CN110636849A - 用于治疗al淀粉样变的经cs1靶向性嵌合抗原受体修饰的t细胞 - Google Patents
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Abstract
描述了使用靶向CS1的嵌合抗原受体治疗AL淀粉样变的方法。
Description
发明背景
轻链淀粉样变(AL淀粉样变)以产生kappa或lambda限制的单克隆轻链的骨髓中的浆细胞的克隆群体为特征。产生淀粉样蛋白的轻链不正确折叠,从而形成组合形成原纤维的β折叠片。这些淀粉样蛋白原纤维沉积到包括心脏、肾脏和外周神经的组织和器官中,在那里它们逐渐干扰结构和功能(Falk et al.1997N Engl J Med 337:898-909)。在不进行治疗的情况下,则预后较差,中位存活仅为8个月(Kyle et al.1997N Engl J Med 336:1202-120)。AL淀粉样变的治疗主要聚焦于靶向潜在的浆细胞克隆以阻止淀粉样蛋白原纤维产生并允许器官恢复。治疗选项包括从用于治疗多发性骨髓瘤的方案中采用的化疗方案以及高剂量美法仑,然后进行自体干细胞移植。尽管AL淀粉样变的患者一般受益于对浆细胞病治疗做出的众多进步,但由于淀粉样蛋白相关的器官功能障碍以及获得快速深度响应以防止残留的克隆引起进一步的原纤维沉积的需要所致的群体脆弱性使治疗变得复杂。尽管用干细胞移植和更新型药剂(包括蛋白体抑制剂和免疫调节药物)均可长期缓解,但仍需要新的耐受性良好且有效的治疗。
发明概述
本文中描述了使用靶向CS1的嵌合抗原受体(CAR)治疗AL淀粉样变的方法,所述CS1是作为信号传导淋巴细胞活化分子(SLAM)受体家族成员的细胞表面糖蛋白。下文描述了评估来自浆细胞疾病患者的骨髓标本的研究结果。患者具有用于多发性骨髓瘤(MM)或AL淀粉样变诊断的全面临床评估,包括血液学克隆以及器官受累的表征。通过分析细胞内kappa/lambda链的异常比率,使用多色流式细胞术分析来区分恶性浆细胞和正常浆细胞。高度倾斜的kappa和lambda比率是AL淀粉样变的恶性克隆的可靠指标。然后,评估浆细胞的克隆群体的B细胞成熟抗原(BCMA)和CS1表达。这些研究表明,CS1在AL淀粉样变患者的克隆浆细胞上表达,而BCMA在AL淀粉样变患者的浆细胞上未明显表达。这与MM相反,在MM中认为BCMA是普遍表达的。下文所述的其他研究显示了CS1靶向性CAR可以有效消除鼠模型中表达CS1的细胞。
本文描述了用于治疗轻链淀粉样变的方法,其包括向有此需要的患者施用由包含编码嵌合抗原受体的表达盒的载体转导的人T细胞群体,其中所述嵌合抗原受体包含:CS1scFv;间隔物区;跨膜域;共信号传导域;和CD3ζ信号传导域。
在各种实施方案中:嵌合抗原受体包含:CS1 scFv;间隔物区;CD28跨膜域;CD28共信号传导域;和CD3ζ信号传导域;嵌合抗原受体包含:CS1scFv;间隔物区;CD4跨膜域;4-1BB共信号传导域;和CD3ζ信号传导域;嵌合抗原受体包含:CS1 scFv;间隔物区,其包含选自SEQ ID No:2-5和9-12的氨基酸序列;CD4跨膜域;4-1BB共信号传导域;和CD3ζ信号传导域;嵌合抗原受体包含:CS1 scFv;间隔物区,其包含选自SEQ ID No:2-5和9-12的氨基酸序列;CD28跨膜域;CD28共信号传导域;和CD3ζ信号传导域;嵌合抗原受体包含:CS1 scFv;间隔物,包含选自SEQ ID No:2-5和9-12的氨基酸序列的间隔物;CD4跨膜域;4-1BB共信号传导域;和CD3ζ信号传导域;嵌合抗原受体包括:间隔物,包含选自SEQ ID No:2-5和9-12的氨基酸序列的间隔物;CD28跨膜域;CD28共信号传导域;和CD3ζ信号传导域;嵌合抗原受体包含与选自下组的氨基酸序列至少95%相同的氨基酸序列:SEQ ID NO:30、31、33、34、36、37、39、40、42、43、44和45;嵌合抗原受体包含与选自下组的氨基酸序列相同的氨基酸序列:SEQID NO:30、31、33、34、36、37、39、40、42、43、44和45;嵌合抗原受体包含与选自下组的氨基酸序列相同的氨基酸序列:SEQ ID NO:30、31、33、34、36、37、39、40、42、43、44和45,每个具有不超过5个单一氨基酸取代;至少20%,30%或40%的经转导的人T细胞是中央记忆T细胞;至少30%的经转导的人T细胞是CD4+和CD62L+,或CD8+和CD62L+;人T细胞群体对患者是自体的;人T细胞的群体对患者是同种异体的。
附图简述
图1A-C描绘了研究结果,显示了优先表达CS1的AL淀粉样变中的赘生性浆细胞。(A)从确诊为AL淀粉样变和多发性骨髓瘤的患者中分离出骨髓单个核细胞,并用针对CS1和BCMA的抗体标记,然后进行κ/λ细胞内染色。对经门控的优势κ轻链分析CS1和BCMA的表达。(B)呈现了AL淀粉样变的优势克隆中CS1和BCMA阳性细胞的百分比(N=14)。(C)呈现了多发性骨髓瘤的优势克隆中CS1和BCMA阳性细胞的百分比(N=10)。
