或膨胀剂(参看例如美国专利号6,685,940、6,566,329以及6,372,716)。在一个实施方案中,包括冻干保护剂,其为非还原糖,诸如蔗糖、乳糖或海藻糖。一般包括的冻干保护剂的量使得在复原后,所得配方将是等张的,不过高张或稍低张配方也可能是适合的。另外,冻干保护剂的量应足以防止蛋白质在冻干后以不可接受的量降解和/或聚集。预冻干配方中糖(例如,蔗糖、乳糖、海藻糖)的例示性冻干保护剂浓度为约10mM至约400mM。在另一个实施方案中,包括表面活性剂,诸如非离子表面活性剂和离子表面活性剂,诸如聚山梨醇酯(例如,聚山梨醇酯20、聚山梨醇酯80);泊洛沙姆(poloxamer)(例如,泊洛沙姆188);聚(乙二醇)苯基醚(例如,Triton);十二烷基硫酸钠(SDS);月桂基硫酸钠;辛基糖苷钠;月桂基-、肉豆蔻基-、亚油基-或硬脂基-磺基甜菜碱;月桂基-、肉豆蔻基-、亚油基-或硬脂基-肌氨酸;亚油基-、肉豆蔻基-或鲸蜡基-甜菜碱;月桂酰胺丙基-、椰油酰胺丙基-、亚油酰胺丙基-、肉豆蔻酰胺丙基-、棕榈酰胺丙基-或异硬脂酰胺丙基-甜菜碱(例如,月桂酰胺丙基);肉豆蔻酰胺丙基-、棕榈酰胺丙基-或异硬脂酰胺丙基-二甲胺;甲基椰油酰基牛磺酸钠或甲基油酰基牛磺酸二钠;以及MONAQUATTM系列(Mona Industries,Inc.,Paterson,N.J.)、聚乙二醇、聚丙二醇,以及乙二醇与丙二醇的共聚物(例如,普朗尼克、PF68等等)。可以存在于预冻干配方中的表面活性剂的例示性量为约0.001-0.5%。高分子量结构添加剂(例如,填充剂、粘合剂)可以包括例如阿拉伯胶、白蛋白、海藻酸、磷酸钙(磷酸氢钙)、纤维素、羧甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、微晶纤维素、葡聚糖、糊精、葡聚糖酸盐(dextrate)、蔗糖、泰乐士(tylose)、预胶凝化淀粉、硫酸钙、直链淀粉、甘氨酸、膨润土、麦芽糖、山梨糖醇、乙基纤维素、磷酸氢二钠、磷酸二钠、焦亚硫酸二钠、聚乙烯醇、明胶、葡萄糖、瓜尔胶、液体葡萄糖、可压缩糖、硅酸镁铝、麦芽糊精、聚氧化乙烯、聚甲基丙烯酸酯、聚维酮(povidone)、海藻酸钠、黄蓍胶微晶纤维素、淀粉以及玉米蛋白。高分子量结构添加剂的例示性浓度为0.1%至10%(按重量计)。在其它实施方案中,可以包括膨胀剂(例如,甘露糖醇、甘氨酸)。
组合物可以适合于肠道外施用。例示性组合物适合于通过熟练技工可用的任何途径注射或输注至动物中,这种途径诸如关节内、皮下、静脉内、肌肉内、腹膜内、脑内(脑实质内)、脑室内、肌肉内、眼内、动脉内或病灶内途径。肠道外配方通常将是无菌、无热原质、等张水溶液,任选地含有医药学上可接受的防腐剂。
非水溶剂的实例是丙二醇、聚乙二醇、植物油(诸如橄榄油)以及可注射有机酯(诸如油酸乙酯)。水性载剂包括水、醇/水溶液、乳液或悬浮液,包括盐水和缓冲介质。肠道外媒剂包括氯化钠溶液、林格氏右旋糖(Ringers'dextrose)、右旋糖和氯化钠、乳酸林格氏液(lactated Ringer's)或非发挥性油。静脉内媒剂包括流体和营养补充剂、电解质补充剂(诸如基于林格氏右旋糖的那些)等等。防腐剂和其它添加剂也可以存在,诸如抗微生物剂、抗氧化剂、螯合剂、惰性气体等等。一般参看《雷明顿氏制药科学(Remington'sPharmaceutical Sciences)》,第16版,Mack编,1980。
可以配制本文所描述的医药组合物用于以提供产品的局部浓度(例如,大丸剂、积存效应)和/或在特定局部环境中增加的稳定性或半衰期的方式控制或持续递送。组合物可以包含本文所公开的CAR-EC开关、多肽、核酸或载体与诸如聚乳酸、聚乙醇酸等等的聚合化合物的颗粒制剂以及诸如以下的试剂的配方:生物可降解基质、可注射微球、微囊粒子、微胶囊、生物可溶蚀粒子小珠、脂质体以及可植入递送装置,这些装置提供活性剂的控制或持续释放,然后可以作为积存注射而递送。用于配制这类持续或控制递送工具的技术是已知的并且已经开发多种聚合物并用于药物的控制释放和递送。这类聚合物通常是生物可降解和生物相容的。因为在捕集生物活性蛋白剂(例如,包含超长CDR3的抗体)中所涉及的温和和水性条件,所以可能需要聚合物水凝胶,包括通过对映体聚合物或多肽区段的复合形成的那些和具有温度或pH敏感特性的水凝胶,用于提供药物积存效应。参看例如WO 93/15722中用于递送医药组合物的控制释放多孔聚合微粒的描述。用于这个目的的适合材料包括聚丙交酯(参看例如美国专利号3,773,919);聚(a-羟基羧酸)的聚合物,诸如聚-D-(-)-3-羟基丁酸(EP 133,988A);L-谷氨酸与γ-L-谷氨酸乙酯的共聚物(Sidman等,《生物聚合物(Biopolymers)》,22:547-556(1983));聚(甲基丙烯酸2-羟乙酯)(Langer等,《生物医学材料研究杂志(J.Biomed.Mater.Res.)》,15:167-277(1981),和Langer,《化学技术(Chem.Tech.)》,12:98-105(1982));乙烯乙酸乙烯酯;或聚-D(-)-3-羟基丁酸。其它生物可降解聚合物包括聚(内酯)、聚(缩醛)、聚(原酸酯)以及聚(原碳酸酯)。持续释放组合物还可以包括脂质体,其可以通过本领域中已知的若干方法中的任一者制备(参看例如Eppstein等,《美国科学院院刊(Proc.Natl.Acad.Sci.USA)》,82:3688-92(1985))。载剂本身或其降解产物应在标靶组织中是无毒的并且不应进一步加重病状。这可以通过在标靶病症的动物模型中常规筛选来确定,或如果这类模型不可用,那么在正常动物中确定。用于持续释放的重组蛋白的微囊化已经用人生长激素(rhGH)、干扰素-(rhIFN-)、白介素-2以及MN rgp120成功地进行。Johnson等,《自然医学(Nat.Med.)》,2:795-799(1996);Yasuda,《生物医学理论(Biomed.Ther.)》,27:1221-1223(1993);Hora等,《生物/技术(Bio/Technology.)》8:755-758(1990);Cleland,"使用聚丙交酯聚乙交酯微球系统的单一免疫疫苗的设计和产生(Design and Production of Single Immunization Vaccines Using PolylactidePolyglycolide Microsphere Systems)",《疫苗设计:亚单元和佐剂方法(VaccineDesign:The Subunit and Adjuvant Approach)》,Powell和Newman编,(Plenum Press:NewYork,1995),第439-462页;WO 97/03692、WO 96/40072、WO 96/07399;以及美国专利号5,654,010。这些蛋白质的持续释放配方使用聚乳酸-共乙醇酸(PLGA)聚合物来开发,这归因于这种聚合物的生物相容性和广泛范围的生物可降解特性。PLGA的降解产物,乳酸和乙醇酸,可以在人体内快速清除。此外,这种聚合物的可降解性可以取决于其分子量和组成。Lewis,"生物活性剂从丙交酯/乙交酯聚合物的控制释放(Controlled release ofbioactive agents from lactide/glycolide polymer)",M.Chasin和R.Langer(编),《作为药物递送系统的生物可降解聚合物(Biodegradable Polymers as Drug DeliverySystems)》(Marcel Dekker:New York,1990),第1-41页。持续释放组合物的额外实例包括例如EP 58,481A;美国专利号3,887,699;EP 158,277A;加拿大专利号1176565;U.Sidman等,《生物聚合物(Biopolymers)》22,547[1983];R.Langer等,《化学技术(Chem.Tech.)》12,98[1982];Sinha等,《控制释放杂志(J.Control.Release)》90,261[2003];Zhu等,《自然生物技术(Nat.Biotechnol.)》18,24[2000];以及Dai等,《胶体表面B生物界面(ColloidsSurf B Biointerfaces)》41,117[2005]。
