CN116997563A - 改良的免疫细胞疗法 - Google Patents
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Abstract
本公开提供用于治疗的经工程改造的人类细胞(例如T细胞)。亦提供用于制造经工程改造的细胞的表达构建体。
Description
对相关申请的交叉引用
本申请要求2021年1月27日提交的美国临时申请63/142,486的优先权,其公开内容通过提述完整并入本文。
序列表
本申请包含以ASCII格式电子提交的序列表,并通过引用将其全部并入本文。该序列表的电子副本创建于2022年1月5日,名称为026225_WO014_SL.txt,大小为23049字节。
发明背景
在过去二十年间,免疫学及肿瘤生物学的根本进展以及大量肿瘤抗原的鉴别促成基于细胞的免疫疗法领域的显著发展。旨在通过将自体及离体扩增的T细胞转移至患者来治疗癌症的T细胞疗法已引起一些显著的抗肿瘤反应(Blattman等人,Science.(2004)305(5681):200-5)。例如,离体扩增的天然存在的肿瘤浸润性淋巴细胞(TIL)的施用介导黑色素瘤患者中50至70%范围内的客观反应率,该等患者包括在涉及肝脏、肺、软组织及脑的多个部位具有大型侵袭性肿瘤的患者(Rosenberg等人,Nat Rev Cancer.(2008)8(4):299-308;Dudley等人,J Clin Oncol.(2005)23(10):2346-57)。
TIL疗法普遍应用的主要限制因素为难以产生具有抗肿瘤潜力的人类T细胞。作为替代方法,可经由T细胞工程改造将外源性高亲和力TCR引入患者的正常自体T细胞中。已显示,将这些细胞过继性转移至淋巴耗乏患者中介导诸如黑色素瘤、结直肠癌及滑膜肉瘤的癌症中的癌症消退(Kunert等人,Front Immunol.(2013)4:363;Robbins等人,Clin CancerRes.(2015)21(5):1019-27)。经TCR工程改造的T细胞疗法的优势之一为其可靶向整个系列的潜在细胞内肿瘤特异性蛋白,该等蛋白经加工且经由MHC呈现递送至细胞表面,且甚至可在较低密度下由抗原特异性细胞毒性T细胞识别(Kunert,见上文)。
已尝试工程改造具有抗体特异性与T细胞受体效应功能的TCR分子。在此等方法中的一些中,TCR(例如αβTCR或γδTCR)的可变域及恒定域经针对肿瘤抗原的抗体的可变域及恒定域置换,从而产生嵌合抗体-TCR,称为“abTCR”或“caTCR”。参见例如WO 2017/070608及WO 2018/200582,其揭示内容以全文引用的方式并入本文中。在该等方法的一者中,组合使用嵌合刺激受体(CSR)与caTCR以增强经工程改造的T细胞的肿瘤杀灭功效。如同嵌合抗原受体(CAR),CSR具有结合目标配体(例如肿瘤抗原)的细胞外域及细胞内共刺激域,但不同于CAR,CSR不具有细胞内初级免疫细胞信号传导域(其通常为CD3ζ链的细胞内域)或不具有功能性初级免疫细胞信号传导域。CSR及caTCR结合于不同目标/抗原或相同目标/抗原的不同表位且协同作用以增强经工程改造的T细胞的细胞毒性。参见例如WO 2018/200583,其揭示内容以全文引用的方式并入本文中。
T细胞疗法所面临的一个挑战为由于称为T细胞耗竭的现象而缺乏T细胞的体内持久性。参见例如Fraietta等人,Nat Med.(2018)24(5):563-71;Long等人,Nat Med.(2015)21(6):581-90;及Eyquem等人,Nature(2017)543(7643):113-7。T细胞耗竭的特征在于代谢功能、转录程序中的显著变化、效应功能缺失(例如降低的细胞因子分泌及细胞毒性)、多种表面抑制性受体的表达及细胞凋亡。T细胞耗竭已归因于持续的抗原暴露,其引起连续TCR信号传导,或经由T细胞上的经工程改造的抗原受体的组成性(tonic)抗原非依赖性信号传导(参见例如Long,见上文)。已寻求防止或逆转T细胞耗竭作为增强T细胞有效性的手段,例如在患有癌症或慢性感染的患者中及在T细胞疗法中。参见例如WO 2019/118902,其揭示内容以全文引用的方式并入本文中。
因此,仍需要改良的T细胞疗法,其中经工程改造的T细胞具有较高且持续的肿瘤杀灭效力。
发明内容
本公开提供用于改良免疫细胞疗法的组合物及方法。在一个方面中,本公开提供一或多种表达构建体,其包含一或多种用于表达以下的表达盒:a)嵌合抗体-T细胞受体(TCR)构建体(caTCR),其包含i)特异性结合于目标抗原的抗原结合模块,及ii)T细胞受体模块(TCRM;例如,源于人类γδTCR的模块),其包含:包含第一TCR跨膜域(TCRD-TM)的第一TCR域(TCRD),及包含第二TCR-TM的第二TCRD,其中TCRM有助于至少一种TCR相关信号传导分子的募集;b)嵌合刺激受体(CSR),其包含i)能够结合目标配体或与目标配体相互作用的配体结合模块,ii)跨膜模块,及iii)能够提供共刺激信号至免疫细胞的共刺激免疫细胞信号传导模块,其中配体结合模块及共刺激免疫细胞信号传导模块并非源于相同分子,且其中CSR缺乏功能性初级免疫细胞信号传导域;及c)人类c-Jun多肽。
在一个方面中,本公开提供一种减少经工程改造的免疫细胞(例如人类免疫细胞;T细胞;及人类T细胞)的耗竭的方法,其包含向经工程改造的免疫细胞中引入增加c-Jun在细胞中的表达的外源核酸分子,其中经工程改造的免疫细胞包含一或多种表达构建体,该一或多种表达构建体包含用于表达以下的一或多种表达盒:a)caTCR,其包含i)特异性结合于目标抗原的抗原结合模块,及ii)TCRM(例如,源于人类γδTCR的TCRM),其包含:包含第一TCR-TM的第一TCRD及包含第二TCR-TM的第二TCRD,其中TCRM有助于至少一种TCR相关信号传导分子的募集;及b)CSR,其包含i)能够结合目标配体或与目标配体相互作用的配体结合模块,ii)跨膜模块,及iii)能够提供共刺激信号至免疫细胞的共刺激免疫细胞信号传导模块,其中配体结合模块及共刺激免疫细胞信号传导模块并非源于相同分子,且其中CSR缺乏功能性初级免疫细胞信号传导域。
在一些实施方案中,c-Jun为野生型人类c-Jun,其任选地包含SEQ ID NO:1。在其他实施方案中,c-Jun为突变人类c-Jun,其任选地在其反式活化域或δ域中包含失活突变。在特定实施方案中,与野生型c-Jun相比,所述c-Jun包含(i)S63A及S73A突变或(ii)残基2与102之间或残基30与50之间的缺失。
在一些实施方案中,CSR中的共刺激免疫细胞信号传导模块源于人类CD30且任选地包含SEQ ID NO:21。
在一些实施方案中,caTCR的目标抗原为与人类MHC I类分子复合的人类AFP肽。在特定实施方案中,目标抗原为与HLA-A2*02:01复合的AFP158。
在一些实施方案中,caTCR的抗原结合模块包含(i)免疫球蛋白(Ig)重链可变域(VH),其包含SEQ ID NO:2中的HCDR1-3;及(ii)Ig轻链可变域(VL),其包含SEQ ID NO:3中的LCDR1-3。在进一步的实施方案中,HCDR1-3分别包含SEQ ID NO:5-7,且LCDR1-3分别包含SEQ ID NO:9-11。在特定实施方案中,VH及VL分别包含SEQ ID NO:8及SEQ ID NO:12。在某些实施方案中,caTCR为异二聚体,其分别包含SEQ ID NO:2及SEQ ID NO:3。
在一些实施方案中,CSR的目标配体为人类磷脂肌醇蛋白聚醣3(glypican 3,GPC3)。在进一步的实施方案中,CSR包含(i)Ig VH,其包含SEQ ID NO:4中的HCDR1-3;及(ii)Ig VL,其包含SEQ ID NO:4中的LCDR1-3。在特定实施方案中,CSR中的HCDR1-3分别包含SEQ ID NO:13-15,且CSR中的LCDR1-3分别包含SEQ ID NO:17-19。在某些实施方案中,CSR中的VH及VL分别包含SEQ ID NO:16及SEQ ID NO:20。在某些实施方案中,CSR包含SEQID NO:4。
在一些实施方案中,本文中的表达构建体为病毒载体,例如慢病毒载体、腺病毒载体、腺相关病毒载体、牛痘载体、单纯疱疹病毒载体及艾-巴二氏(Epstein-Barr)病毒载体。
在一些实施方案中,表达构建体包含用于表达异二聚caTCR、CSR及c-Jun的四顺反子表达盒。四顺反子表达构建体可包含用于表达以下的表达盒:a)caTCR,其包含i)特异性结合于与人类MHC I类分子复合的人类AFP肽(任选地与HLA-A2*02:01复合的AFP158)的抗原结合模块,及ii)源于人类γδTCR的TCRM;b)CSR,其包含i)配体结合模块,其能够与GPC3结合或相互作用,ii)跨膜模块,及iii)共刺激免疫细胞信号传导模块,其源于人类CD30的细胞内域;及c)人类c-Jun多肽。在一些实施方案中,表达盒包含SEQ ID NO:1的编码序列、SEQ ID NO:2及SEQ ID NO:3的编码序列及SEQ ID NO:4的编码序列,任选地其中编码序列在框内通过2A-编码序列或通过内部核糖体进入位点(IRES)分隔开。
本文中的表达构建体(例如,诸如慢病毒载体的病毒载体)可包含组成性或诱导性启动子,任选地,EF-1α启动子,任选地其中一个或多个表达构建体为慢病毒载体。
在一个方面中,本公开提供包含本文中的四顺反子表达构建体的重组病毒,任选地其中表达构建体为慢病毒载体。
在另一个方面中,本公开提供一种工程改造免疫细胞的方法,其包含:(a)提供起始细胞群体(例如,人类细胞群体);(b)将本文中的表达构建体或重组病毒引入起始细胞群体中;(c)任选地选择表达caTCR、CSR及c-Jun的细胞;及(d)自步骤(b)或(c)的细胞衍生经工程改造的免疫细胞。在一些实施方案中,起始细胞群体包含免疫细胞(例如,自体或同种异体T细胞)。在其他实施方案中,起始细胞群体包含富能(pluripotent)或多能(multipotent)细胞,且步骤(d)包含将步骤(b)或(c)的细胞分化成免疫细胞,任选地T细胞。
本公开亦提供包含本文中的表达构建体或病毒的人类和/或免疫细胞(例如,T细胞),以及通过本发明工程改造方法获得的细胞。在一些实施方案中,经工程改造的T细胞包含CD8+ T细胞。在一些实施方案中,相比于不过表达c-Jun的对应细胞,经工程改造的细胞表达更低水平(例如,少至少10%、20%、30%、40%、50%、60%或70%)的耗竭标志物(例如,为CD39、PD-1、TIM-3或LAG-3),且任选地其中耗竭标志物为CD39、PD-1、TIM-3或LAG-3。
本公开亦提供包含本文中的表达构建体、病毒或经工程改造的细胞,及医药学上可接受的载剂的医药组合物。
在另一个方面中,本公开提供一种杀灭目标细胞的方法,其包含使目标细胞与本文中的经工程改造的免疫细胞在允许通过该免疫细胞杀灭目标细胞的条件下接触,其中目标细胞表达目标抗原及目标配体,任选地,其中相比于不包含引起c-Jun过表达的外源核酸分子的对应免疫细胞,免疫细胞在与目标细胞接触时表达更低水平(例如,少至少10%、20%、30%、40%、50%、60%或70%)的耗竭标志物(例如,CD39、PD-1、TIM-3或LAG-3)。在一些实施方案中,免疫细胞为T细胞和/或目标细胞为癌细胞。在一些实施方案中,CSR中的共刺激免疫细胞信号传导模块源于人类CD30,且相比于经工程改造以表现其共刺激免疫细胞信号传导模块源于人类CD28的CSR的对应免疫细胞,免疫细胞表达更低水平(例如,少至少10%、20%、30%、40%、50%、60%或70%)的任选地选自CD39、PD-1、TIM-3及LAG-3的耗竭标志物。