图2A-D描绘了使用CS1靶向性CAR T细胞的研究结果,显示它们对CS1阳性细胞具有细胞毒性,并在小鼠中诱导持久的肿瘤消退。(A)CS1 CAR构建体的示意图,每个构建体均包含抗原特异性scFv、IgG4铰链区和CD28共刺激域以及CD3ζ信号传导域。IgG4铰链区通过删除CH2部分而缩短。CAR序列之后是T2A核糖体跳跃序列,然后是EGFRt追踪/自杀基因的编码序列。(B)将纯化的中央记忆T细胞(TCM)活化,并用编码CS1 CAR的慢病毒载体转导。通过用抗EGFR西妥昔单抗的抗体染色细胞来检测CAR表达。(C)与经51Cr标记的CS1阳性靶细胞MM.1S共培养后,使用4小时的51Cr释放测定法评估繁殖的CS1 CAR T细胞的细胞毒性。表达OKT3的LCL用作阳性对照,并且髓样白血病KG1A用作阴性对照。未转导的模拟T细胞是阴性效应细胞。(D)将2x106个经工程化改造以表达萤光素酶(ffluc)和绿色荧光蛋白(GFP)的fflucGFP MM.1S细胞胫骨内(i.t.)注射到NOD/Scid IL2RγCnull(NSG)小鼠中。接种肿瘤五天后,经静脉(i.v.)给小鼠注射1x106个CS1 CAR T细胞,并且将未转导的模拟细胞输注到对照小鼠中。每周一次用Xenogen成像监测肿瘤信号。
图3是表达CS1 CAR的慢病毒载体(CS1scFv-IgG4(HL-CH3)-CD28gg-Zeta(CO)-T2A-EGFRt_epHIV7)的示意图。CS1 CAR构建体包含:GMCSF信号序列、CS1 scFv、IgG4铰链区、接头、CH3域、CD28共刺激域和CD3ζ信号传导域。CAR构建体之后是T2A核糖体跳跃序列,然后是自杀基因EGFRt编码序列。从单个转录物中表达CAR和EGFRt分子。
图4描绘了包含信号肽、核糖体跳跃序列和EGFRt的CS1 CAR的氨基酸序列(SEQ IDNO:29)。
图5描绘了CS1scFv-IgG4(HL-CH3)-CD4tm-41BB-Zeta-T2A-EGFRt的氨基酸序列(SEQ ID NO:32)。
图6描绘了CS1scFv-IgG4(L235E,N297Q)-CD4tm-41BB-Zeta-T2A-EGFRt的氨基酸序列(SEQ ID NO:35)。
图7描绘了CS1scFv-IgG4(L235E,N297Q)-CD28tm-CD28gg-Zeta-T2A-EGFRt的氨基酸序列(SEQ ID NO:38)。
图8描绘CS1 scFv-Linker-CD4tm-41BB-Zeta-T2A-EGFRt的氨基酸序列(SEQ IDNO:41)。
图9描绘CS1 scFv-Linker-CD28tm-CD28gg-Zeta-T2A-EGFRt的氨基酸序列(SEQID NO:44)。
发明详述
实施例1:AL淀粉样变和多发性骨髓瘤中CS1和BCMA的表达
研究了14例AL淀粉样变患者。对来自这些患者的赘生性浆细胞上的CS1和BCMA表达的分析揭示了,这些细胞优先表达CS1,而不优先表达BCMA。简言之,从确诊为AL淀粉样变的患者中分离出骨髓单个核细胞,并用针对CS和BCMA的抗体标记,然后对kappa/lambda进行染色。图1A中显示了对患有kappa限制性疾病的患者中的浆细胞克隆群体进行门控,随后分析CS1表达的例子。所有AL淀粉样变样品均表达高水平的CS1(76.5±4.7%),但对BCMA呈阴性或证明非常低的BCMA表达(4.9±0.8%)(图1B)。
为了进行比较,在相同的时间段期间使用相同的方法对来自10例MM患者的骨髓样本进行了测试(图1C)。MM患者的克隆浆细胞与在AL中看到的情况类似地表达CS1;然而,BCMA以可比较地多得多的频率得到表达。令人感兴趣的是,AL患者中浆细胞上BCMA表达的缺乏表明与骨髓瘤细胞相比,AL中的克隆浆细胞是独特的。
实施例2:CS1靶向性CAR杀死细胞
为了探索CS1作为用于AL淀粉样变的CAR T细胞疗法的靶标的效用,我们测试了第二代CS1 CAR(图2A),其含有CD28gg共刺激域、核糖体跳跃T2A序列和截短的EGF受体序列(EGFRt)作为选择、跟踪和消融分子,并整合到SIN慢病毒载体中,其在下文进行详细描述。将纯化的中央记忆T细胞(TCM)活化,并用编码CS1 CAR的慢病毒载体转导,并在存在IL-250U/ml和IL-150.5ng/ml的情况下扩增3周。通过用西妥昔单抗-生物素和链霉抗生物素蛋白(SA)染色细胞来监测CAR表达(图2B)。与经51Cr标记的CS1+靶细胞(MM.1S)共培养后使用4小时51Cr释放测定法评估扩增的CS1 CAR T细胞的细胞毒性(图2C)
