CN116997345A - 靶向bcma的嵌合抗原受体 - Google Patents
靶向bcma的嵌合抗原受体 Download PDFInfo
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- CN116997345A CN116997345A CN202180081130.0A CN202180081130A CN116997345A CN 116997345 A CN116997345 A CN 116997345A CN 202180081130 A CN202180081130 A CN 202180081130A CN 116997345 A CN116997345 A CN 116997345A
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Abstract
本公开提供了靶向BCMA的嵌合抗原受体(CAR)及其制备方法和应用。本公开的CAR靶向BCMA阳性细胞,并且可以用于治疗BCMA阳性的B细胞淋巴瘤、多发性骨髓瘤和浆细胞白血病。
Description
相关申请的交互参考
本申请要求美国临时申请号63/120692(于2020年12月2日提交)、美国临时申请号63/153666(于2021年2月25日提交)和美国临时申请号63/212289(2021年6月18日提交)以及美国临时申请号17/476661(2021年9月16日提交)的优先权,其中每一申请都通过引用的方式整体并入本文作为参考。
序列表
本申请包含以ASCII格式以电子方式提交的序列表,并通过引用将其全部并入本文。所述ASCII副本创建于2021年12月1日,名称为11299-008884-WO1_ST25.txt,且大小为41KB。
技术领域
本发明涉及生物医学领域,且更具体地涉及靶向BCMA的嵌合抗原受体及其制备方法和应用。
发明背景
BCMA是B细胞成熟抗原(B cell maturation antigen),也称为CD269或TNFRSF17,是肿瘤坏死因子受体超家族的成员。其配体是B细胞活化因子(B cell activatingfactor,BAFF)和增殖诱导的配体(a proliferation-induced ligand,APRIL)。
BCMA与BAFF和APRIL的结合激活NF-kB并诱导抗凋亡Bcl-2成员如Bcl-xL或Bcl-2和Mcl-1的上调。BCMA与其配体之间的相互作用从不同方面调节体液免疫以及B细胞的生长和分化,以维持人体内的稳定和平衡的环境。
BCMA的表达限于B细胞系。它在成浆细胞、浆细胞和一部分成熟B细胞上表达,并在终末B细胞的分化时增加。而在大多数B细胞中,如幼稚B细胞、记忆B细胞和B细胞生发中心,以及其他器官,BCMA不表达。据报道,BCMA的表达对骨髓中的长寿命、固定的浆细胞是重要的。因此,BCMA缺陷的小鼠骨髓中的浆细胞减少,但脾脏中的浆细胞水平不受影响。在BCMA敲除小鼠中,成熟的B细胞可以正常分化为浆细胞。BCMA敲除小鼠看起来正常,且看起来健康,以及B细胞数量正常,但浆细胞不能长时间存活。
BCMA在恶性浆细胞中也高度表达,如多发性骨髓瘤和浆细胞白血病。霍奇金淋巴瘤患者的HRS细胞中也检测到BCMA。在美国,血液系统恶性肿瘤约占所有恶性肿瘤的10%,且骨髓瘤占所有恶性血液学肿瘤的15%。根据文献,BCMA的表达与多发性骨髓瘤疾病的进展有关。BCMA基因在骨髓瘤样本中高表达,但在慢性淋巴细胞白血病、急性淋巴细胞白血病和急性T细胞淋巴细胞白血病中低表达。在过量表达BCMA配体BAFF和APRIL的小鼠模型中,B细胞淋巴瘤显著增加。已显示与BCMA结合的配体调节表达BCMA的多发性骨髓瘤细胞的生长和存活。BCMA与BAFF和APRIL的结合可以使恶性浆细胞存活。因此,表达BCMA的肿瘤细胞以及BCMA配体和受体之间相互作用的分布的缺失可以改善多发性骨髓瘤或其他BCMA阳性B细胞系恶性淋巴瘤的治疗结果。
多发性骨髓瘤,也称浆细胞瘤或凯勒氏病,是一种难治性B细胞系的恶性肿瘤,其特征是浆细胞异常增殖。浆细胞是一种负责产生抗体的白细胞。根据国家癌症研究所(National Cancer Institute)2017年发布的数据,骨髓瘤占所有肿瘤病例的1.8%,死亡率为2.1%。2010-2014年的统计结果显示,每10万人/年的发病率约为6.6人,死亡率约为50%。多发性骨髓瘤是一种中年疾病。欧洲和美国的发病年龄中位数为68岁。男性比女性多。中国发病高峰年龄为55-65岁,男女比例为2.35:1。中国没有关于多发性骨髓瘤的确认的流行病学数据。通常估计,中国的发病率与周边东南亚和日本相似,约为十万分之一。多发性骨髓瘤的常规治疗方法包括化疗和造血干细胞移植,但这些方法的复发率高。硼替佐米(Bortezomib)(PS-341)是第一种蛋白酶体抑制剂,2003年被美国食品药品监督管理局(FDA)批准用于治疗复发性难治性多发性骨髓瘤,其单独使用或与现有药物联合使用。结果令人满意。该药物也于2005年在中国上市,且已成为沙利度胺(thalidomide)和地塞米松(dexamethasone)治疗多发性骨髓瘤的选择之一。多发性骨髓瘤的治疗通常是联合治疗。但是,如果同时使用多种药物,也会产生昂贵和累积副作用的负面影响。临床上仍然需要开发治疗多发性骨髓瘤的新方法。