生物粘着聚合物也预期用于本发明的组合物中或与本发明的组合物一起使用。生物粘着剂是能够粘着至生物底物持续较长时段的合成和天然存在的材料。举例来说,卡波姆(Carbopol)和聚卡波非(polycarbophil)都是聚(丙烯酸)的合成交联衍生物。基于天然存在的物质的生物粘着递送系统包括例如透明质酸,也称为玻尿酸(hyaluronan)。透明质酸是由D-葡糖醛酸和N-乙酰基-D-葡糖胺的残基组成的天然存在的粘多糖。透明质酸在脊椎动物的细胞外组织基质中发现,包括结缔组织中,以及滑液中和眼睛的玻璃体和房水中。已经使用透明质酸的酯化衍生物来产生用于递送的生物相容和生物可降解的微球(参看例如Cortivo等,《生物材料(Biomaterials)》(1991)12:727-730;EP 517,565;WO 96/29998;Illum等,《控制释放杂志(J.Controlled Rel.)》(1994)29:133-141)。
生物可降解与非生物可降解的聚合基质都可以用于递送本公开的组合物,并且这类聚合基质可以包含天然或合成聚合物。生物可降解基质是优选的。释放发生的时段是基于聚合物的选择。通常,经过范围介于数小时与三至十二个月之间的时段释放是最合乎需要的。可以用于形成生物可降解递送系统的例示性合成聚合物包括:乳酸与乙醇酸的聚合物、聚酰胺、聚碳酸酯、聚烯、聚烷二醇、聚氧化烯、聚对苯二甲酸烷二酯、聚乙烯醇、聚乙烯醚、聚乙烯酯、聚卤乙烯、聚乙烯吡咯烷酮、聚乙交酯、聚硅氧烷、聚酐、聚氨酯和其共聚物、聚(丁酸)、聚(戊酸)、烷基纤维素、羟烷基纤维素、纤维素醚、纤维素酯、硝基纤维素、丙烯酸酯和甲基丙烯酸酯的聚合物、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丁基甲基纤维素、乙酸纤维素、丙酸纤维素、乙酸丁酸纤维素、乙酸邻苯二甲酸纤维素、羧乙基纤维素、三乙酸纤维素、硫酸纤维素钠盐、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸异丁酯)、聚(甲基丙烯酸己酯)、聚(甲基丙烯酸异癸酯)、聚(甲基丙烯酸月桂酯)、聚(甲基丙烯酸苯酯)、聚(丙烯酸甲酯)、聚(丙烯酸异丙酯)、聚(丙烯酸异丁酯)、聚(丙烯酸十八酯)、聚乙烯、聚丙烯、聚(乙二醇)、聚(氧化乙烯)、聚(对苯二甲酸乙二酯)、聚(乙烯醇)、聚乙酸乙烯酯、聚氯乙烯、聚苯乙烯以及聚乙烯吡咯烷酮。例示性天然聚合物包括海藻酸盐和其它多糖,包括葡聚糖和纤维素、胶原蛋白、其化学衍生物(化学基团(例如,烷基、亚烷基)的取代、添加,羟基化,氧化,以及由本领域的技术人员常规制造的其它修饰)、白蛋白和其它亲水蛋白、玉米蛋白和其它醇溶谷蛋白以及疏水蛋白、其共聚物和混合物。一般来说,这些材料通过体内酶促水解或暴露于水、通过表面或本体溶蚀而降解。聚合物任选地呈水凝胶的形式(参看例如WO 04/009664;WO 05/087201;Sawhney等,《大分子(Macromolecules)》,1993,26,581-587),其可以在水中吸收至多其重量的约90%并且进一步任选地与多价离子或其它聚合物交联。
递送系统还包括非聚合物系统,其为脂质,包括固醇,诸如胆固醇、胆固醇酯,以及脂肪酸或中性脂肪,诸如单酸甘油酯、二酸甘油酯以及三酸甘油酯;水凝胶释放系统;硅橡胶系统;基于肽的系统;蜡涂层;使用常规粘合剂和赋形剂的压缩片剂;部分融合植入物;等等。特定实例包括(但不限于):(a)溶蚀系统,其中产品以一定形式含于基质内,诸如美国专利号4,452,775、4,675,189和5,736,152中所描述的那些;以及(b)扩散系统,其中产品以控制的速率从聚合物渗透,诸如美国专利号3,854,480、5,133,974和5,407,686中所描述。含有产品的脂质体可以通过已知的方法制备,诸如(DE 3,218,121;Epstein等,《美国科学院院刊(Proc.Natl.Acad.Sci.USA)》,82:3688-3692(1985);Hwang等,《美国科学院院刊(Proc.Natl.Acad.Sci.USA)》,77:4030-4034(1980);EP 52,322;EP 36,676;EP 88,046;EP143,949;EP 142,641;JP 83-118008;美国专利号4,485,045和4,544,545;以及EP 102,324)。
替代地或另外,组合物可以经由植入膜的受影响区域中、海绵、或本文所公开的CAR-EC开关已经吸收或囊封于上面的其它适当材料来局部施用。在使用植入装置的情况下,装置可以植入任何适合的装置或器官中,并且本文所公开的CAR-EC开关、核酸或载体的递送可以直接通过装置经由大丸剂,或经由连续施用,或经由导管使用连续输注。
可以配制包含本文所公开的CAR-EC开关的医药组合物用于吸入,诸如作为干粉。吸入溶液也可以在液化推进剂中配制用于气雾剂递送。在另一种配方中,可以使溶液雾化。用于肺部施用的额外医药组合物包括例如WO 94/20069中所描述的那些,其公开了化学修饰的蛋白质的肺部递送。对于肺部递送,粒度应适合于递送至远端肺。举例来说,粒度可以为1μm至5μm;然而,举例来说,如果每个粒子是相当多孔的,那么可以使用较大粒子。
含有本文所公开的CAR-EC开关的某些配方可以经口施用。以这种方式施用的配方可以在存在或不存在诸如片剂和胶囊的固体剂型的混配中通常使用的那些载剂的情况下配制。举例来说,可以设计胶囊以在胃肠道中在生物利用度最大化并且全身前降解最小化的点处释放配方的活性部分。可以包括额外的试剂以促进选择性粘合剂的吸收。还可以采用稀释剂、调味剂、低熔点蜡、植物油、润滑剂、悬浮剂、片剂崩解剂以及粘合剂。
另一种制剂可以涉及有效量的本文所公开的CAR-EC开关,其与适合于制造片剂的无毒赋形剂混合。通过将片剂溶解于无菌水或另一种适当媒剂中,可以制备呈单位剂型的溶液。适合的赋形剂包括(但不限于)惰性稀释剂,诸如碳酸钙、碳酸钠或碳酸氢钠、乳糖或磷酸钙;或粘合剂,诸如淀粉、明胶或阿拉伯胶;或润滑剂,诸如硬脂酸镁、硬脂酸或滑石。
适合和/或优选的医药配方可以鉴于本公开和配制技术的一般知识来确定,这取决于预期施用途径、递送格式以及所需剂量。与施用方式无关,有效剂量可以根据患者体重、体表面积或器官尺寸来计算。用于确定涉及本文所描述的配方中的每一者的治疗的适当剂量的计算的进一步细化在本领域中常规地进行并且在本领域中常规执行的任务的范围内。适当剂量可以经由使用适当的剂量-反应数据来确认。
IX.CAR-EC开关产生方法
本文公开了产生CAR-EC开关的方法,其包括从包含具有一个或多个编码嵌合抗原受体效应细胞开关或其一部分的序列的一个或多个聚核苷酸的一个或多个载体表达一个或多个多肽,其中嵌合抗原受体效应细胞开关包含肽抗原(CAR-BP)和靶向多肽。靶向部分可以包含靶向多肽。一般来说,这些方法包括使编码CAR-BP的聚核苷酸融合或嫁接至编码靶向多肽的聚核苷酸。融合或嫁接可以通过本领域的技术人员所知的任何标准克隆方法来进行。融合或嫁接编码CAR-BP和靶向多肽的聚核苷酸可以包括聚核苷酸的酶消化、聚核苷酸的接合和/或聚核苷酸的扩增。
肽抗原可以融合至靶向多肽的N端。肽抗原可以融合至靶向多肽的C端。肽抗原可以嫁接于靶向多肽内。靶向多肽可以包含靶向抗体或抗体片段。肽抗原可以融合至靶向抗体或抗体片段的N端。肽抗原可以融合至靶向抗体或抗体片段的C端。