在一个方面中,本公开提供一种治疗有需要的患者(例如,人类患者)的方法,其包含向患者施用本文中的人类细胞或医药组合物。患者可患有例如癌症或肿瘤(例如,实体肿瘤),诸如肝细胞癌或胃癌。
本公开亦提供本文中的表达构建体、病毒或经工程改造的细胞用于制造供治疗有需要的患者用的药剂的用途。进一步提供表达构建体、病毒、细胞或医药组合物在如本文所描述的治疗方法中用于治疗有需要的患者。
本发明的其他特征、目标及优势在以下发明详述中显而易见。然而,应理解,发明详述虽然指示本发明的实施方案及方面,但仅为了说明而非限制给出。对于熟习此项技术者而言,在本发明的范畴内的各种改变及修改将自发明详述变得显而易见。
附图简述
图1A为caTCR及CSR组合的示意性图示。
图1B为以下的示意性图示:(i)含有三顺反子表达盒的慢病毒载体(称为“构建体1”),该表达盒用于具有γδTCR模块的抗AFP嵌合抗体-TCR(caTCR)及含有CD30跨膜域及细胞内域的抗GPC3嵌合刺激受体(CSR);及(ii)含有编码两条caTCR链及CSR以及人类c-Jun的四顺反子表达盒的慢病毒载体(称为“构建体2”)。EF1a:EF1a启动子。
图1C为显示包含[或含有]慢病毒构建体的质粒的示意性图示。
图2显示比较表达AFP-caTCR、GPC3-CD30-CSR及c-Jun(+cJun)的原代T细胞与仅表达AFP-caTCR及GPC3-CD30-CSR但不表达c-Jun(-cJun)的原代T细胞的长期杀灭测定结果。在此测定中,以1:1的效靶比使用HepG2细胞作为目标细胞。通过FACS染色对T细胞进行计数,且通过使用结晶紫染料染色对HepG2细胞进行计数。E1至E5:依序第一至第五轮T细胞与HepG2细胞的接触(添加新鲜HepG2细胞)。各接触的四个数据点分别代表在各接触后第0天及第3、5及7天所获得的数据。
图3显示比较表达AFP-caTCR、GPC3-CD30-CSR及c-Jun(+cJun)的原代效应T细胞与仅表达AFP-caTCR及GPC3-CD30-CSR但不表达c-Jun(-cJun)的原代效应T细胞的短期(过夜)杀灭测定结果。HepG2细胞用作目标细胞,而SK-Hep-1细胞用作阴性对照物。效靶比为2:1。
图4显示在图3中所示的短期杀灭研究中T细胞的细胞因子IL-2、IFN-γ、TNF-α及GM-CSF分泌。“未刺激”对照:孔中仅T细胞(无目标细胞)。
图5A为显示如通过肿瘤体积减少所测量,c-Jun过表达增强“AFP-caTCR+GPC3-CD30-CSR”T细胞体内的效力的图。模拟组:注射未经转导的人类原代T细胞的动物。T细胞自健康人类供体1分离。
图5B为显示相比于不表达c-Jun的T细胞,在图5A的研究中表达c-Jun的T细胞未引起体重减轻的图。T细胞自供体1分离。
图6为显示注射源于额外人类供体的“AFP-caTCR+GPC3-CD30-CSR”T细胞的小鼠中c-Jun过表达的体内作用的图。T细胞自健康人类供体2分离。
图7A及图7B为显示当T细胞经工程改造以表现AFP-caTCR+GPC3-CD28-CSR构建体时,亦观测到体内c-Jun作用的图。在图7A,向动物注射500万个T细胞,而在图7B中,向动物注射250万个T细胞。T细胞自供体1分离。
发明详述
本申请提供经工程改造的人类细胞(例如,诸如T细胞的免疫细胞),其包含用于表达嵌合抗体-T细胞受体(caTCR)、嵌合刺激受体(CSR;本文中亦称为“嵌合信号传导受体”)及c-Jun蛋白的构建体。caTCR包含特异性结合于目标抗原的抗原结合模块及能够募集至少一种TCR相关信号传导分子的T细胞受体模块(TCRM)。CSR包含特异性结合于目标配体的配体结合域及能够提供刺激信号至免疫细胞的共刺激免疫细胞信号传导域,且不包含功能性初级T细胞信号传导序列。目标抗原及目标配体为在目标细胞(例如,病变细胞)的细胞表面上表达的不同或相同的蛋白或蛋白复合物。在一些实施方案中,目标抗原及目标配体为相同蛋白或蛋白复合物,但caTCR及CSR结合于相同蛋白或蛋白复合物上的不同区域。在一些实施方案中,目标抗原可为蛋白复合物,其包含肽及主要组织相容性复合体(MHC)蛋白,诸如由病变细胞表面上的MHC呈现的疾病相关抗原肽。该疾病可为例如胃癌或肝癌。caTCR通过控制TCR活化的天然存在的机制调节,而CSR增强由caTCR介导的免疫反应。c-Jun表达有助于通过例如缓解或防止T细胞耗竭来维持T细胞的活性状态。
本发明的经工程改造的免疫细胞(诸如T细胞)展现针对携带目标的肿瘤细胞的持续强力的细胞毒性。相比于不过表达c-Jun(例如,经由外源引入的c-Jun基因序列)的T细胞,本发明的经工程改造的T细胞展示较少的T细胞耗竭迹象。经工程改造的细胞可具有以下特征中的一或多者:(i)其随时间推移不具有增加的耗竭标志物PD-1、TIM-3、LAG-3和/或CD39的表达;(ii)具有降低的细胞凋亡速率;(iii)其维持包括分泌包括IL-2、TNF-α、INF-γ及GM-CSF的细胞因子的活性生物状态;(iv)其具有增加的记忆细胞形成和/或记忆标志物(例如CD62L)的维持;(v)其具有增强的细胞毒性;(vi)其展示提高的具有低表面抗原的肿瘤目标的识别;(vii)其具有增强的回应于抗原的增殖;(viii)在重复抗原刺激之后维持存活及功能性;及(ix)其展示提高的肿瘤浸润能力。
在一些实施方案中,CSR包含源于CD30(例如,人类CD30)的细胞内域的共刺激免疫细胞信号传导域。本发明人已意外地发现,c-Jun过表达显著减少经工程改造以表达caTCR(例如,针对AFP的caTCR)及基于CD30的CSR(例如,靶向GPC3的CSR)的T细胞中的耗竭。当CSR具有源于另一免疫细胞信号传导域(诸如源于CD28的免疫细胞信号传导域)的细胞内共刺激域时,未观测到此耗竭显著减少。
I.免疫细胞来源
本公开的经工程改造的免疫细胞的来源可为待治疗的患者(亦即,自体细胞)或来自并非待治疗的患者的供体(例如,同种异体细胞)。在一些实施方案中,经工程改造的免疫细胞为经工程改造的T细胞。本文中的经工程改造的T细胞可为CD4+CD8-(亦即,CD4单阳性)T细胞、CD4-CD8+(亦即,CD8单阳性)T细胞或CD4+CD8+(双阳性)T细胞。功能上,T细胞可为细胞毒性T细胞、辅助T细胞、自然杀伤T细胞、抑制T细胞或其混合物。待工程改造的T细胞可为自体或同种异体的。
包括原代T细胞的原代免疫细胞可获自许多组织来源,其包括外周血单核细胞(PBMC)、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、肋膜积液、脾脏组织和/或肿瘤组织。包括PBMC的白细胞可通过熟知技术(例如FICOLLTM分离及白细胞清除)自其他血液细胞分离。白细胞清除产物通常含有淋巴细胞(包括T细胞及B细胞)、单核球、粒细胞及其他有核白血球。T细胞进一步与其他白细胞分离,例如通过经由PERCOLLTM梯度进行离心或通过逆流式离心淘析分离。T细胞的特定亚群,诸如CD3+、CD25+、CD28+、CD4+、CD8+、CD45RA+、GITR+及CD45RO+ T细胞可通过正向或负向选择技术(例如,使用基于荧光或基于磁性的细胞分选)进一步分离。例如,T细胞可通过与多种可商购的抗体缀合珠粒中的任一者(诸如CELLectionTM、DETACHaBEADTM(Thermo Fisher)或/>细胞分离产品(MiltenyiBiotec))一起培育足以正向选择所要T细胞的时段来分离。
在一些情况下,自体T细胞直接在癌症治疗之后获自癌症患者。已观测到,在某些癌症治疗,尤其是损害免疫系统的癌症治疗之后,在治疗之后不久收集的T细胞的质量可具有提高的离体扩增和/或在离体工程改造之后移植的能力。
不管在基因修饰之前或之后,T细胞可一般使用如例如以下中所描述的方法活化及扩增:美国专利6,352,694;6,534,055;6,905,680;6,692,964;5,858,358;6,887,466;6,905,681;7,144,575;7,067,318;7,172,869;7,232,566;7,175,843;5,883,223;6,905,874;6,797,514;6,867,041;10,786,533;及美国专利公开案20060121005。一般而言,T细胞可通过与表面接触而在体外或离体扩增,该表面附接有刺激CD3/TCR复合物相关信号的试剂及刺激T细胞表面上的共刺激分子的配体。尤其,T细胞群体可诸如通过与抗CD3抗体或其抗原结合片段,或固定于表面上的抗CD3抗体接触,或通过与结合钙离子载体的蛋白激酶C活化因子(例如,苔藓抑素(bryostatin))接触而被刺激。对于T细胞表面上辅助分子的共刺激,可使用结合辅助分子的配体。例如,T细胞群体可与抗CD3抗体及抗CD28抗体在适于刺激T细胞增殖的条件下接触。为了刺激CD4+ T细胞或CD8+ T细胞的增殖,可采用抗CD3抗体及抗CD28抗体。
细胞培养条件可包括以下中的一或多者:特定培养基、温度、氧含量、二氧化碳含量、时间、试剂(例如营养素、氨基酸、抗生素、离子和/或刺激因子(诸如细胞因子、趋化因子、抗原、结合搭配物、融合蛋白、重组可溶性受体)),及任何其他经设计以活化细胞的试剂。在一些实施方案中,培养条件包括添加IL-2、IL-7和/或IL-15。
在一些实施方案中,待工程改造的细胞可为在工程改造之后分化为成熟T细胞的富能或多能细胞。这些非T细胞可为同种异体的,且可为例如人类胚胎干细胞、人类诱导富能干细胞或造血干细胞或祖细胞。为了易于描述,富能及多能细胞在本文中共同称为“祖细胞”。
在使用同种异体细胞的情况下,优选其经工程改造以减少移植物抗宿主排斥反应(例如,通过敲除内源性B2M和/或TRAC基因)。
II.免疫细胞或祖细胞的工程改造
如本文所用,术语“细胞工程改造”或“细胞修饰”(包括其衍生术语)系指细胞(例如本文所揭示的免疫细胞)的靶向修饰。在一些方面中,细胞工程改造包含病毒基因工程改造、非病毒基因工程改造、引入受体以实现肿瘤特异性靶向(例如,抗AFP caTCR及抗GPC3CSR)、引入改良T细胞功能的一或多种内源性基因、引入改良免疫细胞(例如T细胞)功能的一或多种合成基因(例如,编码c-Jun多肽的多核苷酸,从而使免疫细胞相比于未经修饰的对应细胞展现增加的c-Jun表达),或其任何组合。如本公开中其他地方所进一步描述,在一些方面中,细胞可经转录活化因子(例如,基于CRISPR/Cas系统的转录活化因子)工程改造或修饰,其中转录活化因子能够诱导和/或增加所关注的蛋白(例如c-Jun)的内源性表达。
在一些方面中,本文所描述的细胞已经用转录活化因子修饰,该转录活化因子能够诱导和/或增加所关注的蛋白(例如,c-Jun)在细胞中的内源性表达。如本文所用,术语“转录活化因子”指增加基因或一组基因的转录(例如,通过结合至核酸序列的增强子或启动子近端元件且从而诱导其转录)的蛋白。可与本公开一起使用的此类转录活化因子的非限制性实例包括:基于转录活化因子样效应物(TALE)的转录活化因子、基于锌指蛋白(ZFP)的转录活化因子、基于规律间隔重复短回文序列簇(CRISPR)/CRISPR相关蛋白(Cas)系统的转录活化因子、或其组合。参见例如Kabadi等人,Methods(2014)69(2):188-197,其以全文引用的方式并入本文中。