近年来,免疫疗法,特别是过继性T细胞疗法,在治疗血液系统恶性肿瘤的临床试验中显示出强的功效和光明的前景。可以对T细胞进行基因修饰以表达嵌合抗原受体(CAR),其包含抗原识别部分和T细胞活化区。利用单克隆抗体的抗原结合特性,CAR可以以非MHC限制的方式重定向T细胞和靶点的特异性和反应性。这种非MHC限制性抗原识别允许表达CAR的T细胞在没有抗原加工的情况下识别抗原,从而避免肿瘤逃逸的主要机制。此外,CAR不产生内源性TCR的具有α链和β链的二聚体。
目前,两种靶向CD19的嵌合抗原受体T细胞疗法(CAR-T)产品已被批准用于治疗儿童和年轻成人患者的急性淋巴母细胞性白血病(acute lymphoblastic leukemia),以及用于治疗复发或难治性大B细胞淋巴瘤的成人二线或多线系统疗法。但是,CD19很少在多发性骨髓瘤的恶性浆细胞中表达。迫切需要开发一种靶向BCMA的CAR-T产品,用于治疗多发性骨髓瘤。
发明概述
本公开的一个目的是提供靶向BCMA的嵌合抗原受体及其制备方法和应用。
本公开提供了嵌合抗原受体(CAR)。CAR可以包含抗BCMA抗原结合区,其包含轻链可变区(VL)和重链可变区(VH)。
VL可以包含三个互补决定区(CDR),即LCDR1、LCDR2和LCDR3;VH可以包含三个CDR,即HCDR1、HCDR2和HCDR3。
在某些实施方案中,LCDR1、LCDR2和LCDR3可以具有分别与SEQ ID NO:17、SEQ IDNO:19和SEQ ID NO:21中所示的氨基酸序列约80%至约100%同一的氨基酸序列。HCDR1、HCDR2和HCDR3可以具有分别与SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:28中所示的氨基酸序列约80%至约100%同一的氨基酸序列。
在某些实施方案中,LCDR1、LCDR2和LCDR3可以具有分别与SEQ ID NO:31、SEQ IDNO:33、SEQ ID NO:35中所示的氨基酸序列约80%至约100%同一的氨基酸序列。HCDR1、HCDR2和HCDR3可以具有分别与SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42中所示的氨基酸序列约80%至约100%同一的氨基酸序列。
在某些实施方案中,LCDR1、LCDR2和LCDR3可以具有分别与SEQ ID NO:45、SEQ IDNO:47、SEQ ID NO:49中所示的氨基酸序列约80%至约100%同一的氨基酸序列。HCDR1、HCDR2和HCDR3可以具有分别与SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:56中所示的氨基酸序列约80%至约100%同一的氨基酸序列。
CAR的VL和VH可以具有分别与(a)SEQ ID NO:1和SEQ ID NO:2中;分别与(a)SEQIDNO:3和SEQ ID NO:4中;或分别与(a)SEQ ID NO:5和SEQ ID NO:6中所示的氨基酸序列约80%至约100%同一的氨基酸序列。
在某些实施方案中,VL位于VH的N末端。
抗BCMA抗原结合区可以是特异性结合BCMA的单链可变片段(scFv)。
CAR可以进一步包含以下中的一种或多种:(a)信号肽,(b)铰链区,(c)跨膜结构域,(d)共刺激区,和(e)细胞质信号传导结构域。
共刺激区可以包含4-1BB(CD137),CD28,OX40,CD2,CD7,CD27,CD30,CD40,CD70,CD134,PD1,Dap10,CDS,ICAM-1,LFA-1(CD11a/CD18),ICOS(CD278),NKG2D,GITR,TLR2的共刺激区或其组合(或可以衍生自4-1BB(CD137),CD28,OX40,CD2,CD7,CD27,CD30,CD40,CD70,CD134,PD1,Dap10,CDS,ICAM-1,LFA-1(CD11a/CD18),ICOS(CD278),NKG2D,GITR,TLR2或其组合)。
细胞质信号传导结构域可以包含CD3ζ的细胞质信号传导结构域(或可以衍生自CD3ζ)。
铰链区可以包含CD8、CD28、CD137、Ig4的铰链区或其组合(或可以衍生自CD8、CD28、CD 137、Ig4)。
跨膜结构域可以包含CD8,CD28,CD3ε,CD45,CD4,CD5,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137,CD154的跨膜结构域或其组合(或可以衍生自CD8,CD28,CD3ε,CD45,CD4,CD5,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137,CD154或其组合)。
本公开提供了一种表达本发明CAR的免疫细胞。免疫细胞可以是T细胞或自然杀伤(NK)细胞。免疫细胞可以是同种异体的或自体的。
本公开还包含编码本发明CAR的核酸。
本公开进一步提供了包含本发明核酸的载体。
本发明提供了一种治疗癌症的方法。该方法可以包括将免疫细胞施与有需要的受试者。
癌症可能是血液学癌症。癌症可能是浆细胞恶性肿瘤。癌症可能是BCMA阳性的恶性肿瘤。癌症可能是多发性骨髓瘤(MM)或浆细胞白血病。