如本文所用的术语“融合”可以指使CAR-BP的末端与靶向多肽的末端邻接。CAR-BP可以融合至靶向多肽的末端而不会置换或去除靶向多肽的任何氨基酸。使CAR-BP融合至靶向多肽的末端可以包括去除或置换靶向多肽的末端处的氨基酸。去除或置换靶向多肽的末端处的氨基酸可以包括去除或置换靶向多肽的末端处的约1个至约20个氨基酸。CAR-BP可以经由连接子融合至靶向多肽的末端。连接子可以融合至CAR-BP以产生CAR-BP-连接子中间物。连接子可以融合至CAR-BP的N端以产生CAR-BP-连接子中间物。连接子可以融合至CAR-BP的C端以产生CAR-BP-连接子中间物。CAR-BP-连接子中间物可以融合至靶向多肽。CAR-BP-连接子中间物可以融合至靶向多肽的N端。CAR-BP-连接子中间物可以融合至靶向多肽的C端。第一CAR-BP连接子中间物可以融合至靶向多肽的N端并且第二CAR-BP连接子中间物可以融合至靶向多肽的C端。第一CAR-BP连接子中间物的CAR-BP可以与第二CAR-BP连接子中间物的CAR-BP相同或相似。第一CAR-BP连接子中间物的CAR-BP可以不同于第二CAR-BP连接子中间物的CAR-BP。
如本文所用的术语“嫁接”可以指将CAR-BP插入靶向多肽内(例如,靶向多肽的两个氨基酸之间)。CAR-BP可以嫁接于靶向多肽内而不会置换或去除靶向多肽的任何氨基酸。使CAR-BP嫁接于靶向多肽内可以包括去除或置换靶向多肽内的氨基酸。去除或置换靶向多肽内的氨基酸可以包括去除或置换靶向多肽内的约1个至约20个氨基酸。CAR-BP可以经由一个连接子嫁接于靶向多肽内。CAR-BP可以经由两个连接子嫁接于靶向多肽内。连接子可以融合至CAR-BP的N端以产生CAR-BP-连接子中间物。连接子可以融合至CAR-BP的C端以产生CAR-BP-连接子中间物。第一连接子可以融合至CAR-BP的N端并且第二连接子可以融合至CAR-BP的C端以产生CAR-BP-连接子中间物。CAR-BP连接子中间物可以嫁接于靶向多肽内。第一CAR-BP连接子中间物可以嫁接于靶向多肽内并且第二CAR-BP连接子中间物可以嫁接于靶向多肽内。第一CAR-BP连接子中间物可以嫁接于靶向多肽的第一域内并且第二CAR-BP连接子中间物可以嫁接于靶向多肽的第二域内。靶向多肽的第一域可以与靶向多肽的第二域相同。靶向多肽的第一域可以不同于靶向多肽的第二域。第一CAR-BP连接子中间物的CAR-BP可以与第二CAR-BP连接子中间物的CAR-BP相同或相似。第一CAR-BP连接子中间物的CAR-BP可以不同于第二CAR-BP连接子中间物的CAR-BP。除非另有规定,否则如本文所用的术语“嫁接”和“插入”可互换使用。
靶向部分可以包含抗体或抗体片段。抗体或抗体片段可以包含重链和轻链或其片段。这些方法可以包括表达重链,其中肽抗原融合至重链的末端。这些方法可以包括表达重链,其中肽抗原嫁接于重链内。这些方法可以包括表达轻链,其中肽抗原融合至轻链的末端。这些方法可以包括表达轻链,其中肽抗原嫁接于轻链内。
这些方法可以进一步包括将一个或多个编码靶向多肽和/或肽抗原的聚核苷酸克隆至表达载体中。这些方法可以进一步包括一个或多个编码靶向多肽和/或肽抗原的聚核苷酸接合至表达载体中。表达载体可以是原核表达载体。表达载体可以是真核表达载体。表达载体可以是哺乳动物表达载体。表达载体可以是病毒表达载体。这些方法可以进一步包括验证一个或多个编码靶向多肽和/或肽抗原的聚核苷酸克隆至表达载体中,其包括对表达载体进行测序,运作载体的凝胶电泳和/或检视SDS page凝胶上的靶向多肽和/或肽抗原。
这些方法可以进一步包括扩增编码靶向多肽和/或肽抗原的聚核苷酸以及将靶向多肽和/或肽抗原克隆至表达载体中。扩增编码靶向多肽和/或肽抗原的聚核苷酸可以包括合成与基因至少部分互补的寡核苷酸。寡核苷酸可以与基因充分互补以炼合(anneal)至聚核苷酸。寡核苷酸可以包含连接子序列。连接子序列可以选自SEQ ID NO:40-44。
这些方法可以进一步包括用表达载体转染或感染细胞。这些方法可以进一步包括在细胞中表达靶向多肽和/或肽抗原。这些方法可以进一步包括在无细胞系统中表达靶向多肽和/或肽抗原。这些方法可以进一步包括产生包含表达载体的病毒。这些方法可以进一步包括繁殖病毒。这些方法可以进一步包括用包含表达载体的病毒感染细胞。这些方法可以进一步包括繁殖细胞。
本文公开了嫁接抗体或抗体片段、肽抗原或靶向肽以产生CAR-EC开关的方法。这种方法可以包括使CAR-BP嫁接至抗体或抗体片段。这种方法可以包括使CAR-BP嫁接至抗体或抗体片段的N端、C端或内部位点。CAR-BP可以嫁接至抗体或抗体片段的CL域。CAR-BP可以嫁接至抗体或抗体片段的CL域的环。这种方法可以包括使抗体或抗体片段嫁接至CAR-BP。这种方法可以包括使抗体或抗体片段嫁接至CAR-BP的N端、C端或内部位点。这种方法可以包括使CAR-BP嫁接至靶向肽。这种方法可以包括使CAR-BP嫁接至靶向肽的N端、C端或内部位点。这种方法可以包括使靶向肽嫁接至CAR-BP。这种方法可以包括使靶向肽嫁接至CAR-BP的N端、C端或内部位点。
CAR-BP、靶向肽、抗体或抗体片段可以包含一个或多个连接子,其中连接子位于CAR-BP、靶向肽、抗体或抗体片段的N端和/或C端处。这种方法可以包括经由连接子嫁接抗体或抗体片段、CAR-BP或靶向肽。连接子可以包含(GSSSS)n。
嫁接可以包括产生CAR-EC开关编码核酸。产生CAR-EC开关编码核酸可以包括一个或多个聚合酶链反应。产生CAR-EC开关编码核酸可以包括一个或多个核酸酶消化。酶消化可以是位点特异性的。产生CAR-EC开关编码核酸可以包括一个或多个接合。产生CAR-EC开关的方法可以包括将CAR-EC开关编码核酸并入CAR-EC开关载体中。载体可以是表达载体。表达载体可以包含组成性启动子、诱导性启动子和/或条件性启动子。可以在细胞中表达CAR-EC开关编码核酸或CAR-EC开关载体并且分离和纯化所得CAR-EC开关。细胞可以是原核细胞。细胞可以是大肠杆菌。细胞可以是真核细胞。细胞可以是哺乳动物细胞。可以在无细胞系统中表达CAR-EC开关编码核酸或CAR-EC开关载体。替代地或另外,可以从游离氨基酸合成CAR-EC开关。
纯化CAR-EC开关和其部分
本文公开了纯化本文所公开的CAR-EC开关的方法,其包括从CAR-EC开关产生系统的组分(例如,细胞碎片、游离氨基酸)分离本文所公开的CAR-EC开关。纯化CAR-EC开关可以包括使用一个或多个浓缩柱、电泳、过滤、离心、色谱法或其组合。色谱法可以包括尺寸排阻色谱法。额外的色谱方法包括(但不限于)疏水相互作用色谱法、离子交换色谱法、亲和色谱法、金属结合、免疫亲和色谱法以及高效液相色谱法或高压液相色谱法。电泳可以包括变性电泳或非变性电泳。
CAR-EC开关可以包含一种或多种肽标签。纯化CAR-EC开关的方法可以包括使CAR-EC开关的一种或多种肽标签结合至捕获剂。捕获剂可以选自抗体、柱、小珠以及其组合。一种或多种标签可以由一种或多种蛋白酶裂解。标签的实例包括(但不限于)聚组氨酸、标签、HA、c-myc、V5、甲壳质结合蛋白(CBP)、麦芽糖结合蛋白(MBP)以及谷胱甘肽-S-转移酶(GST)。肽标签可以是CAR-BP。肽标签可以是HTP。肽标签可以是酵母转录因子GCN4。
这些方法可以进一步包括CAR-BP、靶向多肽和/或CAR-EC开关的冻干或超速离心。
CAR-BP、靶向多肽和/或CAR-EC开关的纯度可以等于或大于50%、55%、60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高。CAR-BP、靶向多肽和/或CAR-EC开关的纯度可以等于或大于85%。CAR-BP、靶向多肽和/或CAR-EC开关的纯度可以等于或大于90%。CAR-BP、靶向多肽和/或CAR-EC开关的纯度可以等于或大于95%。CAR-BP、靶向多肽和/或CAR-EC开关的纯度可以等于或大于97%。