在一些方面中,本文所描述的细胞已经用基于CRISPR/Cas系统的转录活化因子(诸如CRISPR活化(CRISPRa))修饰。参见例如Nissim等人,Molecular Cell(2014)54(4):698-710;Perez-Pinera等人,Nat.Methods(2013)10(10):973-976;Maeder等人,Nat.Methods(2013)10(10):977-979;Cheng等人,Cell Res.(2013)23(10):1163-71;Farzadfard等人,ACS Synth.Biol.(2013)2(10):604-13;以上所有均以全文引用的方式并入本文中。CRISPRa为一种类型的CRISPR工具,其包含使用缺乏核酸内切酶活性但仍能够结合至其导引RNA及目标DNA核酸序列的经修饰的Cas蛋白。可用于本发明的此类经修饰的Cas蛋白的非限制性实例为本领域中已知的。参见例如Pandelakis等人,Cell Systems(2020)10(1):1-14,其以全文引用的方式并入本文中。在一些方面中,经修饰的Cas蛋白包含经修饰的Cas9蛋白(在本领域中亦称为“dCas9”)。在一些方面中,经修饰的Cas蛋白包含经修饰的Cas12a蛋白。在一些方面中,可用于本公开的经修饰Cas蛋白结合至导引多核苷酸(例如小导引RNA)(“经修饰的Cas-导引复合物”),其中导引多核苷酸包含与编码所关注的蛋白(例如c-Jun)的核酸序列的区域互补的识别序列。在某些方面中,导引多核苷酸包含与编码所关注的蛋白的内源性核酸序列的启动子区互补的识别序列。在一些方面中,一或多种转录活化因子附接至经修饰的Cas-导引复合物(例如,经修饰的Cas蛋白的N端和/或C端),使得当将经修饰的Cas-导引复合物引入至细胞中时,一或多种转录活化因子可结合至内源性基因的调节元件(例如启动子区)且藉此诱导和/或增加编码的蛋白(例如c-Jun)的表达。可使用的常见一般活化因子的说明性实例包括RNAP、VP16、VP64及p65的ω亚基(参见例如Kabadi及Gersbach,Methods(2014)69(2):188-97)。
在一些方面中,一或多种转录抑制因子(例如,克鲁珀相关盒域(Kruppel-associated box domain,KRAB))可附接至经修饰的Cas-导引复合物(例如,经修饰的Cas蛋白的N端和/或C端),使得当引入细胞中时,一或多种转录抑制因子可抑制或减少基因的转录,例如可干扰c-Jun的表达的那些基因(例如Bach2)。参见例如US20200030379A1及Yang等人,J Transl Med.(2021)19:459,其中的每一者以全文引用的方式并入本文中。在一些方面中,可用于本公开的经修饰Cas蛋白可附接至一或多种转录活化因子及一或多种转录抑制因子两者。
不受任一理论束缚,在一些方面中,使用此类经修饰的Cas蛋白可实现所关注的基因的条件性转录及表达。例如,在一些方面中,细胞(例如,T细胞)经修饰以包含与蛋白酶(例如,烟草蚀刻病毒(TEV))及靶向c-Jun的启动子区的单一导引RNA(sgRNA)连接的重组抗原受体(例如,抗AFP caTCR及抗GPC3 CSR)。在一些方面中,细胞经修饰以进一步包含用于活化T细胞的接头(LAT),其与经由接头(例如,TEV可裂解接头)附接至转录活化因子(例如,dCas9-VP64-p65-Rta转录活化因子(VPR))的经修饰Cas蛋白复合。在抗原受体活化下,经修饰的Cas蛋白经释放用于核定位且条件性地且可逆地诱导c-Jun的表达。参见例如Yang等人,J Immunother Cancer(2021)9(增刊2):A164,其以全文引用的方式并入本文中。
如熟习此项技术者将显而易见,在一些方面中,本文所描述的细胞已使用多种方法的组合修饰。例如,在一些方面中,细胞已经修饰以包含(i)编码一或多种蛋白(例如,抗AFP caTCR、抗GPC3 CSR及截短EGFR(EGFRt))的外源性核苷酸序列,及(ii)增加内源性蛋白(例如c-Jun)的表达的外源性转录活化因子(例如,CRISPRa)。在一些方面中,细胞已经修饰以包含(i)编码第一蛋白(例如,抗AFP caTCR)的外源性核苷酸序列,(ii)编码第二蛋白(例如,抗GPC3 CSR)的外源性核苷酸序列,及(iii)编码蛋白(例如,c-Jun蛋白)的外源性核苷酸序列。在一些方面中,经修饰的细胞可进一步包含编码第三蛋白(例如,EGFRt)的外源核苷酸序列。如本文所描述,在一些方面中,编码第一、第二及第三蛋白的外源性核苷酸序列可为单一多顺反子载体的部分。
除非另外指明,否则可使用本领域中已知的任何适合的方法将一或多种外源性核苷酸序列和/或转录活化因子引入至细胞中。用于向细胞递送一或多种外源性核苷酸序列的适合方法的非限制性实例包括:转染(亦称为转化及转导)、电穿孔、非病毒递送、病毒转导、脂质纳米粒子递送及其组合。
在一些方面中,细胞已经用转录活化因子(例如,基于CRISPR/Cas系统的转录活化因子,例如CRISPRa)修饰,使得内源性c-Jun蛋白的表达相比于尚未经转录活化因子修饰的相应细胞增加。
尽管本文所提供的某些揭示内容大体上关于修饰免疫细胞以包含编码c-Jun蛋白(野生型c-Jun或其变体)的外源性核苷酸序列,但本领域技术人员应显而易见,可使用其他适合方法诱导和/或增加细胞中的c-Jun蛋白表达(野生型或其变体)。例如,如本文所描述,在一些方面中,内源性c-Jun蛋白表达可通过转录活化因子(例如,CRISPRa)增加。除非另外指明,否则使用外源性核苷酸序列的本文所提供的揭示内容同样适用于本文所提供的诱导和/或增加细胞中的c-Jun蛋白表达的其他方法(例如,转录活化因子,例如CRISPRa)。
本文中的免疫细胞(例如,T细胞)或祖细胞可经工程改造以表达caTCR及CSR,且过表达c-Jun(例如,人类c-Jun)。caTCR可特异性结合于肿瘤细胞上的配体(例如,肿瘤抗原),且CSR可特异性结合于肿瘤细胞上相同或不同的配体。如本文所用,当结合的KD≤100nM(例如≤10nM或≤1nM)时,称受体(例如,caTCR或CSR)特异性结合于配体(例如,抗原)。KD结合亲和力常数可例如通过表面等离子体共振(使用例如BiacoreTM或OctetTM系统)测量。
A.caTCR
caTCR为经工程改造的构建体,其包含特异性结合于目标抗原的抗原结合模块及能够募集至少一种TCR相关信号传导分子的T细胞受体模块(TCRM)。抗原结合模块可源于免疫球蛋白或抗体的可变域。TCRM可包含:包含第一TCR跨膜域(TCR-TM)的第一TCR域(TCRD)及包含第二TCR-TM的第二TCRD,其中TCRM有助于至少一种TCR相关信号传导分子的募集。TCR相关信号传导分子指具有基于细胞质免疫受体酪氨酸的活化基序(ITAM)(其为TCR-CD3复合物的一部分)的分子。TCR相关信号传导分子包括CD3γε、CD3δε及ζζ(亦称为CD3ζ或CD3ζζ)。caTCR进一步包含稳定化模块,该稳定化模块包含第一稳定化域及第二稳定化域,且其中稳定化模块可为免疫球蛋白恒定域,例如选自下组:CH1-CL模块、CH2-CH2模块、CH3-CH3模块、CH4-CH4模块及TCR恒定区模块,诸如一对γ及δTCR恒定区。Ig恒定域可来自IgG重链同种型(例如,IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD)或轻链型(κ或λ轻链)中的任一者。
在一些实施方案中,caTCR为包含源于γδTCR的TCRM的经工程改造的构建体,其中γTCR链的可变域及恒定域被Ig可变域(VH)及Ig CH域(例如CH1)置换,而δTCR链的可变域及恒定域被Ig可变域(VL)及Ig CL域置换。在一些实施方案中,caTCR包含源于γδTCR的TCRM,其中δTCR链的可变域及恒定域被Ig VH及Ig CH域(例如CH1)置换,而γTCR链的可变域及恒定域被Ig VL及Ig CL域置换。将caTCR链二聚以形成由分别的恒定域所支撑的VH及VL形成的抗原结合域。TCR的细胞内部分仍能够募集一或多种CD3链以形成功能性TCR复合物(例如CD3δε、CD3γε及CD3ζζ)。本文所描述的caTCR缺乏功能性初级免疫细胞信号传导序列,诸如包含ITAM(例如CD3ζ的细胞内域)的功能性信号传导序列。在一些实施方案中,caTCR不具有任何初级免疫细胞信号传导序列。“功能性”初级免疫细胞信号传导序列为能够在以可操作方式偶联至适当受体(例如CD3ζ的细胞内域)时转导免疫细胞活化信号的序列。可包含初级免疫细胞信号传导序列的片段或变体的“非功能性”初级免疫细胞信号传导序列不能转导免疫细胞活化信号。
caTCR的抗原结合模块可结合于细胞表面抗原,该细胞表面抗原选自例如蛋白、碳水化合物及脂质。在一些实施方案中,细胞表面抗原为在病变细胞中表达的疾病相关抗原。在一些实施方案中,疾病为癌症且疾病相关抗原为癌细胞中表达的癌症相关抗原,例如癌蛋白。在一些实施方案中,疾病为病毒感染且疾病相关抗原为在感染细胞中表达的病毒相关抗原。
在一些实施方案中,caTCR特异性结合于选自CD19、CD20、CD22、CD47、GPC-3、ROR1、ROR2、BCMA、GPRC5D或FCRL5(包括其变体或突变体)的细胞表面抗原。
在一些实施方案中,抗原结合模块特异性结合包含肽及MHC蛋白的复合物。肽/MHC复合物包括例如表面呈现的复合物,其包含源于在病变细胞中表达的疾病相关抗原的肽及MHC蛋白。肽可源于例如WT-1、AFP、HPV16-E7、NY-ESO-1、PRAME、EBV-LMP2A、HIV-1、KRAS、组蛋白H3.3及PSA,包括其变体或突变体。特异性结合于包含肽及MHC蛋白的复合物有时称为“MHC受限结合”。MHC蛋白可为MHC I类蛋白,诸如HLA-A、HLA-B、HLA-C、HLA-E、HLA-F或HLA-G。在一些实施方案中,MHC I类蛋白为HLA-A01、HLA-A02、HLA-A03、HLA-A09、HLA-A10、HLA-A11、HLA-A19、HLA-A23、HLA-A24、HLA-A25、HLA-A26、HLA-A28、HLA-A29、HLA-A30、HLA-A31、HLA-A32、HLA-A33、HLA-A34、HLA-A36、HLA-A43、HLA-A66、HLA-A68、HLA-A69、HLA-A74或HLA-A80。在一些实施方案中,MHC I类蛋白为HLA-A02。在一些实施方案中,MHC I类蛋白为HLA-A*02:01-555中的任一者,诸如HLA-A*02:01、HLA-A*02:02、HLA-A*02:03、HLA-A*02:04、HLA-A*02:05、HLA-A*02:06、HLA-A*02:07、HLA-A*02:08、HLA-A*02:09、HLA-A*02:10、HLA-A*02:11、HLA-A*02:12、HLA-A*02:13、HLA-A*02:14、HLA-A*02:15、HLA-A*02:16、HLA-A*02:17、HLA-A*02:18、HLA-A*02:19、HLA-A*02:20、HLA-A*02:21、HLA-A*02:22或HLA-A*02:24。在一些实施方案中,MHC I类蛋白为HLA-A*02:01。
在一些实施方案中,caTCR包含特异性结合于复合物的抗原结合模块,该复合物包含源于疾病相关抗原(诸如肿瘤相关或病毒编码抗原)的肽及MHC II类蛋白,其中MHC II类蛋白为HLA-DP、HLA-DQ或HLA-DR。在一些实施方案中,MHC II类蛋白为HLA-DP。在一些实施方案中,MHC II类蛋白为HLA-DQ。在一些实施方案中,MHC II类蛋白为HLA-DR。
在特定实施方案中,caTCR特异性结合于包含α-胎蛋白(AFP)肽及主要组织相容性复合体(MHC)I类蛋白的复合物。此类caTCR称为抗AFP caTCR或抗AFP/MHC caTCR。在某些实施方案中,caTCR特异性结合于人类AFP的肽片段AFP158肽(FMNKFIYEI;SEQ ID NO:22),其与MHC I的HLA-A*02血清型复合(亦称为“通过其呈递”)。在某些实施方案中,HLA-A*02具有亚型HLA-A*02:01、HLA-A*02:02、HLA-A*02:03、HLA-A*02:05、HLA-A*02:06、HLA-A*02:07或HLA-A*02:11。例如,抗AFP caTCR具有图1A中所示的结构,其中AFP-结合域由结合于由HLA-A*02:01呈现的AFP158肽的人类抗体的重链及轻链可变域(VH及VL)形成。亦参见WO 2016/161390。在caTCR中,Ig VH及VL域分别置换人类γδTCR的δ及γ链的可变域;且人类IgG1CH1恒定域及人类Igκ恒定域分别置换人类γδTCR的δ及γ链的恒定域。