免疫细胞可以通过输注、注射、转输、植入和/或移植来施用。
免疫细胞可以静脉内、皮下、皮内、结节内(intranodally)、肿瘤内、髓内(intramedullary)、肌内或腹膜内施用。
免疫细胞可以通过静脉内输注施用。
受试者可以是人。
本公开提供一种治疗癌症的方法。该方法可以包括将本发明的免疫细胞施与有需要的受试者。
嵌合抗原受体(CAR)在施用后约28天在受试者的血液中可以产生从约5.0e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3e+07个拷贝/gDNA,从约5.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.0e+07个拷贝/gDNA,从约5.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3e+07个拷贝/gDNA,或从约7.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.0e+07个拷贝/gDNA范围的曲线下面积(AUC)。
嵌合抗原受体(CAR)可以在受试者的血液中产生从约5x104个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3x106个拷贝/gDNA,从约5x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3x106个拷贝/gDNA,或从约7.5x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1x106个拷贝/gDNA范围的最大血浆浓度(Cmax)。
CAR可以具有范围为约12天至约25天、约14天至约20天、或约6天至约22天的Tmax。
在某些实施方案中,抗BCMA抗原结合区包括轻链可变区(VL),所述轻链可变区包含与SEQ ID NO:1、SEQ ID NO:3或SEQ ID NO:5中所示的氨基酸序列至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一的氨基酸序列。
在某些实施方案中,抗BCMA抗原结合区包括重链可变区(VH),所述重链可变区包含与SEQ ID NO:2、SEQ ID NO:4或SEQ ID NO:6中所示的氨基酸序列至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一的氨基酸序列。
抗BCMA抗原结合区的轻链可变区可以包含一个、两个或三个互补决定区(CDR),所述互补决定区与BCMA-20抗体轻链可变区的CDR(分别为SEQ ID NO:1的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)、或与BCMA-CA8抗体轻链可变区的CDR(分别为SEQID NO:3的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)、或与BCMA-MO6抗体轻链可变区的CDR(分别为SEQ ID NO:5的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一。
抗BCMA抗原结合区的重链可变区可以包含一个、两个或三个互补决定区(CDR),所述互补决定区与BCMA-20抗体重链可变区的CDR(分别为SEQ ID NO:2的位置31-35、位置50-66、位置99-110所示的CDR1、CDR2和CDR3)、或与BCMA-CA8抗体重链可变区的CDR(分别为SEQID NO:4的位置31-35、位置50-66、位置99-110所示的CDR1、CDR2和CDR3)、或与BCMA-MO6抗体重链可变区的CDR(分别为SEQ ID NO:6的位置31-35、位置50-66、位置99-110所示的CDR1、CDR2和CDR3)至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一。
抗BCMA抗原结合区的轻链可变区可以包含一个、两个或三个互补决定区(CDR),所述互补决定区与BCMA-20抗体轻链可变区的CDR(分别为SEQ ID NO:17、SEQ ID NO:19、SEQID NO:21所示的CDR1、CDR2和CDR3)、或与BCMA-CA8抗体轻链可变区的CDR(分别为SEQ IDNO:31、SEQ ID NO:33、SEQ ID NO:35所示的CDR1、CDR2和CDR3)、或与BCMA-MO6抗体轻链可变区的CDR(分别为SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49所示的CDR1、CDR2和CDR3)至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一。