给六至十周龄的NOD/Scid IL2RγCnull小鼠胫骨内注射(i.t.)注射2x106个fflucGFP MM.1S,其经过工程化改造以表达萤光素酶(ffluc)和绿色荧光蛋白(GFP)。接种肿瘤五天后,给小鼠静脉内(i.v.)注射1x106个CS1 CAR T细胞,并将未转导的模拟细胞输注入对照小鼠中。使用Xenogen IVIS 100系列系统(Xenogen,Alameda,CA)每周对麻醉的小鼠进行成像。使用软件程序Living Image(Xenogen)对来自ffLuc+肿瘤异种移植物的光子进行定量,并且生物发光信号以针对暴露时间和表面积标准化的总光子通量测量,并以每球面度每cm2每秒光子的单位表示。
为了测试抗肿瘤活性,将MM.1S通过胫骨内注射接种到NSG小鼠中。确认肿瘤植入后,将1x106个CS1 CAR T细胞静脉内输注到荷瘤小鼠中。CS1CAR T细胞表现出对CS1阳性细胞(MM.1S)的特异性且高效的杀伤(图2C)。在动物模型中的抗肿瘤研究显示了与经模拟T细胞处理的小鼠相比,CS1 CAR T细胞诱导显著的肿瘤消退(图2D)。
这些发现支持CS1指导的CAR T细胞疗法用于AL淀粉样变患者的用途。AL是探索CAR介导的疗法的理想背景。要被靶向的恶性细胞的相对较少数量提供了成功根除小但具破坏性的克隆的机会以及与细胞因子释放综合征相关的并发症的最小风险。此外,CS1靶向性抗体埃罗妥珠单抗(elotuzumab)的相对安全的概况指示,CS1 CAR T细胞在这方面可能同样产生有利的结果。我们的工作代表了CS1指导的CAR T细胞的一种新型应用,且揭示了与MM的临床前经验相反,BCMA不是合适的靶标。我们的临床前数据显示了CS1指导的CAR T细胞的功效,我们计划继续进行使用CS1 CAR T细胞治疗AL的临床试验。
实施例3:CS1靶向性CAR
适合用于治疗AL淀粉样变的CS1靶向性CAR包括CAR,其包含胞外域、跨膜域和胞内信号传导域。胞外域包含CS1特异性scFv区或其变体和间隔物,其包含例如人Fc域的一部分。胞外域使CAR在T细胞表面上表达时能够将T细胞活性引导至表达CS1的细胞。跨膜域包括例如CD4跨膜域、CD8跨膜域、CD28跨膜域或CD3跨膜域。胞内信号传导域包含来自人CD3复合物的zeta链(CD3ζ)的信号传导域和一个或多个共刺激域,例如4-1BB共刺激域。在胞内区中与CD3ζ串联的共刺激域,诸如4-1BB(CD137)共刺激域的纳入使T细胞能够接收共刺激信号。T细胞(例如患者特异性的自体T细胞)可以工程化改造以表达本文所述的CAR,并且可以将工程化的细胞可以扩增并治疗使用。可以使用各种T细胞子集,包括alpha beta T细胞和gamma delta T细胞。另外,CAR可以在其他免疫细胞如NK细胞中表达。当用表达本文所述的CAR的免疫细胞治疗患者时,该细胞可以是自体T细胞或同种异体T细胞。在一些情况下,所使用的细胞是包括CD4+和CD8+中央记忆T细胞(TCM)的细胞群体,它们是CD62L+,CCR7+,CD45RO+和CD45RA-。细胞群体也可以包括其他类型的T细胞。在WO 2016/090369中详细描述了几种靶向CS1的CAR。
CS-1靶向性scFv
本文所述的CS1靶向性CAR包括靶向CS1的scFv(例如,包含以下序列的scFv:
EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVTVSSGSTSGGGSGGGSGGGGSSDIQMTQSPSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSYPYTFGQGTKVEIK;SEQ ID NO:1)或其具有1-5(例如1或2)个氨基酸修饰(例如取代)的变体。
有用的CS1 CAR由以下的氨基酸序列组成或包含以下的氨基酸序列:SEQ ID No:31、34、37、40、43和46中的任一个(缺少信号序列的成熟CAR),或CS1 CAR由以下的氨基酸序列组成或包含以下的氨基酸序列:SEQ ID No:30、33、36、39、42和45中任一个(具有GMCSFRa信号序列的未成熟CAR)。CAR和可以以包括信号序列例如人GM-CSF受体alpha信号序列(MLLLVTSLLLCELPHPAFLLIP;SEQ ID NO:26)的形式表达。CAR可以与可用于监测表达的其他序列,例如T2A跳跃序列和截短的EGFRt一起表达CAR。因此,CAR可以包含以下氨基酸序列或由以下氨基酸序列组成:SEQ ID No:29-46中任一个或可以包含以下氨基酸序列或由以下氨基酸序列组成,所述氨基酸序列与SEQ ID NO:29-46中的任一个是至少95%,96%,97%,98%或99%相同的。CAR可以包含以下氨基酸序列或由以下氨基酸序列组成:SEQ ID No:29-46中任一个中具有最多1、2、3、4或5个氨基酸变化(优选保守性氨基酸变化)的氨基酸序列。
间隔物区
本文所述的CAR可以包含位于CS1靶向域(即CS1 ScFv或其变体)和跨膜域之间的间隔物。可以使用多种不同间隔物。它们中的一些包含人Fc区的至少一部分,例如人Fc区的铰链部分或CH3域或其变体。下表1提供了可用于本文所述的CAR中的各种间隔物。
表1:间隔物的实例