在某些实施方案中,caTCR的δ链为抗AFP158/HLA-A*02:01-caTCR-1-0δ且具有以下氨基酸序列,其中Ig VH域带下划线且为粗体字,例示性HCDR呈斜体,IgG1 CH1域带双下划线,TCRδ细胞内尾区带点式下划线,且TCRδ跨膜域加框:
在这样的某些实施方案中,caTCR的γ链为抗AFP158/HLA-A*02:01-caTCR-1-0γ且具有以下氨基酸序列,其中IgVL域带下划线且为粗体字,例示性LCDR呈斜体,IgκCL域带双下划线,TCRγ细胞外茎区(stem region)带点式下划线,TCRγ跨膜域加框,且TCRγ细胞内域带单下划线:
caTCR链的前体可含有信号肽,诸如源于例如鼠类或人类来源的免疫球蛋白κ轻链信号肽。
亦可使用作为以上多肽序列的变体的caTCR链,只要其可结合AFP158/HLA-A2复合物且充当嵌合TCR,例如其可募集至少一种TCR相关信号传导分子,诸如CD3δ、CD3γ、CD3ε及CD3ζ链,其可为细胞内源性的或外源性地引入至细胞中。
在一些实施方案中,本公开的caTCR包含SEQ ID NO:2及SEQ ID NO:3中的互补决定区(CDR;例如所有六个CDR)。CDR的定界可根据熟知系统中的一者进行。参见例如Kabat等人,J Biol Chem.(1977)252:6609-16(1977);Kabat等人,美国卫生与公众服务部(U.S.Dept.of Health and Human Services),「Sequences of proteins ofimmunological interest」(1991);Chothia等人,J Mol Biol.(1987)196:901-17;Al-Lazikani等人,J Mol Biol.(1997)273:927-48;MacCallum等人,J Mol Biol.(1996)262:732-45;Abhinandan及Martin,Mol Immunol.(2008)45:3832-9(2008);Lefranc等人,DevComp Immunol.(2003)27:55-77(“IMGT”);及Honegger及Pliickthun,J Mol Biol.(2001)(“AHo”)。涵盖如上文所引用的参考文献中的每一者所定义的CDR的氨基酸残基阐述于下表1中作为比较。CDR预测算法及接口为本领域中已知的,包括例如Abhinandan及Martin,2008,见上文;Ehrenmann等人,Nucleic Acids Res.(2010)38:D301-D307;及Adolf-Bryfogle等人,Nucleic Acids Res.(2015)43:D432-D438。在特定实施方案中,caTCR包含分别包含SEQ ID NO:5-7的HCDR1-3及分别包含SEQ ID NO:9-11的LCDR1-3。
表1
CDR | Kabat | Chothia | MacCallum | IMGT | AHo |
HCDR1 | 31-35 | 26-32 | 30-35 | 27-38 | 25-40 |
HCDR2 | 50-65 | 53-55 | 47-58 | 56-65 | 58-77 |
HCDR3 | 95-102 | 96-101 | 93-101 | 105-117 | 109-137 |
LCDR1 | 24-34 | 26-32 | 30-36 | 27-38 | 25-40 |
LCDR2 | 50-56 | 50-52 | 46-55 | 56-65 | 58-77 |
LCDR3 | 89-97 | 91-96 | 89-96 | 105-117 | 109-137 |
在一些实施方案中,本公开的caTCR分别包含SEQ ID NO:2及SEQ ID NO:3中的VH及VL序列(SEQ ID NO:8及SEQ ID NO:12)。
B.CSR
CSR特异性结合于目标配体(诸如细胞表面抗原或肽/MHC复合体)且能够在目标配体结合下刺激其功能性表达于表面上的免疫细胞。CSR包含提供配体结合特异性的配体结合模块、跨膜模块及实现刺激免疫细胞的共刺激免疫细胞信号传导模块。CSR缺乏功能性初级免疫细胞信号传导序列。
在一些实施方案中,目标配体为疾病相关配体,诸如癌症相关配体或病原体相关配体(例如,病毒相关配体)。在一些实施方案中,目标配体为免疫调节分子,例如免疫抑制受体,在此情况下CSR可包含免疫抑制受体的拮抗剂或激动剂的片段。在一些实施方案中,目标配体为免疫检查点分子、抑制性细胞因子或细胞凋亡分子。
在一些实施方案中,CSR中的配体结合模块为抗体部分。在一些实施方案中,配体结合模块源于受体的细胞外域。
目标配体可为细胞表面抗原或肽/MHC复合体。在一些实施方案中,目标配体与表达于相同免疫细胞中的caTCR的目标抗原相同或不同。例如,caTCR的目标抗原为呈现于癌细胞上的癌症相关抗原,且目标配体为表达于癌细胞表面上的普遍存在的分子,诸如整联蛋白。在一些实施方案中,目标配体为疾病相关配体,例如癌症相关配体,诸如CD19、CD20、CD22、CD47、IL4、GPC-3、ROR1、ROR2、BCMA、GPRC5D或FCRL5。在一些实施方案中,癌症相关配体为肽/MHC复合体,其包含源于包括WT-1、AFP、HPV16-E7、NY-ESO-1、PRAME、EBV-LMP2A及PSA的蛋白的肽。在一些实施方案中,目标配体为病毒相关配体。在一些实施方案中,目标配体为免疫检查点分子,诸如PD-L1、PD-L2、CD80、CD86、ICOSL、B7-H3、B7-H4、HVEM、4-1BBL、OX40L、CD70、CD40及GAL9。在一些实施方案中,目标配体为细胞凋亡分子,诸如FasL、FasR、TNFR1及TNFR2。在一些实施方案中,配体结合模块为(或源于)目标配体的受体的细胞外域的全部或部分。在一些实施方案中,受体包括例如FasR、TNFR1、TNFR2、PD-1、CD28、CTLA-4、ICOS、BTLA、KIR、LAG-3、4-1BB、OX40、CD27及TIM-3。
在一些实施方案中,跨膜域包含源于跨膜蛋白的跨膜域,该跨膜蛋白包括例如CD28、CD3.ε、CD3.ζ、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154。在一些实施方案中,CSR包含跨膜蛋白的片段(fTMP)。
在一些实施方案中,共刺激信号传导域包含免疫细胞共刺激分子的细胞内域的全部或部分、基本上由其组成或由其组成,该分子包括例如CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3、与CD83特异性结合的配体等等。
用于本发明的CSR的共刺激免疫细胞信号传导域的实例包括T细胞受体(TCR)的共受体的细胞质序列,其可与caTCR协同作用以在caTCR接触之后起始信号转导;以及这些序列的任何衍生物或变体及具有相同功能能力的任何合成序列。在一些情形下,经由TCR单独产生的信号不足以完全活化T细胞且亦需要二级或共刺激信号。因此,在一些实施方案中,T细胞活化系由两种相异类别的细胞内信号传导序列介导:经由TCR起始抗原依赖性初级活化的那些序列(在本文中称为“初级T细胞信号传导序列”)及以抗原非依赖性方式作用以提供二级或共刺激信号的那些序列(在本文中称为“共刺激T细胞信号传导序列”)。
以刺激方式作用的初级免疫细胞信号传导序列可含有信号传导基序,其称为基于免疫受体酪氨酸的活化基序或ITAM。含ITAM的初级免疫细胞信号传导序列的实例包括源于CD3ζ、CD3γ、CD3δ、CD3ε、FcRγ、FcRβ、CD5、CD22、CD79a、CD79b及CD66d的那些序列。“功能性”初级免疫细胞信号传导序列为能够在以可操作方式偶联至适当受体时转导免疫细胞活化信号的序列。可包含初级免疫细胞信号传导序列的片段或变体的“非功能性”初级免疫细胞信号传导序列不能转导免疫细胞活化信号。本文所描述的CSR缺乏功能性初级免疫细胞信号传导序列,诸如包含ITAM(例如CD3ζ的细胞内域)的功能性信号传导序列。在一些实施方案中,CSR不具有任何初级免疫细胞信号传导序列。
在一些实施方案中,CSR可含有源于来自CD30(诸如人类CD30)的细胞内域的共刺激域。在一些实施方案中,CD30共刺激域包含SEQ ID NO:21或其功能等效物(例如与SEQ IDNO:21至少90%、95%、98%或99%同源的序列)。CSR可具有源于CD30、CD8、CD28、41-BB、CD27、OX40或另一细胞表面蛋白的跨膜域的跨膜域。
在其他实施方案中,CSR特异性结合于人类磷脂肌醇蛋白聚醣-3(GPC3)且含有人类CD30共刺激域。例如,具有人类CD30共刺激域的抗GPC3 CSR为抗GPC3 scFv CSR7且具有以下序列,其中人类抗GPC3scFv的Ig VL及VH域分别呈斜体且为粗体字,例示性LCDR及HCDR带点式下划线,肽接头加框,CD30序列(表示人类CD30的215至484的氨基酸残基)带下划线,且myc标签带双下划线:
亦可使用以上多肽序列的变体,只要其可以结合GPC3且如CD30提供共刺激即可。
在一些实施方案中,本公开的CSR包含SEQ ID NO:4中的CDR,例如所有六个CDR。CDR的定界可根据如上文所揭示的熟知系统中的一者进行。在一些实施方案中,CSR包含分别包含SEQ ID NO:13-15的HCDR1-3及分别包含SEQ ID NO:17-19的LCDR1-3。
在一些实施方案中,CSR包含SEQ ID NO:4中的VH及VL序列(SEQ ID NO:16及SEQ IDNO:20)。
C.c-Jun
在一些实施方案中,c-Jun为人类c-Jun,诸如具有以下序列的野生型人类c-Jun(可在GenBank以登录号AAA59197.1或在UniProtKB以登录号P05412.2获得)。
亦参见Hattori等人,PNAS(1988)85:9148-52。替代地,c-Jun为突变人类c-Jun,只要突变c-Jun不影响突变体补救异常(耗竭)T细胞的能力即可。在一些实施方案中,突变c-Jun包含与野生型c-Jun的C末端氨基酸残基(例如,C末端50、75、100、150、200或250或更多个残基)、C末端部分(例如,四分之一、三分之一或二分之一)或C末端域(例如ε、bZIP及其C末端氨基酸)至少70%(例如,至少75%、80%、85%、90%、95%或99%)的序列同一性。在一些实施方案中,野生型c-Jun的N末端氨基酸残基(例如,N末端50、75、100或150或更多个)、N末端部分(例如,四分之一、三分之一或二分之一)或N末端域(例如,δ、反式活化域及其N末端氨基酸)为缺失、突变或另外失活的。
在一些实施方案中,c-Jun在其反式活化域和/或其δ域中包含失活突变(例如,取代、缺失或插入)。在一些实施方案中,c-Jun包含S63A及S73A突变中的一或两者(位置为上文加框处)。在一些实施方案中,相比于野生型人类c-Jun,c-Jun在残基2与102之间或在残基30与50之间具有缺失。
归因于引入外源引入的c-Jun编码序列,经工程改造的T细胞过表达c-Jun,亦即表达的c-Jun水平高于不具有这种序列的T细胞(例如,多至少10%、20%、30%、40%、50%、60%、70%、80%、90%或100%,或多至少2、3、4、5或10倍)。