产生本文所公开的CAR-EC开关的方法可以包括产生结构上均质的CAR-EC开关。从聚核苷酸产生CAR-EC开关的方法可以得到一个或多个CAR-EC开关,其具有相同或相似的形式、特征、结合亲和力(例如,对CAR或标靶)、几何结构和/或尺寸。CAR-EC开关的均质度可以等于或大于50%、55%、60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高。CAR-EC开关的均质度可以等于或大于85%。CAR-EC开关的均质度可以等于或大于90%。CAR-EC开关的均质度可以等于或大于95%。CAR-EC开关的均质度可以等于或大于97%。均质度可以是结构均质度。均质度可以是在将细胞施用于受试者之前的结构均质度。均质度可以是在通过细胞活动(甲基化、乙酰化、糖基化等等)修饰成CAR-EC开关之前的结构均质度。均质度的这些高百分比可以提供CAR-EC开关的更加可预测的效应。均质度的这些高百分比可以提供当与CAR-EC组合治疗受试者的病状时CAR-EC开关的更少脱靶效应。
实施例
以下说明性实施例代表本文所描述的软件应用、系统以及方法的实施方案并且不意欲以任何方式限制。
实施例1-可开关CAR-T平台的产生和评价
在选择CAR-EC开关肽抗原中考虑所开发的抗体的人类蛋白质组中交叉反应性表位的溶解度、稳定性、亲和力以及潜力。基于这些标准,选择来自酵母转录因子GCN4的线性氨基酸表位(7P14P)。具有从2.6nM至5.2pM变化的亲和力的单链抗体能够经由结合动力学优化CAR-EC。另外,这些抗体在对线性表位最高亲和力的抗肽单链抗体当中。对于具有序列NYHLENEVARLKKL(SEQ ID NO.3)的所选GCN4表位(7P14P)和GCN4结合scFv(52SR4)的离解常数(Kd)是5.2pM。
开发基于常用标签的小亲水标靶肽(HTP)。具有低抗原性,高度可溶,并且已经融合至众多蛋白质而对蛋白质折叠或稳定性有极小影响。在将FLAG修饰成HTP中,在末端赖氨酸之后并入脯氨酸残基以力图增加蛋白水解稳定性。通过传统小鼠免疫和后续人源化或通过人类文库的噬菌体淘选来开发针对这个表位的抗体。充分表征演化的scFv的结合动力学并且形成肽-CAR-EC并且如所描述测试脱靶特异性。
可开关CAR-T平台在异种移植模型中的评价
为了评价功效,小鼠异种移植模型用于比较这些可开关平台与先前开发的CAR-T开关平台。为此目的,RS4;11、NALM-6、Raji或其它CD19阳性细胞系用于在非肥胖性糖尿病-重症联合免疫缺陷(NOD-SCID-γ -/-,NSG)小鼠中确立肿瘤模型。通过静脉内施用递送CAR-T。对于肽抗CD19开关进行剂量范围的发现,并且与野生型CD19Fab对照相比较。基于肿瘤负荷和总存活期来判断功效。在每周抽取血液下监测小鼠以监测外周血中CAR-EC的增殖。CAR-EC的详细免疫表型表征集中于根据标准表型参数使用多通道流式细胞术定义的效应、记忆、衰老(终末分化)或无能表型。
按照所观测的PK数据以适当剂量递送Fab和基于IgG的开关的功效并且进行比较。IgG在这个模型中由于其在体内的长停留时间而最有效。对于这个概念的进一步探查在同基因模型中进行。
获得初级源自患者的ALL或CLL样品并且用于在NSG小鼠中产生异种移植模型。通过流式细胞术表征初级样品的CD19表达。在施用疗法之前2-3周在小鼠中确立白血病。通过监测外周血中的CD19+ALL胚细胞计数来判断对CAR-T-19的功效。在未控制或消除白血病的情况下,对增殖的胚细胞进行免疫分型(特别寻找CD19抗原表达的损失,对于进一步研究参看下文)。还监测CAR-EC的持久性(不过后者并不预期与基于RS4;11的异种移植有实质性不同)。
可开关CAR-T平台在同基因模型中的评价
尽管免疫缺陷小鼠中的异种移植模型允许测量可开关平台的功效,但这个模型对于评估用于缓和与CAR-T-19疗法相关的长期淋巴细胞减少的方法不是最佳的。测试可开关CAR-EC在有免疫能力的B细胞淋巴瘤小鼠模型中逆转B细胞发育不全的能力。为了形成鼠类替代品CAR-T,将工程改造的基于肽的嵌合受体克隆至莫洛尼鼠(Moloney murine)基于白血病的逆转录病毒载体用于转导至鼠类脾细胞中。使用源自鼠类的信号传导域CD28和CD3z。抗人CD19抗体不与小鼠CD19交叉反应;因此,获得大鼠抗小鼠CD19杂交瘤1D3(来自ATCC)并且对可变区进行测序。将这个序列克隆至表达载体中用于肽融合以形成开关并且克隆至嵌合抗原受体中以形成CAR-T-19小鼠替代品。
在体外优化转导和评估功效之后,使用Myc5-CD19细胞系在野生型C57BL/6小鼠中确立B细胞淋巴瘤。基于使用替代品系统的异种移植研究和体外检验以给药时程施用CAR-EC和开关。在这个模型中特别关注的是在Myc5-CD19消失和B细胞剔除的速率上比较Fab和基于IgG的开关。如同异种移植研究一样,监测CAR-T增殖并且离体进行免疫表型表征。在根除淋巴瘤细胞之后,停止开关施用并且监测外周血中B细胞的再增殖。替代品CAR-T-19与替代品可开关CAR-T都预期能够长期缓解,但只有可开关平台能够使B细胞再群体化。在预定义的组群上经由组织学监测CAR-T对主要器官的浸润并且在疗法后进行细胞分析。追踪在不存在刺激的情况下CAR-EC的长期持久性。
可开关CAR-T平台在异质性癌症模型中的评价
依序或同时使用含有抗CD19靶向抗体的第一开关和含有抗CD20靶向抗体利妥昔单抗的第二开关以使用单一过继转移的CAR-T靶向相同患者中的不同抗原来力图对抗在CAR-T-19疗法期间归因于CD19逃逸变体所致的ALL复发。
以类似于抗CD19开关的方式使用实施例3中所确定的最佳特征形成抗CD20开关。构建基于利妥昔单抗的CAR-T-20用于比较。体外测试对CD20阳性IM-9和Daudi细胞系的功效。为了形成异质性B细胞成淋巴细胞,使用慢病毒载体用CD19抗原稳定地转导源自慢性骨髓性白血病的K562细胞系(其对于CD20和CD19是阴性的)。经由流式分选获得单细胞克隆体以获得具有均质的CD19表达的群体。然后用CD20转导这个细胞系并且通过高(CD20hi)或低(CD20low)水平的抗原表达进行分选。使用CD19和CD20开关(同时或依序施用)体外评估可开关CAR-T对CD19+CD20-与CD19+CD20hi或CD19+CD20low的混合物的活化和细胞毒性。这种方法提供了研究在群体中用利妥昔单抗开关刺激CAR-T所必需的CD20hi或CD20low细胞的最低百分比的机会。这可能比均质群体更加生理上相关。然后在异种移植小鼠模型中测试这个系统。CD19+CD20-与CD19+CD20+的混合物用于确立异种移植。或者,如果发现在我们的初始异种移植研究中对于CD19或CD20表达是异质的,那么初级源自患者的ALL样品用于这个实验。施用具有抗CD20开关的可开关CAR-EC以消除CD19+CD20+群体并且允许CD19+CD20-细胞外生。为了展示重靶向相同CAR-T的可行性,随后给予抗CD19开关并且监测剩余异种移植物的生长。在处死的小鼠组群中或在初级胚细胞中评价肿瘤的抗原表达。还评估同时靶向。将处理与CAR-T-19、CAR-T-20或两者同时相比较。
实施例2.CAR构建
CAR如下构建:
设计LV-EF1a-GCN4-BBZ以靶向酵母转录因子GCN4(序列RMKQLEPKVEELLPKNYHLEN EVARLKKLVGER(SEQ ID NO.2))的7P14P表位,其中加下划线的氨基酸已经显示结合至来自PDB的1P4B晶体结构中的c11L32Ser scFv。根据参考文献:Zahnd,C.,Spinelli,S.,Luginbuhl,B.,Amstutz,P.,Cambillau,C.以及Pluckthun,A.(2004)具有低皮摩尔亲和力的肽结合单链抗体片段(scFv)的定向体外演化和晶体学分析(Directed in vitroevolution and crystallographic analysis of a peptide-binding single chainantibody fragment(scFv)with low picomolar affinity),《生物化学杂志(The Journalof Biological Chemistry)》279,18870-18877,从52SR4(具有与c11L32Ser相似的序列的高亲和力突变体)抗体scFv构建scFv。
实施例3.抗CD19-Fab-GCN4HC1的克隆、表达以及纯化