一些间隔物区包含免疫球蛋白(例如IgG1,IgG2,IgG3,IgG4)铰链区的全部或部分,即落在免疫球蛋白的CH1和CH2域之间的序列,例如IgG4 Fc铰链或CD8铰链。一些间隔物区包含免疫球蛋白CH3域或CH3域和CH2域两者。免疫球蛋白衍生的序列可包含一个或多个氨基酸修饰,例如1、2、3、4或5个取代,例如减少脱靶结合的取代。
铰链/接头区也可以包含具有序列ESKYGPPCPSCP(SEQ ID NO:4)或ESKYGPPCPPCP(SEQ ID NO:3)的IgG4铰链区。
铰链/接头区也可以包含序列ESKYGPPCPPCP(SEQ ID NO:3),后有接头序列GGGSSGGGSG(SEQ ID NO:2),后有IgG4 CH3序列GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:12)。因此,整个接头/间隔物区可以包含以下序列:ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:11)。在一些情况下,与SEQ ID NO:11相比,间隔物区具有1、2、3、4或5个单一氨基酸变化(例如,保守变化)。在某些情况下,以减少Fc受体(FcR)结合的方式在两个位置(L235E;N297Q)突变的IgG4 Fc铰链/接头区。
跨膜域
多种跨膜域可用于CARS中。表2包含合适的跨膜域的实例。在存在间隔物区的情况下,跨膜域位于间隔物区的羧基末端。
表2:跨膜域的实例
共刺激域
共刺激域可以是适合与CD3ζ信号传导域一起使用的任何域。在一些情况下,共刺激域是CD28共刺激域,其包含与以下序列至少90%,至少95%,至少98%相同或相同的序列:
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(SEQ ID NO:23;LL到GG氨基酸变化加双下划线)。在一些情况下,与SEQ ID NO:23相比,CD28共信号传导域具有1、2、3、4或5个氨基酸变化(优选保守的,优选不在加下划线的GG序列中)。在一些情况下,共信号传导域是4-1BB共信号传导域,其包括与以下序列至少90%,至少95%,至少98%相同或相同的序列:KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO:24)。在某些情况下,与SEQ ID NO:24相比,4-1BB共信号传导域具有1、2、3、4或5个氨基酸变化(优选保守的)。
共刺激域位于跨膜域和CD3ζ信号传导域之间。表3包括合适的共刺激域以及CD3ζ信号传导域的序列的实例。
表3:CD3ζ域和共刺激域的实例
在各种实施方案中:共刺激域选自下组:表3中描述的共刺激域或其具有1-5个(例如1或2个)氨基酸修饰的变体、CD28共刺激域或具有1-5个(例如1或2个)氨基酸修饰的变体、4-1BB共刺激域或其具有1-5个(例如1个或2个)氨基酸修饰的变体和OX40共刺激域或其具有1-5(例如1或2)个氨基酸修饰的变体。在某些实施方案中,存在有4-1BB共刺激域或其具有1-5(例如1或2)个氨基酸修饰的变体。在一些实施方案中,存在有两个共刺激域,例如CD28共刺激域或其具有1-5个(例如1个或2个)氨基酸修饰(例如取代)的变体和4-1BB共刺激域或其具有1-5(例如1或2)个氨基酸修饰(例如取代)的变体。在各种实施方案中,1-5(例如1或2)个氨基酸修饰是取代。共刺激域在CD3ζ信号传导域的氨基末端,并且在某些情况下,由2-10个,例如3个氨基酸(例如,GGG)组成的短接头位于共刺激域和CD3ζ信号传导域之间。
CD3ζ信号传导域
CD3ζ信号传导域可以是适合与CD3ζ信号传导域一起使用的任何域。在某些情况下,CD3ζ信号传导域包含与以下序列至少90%,至少95%,至少98%相同或相同的序列:RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:21)。在一些情况下,与SEQ ID NO:21相比,CD3ζ信号传导具有1、2、3、4或5个氨基酸变化(优选保守的)。
截短的EGFR
CD3ζ信号传导域后面可以有核糖体跳跃序列(例如,LEGGGEGRGSLLTCGDVEENPGPR;SEQ ID NO:27)和与以下序列至少90%,至少95%,至少98%相同或者相同的序列的截短的EGFR:LVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM(SEQ ID NO:28)。在一些情况中,与SEQ ID NO:28相比,截短的EGFR具有1、2、3、4或5个氨基酸变化(优选保守的)。
可以给患有AL淀粉样变的患者施用由载体转导的人T细胞群体,所述载体包含编码本文所述的CS1嵌合抗原受体的表达盒(例如,CAR,其包含以下氨基酸序列或由以下氨基酸序列组成:SEQ ID No:29-46中任一个的氨基酸序列或与SEQ ID No:29-46中任一个至少95%,96%,97%,98%或99%相同的氨基酸序列或SEQ ID NO:29-46中任一个中具有多至1、2、3、4或5个氨基酸变化(优选保守性氨基酸变化)的氨基酸序列)。在各种实施方案中:人T细胞群体是中央记忆T细胞(TCM),例如,CD8+/CD4+TCM。