在某些实施方案中,caTCR和/或CSR和/或c-Jun多肽进一步包含可供用于各种用途目的的亲和力或纯化标签;例如,其可用于增强目标多肽的纯化效率。在一个实施方案中,标签为myc、HIS或HA标签。
在一些实施方案中,如上文所描述,本文中的免疫细胞经工程改造以经由细胞中的内源性c-Jun基因的活化而过表达c-Jun。
D.核酸
caTCR、CSR及c-Jun可经由一或多种核酸分子(例如,DNA或RNA,诸如mRNA)引入至T细胞或祖细胞中。在一些实施方案中,核酸分子可置于一或多种DNA或RNA载体上以引入宿主细胞中。
核酸分子(例如,含有其的DNA或RNA载体)可通过熟知技术引入至细胞中,该等技术包括但不限于电穿孔、磷酸钙沈淀、脂质转染、粒子轰击、显微注射、胶体分散系统(例如,作为大分子复合物、纳米胶囊、微球体及珠粒)及基于脂质的系统(例如,水包油乳液、微团、混合微团及脂质体)。替代地,核酸分子可通过重组病毒的转导引入至细胞中,该重组病毒的基因组包含该核酸分子。病毒载体的实例包括但不限于衍生自慢病毒、反转录病毒、腺病毒、腺相关病毒、单纯疱疹病毒、仙台病毒(Sendai virus)及牛痘病毒的载体。
在一些实施方案中,caTCR、CSR及c-Jun的两条多肽链的编码序列可置于单一表达构建体上。四种编码序列可置于构建体上的一或多个表达盒中,各盒为其自身的转录单元(例如,具有其自身的启动子及聚腺苷酸化位点及其他转录控制元件)。在特定实施方案中,四种编码序列可置于单一表达盒(例如四顺反子表达盒)中,其中四种编码序列在共同启动子下转录。在多顺反子排列中,编码序列同框且通过自裂解肽(例如,2A自裂解肽,诸如T2A、P2A、E2A或F2A肽)的编码序列彼此分隔开。替代地,编码序列可通过核糖体内部进入位点(IRES)彼此分隔开。因此,多顺反子(例如四顺反子)表达盒转录成单一RNA,但最终单一RNA加工且翻译成分别的多肽。
表达盒(多顺反子或单顺反子)可含有在哺乳动物(例如,人类或人类T)细胞中具有组成性活性的启动子。此类启动子包括但不限于即刻早期巨细胞病毒(CMV)启动子、猿猴病毒40(SV40)早期启动子、人类免疫缺陷病毒(HIV)长末端重复序列(LTR)启动子、艾-巴二氏病毒即刻早期启动子、劳斯氏肉瘤病毒(Rous sarcoma virus)启动子、伸长因子-1α(EF-1α)启动子、MND启动子、肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子及肌酸激酶启动子。亦考虑源于前述启动子的核心或最小启动子。替代地,表达盒可包含诱导性启动子系统。例示性的诱导性启动子系统包括但不限于激素调节的元件、合成配体调节的元件、电离辐射调节的元件、四环素(Tet)系统(例如,“Tet-Off”及“Tet-On”系统)及NFAT系统(参见例如Kallunki等人,Cells(2019)8(8):796;Uchibori等人,Mol TherOncolytics.(2018)12:16-25)。
在一些实施方案中,表达盒亦包括Kozak序列、聚腺苷酸化位点及有助于编码序列的转录和/或翻译的其他元件。例如,土拨鼠肝炎病毒转录后应答元件(WPRE)或其变体可包括在表达盒的3'不翻译区域处。
在表达盒中,转录/翻译调节元件,诸如启动子、任何增强子及其类似物可操作地连接于编码序列,以便实现编码序列的有效表达及RNA转录物的有效翻译。
在某些实施方案中,本公开提供包含四顺反子表达盒的单一载体构建体(例如慢病毒载体),其包含哺乳动物启动子、c-Jun编码序列、两条caTCR链的编码序列、CSR的编码序列及聚腺苷酸化信号序列。编码序列系通过核苷酸接头连接,该核苷酸接头可为IRES或自裂解肽(例如,P2A、T2A、E2A、F2A或其功能性等效物)的编码序列。藉助于实例,图1B绘示此类表达盒,其中启动子为EF-1α启动子。在其他实施方案中,caTCR结合于由HLA-A2呈现的AFP肽,CSR结合于GPC3且含有CD30共刺激域,且c-Jun为人类c-Jun。
在特定实施方案中,表达盒编码包含SEQ ID NO:1的c-Jun、包含分别包含SEQ IDNO:2及SEQ ID NO:3的两条多肽链的caTCR及包含SEQ ID NO:4的CSR。构建体可为重组慢病毒载体且可进一步包含在EF-1α启动子上游的中心多嘌呤区(central polypurine tract,cPPT),及CSR编码序列与SV40 EEL聚腺苷酸化信号之间的WPRE序列(参见例如图1C)或用于在哺乳动物细胞中有效转导及表达的其他序列。
表达盒中的编码序列可经密码子优化以获得所关注的宿主细胞(例如,人类细胞)中的最佳表达水平。
编码caTCR、CSR及c-Jun的核酸分子可整合至经工程改造的细胞的基因组中,或保持游离。整合可为经由基因编辑进行的靶向整合(例如,由CRISPR、TALEN、锌指核酸酶及巨核酸酶介导)。
经工程改造的细胞可通过正向选择技术富集。例如,细胞可在例如流式细胞术测定中针对其结合于目标抗原(AFP或AFP158/HLA-A2)和/或GPC3的能力来选择。为证实c-Jun表达,可对经工程改造的T细胞进行RT-PCT。正向选择可引起细胞群体中caTCR+CSR+c-Jun+细胞的富集,其中三阳性T细胞构成总细胞群体的超过30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或95%。可冷冻保存经工程改造的细胞直至使用。
III.医药组合物及用途
本公开提供包含本文所描述的经工程改造的T细胞的医药组合物。医药组合物可包含医药学上可接受的载剂,其适合于在引入患者体内之前维持细胞健康。
在一些实施方案中,经工程改造的细胞可自培养基收集,且洗涤及以治疗有效量浓缩至载剂中。例示性载剂包括盐水、缓冲盐水(例如磷酸盐缓冲盐水)、生理盐水、水、汉克氏溶液(Hanks'solution)、林格氏溶液(Ringer's solution)、Nonnosol-R(Abbott Labs)、Plasma-Lyte A(R)(Baxter Laboratories公司,Morton Grove,IL)、甘油、乙醇及其组合。优选地,载剂为等张的。在一些实施方案中,载剂可补充有成分,诸如人类血清白蛋白(HSA)或其他人类血清组分、5%葡萄糖或右旋糖。另外的等张剂包括多元糖醇,其包括三元或更高级糖醇,亦可包括诸如甘油、赤藻糖醇、阿拉伯糖醇(arabitol)、木糖醇(xylitol)、山梨糖醇或甘露糖醇。
可以治疗有效量向癌症患者全身性施用(例如,经由静脉内或门静脉注射)或局部施用(例如,经由瘤内注射)医药T细胞组合物。在一些实施方案中,使用诸如靶向AFP的组合物治疗患有肝细胞癌(HCC)、胃癌、胰脏癌或生殖系统中的癌症的患者(参见例如Wang及Wang,Canadian J Gastroent Hep.(2018)文章9049252)。如本文所用,术语“治疗”或“处理”指在所治疗的受试者中获得有益或所要结果的方法。此类结果包括但不限于:缓解由疾病(例如,HCC)引起的一或多种症状、降低疾病程度(例如,减小肿瘤体积)、使疾病稳定化(例如,预防或推迟疾病恶化)、预防或推迟疾病扩散(例如,转移)、预防或推迟疾病反复或复发、改善疾病状态、提供疾病的缓和(部分或全部)、减少治疗疾病所需要的一或多种其他药品的剂量、提高生活质量、恢复体重和/或延长存活(例如总存活或无进展存活)。
组合物的治疗有效量指足以实现所要临床终点的经工程改造的T细胞的数目。在一些实施方案中,治疗有效量含有超过104、105、106、107、108或109个经工程改造的细胞。
在一些实施方案中,医药组合物包含可有效治疗或预防疾病或病状的量(诸如治疗有效或预防有效量)的细胞。在一些实施方案中,治疗或预防功效是通过定期评估所治疗的受试者来监测的。对于历经数日或更长时间的重复施用,视病状而定,重复治疗直至出现疾病症状的所要抑制为止。然而,其他给药方案可为有用的且可加以确定。所要剂量可通过单次推注施用组合物、通过多次推注施用组合物或通过连续输注施用组合物来递送。
在某些实施方案中,向受试者施用约一百万个至约1000亿个范围内的细胞,诸如100万个至约500亿个细胞(例如,约500万个细胞、约2500万个细胞、约5亿个细胞、约10亿个细胞、约50亿个细胞、约200亿个细胞、约300亿个细胞、约400亿个细胞或由前述值中的任两者定义的范围);诸如约1000万至约1000亿个细胞(例如,约2000万个细胞、约3000万个细胞、约4000万个细胞、约6000万个细胞、约7000万个细胞、约8000万个细胞、约9000万个细胞、约100亿个细胞、约250亿个细胞、约500亿个细胞、约750亿个细胞、约900亿个细胞或由前述值中的任两者定义的范围);且在一些情况下,约1亿个细胞至约500亿个细胞(例如,约1.2亿个细胞、约2.5亿个细胞、约3.5亿个细胞、约4.5亿个细胞、约6.5亿个细胞、约8亿个细胞、约9亿个细胞、约30亿个细胞、约300亿个细胞、约450亿个细胞)或介于这些范围之间的任何值。
在一些实施方案中,细胞及组合物系使用标准施用技术、配制剂和/或装置施用。提供配制剂及用于储存及施用组合物的装置,诸如注射器及小瓶。施用可为自体或异源的。例如,免疫应答性细胞或祖细胞可自一个受试者获得且向同一受试者或不同的相容受试者施用。源于外周血的免疫应答性细胞或其后代(例如,体内、离体或体外衍生)可经由局部注射施用,其包括导管施用、全身性注射、局部注射、静脉内注射或胃肠外施用。当施用本公开的治疗性组合物(例如,含有经基因修饰的细胞的医药组合物)时,其将一般配制成单位剂量可注射形式(溶液、悬浮液、乳液)。
在一个方面中,本公开提供医药组合物,其包含用于表达caTCR、CSR及c-Jun的核酸分子。核酸分子可如上文所描述,诸如上文所描述的病毒载体(例如,慢病毒载体)。离体使用医药组合物以工程改造T细胞或祖细胞,随后将其引入至患者中。医药组合物包含核酸分子或重组病毒,其基因组包含caTCR、CSR及c-Jun的表达盒以及医药学上可接受的载剂(诸如缓冲溶液),该载剂任选地包含其他试剂,诸如防腐剂、稳定剂及其类似物。
医药组合物可提供为诸如试剂盒的制品,其包括包含生物材料(细胞或核酸分子或重组病毒)的小瓶(例如,单剂量小瓶)及任选地使用说明书。
除非本文中另外定义,否则结合本公开使用的科学与技术术语应具有本领域普通技术人员通常所了解的含义。下文描述例示性方法及材料,但亦可在本公开的实践或测试中使用类似或等效于本文所描述者的方法及材料。在有矛盾的情况下,将以本说明书(包括定义)为准。一般而言,结合使用的命名法,及本文所描述的免疫学、医学、药物及医药化学以及细胞生物学的技术为本领域中熟知且常用的。此外,除非上下文另外要求,否则单数术语应包括复数且复数术语应包括单数。在整个本说明书及实施方案中,词组“具有”及“包含/包括”或诸如“具有(has/having)”或“包含(comprises/comprising)”的变化形式应理解为暗示包括所陈述整数或整数的组,但不排除任何其他整数或整数的组。本文所提及的所有出版物及其他参考文献均以全文引用的方式并入本文中。尽管本文中引用多个文件,但此引用并不构成此等文件中的任一者形成本领域中公共常识的一部分的承认。如本文所用,如应用于一或多个所关注值的术语“大致”或“约”指类似于所陈述参考值的值。在某些实施方案中,除非另外说明或另外自上下文显而易见,否则该术语指在陈述参考值任一方向上(大于或小于)10%、9%、8%、7%、6%、5%、4%、3%、2%、1%或更小范围内的值。
为了能更好地理解本发明,阐述以下实例。此等实例仅出于说明的目的,且不应理解为以任何方式限制本发明的范畴。
实施例