克隆:通过扩增的CD19Fab重链(VH和CH1)接合至不含Fc片段的pFuse-hIgG1-Fc骨架载体(InvivoGen,CA)来产生CD19Fab重链的哺乳动物表达载体。扩增编码抗体CD19轻链的基因并且克隆至不含hIgG1Fc片段的pFuse载体中。将编码GCN4(NYHLENEVARLKKL=SEQID NO:3)的基因合成为寡核苷酸。随后,通过使GCN4在CD19Fab重链的S135之后嫁接至CD19Fab的成熟重链中来形成抗CD1-Fab-GCN4HC1融合蛋白。通过DNA测序确认所得哺乳动物表达载体。
表达和纯化:根据制造商的方案,经由用CD19-Fab轻链和GCN4-CD19-HC1的表达载体瞬时转染FreeStyle HEK 293细胞来表达抗CD19-Fab-GCN4HC1。简单地说,将含有3×107个细胞的28mL FreeStyle HEK 293细胞接种于125mL摇瓶中。将稀释于1mL Opti-MEM培养基中的15μg轻链质粒和15μg重链质粒添加至含有60μL 293fectin(Invitrogen,Inc)的1mLOpti-MEM中。将质粒与293fectin一起孵育30分钟后,将lipoplex混合物添加至细胞悬浮液中。然后在37℃下在5%CO2环境中以125rpm振荡细胞。在转染后48和96小时收集含有分泌蛋白的培养基。通过蛋白质G色谱法(Thermo Fisher Scientific,IL)纯化抗CD1-Fab-GCN4HC1。通过SDS-PAGE凝胶分析纯化的蛋白质。图5A和5B分别示出了在非还原性和还原性(具有50mM DTT)条件下抗CD1-Fab-GCN4HC1(泳道7)的SDS凝胶图像。
实施例4.抗CD19-IgG-GCN4HC1的克隆、表达以及纯化
克隆:通过扩增的CD19Fab重链(VH和CH1)框内接合至pFuse-hIgG1-Fc骨架载体(InvivoGen,CA)来产生CD19IgG重链的哺乳动物表达载体。扩增编码抗体CD19轻链的基因并且克隆至不含hIgG1Fc片段的pFuse载体中。将编码GCN4(NYHLENEVARLKKL=SEQ ID NO:3)的基因合成为寡核苷酸。随后,通过在CD19IgG的成熟重链的S135之后插入GCN4来形成抗CD19-IgG-GCN4HC1融合蛋白。通过DNA测序确认所得哺乳动物表达载体。
表达和纯化:根据制造商的方案,经由用CD19-IgG轻链和GCN4-CD19重链的表达载体瞬时转染FreeStyle HEK 293细胞来表达抗CD19-IgG-GCN4HC1。简单地说,将含有3×107个细胞的28mL FreeStyle HEK 293细胞接种于125mL摇瓶中。将稀释于1mL Opti-MEM培养基中的15μg轻链质粒和15μg重链质粒添加至含有60μL 293fectin(Invitrogen,Inc)的1mLOpti-MEM中。将质粒与293fectin一起孵育30分钟后,将lipoplex混合物添加至细胞悬浮液中。然后在37℃下在5%CO2环境中以125rpm振荡细胞。在转染后48和96小时收集含有分泌蛋白的培养基。通过蛋白质G色谱法(Thermo Fisher Scientific,IL)纯化GCN4-CD19重链。通过SDS-PAGE凝胶分析纯化的蛋白质。图5A和5B分别示出了在非还原性和还原性(具有50mM DTT)条件下抗CD19-IgG-GCN4HC1(泳道3)的SDS凝胶图像。
实施例5.抗CD19-Fab-GCN4C端的克隆、表达以及纯化
克隆:通过扩增的CD19Fab重链(VH和CH1)接合至不含Fc片段的pFuse-hIgG1-Fc骨架载体(InvivoGen,CA)来产生CD19IgG重链的哺乳动物表达载体。扩增编码抗体CD19轻链的基因并且克隆至不含hIgG1Fc片段的pFuse载体中。将编码在GCN4的N端处具有GGGGS(SEQID NO:40,其中n=1)连接子的GCN4(NYHLENEVARLKKL=SEQ ID NO:3)的基因合成为寡核苷酸。随后,通过使连接子-GCN4在C223处融合至Fab重链的C端来形成抗CD19-Fab-GCN4C端融合蛋白。通过DNA测序确认所得哺乳动物表达载体。
表达和纯化:根据制造商的方案,经由用CD19-Fab轻链和抗CD19-Fab-GCN4C端的表达载体瞬时转染FreeStyle HEK 293细胞来表达抗CD19-Fab-GCN4C端。简单地说,将含有3×107个细胞的28mL FreeStyle HEK 293细胞接种于125mL摇瓶中。将稀释于1mL Opti-MEM培养基中的15μg轻链质粒和15μg重链质粒添加至含有60μL 293fectin(Invitrogen,Inc)的1mL Opti-MEM中。将质粒与293fectin一起孵育30分钟后,将lipoplex混合物添加至细胞悬浮液中。然后在37℃下在5%CO2环境中以125rpm振荡细胞。在转染后48和96小时收集含有分泌蛋白的培养基。通过蛋白质G色谱法(Thermo Fisher Scientific,IL)纯化抗CD19-Fab-GCN4C端。通过SDS-PAGE凝胶分析纯化的蛋白质。图5A和5B分别示出了在非还原性和还原性(具有50mM DTT)条件下抗CD19-Fab-GCN4C端(泳道9)的SDS凝胶图像。
实施例6.抗CD19-IgG-GCN4铰链的克隆、表达以及纯化
克隆:通过扩增的CD19Fab重链(VH和CH1)框内接合至pFuse-hIgG1-Fc骨架载体(InvivoGen,CA)来产生CD19IgG重链的哺乳动物表达载体。扩增编码抗体CD19轻链的基因并且克隆至不含hIgG1Fc片段的pFuse载体中。将编码在GCN4的N端处具有GGGGS(SEQ IDNO:40,其中n=1)连接子并且在GCN4的C端处具有GGS(SEQ ID NO.42,其中n=1)的GCN4(NYHLENEVARLKKL=SEQ ID NO:3)(“连接子-GCN4-连接子”)的基因合成为寡核苷酸。随后,通过使连接子-GCN4-连接子嫁接于在C223处Fab重链的C端与铰链区之间来形成抗CD19-IgG-GCN4铰链融合蛋白。因此,连接子-GCN4-连接子延伸IgG的铰链区,这模拟具有延长的铰链区的IgG3结构。通过DNA测序确认所得哺乳动物表达载体。
表达和纯化:根据制造商的方案,经由用CD19-IgG轻链和GCN4-CD19铰链重链的表达载体瞬时转染FreeStyle HEK 293细胞来表达抗CD19-IgG-GCN4铰链。简单地说,将含有3×107个细胞的28mL FreeStyle HEK 293细胞接种于125mL摇瓶中。将稀释于1mL Opti-MEM培养基中的15μg轻链质粒和15μg重链质粒添加至含有60μL 293fectin(Invitrogen,Inc)的1mL Opti-MEM中。将质粒与293fectin一起孵育30分钟后,将lipoplex混合物添加至细胞悬浮液中。然后在37℃下在5%CO2环境中以125rpm振荡细胞。在转染后48和96小时收集含有分泌蛋白的培养基。通过蛋白质G色谱法(Thermo Fisher Scientific,IL)纯化GCN4-CD19铰链IgG。通过SDS-PAGE凝胶分析纯化的蛋白质。图5A和5B分别示出了在非还原性和还原性(具有50mM DTT)条件下抗CD19-IgG-GCN4铰链(泳道5)的SDS凝胶图像。
实施例7.抗CD19-IgG-GCN4CL1的克隆、表达以及纯化
克隆:通过扩增的CD19Fab重链(VH和CH1)框内接合至pFuse-hIgG1-Fc骨架载体(InvivoGen,CA)来产生CD19IgG重链的哺乳动物表达载体。扩增编码抗体CD19轻链的基因并且克隆至不含hIgG1Fc片段的pFuse载体中。将编码在两个末端处具有GGGGS(SEQ ID NO:40,其中n=1)连接子的GCN4(NYHLENEVARLKKL=SEQ ID NO:3)的基因合成为寡核苷酸。随后,通过用在两个末端处具有连接子序列的GCN4置换CD19轻链的CL区中的K169来形成抗CD19-IgG-GCN4CL1融合蛋白。通过DNA测序确认所得哺乳动物表达载体。