氨基酸修饰是指蛋白质或肽序列中的氨基酸取代、插入和/或缺失。“氨基酸取代”或“取代”是指用另一种氨基酸置换亲本肽或蛋白质序列中特定位置处的氨基酸。可以进行取代,从而以非保守方式(即,通过将密码子从属于具有特定大小或特征的氨基酸分组的氨基酸改变为属于另一种分组的氨基酸)或以保守的方式(即,通过将密码子从属于具有特定大小或特征的氨基酸分组的氨基酸改变为属于相同分组的氨基酸)改变所得蛋白质中的氨基酸。此类保守的变化通常导致所得蛋白质的结构和功能的较少变化。以下是各种氨基酸分组的实例:1)具有非极性R基团的氨基酸:丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、甲硫氨酸;2)具有不带电荷的极性R基团的氨基酸:甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺;3)具有带电荷的极性R基团的氨基酸(在pH 6.0下带负电荷):天冬氨酸,谷氨酸;4)碱性氨基酸(在pH 6.0时带正电荷):赖氨酸、精氨酸、组氨酸(在pH 6.0时)。另一种分组可以是具有苯基的那些氨基酸:苯丙氨酸、色氨酸和酪氨酸。
CS1 CAR可以包含与图4-9中所示的氨基酸序列(SEQ ID No:29-46,包含或不包含GMCSFRa信号序列,或者包含或不包含T2A核糖体跳跃序列和截短的EGFRt)至少90%,至少95%,至少98%相同或相同的序列。
WO 2016/090369中描述了多种CS-1靶向性CAR,并且这些CAR可用于治疗AL淀粉样变。
本文所述的靶向CS1的CAR是表4中总结的那些,其中指出了每种CAR的间隔物区、跨膜域和共刺激域。
表4:靶向CS1的CAR的实例
*SEQ ID NO代表:描绘的整个序列,包含GMCSFRa信号序列、T2A和EGFRt//包含GMCSFRa信号序列但不包含T2A和EGFRt的序列//不包含GMCSFRa信号序列、T2A和EGFRt的序列。
在某些情况下,可以使用载体产生CS1 CAR,其中CAR开放阅读框后面有T2A核糖体跳跃序列和截短的EGFR(EGFRt),其缺乏胞质信号传导尾部。在此种排列中,EGFRt的共表达提供了一种惰性的非免疫原性的表面标志物,其允许精确测量经基因修饰的细胞,并实现经基因修饰的细胞的阳性选择,以及过继转移后体内的治疗性T细胞的有效追踪。有效控制增殖以避免细胞因子风暴和脱靶毒性是T细胞免疫疗法成功的重要障碍。在与治疗有关的毒性情况下,掺入CS1CAR慢病毒载体中的EGFRt可以充当自杀基因来消减CAR+T细胞。
本文描述的CAR可以通过本领域已知的任何手段产生,尽管优选地它是使用重组DNA技术产生的。可以通过常规的本领域已知的分子克隆标准技术(基因组文库筛选、重叠PCR、引物辅助的连接、定点诱变等)制备编码嵌合受体的几个区域的核酸并将它们组装成完整的编码序列。优选地,将所得的编码区插入表达载体中,并用于转化合适的表达宿主细胞系,优选T淋巴细胞细胞系,最优选自体T淋巴细胞细胞系。
可以用用于CAR表达的载体转导从患者分离的各种T细胞亚组。中央记忆T细胞是一种有用的T细胞亚组。可以通过分选CD45RO+/CD62L+细胞,例如使用设备以免疫磁性方式选择表达期望受体的细胞,从而从外周血单个核细胞(PBMC)中分离中央记忆T细胞。富含中枢记忆T细胞的细胞可以用抗CD3/CD28活化,用例如慢病毒载体转导,所述慢病毒载体指导CS1 CAR以及非免疫原性表面标志物的表达,以进行体内检测。消融和潜在的离体选择。经活化/遗传修饰的CS1中央记忆T细胞可以在体外用IL-2/IL-15扩增,然后冷冻保存。
实施例4:用于表达CS1特异性CAR的epHIV7的构建和结构
pHIV7质粒是可以衍生出表达CS1 CAR的临床载体的亲本质粒。用于表达CAR的epHIV7载体由pHIV7载体产生(Wang et al.2011Blood 118:1255)。重要的是,该载体使用人EF1启动子来驱动CAR的表达。载体的5’和3’序列均源自先前源自HXBc2原病毒的pv653RSN。多嘌呤束DNA瓣(flap)序列(cPPT)源自来自NIH AIDS Reagent Repository的HIV-1株pNL4-3。