在描述于以下实施例中的研究中,细胞系HepG2(ATCC HB-8065)及SK-Hep-1(ATCCHTB-52)获自美国典型培养物中心(American Type Culture Collection)。HepG2为表达HLA-A2、AFP及GPC3的肝细胞癌细胞系。SK-HEP1为表达HLA-A2但不表达AFP或GPC3的肝腺癌细胞系。在37℃/5%CO2下,在补充有10%FBS及2mM谷氨酰胺的RPMI 1640或DMEM中培养细胞系。
构筑两种慢病毒载体。本文中称为“AFP-caTCR+GPC3-CD30-CSR”或“构建体1”的第一种慢病毒载体含有三顺反子表达盒,其编码AFP158/HLA-A*02:01特异性caTCR(SEQ IDNO:2及SEQ ID NO:3)及GPC3-CD30-CSR(SEQ ID NO:4)。本文中称为“c-Jun+AFP-caTCR+GPC3-CD30-CSR”或“构建体2”的第二种载体含有四顺反子表达盒,其编码caTCR、CSR及人类c-Jun(SEQ ID NO:1;置于caTCR及CSR编码序列的上游)。对于两种载体,表达盒在EF-1α启动子的转录控制下且不同多肽的编码序列通过2A肽(F2A或P2A)的编码序列而框内连接。重组病毒系通过使用已知慢病毒生产方案及包装系统用编码构建体的载体转染293T细胞而产生。
对于体外研究,原代人类T细胞用于在100U/ml的白介素-2(IL-2)存在下使用CD3/CD28珠粒(Invitrogen)刺激一天之后的慢病毒转导。将经浓缩的慢病毒施用于涂布有/>(Takara)的6孔板中的T细胞且培育96小时。转导效率通过流式细胞术,使用经生物素标记的AFP158/HLA-A*02:01四聚体(“AFP158四聚体”)与缀合PE的链霉抗生物素蛋白(streptavidin)来评估。对于抗GPC3 CSR,使用抗myc抗体。在第5天及其后每3或4天重复流式细胞术分析。
通过Cytox非放射性细胞毒性测定(Promega)分析肿瘤细胞毒性,该分析定量测量乳酸脱氢酶(LDH),一种在细胞溶解时释放的稳定胞溶质酶。CD3+ T细胞使用EasySepTM人类T细胞分离试剂盒(StemCell Technologies)由PBMC富集的全血制备,该试剂盒反向消耗表达CD14、CD16、CD19、CD20、CD36、CD56、CD66b、CD123及血型糖蛋白A的细胞。根据制造商的方案通过CD3/CD28/>(Invitrogen)活化及扩增人类T细胞。活化T细胞(ATC)在具有10%FBS加100U/ml IL-2的RPMI1640培养基中培养及维持,且在第7至14天使用。活化T细胞及目标细胞以各种效靶比(例如,2.5:1或5:1)共培养16小时且随后分析细胞毒性。
(自Invitrogen)购买与FITC或APC缀合的针对人类HLA-A02的单克隆抗体(克隆BB7.2)及其同种型对照物-与FITC或APC缀合的小鼠IgG2b;及针对人类或小鼠CD3的抗体、人类TCR的各种亚基、3xFLAG标签、HA标签、与PE或FITC缀合的山羊F(ab)2抗人类IgG,及荧光缀合的山羊F(ab')2抗小鼠免疫球蛋白。研发针对AFP158/HLA-A*02:01特异性抗体的抗独特型抗体且内部产生。使用BD FACSCanto IITM收集流式细胞术数据且使用FlowJo软件包分析。
对于体内研究,在已建立的HepG2肝癌异种移植模型中测试表达构建体1或构建体2的原代人类T细胞的抗肿瘤活性。在NSG小鼠的右侧腹皮下(s.c.)植入HepG2细胞。当肿瘤尺寸达至约200mm3时,向小鼠瘤内(i.t.)注射(1)5×106个未转导的供体匹配(模拟)的原代人类T细胞;(2)5×106个表达构建体1的原代人类T细胞;或(3)5×106个表达构建体2的原代人类T细胞(n=6只小鼠/组)。由小鼠中的T细胞输注产生的健康作用通过监测动物的总体外观、体重及不良反应的其他临床征象(包括体温过低、呼吸困难及后肢麻痹/无力)来评估。
实施例1:过表达c-Jun的抗AFP/MHC+GPC3 CSR T细胞的增强的长期效力及存活
此实施例描述一种研究,其评价c-Jun过表达对经工程改造以表达AFP-caTCR及GPC3-CD30-CSR的人类效应T细胞的细胞毒性及存活的影响。
自健康人类供体分离的原代T细胞用慢病毒构建体1或构建体2转导7至9天。基于AFP158四聚体染色将效应细胞标准化为30%caTCR+(使用未转导/模拟转导的T细胞,将所有效应细胞样品调整至T细胞的总数目中相同百分比的受体+(caTCR+或CAR+)细胞)。用于计数效应细胞的基于FACS的测定用于比较转导细胞的长期杀灭潜力。
用于细胞毒性测定的目标细胞为HepG2细胞(HLA-A2+AFP+GPC3+)。效靶比(E:T比率)为1:1。尤其,50,000个caTCR+ T细胞及50,000个HepG2细胞在各孔中在无细胞因子的RPMI+10%FBS中共同培育。细胞每7天用每孔100,000个HepG2细胞再挑战。细胞在第14天及第21天再挑战之前以1:3分割,且在第28天以1:6分割以降低E:T比率且使效应细胞应激。在各目标细胞接触之后,在选定日定量剩余目标细胞及caTCR+ T细胞的数目。长期杀灭结果(由相对于与经模拟转导的T细胞一起培育的目标细胞的剩余目标细胞的百分比表示)及T细胞存活结果示于图2中。图的左图区中的数据显示表达构建体1的T细胞及表达构建体2的T细胞均有效地介导杀灭几乎所有最初接触的目标细胞以及再挑战的目标细胞。但自第五轮接触(E5)开始,表达构建体2的T细胞相较于表达构建体1的T细胞杀灭的目标细胞多得多。图的右图区中的数据显示,尽管多轮添加目标细胞且不补充T细胞,但在目标细胞的第三及第四轮接触之后,表达构建体2的T细胞相较于表达构建体1的T细胞更好地存活及扩增。即使在第五轮目标细胞接触/添加之后,表达构建体2的T细胞仍比表达构建体1的T细胞存活得更佳。总之,这些结果显示c-Jun促进延长共表达AFP-caTCR及GPC3-CD30-CSR的T细胞的存活且维持其长期目标细胞杀灭能力。
实施例2:过表达c-Jun的抗AFP/MHC+GPC3 CSR T细胞的增强的短期效力
此实施例描述一种研究,其关于相比于表达构建体1的T细胞,表达构建体2的T细胞的短期杀灭效率。CD3+ T细胞使用人类T细胞分离试剂盒(StemCellTechnologies)由PBMC富集的全血制备且用CD3/CD28/>活化。如通过流式细胞术所测定,活化及扩增的细胞群体为>99%CD3+。原代T细胞经模拟转导(未添加DNA)或通过慢病毒构建体1或构建体2转导7至9天。通过用经PE标记的AFP158/HLA-A*02:01四聚体(“AFP158四聚体”)染色来测定转导效率。将T细胞标准化为30%caTCR+且在如上所描述的基于LDH的测定中测试其杀灭癌细胞的能力。活化T细胞及目标细胞HepG2以2:1的效靶比共培养。抗原阴性目标细胞SK-Hep-1用作阴性对照物,以确认不存在抗原非依赖性杀灭。如图3中所示,经构建体2转导的T细胞(+cJun)具有比经构建体1转导的对应T细胞(-cJun)高的体外肿瘤细胞杀灭功效。
实施例3:在与目标细胞共培养之后过表达c-Jun的抗AFP/MHC+GPC3CSR T细胞的表征
此实施例描述在与目标细胞共培养之后表达构建体2的T细胞的表征。使用Bio-Plex ProTM人类细胞因子8-Plex测定试剂盒(Bio-Rad)通过200系统(Bio-Rad)测量体外杀灭实验的上清液中所释放的细胞因子的浓度。数据显示当与HepG2目标细胞共培养时,表达构建体2的T细胞(+cJun)比表达构建体1的T细胞(-cJun)释放更多细胞因子,其包括IL-2、IFN-γ、TNF-α、GM-CSF(图4)。
为了检查在抗原刺激时表达于T细胞上的耗竭标志物的水平,如上文所描述制备CD3+ T细胞且用CD3/CD28活化。通过流式细胞术,活化及扩增的细胞群体为>99%CD3+。将T细胞用慢病毒构建体1或构建体2转导7至9天。基于AFP158四聚体染色,将效应细胞标准化为30%caTCR+。如实施例1中所描述培育T细胞且用HepG2细胞再挑战。caTCR+CD8+ T细胞上耗竭标志物CD39、PD-1、LAG-3及TIM-3的表达水平在各目标细胞接触之后在选定日通过流式细胞术分析/>CD39、PD-1、LAG-3及TIM-3为随T细胞失去功能而积聚于T细胞上的抑制性受体;因此,这些分子用作T细胞耗竭的标志物。相对于不表达c-Jun的T细胞,表达c-Jun的T细胞上耗竭标志物的表达水平(平均荧光强度)的差异倍数示于下表2中(E:与目标细胞接触;D:接触后的天数;n=2(供体1及供体2))。
表2具有CD28-CSR或CD30-CSR的T细胞中的耗竭标志物表达水平
如上文所示,在接触之前,两组T细胞展示类似水平的耗竭标志物(比率接近1)。在第五轮目标细胞接触之后七天,表达构建体2的T细胞展示耗竭标志物CD39、PD-1及TIM-3的水平为表达构建体1的T细胞上的水平的一半或低于一半。这些结果表明c-Jun的过表达产生在长期中显著更具功能性且耗竭较少的T细胞。
然而,经工程改造以表达相同caTCR及抗GPC3 CSR只不过CSR含有CD28而非CD30共刺激域的T细胞未观测到此效果。如上表2中所示,在E5D7,经CD28-CSR工程改造的T细胞展示相比于不表达c-Jun的T细胞,表达c-Jun的T细胞中的显著增加的耗竭标志物CD39、LAG-3及TIM-3。数据显示在表达抗AFP/MHC caTCR及抗GPC3-CD28-CSR的T细胞中,c-Jun过表达并不缓解T细胞耗竭。因此,结果表明c-Jun表达对缓解经工程改造以表达caTCR及基于CD30的CSR的T细胞中的T细胞耗竭产生尤其积极的影响。
另外,在各目标细胞接触之后,在选定日通过流式细胞术分析CD4或CD8单阳性及CD4/CD8双阳性caTCR+ T细胞的亚群。表3中的数据显示c-Jun过表达产生较高百分比的CD4-CD8+ T细胞(E:与目标细胞接触;D:接触后的天数)。
表3 HepG2目标细胞接触之后受体+ T细胞中CD4+和/或CD8+细胞的百分比
如上表中所示,在E5D7,CD8单阳性群体自总T细胞群体的60.3%扩增至总T细胞群体的79.9%。这些结果表明c-Jun表达促进CD8单阳性T细胞的优先扩增。
实施例4:过表达c-Jun的抗AFP/MHC+GPC3 CSR T细胞的体内功效研究
如上文所描述,评估表达构建体1或2的来自供体1的原代人类T细胞的体内细胞毒性效力。数据显示,c-Jun过表达显著增强了“AFP-caTCR+GPC3-CD30-CSR”T细胞的肿瘤杀灭潜力。在注射表达构建体2的T细胞(+cJun)后约第10天,肿瘤开始消退;约60至70天达成肿瘤完全消退(图5A)。相比之下,在注射表达构建体2的T细胞(-cJun)的动物中,肿瘤在约第40天复发(在初始下降后)且持续生长,在约第60天到达峰值(图5A)。数据亦显示注射表达构建体1的T细胞及表达构建体2的T细胞的动物的体重变化无显著差异,其表明过表达c-Jun的T细胞在动物中不产生更多不良作用(图5B)。
类似地,当经构建体2转导且在第17天给药时,自另一供体(供体2)获得的T细胞在整个研究期间防止肿瘤复发且维持肿瘤抑制(图6)。但经构建体1转导的T细胞未长期抑制肿瘤生长;其仅推迟了肿瘤生长(图6)。
有趣地,尽管不太明显,但亦在表达AFP-caTCR与GPC3-CD28-CSR的T细胞上观测到c-Jun的增强作用(图7A及图7B)。相比于GPC3-CD28 CSR,c-Jun对GPC3-CD30 CSR提供增加的益处。因此,似乎c-Jun过表达与AFP-caTCR背景中的CD30反式信号传导协同作用。
本公开的例示性序列提供于下表4中(SEQ:SEQ ID NO)。
表4
/>
/>
序列表
<110> LYELL IMMUNOPHARMA, INC.