表达和纯化:根据制造商的方案,经由用CD19-IgG重链和GCN4-CD19-CL1轻链的表达载体瞬时转染FreeStyle HEK 293细胞来表达抗CD19-IgG-GCN4CL1。简单地说,将含有3×107个细胞的28mL FreeStyle HEK 293细胞接种于125mL摇瓶中。将稀释于1mL Opti-MEM培养基中的15μg轻链质粒和15μg重链质粒添加至含有60μL 293fectin(Invitrogen,Inc)的1mL Opti-MEM中。将质粒与293fectin一起孵育30分钟后,将lipoplex混合物添加至细胞悬浮液中。然后在37℃下在5%CO2环境中以125rpm振荡细胞。在转染后48和96小时收集含有分泌蛋白的培养基。通过蛋白质G色谱法(Thermo Fisher Scientific,IL)纯化抗CD19-IgG-GCN4CL1。通过SDS-PAGE凝胶分析纯化的蛋白质。图5A和5B分别示出了在非还原性和还原性(具有50mM DTT)条件下抗CD19-IgG-GCN4CL1(泳道4)的SDS凝胶图像。
实施例8.抗CD19-Fab-GCN4CL1的克隆、表达以及纯化
克隆:通过扩增的CD19Fab重链(VH和CH1)接合至不含Fc片段的pFuse-hIgG1-Fc骨架载体(InvivoGen,CA)来产生CD19Fab重链的哺乳动物表达载体。扩增编码抗体CD19轻链的基因并且克隆至不含hIgG1Fc片段的pFuse载体中。将编码在两个末端处具有GGGGS(SEQID NO:40,其中n=1)连接子的GCN4(NYHLENEVARLKKL=SEQ ID NO:3)的基因合成为寡核苷酸。随后,通过用在两个末端处具有连接子序列的GCN4置换CD19轻链的CL区中的K169来形成抗CD19-Fab-GCN4CL1融合蛋白。通过DNA测序确认所得哺乳动物表达载体。
表达和纯化:根据制造商的方案,经由用CD19-Fab重链和GCN4-CD19-CL轻链的表达载体瞬时转染FreeStyle HEK 293细胞来表达抗CD19-Fab-GCN4CL1。简单地说,将含有3×107个细胞的28mL FreeStyle HEK 293细胞接种于125mL摇瓶中。将稀释于1mL Opti-MEM培养基中的15μg轻链质粒和15μg重链质粒添加至含有60μL 293fectin(Invitrogen,Inc)的1mL Opti-MEM中。将质粒与293fectin一起孵育30分钟后,将lipoplex混合物添加至细胞悬浮液中。然后在37℃下在5%CO2环境中以125rpm振荡细胞。在转染后48和96小时收集含有分泌蛋白的培养基。通过蛋白质G色谱法(Thermo Fisher Scientific,IL)纯化抗CD19-Fab-GCN4CL1。通过SDS-PAGE凝胶分析纯化的蛋白质。图5A和5B分别示出了在非还原性和还原性(具有50mM DTT)条件下抗CD19-Fab-GCN4CL1(泳道8)的SDS凝胶图像。
实施例9.抗CD19-Fab-GCN4LC1-N端的克隆、表达以及纯化
克隆:通过扩增的CD19Fab重链(VH和CH1)接合至不含Fc片段的pFuse-hIgG1-Fc骨架载体(InvivoGen,CA)来产生CD19Fab重链的哺乳动物表达载体。扩增编码抗体CD19轻链的基因并且克隆至不含hIgG1Fc片段的pFuse载体中。将编码在GCN4的C端处具有GGGGS(SEQID NO:40,其中n=1)连接子的GCN4(NYHLENEVARLKKL=SEQ ID NO:3)的基因合成为寡核苷酸。随后,通过使连接子-GCN4融合至Fab轻链的N端来形成抗CD19-Fab-GCN4LC1-N端融合蛋白。通过DNA测序确认所得哺乳动物表达载体。
表达和纯化:根据制造商的方案,经由用CD19-Fab轻链和GCN4-CD19-C端的表达载体瞬时转染FreeStyle HEK 293细胞来表达抗CD19-Fab-GCN4LC1-N端。简单地说,将含有3×107个细胞的28mL FreeStyle HEK 293细胞接种于125mL摇瓶中。将稀释于1mL Opti-MEM培养基中的15μg轻链质粒和15μg重链质粒添加至含有60μL 293fectin(Invitrogen,Inc)的1mL Opti-MEM中。将质粒与293fectin一起孵育30分钟后,将lipoplex混合物添加至细胞悬浮液中。然后在37℃下在5%CO2环境中以125rpm振荡细胞。在转染后48和96小时收集含有分泌蛋白的培养基。通过蛋白质G色谱法(Thermo Fisher Scientific,IL)纯化抗CD19-Fab-GCN4LC1-N端。通过SDS-PAGE凝胶分析纯化的蛋白质。图5A和5B分别示出了在非还原性和还原性(具有50mM DTT)条件下抗CD19-Fab-GCN4LC1-N端(泳道10)的SDS凝胶图像。
实施例10.抗CD19Fab-GCN4CL1、抗CD19IgG无Fc-GCN4以及抗CD19Fab-GCN4C端CAR-EC开关的细胞毒性
通过融合GCN4酵母转录因子肽序列7P14P(定义于Zahnd等(2004)具有低皮摩尔亲和力的肽结合单链抗体片段(scFv)的定向体外演化和晶体学分析(Directed in vitroevolution and crystallographic analysis of a peptide-binding single chainantibody fragment(scFv)with low picomolar affinity),《生物化学杂志(The Journalof Biological Chemistry)》279,18870-18877中)的14个氨基酸形成肽CAR-EC开关。基于具有scFv c11L32Ser的GCN4肽7P14P的晶体结构1P4B中所定义的那些来选择14个氨基酸。通过使GCN4肽序列融合至Fab抗体的重链的C端或通过使GCN4肽序列融合于Fab或IgG抗体的轻链的CL环中来构建开关。在CHO或HEK细胞中进行所有表达。
为了形成基于嫁接的GCN4肽的抗CD19CAR-T开关(SEQ ID NO:30),使被提议为根据来自酵母转录因子GCN4肽(7P14P)RMKQLEPKVEELLPKNYHLENEVARLKKLVGER(SEQ ID NO:2)的晶体结构(PDB:1P4B)(参看图2)的最小结合表位的肽NYHLENEVARLKKL(SEQ ID NO:3)嫁接至小鼠抗人CD19Fab克隆体FMC63。通过用序列GGGGSNYHLENEVARLKKLGGGGS(SEQ IDNO.4)-由GGGGS连接子(SEQ ID NO:40,其中n=1)侧接的GCN4表位置换K63(如从恒定区的N端计数,当从成熟蛋白的N端计数时将为K169)进行嫁接。抗CD19FabCL1-GCN4的质谱提供于下文(图3)。或者,使肽嫁接至重链(SEQ ID NO:29)。
使用经LV-EF1a-GCN4(52SR4)转导的人类PBMC评估抗CD19FabCL1-GCN4开关的细胞毒性活性以在10:1的E:T比率和24小时孵育下形成CAR-T-GCN4。评估针对NALM-6(CD19+)、RS4;11(CD19+)或RPMI-8226(CD19-)的活性(表1)。评估IgG(无Fc)开关针对RS4;11(CD19+)或K562(CD19-)的活性(表2)。评估C端开关针对RS4;11(CD19+)或K562(CD19-)的活性(表3)。
表1.抗CD19FabCL1-GCN4开关的细胞毒性
表2.抗CD19IgG无Fc-GCN4开关的细胞毒性
表3.抗CD19FabC端-GCN4开关的细胞毒性
实施例11.具有嫁接/融合至抗CD19抗体或抗体片段的不同区域的GCN4的各种抗CD19-GCN4CAR-EC开关的细胞毒性