pHIV7的构建如下进行。简而言之,如下将含有来自gag-pol的653bp加上5'和3'长末端重复序列(LTR)以及居间的SL3-新霉素磷酸转移酶基因(Neo)的pv653RSN亚克隆到pBluescript中:在步骤1中,从5’LTR至rev响应元件(RRE)的序列产生p5’HIV-1 51,然后通过除去TATA框上游的序列修饰5’LTR,首先连接到CMV增强子,然后连接到SV40复制起点(p5'HIV-2)。在步骤2中,在将3'LTR克隆到pBluescript中以产生p3’HIV-1后,进行3'LTR增强子/启动子中的400-bp缺失以除去HIV U3中的顺式调节元件并且形成p3'HIV-2。在步骤3中,将从p5'HIV-3和p3'HIV-2分离的片段连接以产生pHIV-3。在步骤4中,通过取出额外的上游HIV序列进一步修饰p3'HIV-2以产生p3’HIV-3,并且将含有WPRE的600-bp BamHI-SalI片段添加到p3’HIV-3以产生p3'HIV-4。在步骤5中,通过PCR在大小上降低pHIV-3RRE,并且将其连接到来自pHIV-3的5’片段(未显示)以及连接到p3’HIV-4,以产生pHIV-6。在步骤6中,从pNL4-3扩增含有来自HIV-1pNL4-3(55)的cPPT DNA瓣序列的190-bp BglII-BamHI片段,并且置于pHIV6中的RRE和WPRE序列之间以产生pHIV-7。使用四质粒系统,使用此亲本质粒pHIV7-GFP(GFP,绿色荧光蛋白)包装亲本载体。
为了将病毒基因组有效包装到载体中,需要包装信号psiψ。RRE和WPRE增强RNA转录物转运和转基因的表达。已证明与WPRE组合的瓣序列增强哺乳动物细胞中慢病毒载体的转导效率。
产生病毒载体所需要的辅助功能分成三个单独的质粒,以减少通过重组产生具有复制能力的慢病毒的可能性:1)pCgp编码病毒载体装配所需要的gag/pol蛋白;2)pCMV-Rev2编码Rev蛋白,该蛋白作用于RRE序列以协助病毒基因组的运输以进行有效包装;3)pCMV-G编码水泡口炎病毒(VSV)的糖蛋白,其是病毒载体感染性所需要的。
在pHIV7编码的载体基因组和辅助质粒之间存在最小的DNA序列同源性。同源性区域包括位于pCgp辅助质粒的gag/pol序列中的约600个核苷酸的包装信号区;所有三个辅助质粒中的CMV启动子序列;和辅助质粒pCgp中的RRE序列。极不可能可以由于在这些区域中的同源性而产生具有复制能力的重组病毒,因为它将需要多次重组事件。另外,任何所得的重组体都将缺少慢病毒复制所需要的功能性LTR和tat序列。
将CMV启动子替换为EF1α-HTLV启动子(EF1p),并且新质粒命名为epHIV7。EF1p具有563bp,并在切除CMV启动子后使用NruI和NheI引入epHIV7。
已从此系统中除去慢病毒基因组,该基因组不包括野生型病毒的致病性所需要并且靶细胞生产性感染所需要的gag/pol和rev。此外,epHIV7载体构建体不含完整的3’LTR启动子,因此在靶定的细胞中所得的表达并且逆转录的DNA原病毒基因组将具有无活性的LTR。由于此种设计,无HIV-I衍生的序列会从原病毒中转录出来,并且仅从它们各自的启动子中表达治疗序列。SIN载体中LTR启动子活性的除去预期显著降低宿主基因的意外激活的可能性。表5总结了epHIV7中存在的各种调节物元件。
图1是含有CAR构建体的慢病毒载体CS1 CAR(CS1scFv-IgG4(HL-CH3)-CD28gg-Zeta(CO)-T2A-EGFRt_epHIV7)的示意图,该CAR构建体由CS1 scFv、IgG4铰链区、接头、CD28共刺激域和CD3ζ信号传导域构成。CAR构建体后面有T2A核糖体跳跃序列,然后是自杀基因EGFRt编码序列。CAR和EGFRt分子由单个转录物表达。表5呈现了载体的各种元件的位置。
实施例5:用于转导患者T细胞的载体的产生
对于每个质粒(CS1 CAR_epHIV7;pCgp;pCMV-G;和pCMV-Rev2),产生种子库,其用于接种发酵罐以产生足够量的质粒DNA。对质粒DNA进行身份、无菌性和内毒素测试,之后将其用于产生慢病毒载体。
简言之,已经从293T工作细胞(WCB)扩增细胞,该293T工作细胞已经经过测试以确认无菌性和无病毒污染。将来自293T WCB的293T细胞小瓶融化。将细胞培养并扩增,直到存在足够数量的细胞以铺板适当数量的10层细胞工厂(CF),用于载体生产和细胞株维持。单一细胞株可用于生产。
在多至10个CF的亚批次中生产慢病毒载体。可以在同一周内生产两个亚批次,导致约20升慢病毒上清液/周的生产。在下游处理阶段期间合并从所有亚批次生产的材料,以生产一批产物。将293T细胞接种到293T培养基(含10%FBS的DMEM)中的CF中。将工厂置于37℃的培养箱中并水平调平,以使细胞在CF的所有层上均匀分布。两天后,使用CaPO4方法用上述四种慢病毒质粒转染细胞,该CaPO4方法涉及Tris:EDTA、2M CaCl2、2XHBS和四种DNA质粒的混合物。转染后第3天,将含有分泌的慢病毒载体的上清液收集,纯化并且浓缩。从CF中除去上清液后,从每个CF中收集生产终止细胞。将来自每个工厂的细胞进行胰蛋白酶处理,并通过离心收集。将细胞重悬于冷冻培养基中并冷冻保存。这些细胞随后用于有复制能力的慢病毒(RCL)测试。