EUREKA THERAPEUTICS, INC.
<120> 改良的免疫细胞疗法
<130> 026225.WO014
<140>
<141>
<150> 63/142,486
<151> 2021-01-27
<160> 22
<170> PatentIn version 3.5
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<211> 331
<212> PRT
<213> 人
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Met Thr Ala Lys Met Glu Thr Thr Phe Tyr Asp Asp Ala Leu Asn Ala
1 5 10 15
Ser Phe Leu Pro Ser Glu Ser Gly Pro Tyr Gly Tyr Ser Asn Pro Lys
20 25 30
Ile Leu Lys Gln Ser Met Thr Leu Asn Leu Ala Asp Pro Val Gly Ser
35 40 45
Leu Lys Pro His Leu Arg Ala Lys Asn Ser Asp Leu Leu Thr Ser Pro
50 55 60
Asp Val Gly Leu Leu Lys Leu Ala Ser Pro Glu Leu Glu Arg Leu Ile
65 70 75 80
Ile Gln Ser Ser Asn Gly His Ile Thr Thr Thr Pro Thr Pro Thr Gln
85 90 95
Phe Leu Cys Pro Lys Asn Val Thr Asp Glu Gln Glu Gly Phe Ala Glu
100 105 110
Gly Phe Val Arg Ala Leu Ala Glu Leu His Ser Gln Asn Thr Leu Pro
115 120 125
Ser Val Thr Ser Ala Ala Gln Pro Val Asn Gly Ala Gly Met Val Ala
130 135 140
Pro Ala Val Ala Ser Val Ala Gly Gly Ser Gly Ser Gly Gly Phe Ser
145 150 155 160
Ala Ser Leu His Ser Glu Pro Pro Val Tyr Ala Asn Leu Ser Asn Phe
165 170 175
Asn Pro Gly Ala Leu Ser Ser Gly Gly Gly Ala Pro Ser Tyr Gly Ala
180 185 190
Ala Gly Leu Ala Phe Pro Ala Gln Pro Gln Gln Gln Gln Gln Pro Pro
195 200 205
His His Leu Pro Gln Gln Met Pro Val Gln His Pro Arg Leu Gln Ala
210 215 220
Leu Lys Glu Glu Pro Gln Thr Val Pro Glu Met Pro Gly Glu Thr Pro
225 230 235 240
Pro Leu Ser Pro Ile Asp Met Glu Ser Gln Glu Arg Ile Lys Ala Glu
245 250 255
Arg Lys Arg Met Arg Asn Arg Ile Ala Ala Ser Lys Cys Arg Lys Arg
260 265 270
Lys Leu Glu Arg Ile Ala Arg Leu Glu Glu Lys Val Lys Thr Leu Lys
275 280 285
Ala Gln Asn Ser Glu Leu Ala Ser Thr Ala Asn Met Leu Arg Glu Gln
290 295 300
Val Ala Gln Leu Lys Gln Lys Val Met Asn His Val Asn Ser Gly Cys
305 310 315 320
Gln Leu Met Leu Thr Gln Gln Leu Gln Thr Phe
325 330
<210> 2
<211> 288
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
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Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Thr Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asn Tyr
20 25 30
Trp Ile Thr Trp Val Arg Gln Met Ser Gly Gly Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Gly Asp Ser Tyr Thr Thr Tyr Asn Pro Ser Phe
50 55 60
Gln Gly His Val Thr Ile Ser Ile Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu His Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Val Ser Leu Val Asp Ile Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Glu Val Lys Thr
210 215 220
Asp Ser Thr Asp His Val Lys Pro Lys Glu Thr Glu Asn Thr Lys Gln
225 230 235 240
Pro Ser Lys Ser Cys His Lys Pro Lys Ala Ile Val His Thr Glu Lys
245 250 255
Val Asn Met Met Ser Leu Thr Val Leu Gly Leu Arg Met Leu Phe Ala
260 265 270
Lys Thr Val Ala Val Asn Phe Leu Leu Thr Ala Lys Leu Phe Phe Leu
275 280 285
<210> 3
<211> 283
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
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<400> 3
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Glu Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Gly
85 90 95
Ser Arg Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser Pro Ile Lys Thr Asp Val Ile Thr
210 215 220
Met Asp Pro Lys Asp Asn Cys Ser Lys Asp Ala Asn Asp Thr Leu Leu
225 230 235 240
Leu Gln Leu Thr Asn Thr Ser Ala Tyr Tyr Met Tyr Leu Leu Leu Leu
245 250 255
Leu Lys Ser Val Val Tyr Phe Ala Ile Ile Thr Cys Cys Leu Leu Arg
260 265 270
Arg Thr Ala Phe Cys Cys Asn Gly Glu Lys Ser
275 280
<210> 4
<211> 535
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
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<400> 4
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp
20 25 30
Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu
85 90 95
Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser
100 105 110
Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
145 150 155 160
Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr
180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
195 200 205
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Gln Lys Leu Ile Ser
245 250 255
Glu Glu Asp Leu Ala Ala Ala Thr Gly Ala Pro Pro Leu Gly Thr Gln
260 265 270
Pro Asp Cys Asn Pro Thr Pro Glu Asn Gly Glu Ala Pro Ala Ser Thr
275 280 285
Ser Pro Thr Gln Ser Leu Leu Val Asp Ser Gln Ala Ser Lys Thr Leu
290 295 300
Pro Ile Pro Thr Ser Ala Pro Val Ala Leu Ser Ser Thr Gly Lys Pro
305 310 315 320
Val Leu Asp Ala Gly Pro Val Leu Phe Trp Val Ile Leu Val Leu Val
325 330 335
Val Val Val Gly Ser Ser Ala Phe Leu Leu Cys His Arg Arg Ala Cys
340 345 350
Arg Lys Arg Ile Arg Gln Lys Leu His Leu Cys Tyr Pro Val Gln Thr
355 360 365
Ser Gln Pro Lys Leu Glu Leu Val Asp Ser Arg Pro Arg Arg Ser Ser
370 375 380
Thr Gln Leu Arg Ser Gly Ala Ser Val Thr Glu Pro Val Ala Glu Glu
385 390 395 400
Arg Gly Leu Met Ser Gln Pro Leu Met Glu Thr Cys His Ser Val Gly
405 410 415
Ala Ala Tyr Leu Glu Ser Leu Pro Leu Gln Asp Ala Ser Pro Ala Gly
420 425 430
Gly Pro Ser Ser Pro Arg Asp Leu Pro Glu Pro Arg Val Ser Thr Glu
435 440 445
His Thr Asn Asn Lys Ile Glu Lys Ile Tyr Ile Met Lys Ala Asp Thr
450 455 460
Val Ile Val Gly Thr Val Lys Ala Glu Leu Pro Glu Gly Arg Gly Leu
465 470 475 480
Ala Gly Pro Ala Glu Pro Glu Leu Glu Glu Glu Leu Glu Ala Asp His
485 490 495
Thr Pro His Tyr Pro Glu Gln Glu Thr Glu Pro Pro Leu Gly Ser Cys
500 505 510
Ser Asp Val Met Leu Ser Val Glu Glu Glu Gly Lys Glu Asp Pro Leu
515 520 525
Pro Thr Ala Ala Ser Gly Lys
530 535
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<213> 人工序列
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<221> 来源
<223> /note="人工序列描述: 合成
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Gly Tyr Ser Phe Pro Asn Tyr Trp
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<213> 人工序列
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<221> 来源
<223> /note="人工序列描述: 合成
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Ile Asp Pro Gly Asp Ser Tyr Thr
1 5
<210> 7
<211> 10
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
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<400> 7
Ala Arg Tyr Tyr Val Ser Leu Val Asp Ile
1 5 10
<210> 8
<211> 117
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
多肽"
<400> 8
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Thr Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asn Tyr
20 25 30
Trp Ile Thr Trp Val Arg Gln Met Ser Gly Gly Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Gly Asp Ser Tyr Thr Thr Tyr Asn Pro Ser Phe
50 55 60
Gln Gly His Val Thr Ile Ser Ile Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu His Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Val Ser Leu Val Asp Ile Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 9
<211> 9
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 9
Ser Ser Asp Val Gly Gly Tyr Asn Tyr
1 5
<210> 10
<211> 3
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 10
Asp Val Asn
1
<210> 11
<211> 10