使用经LV-EF1a-GCN4(52SR4)转导的人类PBMC评估嫁接/融合至抗CD19FMC63抗体或抗体片段的不同区域的各种抗CD19-GCN4CAR-EC开关的细胞毒性活性以在10:1的E:T比率和24小时孵育下形成CAR-T-GCN4。所测试的开关是抗CD19FabCL1-GCN4(“CL1Fab”)、抗CD19-GCN4FabC端(“C端Fab”)、抗CD19IgGHC1-GCN4(“HC1IgG”)、抗CD19IgGCL1-GCN4(“CL1IgG”)、抗CD19IgG铰链-GCN4(“铰链IgG”)、抗CD19IgGWT-GCN4(“Wt IgG”)、抗CD19FabHC1-GCN4(“HC1Fab”)以及抗CD19FabN端LC1-GCN4(“N端LC1Fab”)。评估针对RS4;11(CD19+)的活性(图4,表4)。图6描绘了这个实施例中所描述的开关的嫁接位置。将CL1和HC1嫁接位置应用于Fab与IgG格式。N端嫁接如嫁接至轻链所示,然而,N端嫁接并不限于轻链或Fab并且还可以嫁接至重链以及IgG格式。在Fab上的C端位置与铰链IgG是等排的。在这个情形中,所有Fab构建体是单价的并且所有IgG构建体是二价的,但这些一般不是CAR-EC开关的必要要求。
表4.抗CD19-GCN4开关的细胞毒性
实施例12.抗CD19-Fab-GCN4CL1CAR-EC开关和抗GCN4CAR T细胞(swiCAR T细胞)在异种移植肿瘤小鼠模型中的体内功效
为了评估swiCAR-T细胞的体内活性,使用基于荧光素化NALM-6细胞的原位(液体)异种移植肿瘤模型进行初步研究。在这个模型中,在用0.5mg/kg抗CD19(GCN4)CL1Fab每日处理仅5天后swiCAR T细胞展示消退。用野生型抗CD19Fab与swiCAR T细胞处理并不能够介导肿瘤消退(通过单因素ANOVA不是显著的)。这些结果展示体内重定向swiCAR T细胞的能力。实验细节:将106个荧光素化NALM-6细胞静脉内(I.V.)注射至非肥胖性糖尿病重症联合免疫缺陷(NOD-SCID-γ-/-,NSG)小鼠中。六天后,静脉内输注30×106个swiCAR T细胞或CART-19细胞(50%转导)。αCD19-Fab-GCN4-CL1的给药(静脉内)在同一天开始,每天四次(q.d.),0.5mg/kg。给药5天后(第11天),向小鼠注射荧光素并且在体内成像系统(IVIS)上成像,n=3或4,绘制每只小鼠测量的平均辐射率(p/s/cm2/sr),并且绘制平均值±SEM,**p≤0.05,单因素ANOVA。无处理与swiCAR-T+WT Fab之间的差异不是统计上显著的。结果示于图7A中。
实施例13.抗BCMA-IgG-GCN4CL1的克隆、表达以及纯化
克隆:通过扩增的抗BCMA IgG重链(VH和CH1)框内接合至pFuse-hIgG1-Fc骨架载体(InvivoGen,CA)来产生CD19IgG重链的哺乳动物表达载体。扩增编码抗体BCMA轻链的基因并且克隆至不含hIgG1Fc片段的pFuse载体中。将编码在两个末端处具有GGGGS(SEQ IDNO:40,其中n=1)连接子的GCN4(NYHLENEVARLKKL=SEQ ID NO:3)的基因合成为寡核苷酸。随后,通过使在两个末端处具有连接子序列的GCN4嫁接至抗BCMA轻链的CL区中来形成抗BCMA-IgG-GCN4CL1融合蛋白。通过DNA测序确认所得哺乳动物表达载体。
表达和纯化:根据制造商的方案,经由用BCMA-IgG重链和GCN4-BCMA-CL1轻链的表达载体瞬时转染FreeStyle HEK 293细胞来表达抗BCMA-IgG-GCN4CL1。简单地说,将含有3×107个细胞的28mL FreeStyle HEK 293细胞接种于125mL摇瓶中。将稀释于1mL Opti-MEM培养基中的15μg轻链质粒和15μg重链质粒添加至含有60μL 293fectin(Invitrogen,Inc)的1mL Opti-MEM中。将质粒与293fectin一起孵育30分钟后,将lipoplex混合物添加至细胞悬浮液中。然后在37℃下在5%CO2环境中以125rpm振荡细胞。在转染后48和96小时收集含有分泌蛋白的培养基。通过蛋白质G色谱法(Thermo Fisher Scientific,IL)纯化抗BCMA-IgG-GCN4CL1。
实施例14.具有嫁接至抗BCMA抗体或抗体片段的轻链的GCN4的抗BCMA-IgG-GCN4CL1CAR-EC开关的细胞毒性
使用经LV-EF1a-GCN4(52SR4)转导的人类PBMC评估抗BCMA-IgG-GCN4CL1CAR-EC开关的细胞毒性活性以在10:1的E:T比率和24小时孵育下形成CAR-T-GCN4。PBMC的转导效率为约50%。通过定量因标靶细胞的细胞溶解产生的乳酸脱氢酶来评估针对OPM2(BCMA+)的活性(图8,表5)。
表5.抗BCMA-IgG-GCN4CL1CAR-EC开关和抗GCN4CAR-T细胞的细胞毒性
虽然本文已经示出和描述本发明的优选实施方案,但本领域的技术人员将显而易见,这类实施方案仅作为实例而提供。在不脱离本发明的情况下众多变更、变化以及取代现在将为本领域的技术人员所想到。应了解,在实施本发明中可以采用本文所描述的本发明实施方案的各种替代物。
Claims (39)
1.一种嵌合抗原受体效应细胞开关,其包含:
a.结合效应细胞上的嵌合抗原受体的肽抗原,所述肽抗原为酵母转录因子GCN4肽的线性氨基酸表位,所述线性氨基酸表位如SEQ ID NO:3所示;以及
b.结合标靶细胞的表面CD19的靶向抗体或抗体片段,其中所述靶向抗体或抗体片段包含所述抗体的至少轻链可变(VL)域和重链可变(VH)域,并且其中所述肽抗原嫁接或融合至所述VL域的N端。
2.如权利要求1所述的嵌合抗原受体效应细胞开关,其中所述靶向抗体或抗体片段选自由以下组成的群组:免疫球蛋白、无Fc的免疫球蛋白、和Fab,以及其片段。
3.如权利要求1所述的嵌合抗原受体效应细胞开关,其中所述靶向抗体或抗体片段包含轻链和重链对,其中所述轻链和重链由基于或来源于选自由以下组成的群组的核酸序列对的核酸序列编码:SEQ ID NO:8和9;SEQ ID NO:8和10。
4.如权利要求1所述的嵌合抗原受体效应细胞开关,其中所述靶向抗体或抗体片段包含轻链和重链对,其中所述轻链和重链分别包含基于或来源于选自由以下组成的群组的氨基酸序列对的氨基酸序列:SEQ ID NO:27和28;以及SEQ ID NO:27和29。
5.如权利要求1所述的嵌合抗原受体效应细胞开关,其中所述嵌合抗原受体效应细胞开关包含轻链和重链对,其中所述轻链和重链分别包含基于或来源于SEQ ID NO:36和29的氨基酸序列。
6.如权利要求1所述的嵌合抗原受体效应细胞开关,其中所述肽抗原置换所述靶向抗体或抗体片段的一个或多个氨基酸。
7.如权利要求1所述的嵌合抗原受体效应细胞开关,其中所述肽抗原嫁接至所述靶向抗体或抗体片段中而不置换氨基酸。
8.如权利要求1所述的嵌合抗原受体效应细胞开关,其进一步包含连接所述肽抗原和所述靶向抗体或抗体片段的连接子。
9.如权利要求8所述的嵌合抗原受体效应细胞开关,其中所述连接子是连接所述肽抗原和所述靶向抗体或抗体片段的肽。
10.如权利要求8所述的嵌合抗原受体效应细胞开关,其中所述连接子包含1个至20个氨基酸。
11.如权利要求8所述的嵌合抗原受体效应细胞开关,其中所述连接子包含以下序列:基于或来源于选自SEQ ID NO:40-44的序列。
12.如权利要求1所述的嵌合抗原受体效应细胞开关,其中所述标靶细胞是癌细胞。
13.如权利要求1所述的嵌合抗原受体效应细胞开关,其中所述嵌合抗原受体效应细胞开关的均质度为至少90%。
14.一种医药组合物,其包含:
a.包含以下的嵌合抗原受体效应细胞开关:
i.结合效应细胞上的嵌合抗原受体的肽抗原,所述肽抗原为酵母转录因子GCN4肽的线性氨基酸表位,所述线性氨基酸表位如SEQ ID NO:3所示;和
ii.结合标靶细胞的表面CD19的靶向抗体或抗体片段,其中所述靶向抗体或抗体片段包含所述抗体的至少轻链可变(VL)域和重链可变(VH)域,并且其中所述肽抗原嫁接或融合至所述VL域的N端;以及