为了纯化和配制载体,通过膜过滤来使粗上清液澄清以除去细胞碎片。通过内切核酸酶消化降解宿主细胞DNA和残留的质粒DNA。使用0.45μm滤器使病毒上清液澄清除掉细胞碎片。将澄清的上清液收集到预先称重的容器中,向该容器中加入(终浓度50U/mL)。残留质粒DNA和宿主基因组DNA的内切核酸酶消化在37℃进行6小时。使用内切核酸酶处理的上清液的初始切向流超滤(TFF)浓度从粗上清液中除去残留的低分子量成分,而将病毒浓缩约20倍。将澄清的经内切核酸酶处理的病毒上清液通过具有500kD的NMWCO的中空纤维筒以设计为将剪切速率维持于约4,000sec-1或更小,而使流量速率最大化的流速循环。在浓缩过程期间开始经核酸酶处理的上清液的渗滤,以维持柱性能。使用PBS中的4%乳糖作为渗滤缓冲液,建立80%的渗透物置换率。使病毒上清液达到目标体积,表示粗上清液的20倍浓缩,并继续渗滤4个另外的交换体积,渗透物置换率为100%。
通过使用高速离心技术完成病毒产物的进一步浓缩。使用Sorvall RC-26plus离心机在6℃以6000RPM(6,088RCF)沉淀慢病毒的每个亚批次达16-20h。然后,将来自每个亚批次的病毒团粒在50%具有PBS中的4%乳糖的体积中重建。在该缓冲液中重建的团粒代表用于病毒制备的最终制剂。整个载体浓缩过程导致体积减少约200倍。完成所有亚批次后,将材料置于-80℃,且测试每个亚批次的样品的无菌性。确认样品无菌性后,在37℃在频繁搅拌下将亚批次快速融化。然后将材料合并,并在病毒载体套件中在II类A/B3型生物安全柜中手动等取样。使用无菌USP 6级,外螺纹O形环冷冻管中的1mL浓缩慢病毒的填充配置。COH应用技术开发中心(CATD)的质量体系(QS)根据CBG政策和标准操作程序并符合当前的良好生产规范(cGMP)释放所有材料。
为了确保慢病毒载体制剂的纯度,对它测试了残留宿主DNA污染物以及残留宿主和质粒DNA的转移。在其他测试中,通过RT-PCR评估载体身份,以确保存在正确的载体。意图用于本研究的载体符合所有释放标准。
实施例6:适于表达CS-1CAR的TCM细胞的制备
通过白细胞单采术(leukopheresis)从患者获得T淋巴细胞,并且将适当的同种异体或自体T细胞亚组,例如中央记忆T细胞(TCM)经过遗传改造以表达CAR,然后通过任何临床可接受方式施用于患者,以实现抗癌疗法。
CD8+的TCM基本上如Wang et al.(J Immunology 35:689,2012)中所述分离。简而言之,在白细胞单采术的当天,通过在Ficoll-Paque上进行密度梯度离心来分离PBMC,然后在PBS/EDTA中进行两次洗涤。然后将PBMC在PBS中洗涤一次,重悬于含有10%胎牛血清(FCS)的X Vivo15培养基中,转移至300cc转移袋中,并在3-D旋转器上于室温(RT)储存过夜。第二天,将多达5x109个PBMC在装有临床级抗CD4(2.5mL)、抗CD14(1.25mL)和抗CD45RA(2.5mL)微珠(MiltenyiBiotec)的300cc转移袋中在含有10%FCS的X Vivo15中于室温温育30分钟。然后根据制造商的说明(MiltenyiBiotec),使用CliniMACSTM消减模式立即消减CD4+、CD14+和CD45RA+细胞。离心后,将未标记的阴性细胞级份重悬于含有0.5%人血清白蛋白(HSA)的CliniMACSTMPBS/EDTA缓冲液(MiltenyiBiotec)中,然后以0.1mg/106细胞用临床级生物素化DREG56mAb(COHNMC CBG)在室温标记30分钟。然后洗涤细胞,并将其重悬于最终体积100mL的含0.5%HSA的CliniMACSTMPBS/EDTA中,并转移到新的300cc转移袋中。与1.25mL抗生物素微珠(MiltenyiBiotec)温育30分钟后,根据制造商的说明通过CliniMACSTM上进行的阳性选择纯化PBMC的CD62L+级分(CD8+TCM),并将其重悬于含有10%FCS的X Vivo15中。
通过将CD4+,CD14+和CD45RA+选择修改为CD14+和CD45RA+选择使用上述方法的修改制备CD8+/CD4+的TCM。方法在CliniMACSTM设备上使用两步过程,首先消耗CD14+和CD45RA+细胞,然后阳性选择CD62L+细胞。此种经修改的平台从单个白细胞单采术中生成50x106批量TCM。
富集后,将TCM细胞在完整的X-Vivo15加上50IU/mL IL-2和0.5ng/mL IL-15中配制,并转移到Teflon细胞培养袋中,在那里用DynalClinExTM VivoCD3/CD28珠刺激它们。刺激后多至5天,用编码CS1 CAR的慢病毒载体以约3的感染复数(MOI)转导细胞。将培养物保持多至42天,期间添加完整的X-Vivo15和IL-2和IL-15细胞因子,如根据细胞扩增所需(保持细胞密度于3x105和2x106个活细胞之间/mL,并在培养的每个星期一、星期三和星期五补充细胞因子)。典型地,在这些条件下在21天内将细胞扩增到约109个细胞。在培养期结束时,收获细胞,洗涤两次,并配制在临床级冷冻保存培养基中。