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 11
Ser Ser Tyr Thr Thr Gly Ser Arg Ala Val
1 5 10
<210> 12
<211> 110
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
多肽"
<400> 12
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Glu Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Gly
85 90 95
Ser Arg Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 13
<211> 8
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 13
Gly Phe Thr Phe Ser Ser Tyr Ala
1 5
<210> 14
<211> 8
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 14
Ile Tyr Ser Gly Gly Ser Ser Thr
1 5
<210> 15
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 15
Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr
1 5 10
<210> 16
<211> 118
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
多肽"
<400> 16
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 17
<211> 8
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 17
Arg Ser Asn Ile Gly Ser Asp Tyr
1 5
<210> 18
<211> 3
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 18
Gly Asp Asn
1
<210> 19
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
肽"
<400> 19
Gly Thr Trp Asp Tyr Thr Leu Asn Gly Val Val
1 5 10
<210> 20
<211> 111
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /note="人工序列描述: 合成
多肽"
<400> 20
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp
20 25 30
Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu
85 90 95
Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 21
<211> 270
<212> PRT
<213> 人
<400> 21
Ala Pro Pro Leu Gly Thr Gln Pro Asp Cys Asn Pro Thr Pro Glu Asn
1 5 10 15
Gly Glu Ala Pro Ala Ser Thr Ser Pro Thr Gln Ser Leu Leu Val Asp
20 25 30
Ser Gln Ala Ser Lys Thr Leu Pro Ile Pro Thr Ser Ala Pro Val Ala
35 40 45
Leu Ser Ser Thr Gly Lys Pro Val Leu Asp Ala Gly Pro Val Leu Phe
50 55 60
Trp Val Ile Leu Val Leu Val Val Val Val Gly Ser Ser Ala Phe Leu
65 70 75 80
Leu Cys His Arg Arg Ala Cys Arg Lys Arg Ile Arg Gln Lys Leu His
85 90 95
Leu Cys Tyr Pro Val Gln Thr Ser Gln Pro Lys Leu Glu Leu Val Asp
100 105 110
Ser Arg Pro Arg Arg Ser Ser Thr Gln Leu Arg Ser Gly Ala Ser Val
115 120 125
Thr Glu Pro Val Ala Glu Glu Arg Gly Leu Met Ser Gln Pro Leu Met
130 135 140
Glu Thr Cys His Ser Val Gly Ala Ala Tyr Leu Glu Ser Leu Pro Leu
145 150 155 160
Gln Asp Ala Ser Pro Ala Gly Gly Pro Ser Ser Pro Arg Asp Leu Pro
165 170 175
Glu Pro Arg Val Ser Thr Glu His Thr Asn Asn Lys Ile Glu Lys Ile
180 185 190
Tyr Ile Met Lys Ala Asp Thr Val Ile Val Gly Thr Val Lys Ala Glu
195 200 205
Leu Pro Glu Gly Arg Gly Leu Ala Gly Pro Ala Glu Pro Glu Leu Glu
210 215 220
Glu Glu Leu Glu Ala Asp His Thr Pro His Tyr Pro Glu Gln Glu Thr
225 230 235 240
Glu Pro Pro Leu Gly Ser Cys Ser Asp Val Met Leu Ser Val Glu Glu
245 250 255
Glu Gly Lys Glu Asp Pro Leu Pro Thr Ala Ala Ser Gly Lys
260 265 270
<210> 22
<211> 9
<212> PRT
<213> 人
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Phe Met Asn Lys Phe Ile Tyr Glu Ile
1 5
Claims (38)
1.一或多种表达构建体,其包含用于表达以下的一或多种表达盒:
a)嵌合抗体-T细胞受体(TCR)构建体(caTCR),其包含:
i)抗原结合模块,其特异性结合于目标抗原;及
ii)T细胞受体模块(TCRM),其包含:包含第一TCR跨膜域(TCR-TM)的第一TCR域(TCRD)及包含第二TCR-TM的第二TCRD,其中该TCRM有助于至少一种TCR相关信号传导分子的募集;
b)嵌合刺激受体(CSR),其包含:
i)配体结合模块,其能够与目标配体结合或相互作用;
ii)跨膜模块;及
iii)共刺激免疫细胞信号传导模块,其能够提供共刺激信号至免疫细胞,其中该配体结合模块及该共刺激免疫细胞信号传导模块非源于相同分子,且其中该CSR缺乏功能性初级免疫细胞信号传导域;及
c)人类c-Jun多肽。
2.一种减少经工程改造的免疫细胞的耗竭的方法,其包括向该经工程改造的免疫细胞中引入增加c-Jun在细胞中表达的外源核酸分子,其中该经工程改造的免疫细胞包含一或多种表达构建体,该一或多种表达构建体包含用于表达以下的一或多种表达盒:
a)嵌合抗体-T细胞受体(TCR)构建体(caTCR),其包含:
i)抗原结合模块,其特异性结合于目标抗原;及
ii)T细胞受体模块(TCRM),其包含:包含第一TCR跨膜域(TCR-TM)的第一TCR域(TCRD)及包含第二TCR-TM的第二TCRD,其中该TCRM有助于至少一种TCR相关信号传导分子的募集;及
b)嵌合刺激受体(CSR),其包含:
i)配体结合模块,其能够与目标配体结合或相互作用;
ii)跨膜模块;及
iii)共刺激免疫细胞信号传导模块,其能够提供共刺激信号至该免疫细胞,其中该配体结合模块及该共刺激免疫细胞信号传导模块非源于相同分子,且其中该CSR缺乏功能性初级免疫细胞信号传导域,
任选地其中该免疫细胞为T细胞。
3.如权利要求1或2的表达构建体或方法,其中该c-Jun为野生型人类c-Jun,其任选地包含SEQ ID NO:1。
4.如权利要求1或2的表达构建体或方法,其中该c-Jun为突变人类c-Jun,其任选地在其反式活化域或δ域中包含失活突变。
5.如权利要求4的表达构建体或方法,其中与野生型c-Jun相比,该c-Jun包含(i)S63A及S73A突变,或(ii)残基2与102之间或残基30与50之间的缺失。
6.如前述权利要求中任一项的表达构建体或方法,其中该共刺激免疫细胞信号传导模块源于人类CD30且任选地包含SEQ ID NO:21。
7.如前述权利要求中任一项的表达构建体或方法,其中该目标抗原为与人类MHCI类分子复合的人类AFP肽。
8.如权利要求7的表达构建体或方法,其中该目标抗原为与HLA-A2*02:01复合的AFP158。
9.如前述权利要求中任一项的表达构建体或方法,其中该TCRM源于人类γδTCR。
10.如前述权利要求中任一项的表达构建体或方法,其中该抗原结合模块包含(i)免疫球蛋白(Ig)重链可变域(VH),其包含SEQ ID NO:2中的HCDR1-3;及(ii)Ig轻链可变域(VL),其包含SEQ ID NO:3中的LCDR1-3。
11.如权利要求10的表达构建体或方法,其中该HCDR1-3分别包含SEQ ID NO:5-7,且该LCDR1-3分别包含SEQ ID NO:9-11。
12.如权利要求11的表达构建体或方法,其中该VH及该VL分别包含SEQ ID NO:8及SEQID NO:12。
13.如权利要求12的表达构建体或方法,其中该caTCR为异二聚体,其分别包含SEQ IDNO:2及SEQ ID NO:3。
14.如前述权利要求中任一项的表达构建体或方法,其中该目标配体为人类磷脂肌醇蛋白聚醣3(glypican 3,GPC3)。
15.如权利要求14的表达构建体或方法,其中该CSR包含(i)Ig VH,其包含SEQ ID NO:4中的HCDR1-3;及(ii)Ig VL,其包含SEQ ID NO:4中的LCDR1-3。
16.如权利要求15的表达构建体或方法,其中该CSR中的该HCDR1-3分别包含SEQ IDNO:13-15,且该CSR中的该LCDR1-3分别包含SEQ ID NO:17-19。
17.如权利要求16的表达构建体或方法,其中该CSR中的该VH及该VL分别包含SEQ IDNO:16及SEQ ID NO:20。
18.如权利要求17的表达构建体或方法,其中该CSR包含SEQ ID NO:4。
19.如前述权利要求中任一项的表达构建体或方法,其中该一或多种构建体为病毒载体,任选地选自慢病毒载体、腺病毒载体、腺相关病毒载体、牛痘载体、单纯疱疹病毒载体及艾-巴二氏(Epstein-Barr)病毒载体。
20.如前述权利要求中任一项的表达构建体或方法,其中该表达构建体包含用于表达该caTCR、该CSR及该c-Jun的四顺反子表达盒。
21.一种四顺反子表达构建体,其包含用于表达以下的表达盒:
a)嵌合抗体-T细胞受体(TCR)构建体(caTCR),其包含:
i)抗原结合模块,其特异性结合于与人类MHC I类分子的人类AFP肽复合物,任选地与HLA-A2*02:01复合的AFP158;及
ii)T细胞受体模块(TCRM),其源于人类γδTCR;
b)嵌合刺激受体(CSR),其包含:
i)配体结合模块,其能够与GPC3结合或相互作用;
ii)跨膜模块;及
iii)共刺激免疫细胞信号传导模块,其源于人类CD30的细胞内域;及
c)人类c-Jun多肽。
22.如权利要求21的表达构建体,其中该表达盒包含SEQ ID NO:1的编码序列、SEQ IDNO:2及SEQ ID NO:3的编码序列及SEQ ID NO:4的编码序列,任选地其中该编码序列是通过2A-编码序列或通过内部核糖体进入位点(IRES)以同框方式分隔开的。
23.如前述权利要求中任一项的表达构建体或方法,其中该一或多种表达盒包含组成性或诱导性启动子,任选地EF-1α启动子,任选地其中该一或多种表达构建体为慢病毒载体。
24.一种重组病毒,其包含如权利要求21至23的四顺反子表达构建体,任选地其中该表达构建体为慢病毒载体。
25.一种工程改造免疫细胞的方法,其包含:
(a)提供起始细胞群体,
(b)将如权利要求1及3至23中任一项的表达构建体或如权利要求24的重组病毒引入至该起始细胞群体中,
(c)任选地选择表达该caTCR、该CSR及该c-Jun的细胞,及
(d)自步骤(b)或(c)的细胞衍生经工程改造的免疫细胞,
任选地其中该免疫细胞为人类细胞。
26.如权利要求25的方法,其中该起始细胞群体包含免疫细胞,任选地该免疫细胞为自体或同种异体T细胞。
27.如权利要求25的方法,其中该起始细胞群体包含富能或多能细胞且步骤(d)包含将步骤(b)或(c)的细胞分化成免疫细胞,任选地是T细胞。
28.一种人类细胞群体,其包含如权利要求1及3至23中任一项的表达构建体或如权利要求24的重组病毒,任选地其中该人类细胞为免疫细胞。
29.一种免疫细胞群体,其通过如权利要求2至20及25至27中任一项的方法获得,任选地其中该免疫细胞为人类细胞。
30.如权利要求28或29的细胞,其中该细胞为T细胞,任选地为CD8+T细胞。
31.如权利要求28至30中任一项的细胞,其中相比于不过表达c-Jun的相应细胞,该细胞表达更低水平的耗竭标志物,且任选地其中该耗竭标志物为CD39、PD-1、TIM-3或LAG-3。
32.一种医药组合物,其包含如权利要求1及3至23中任一项的表达构建体、如权利要求24的重组病毒或如权利要求28至31中任一项的细胞,及
医药学上可接受的载剂。
33.一种杀灭目标细胞的方法,其包括使该目标细胞与如权利要求28至31中任一项的免疫细胞或如权利要求32的医药组合物在允许通过该免疫细胞杀灭该目标细胞的条件下接触,
其中该目标细胞表达该目标抗原及该目标配体,
任选地,其中相比于未包含引起c-Jun过表达的外源核酸分子的对应免疫细胞,该免疫细胞在与该目标细胞接触时表达更低水平的耗竭标志物,任选地其中该耗竭标志物为CD39、PD-1、TIM-3或LAG-3,及任选地其中该免疫细胞包含T细胞,任选地是CD8+T细胞,和/或该目标细胞为癌细胞。
34.如权利要求33的方法,其中该CSR中的该共刺激免疫细胞信号传导模块源于人类CD30,且相比于经工程改造以表达其共刺激免疫细胞信号传导模块源于人类CD28的CSR的对应免疫细胞,该免疫细胞表达更低水平的耗竭标志物,该耗竭标志物任选地选自CD39、PD-1、TIM-3及LAG3。
35.一种治疗有需要的患者的方法,其包括向该患者施用如权利要求28至31中任一项的人类细胞或如权利要求32的医药组合物。
36.如权利要求35的方法,其中该患者患有癌症,任选地肝细胞癌或胃癌。
37.如权利要求1及3至23中任一项的表达构建体、如权利要求24的重组病毒或如权利要求28至31中任一项的人类细胞在制备用于在如权利要求33至36中任一项的方法中治疗有需要的患者的药物中的用途。
38.如权利要求1及3至23中任一项的表达构建体、如权利要求24的重组病毒、如权利要求28至31中任一项的人类细胞或如权利要求32的医药组合物,其用于在如权利要求33至36中任一项的方法中治疗有需要的患者。
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