b.医药学上可接受的盐、赋形剂和/或媒剂。
15.一种试剂盒,其包含:
a.包含以下的嵌合抗原受体效应细胞开关:
i.结合效应细胞上的嵌合抗原受体的肽抗原,所述肽抗原为酵母转录因子GCN4肽的线性氨基酸表位,所述线性氨基酸表位如SEQ ID NO:3所示;和
ii.结合标靶细胞的表面CD19的靶向抗体或抗体片段,其中所述靶向抗体或抗体片段包含所述抗体的至少轻链可变(VL)域和重链可变(VH)域,并且其中所述肽抗原嫁接或融合至所述VL域的N端;以及
b.包含结合至所述嵌合抗原受体效应细胞开关的所述肽抗原的嵌合抗原受体的嵌合抗原受体效应细胞。
16.如权利要求15所述的试剂盒,其包含第一嵌合抗原受体效应细胞开关和第二嵌合抗原受体效应细胞开关,其中所述第一嵌合抗原受体效应细胞开关包含第一肽抗原和第一靶向部分并且所述第二嵌合抗原受体效应细胞开关包含第二肽抗原和第二靶向部分。
17.如权利要求16所述的试剂盒,其中所述第一肽抗原和所述第二肽抗原是相同的。
18.如权利要求17所述的试剂盒,其中所述第一靶向部分结合第一标靶细胞上的第一细胞表面分子并且所述第二靶向部分结合第二标靶细胞上的第二细胞表面分子,其中所述第一细胞表面分子和所述第二细胞表面分子是不同的。
19.如权利要求15所述的试剂盒,其中所述效应细胞选自T细胞、效应B细胞、自然杀伤细胞、巨噬细胞以及其祖细胞。
20.如权利要求19所述的试剂盒,其中所述效应细胞选自初始T细胞、记忆性干细胞T细胞、中枢记忆性T细胞、效应记忆性T细胞、辅助T细胞、CD4+T细胞、CD8+T细胞、CD8/CD4+T细胞、αβT细胞、γδT细胞、细胞毒性T细胞、自然杀伤细胞以及巨噬细胞。
21.一种嵌合抗原受体,其在其胞外结构域中包含能够结合权利要求1所述的嵌合抗原受体效应细胞开关的肽抗原的抗GCN-4,其中所述抗GCN-4包含在SEQ ID NO:1所示的聚核苷酸所编码的多肽的胞外结构域中。
22.如权利要求21所述的嵌合抗原受体,其中所述抗GCN-4是scFv。
23.如权利要求21或22所述的嵌合抗原受体,其中所述嵌合抗原受体由基于或来源于SEQ ID NO:1的聚核苷酸编码。
24.一种效应细胞,其包含权利要求21所述的嵌合抗原受体。
25.如权利要求24所述的效应细胞,其中所述效应细胞是T细胞。
26.如权利要求24所述的效应细胞,其包含一个或多个基于或来源于SEQ ID NO:1的聚核苷酸。
27.一种包含具有编码嵌合抗原受体效应细胞开关的序列的聚核苷酸的载体,其中所述嵌合抗原受体效应细胞开关包含肽抗原和靶向抗体或抗体片段,其中所述靶向抗体或抗体片段包含所述抗体的至少轻链可变(VL)域和重链可变(VH)域,并且结合标靶细胞的表面CD19;并且其中所述肽抗原嫁接或融合至所述VL域的N端,并且其中所述肽抗原结合效应细胞上的嵌合抗原受体,所述肽抗原为酵母转录因子GCN4肽的线性氨基酸表位,所述线性氨基酸表位如SEQ ID NO:3所示。
28.一种载体,其包含具有编码靶向抗体或抗体片段的重链的第一序列的第一聚核苷酸;具有编码靶向抗体或抗体片段的轻链的第二序列的第二聚核苷酸;以及具有编码肽抗原的第三序列的第三聚核苷酸,其中所述载体的表达产生嵌合抗原受体效应细胞开关,所述嵌合抗原受体效应细胞开关包含嫁接或融合至抗体或抗体片段VL域的N端的肽抗原,并且其中所述肽抗原结合效应细胞上的嵌合抗原受体,所述肽抗原为酵母转录因子GCN4肽的线性氨基酸表位,所述线性氨基酸表位如SEQ ID NO:3所示。
29.如权利要求28所述的载体,其中所述第三序列与选自所述第一序列和所述第二序列的序列相邻。
30.如权利要求28所述的载体,其中所述第三序列在选自所述第一序列和所述第二序列的序列内。
31.一种产生嵌合抗原受体效应细胞开关的方法,其包括从一个或多个聚核苷酸载体表达:
a.编码靶向抗体或抗体片段的重链的第一序列;
b.编码靶向抗体或抗体片段的轻链的第二序列;以及
c.编码肽抗原的第三序列,其中所述载体的表达产生嵌合抗原受体效应细胞开关,所述嵌合抗原受体效应细胞开关包含嫁接或融合至抗体或抗体片段VL域的N端的肽抗原,并且其中所述肽抗原结合效应细胞上的嵌合抗原受体,所述肽抗原为酵母转录因子GCN4肽的线性氨基酸表位,所述线性氨基酸表位如SEQ ID NO:3所示。
32.如权利要求1所述的嵌合抗原受体效应细胞开关,其用于治疗癌症。
33.如权利要求1所述的嵌合抗原受体效应细胞开关,其与嵌合抗原受体效应细胞组合用于治疗癌症,其中所述嵌合抗原受体效应细胞包含与嵌合抗原受体效应细胞开关的GCN4肽抗原结合的抗GCN4嵌合抗原受体。
34.一种医药组合物,其包含权利要求1所述的嵌合抗原受体效应细胞开关和医药学上可接受的盐、赋形剂和/或媒剂。
35.一种试剂盒,其包含权利要求1所述的嵌合抗原受体效应细胞开关和包含与所述嵌合抗原受体效应细胞开关的肽抗原结合的嵌合抗原受体的CAR-EC。
36.权利要求1所述的嵌合抗原受体效应细胞(CAR-EC)开关,其与嵌合抗原受体效应细胞组合应用于癌症的治疗,其中所述应用还包括与一种或多种第二CAR-EC开关组合,每种第二CAR-EC开关包含:
a.与效应细胞上的嵌合抗原受体结合的抗原;和
b.与标靶细胞上的细胞表面分子结合的第二靶向部分,
其中每种第二CAR-EC开关的第二靶向部分与所述第一CAR-EC开关所包含的第一靶向部分不同;以及
其中所述第二CAR-EC开关所包含的抗原任选为:
(i)与所述第一CAR-EC开关所包含的第一肽抗原相同,或者
(ii)与所述第一CAR-EC开关所包含的第一肽抗原不同的第二抗原;
如果所述第二CAR-EC开关包含第二抗原,所述方法还包括施用包含与所述第二CAR-EC开关的第二抗原结合的嵌合抗原受体的第二嵌合抗原受体效应细胞。
37.如权利要求36所述的嵌合抗原受体效应细胞(CAR-EC)开关,其与嵌合抗原受体效应细胞组合且进一步与一种或多种第二CAR-EC开关组合应用于癌症的治疗,其中:
所述第二靶向部分包含抗CD20抗体或其抗原结合部分。
38.如权利要求36所述的嵌合抗原受体效应细胞(CAR-EC)开关,其与第一嵌合抗原受体效应细胞组合且进一步与一种或多种第二CAR-EC开关组合应用于癌症的治疗,其中:
所述与第二CAR-EC开关的组合仅在需要这种治疗的受试者已被诊断为具有与所述第一靶向部分结合的第一细胞表面分子的调节表达且已被治疗之后用于癌症的治疗。
39.如权利要求38所述的嵌合抗原受体效应细胞(CAR-EC)开关,其与第一嵌合抗原受体效应细胞组合且进一步与一种或多种第二CAR-EC开关组合应用于癌症的治疗,其中:
所述第二靶向部分包含抗CD20抗体或其抗原结合部分。
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CA2927543C (en) | 2021-07-20 |
AU2014337367B2 (en) | 2020-04-30 |
JP2016533174A (ja) | 2016-10-27 |
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JP2020096644A (ja) | 2020-06-25 |
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US20170246270A1 (en) | 2017-08-31 |
EP3057994B1 (en) | 2020-09-23 |
CN105829349A (zh) | 2016-08-03 |
KR20160062760A (ko) | 2016-06-02 |
US20200197497A1 (en) | 2020-06-25 |
AU2020207804A1 (en) | 2020-08-06 |
WO2015057834A1 (en) | 2015-04-23 |
EP3057994A1 (en) | 2016-08-24 |
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