在T细胞输注的当天,将冷冻保存并且释放的产物融化,洗涤并配制用于重新输注。从液氮储存中取出包含释放的细胞产物的冷冻保存的小瓶,融化,冷却并用PBS/2%人血清白蛋白(HSA)洗涤缓冲液洗涤。离心后,将除去上清液,并将细胞重悬于无防腐剂的生理盐水(PFNS)/2%HSA输注稀释液中。取出样品以进行质量控制测试。
实施例7:CS1 CAR(CS1scFv-IgG4(HL-CH3)-CD28tm-CD28gg-Zeta-T2A-EGFRt)的 氨基酸序列
图4中描绘了CS1scFv-IgG4(HL-CH3)-CD28tm-CD28gg-Zeta-T2A-EGFRt的完整氨基酸序列。整个序列(SEQ ID NO:29)包括:22个氨基酸的GMCSF信号肽(SEQ ID NO:26)、CS1scFv序列(SEQ ID NO:1);IgG4铰链序列(SEQ ID NO:3;氨基酸取代S至P,加阴影);10个氨基酸的接头(SEQ ID NO:2);IgG4 CH3序列(SEQ ID NO:12);28个氨基酸的CD28跨膜域序列(SEQ ID NO:14);CD28gg共刺激域序列(SEQ ID NO:23;LL至GG氨基酸变化突出显示);3个氨基酸的Gly接头;112个氨基酸的CD3ζ序列(SEQ ID NO:21);24个氨基酸的T2A跳跃序列(SEQ ID NO:27);和EGFRt序列(SEQ ID NO:28)。
Claims (14)
1.用于治疗轻链淀粉样变的方法,所述方法包括向有此需要的患者施用由载体转导的人T细胞群体,所述载体包含编码嵌合抗原受体的表达盒,其中嵌合抗原受体包含:CS1scFv;间隔物区;跨膜域;共信号传导域;和CD3ζ信号传导域。
2.权利要求1的方法,其中所述嵌合抗原受体包含:CS1scFv;间隔物区;CD28跨膜域;CD28共信号传导域;和CD3ζ信号传导域。
3.权利要求1的方法,其中所述嵌合抗原受体包含:CS1scFv;间隔物区;CD4跨膜域;4-1BB共信号传导域;和CD3ζ信号传导域。
4.权利要求1的方法,其中所述嵌合抗原受体包含:CS1scFv;间隔物区,其包含选自SEQID No:2-5和9-12的氨基酸序列;CD4跨膜域;4-1BB共信号传导域;和CD3ζ信号传导域。
5.权利要求1的方法,其中所述嵌合抗原受体包含:CS1scFv;间隔物区,其包含选自SEQID No:2-5和9-12的氨基酸序列;CD28跨膜域;CD28共信号传导域;和CD3ζ信号传导域。
6.权利要求1的方法,其中所述嵌合抗原受体包含:CS1scFv;间隔物,包含选自SEQ IDNo:2-5和9-12的氨基酸序列的间隔物;CD4跨膜域;4-1BB共信号传导域;和CD3ζ信号传导域。
7.权利要求1的方法,其中所述嵌合抗原受体包含:间隔物,包含选自SEQ ID No:2-5和9-12的氨基酸序列的间隔物;CD28跨膜域;CD28共信号传导域;和CD3ζ信号传导域。
8.权利要求1的方法,其中所述嵌合抗原受体包含与选自下组的氨基酸序列至少95%相同的氨基酸序列:SEQ ID NO:30、31、33、34、36、37、39、40、42、43、44和45。
9.权利要求1的方法,其中所述嵌合抗原受体包含与选自下组的氨基酸序列相同的氨基酸序列:SEQ ID NO:30、31、33、34、36、37、39、40、42、43、44和45。
10.权利要求1的方法,其中所述嵌合抗原受体包含与选自下组的氨基酸序列相同的氨基酸序列:SEQ ID NO:30、31、33、34、36、37、39、40、42、43、44和45,每个具有不超过5个单一氨基酸取代。
11.权利要求1的方法,其中至少20%,30%或40%的经转导的人T细胞是中央记忆T细胞。
12.权利要求1的方法,其中至少30%的经转导的人T细胞是CD4+和CD62L+,或CD8+和CD62L+。
13.权利要求1的方法,其中所述人T细胞群体对于所述患者是自体的。
14.权利要求1的方法,其中所述人T细胞群体对所述患者是同种异体的。
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BR112020014913A2 (pt) | 2018-01-22 | 2020-12-08 | Seattle Children's Hospital (dba Seattle Children's Research Institute) | Métodos para uso de células t car |
WO2023086829A1 (en) * | 2021-11-09 | 2023-05-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Igg4 hinge-containing chimeric antigen receptors targeting glypican-3 (gpc3) and use thereof |
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