抗BCMA抗原结合区的重链可变区可以包含一个、两个或三个互补决定区(CDR),所述互补决定区与BCMA-20抗体重链可变区的CDR(分别为SEQ ID NO:24、SEQ ID NO:26、SEQID NO:28所示的CDR1、CDR2和CDR3)、或与BCMA-CA8抗体重链可变区的CDR(分别为SEQ IDNO:38、SEQ ID NO:40、SEQ ID NO:42所示的CDR1、CDR2和CDR3)、或与BCMA-MO6抗体重链可变区的CDR(分别为SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:56所示的CDR1、CDR2和CDR3)至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一。
在某些实施方案中,抗BCMA抗原结合区的轻链可变区包括与BCMA-20抗体的重链可变区的CDR(SEQ ID NO:1的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR,以及抗BCMA抗原结合区的重链可变区包括与BCMA-20抗体的重链可变区CDR(分别为SEQ ID NO:2的位置31-35、位置50-66、位置99-110所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR。
在某些实施方案中,抗BCMA抗原结合区的轻链可变区包括与BCMA-20抗体的轻链可变区的CDR(分别为SEQ ID NO:17、SEQ ID NO:19、SEQ ID NO:21所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR,以及抗BCMA抗原结合区的重链可变区包括与BCMA-20抗体的重链可变区CDR(分别为SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:28所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR。
在某些实施方案中,抗BCMA抗原结合区的轻链可变区包括与BCMA-CA8抗体的轻链可变区的CDR(分别为SEQ ID NO:3的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR,以及抗BCMA抗原结合区的重链可变区包括与BCMA-CA8抗体的重链可变区的CDR(分别为SEQ ID NO:4的位置31-35、位置50-66、位置99-110所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR。
在某些实施方案中,抗BCMA抗原结合区的轻链可变区包括与BCMA-CA8抗体的轻链可变区的CDR(分别为SEQ ID NO:31、SEQ ID NO:33、SEQ ID NO:35所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR,以及抗BCMA抗原结合区的重链可变区包括与BCMA-CA8抗体的重链可变区CDR(分别为SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR。
在某些实施方案中,抗BCMA抗原结合区的轻链可变区包括与BCMA-MO6抗体的轻链可变区的CDR(分别为SEQ ID NO:5的位置24-34、位置50-56、位置89-97所示的CDR1、CDR2和CDR3)同一的三个CDR,以及抗BCMA抗原结合区的重链可变区包括与BCMA-MO6抗体的重链可变区的CDR(分别为SEQ ID NO:6的位置31-35、位置50-66、位置99-110所示的CDR1、CDR2和CDR3)同一的三个CDR。
在某些实施方案中,抗BCMA抗原结合区的轻链可变区包括与BCMA-MO6抗体的轻链可变区的CDR(分别为SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR,以及抗BCMA抗原结合区的重链可变区包括与BCMA-MO6抗体的重链可变区CDR(分别为SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:56所示的CDR1、CDR2和CDR3)同一的(例如80%-100%同一的)三个CDR。
在某些实施方案中,CAR可以包含与SEQ ID NO:59、SEQ ID NO:61或SEQ ID NO-63中所示的氨基酸序列约80%至约100%、约85%至约100%、约90%至约100%、约95%至约100%、至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一的氨基酸序列。
在某些实施方案中,编码CAR的核酸可以包含编码与SEQ ID NO:58、SEQ ID NO:60或SEQ ID NO:62中所示的氨基酸序列约80%至约100%、约85%至约100%、约90%至约100%、约95%至约100%、至少或约70%、至少或约75%、至少或约80%、至少或约85%、至少或约90%、至少或约95%、至少或约99%、至少或约81%、至少或约82%、至少或约83%、至少或约84%、至少或约85%、至少或约86%、至少或约87%、至少或约88%、至少或约89%、至少或约90%、至少或约91%、至少或约92%、至少或约93%、至少或约94%、至少或约95%、至少或约96%、至少或约97%、至少或约98%、至少或约99%、或约100%同一的核酸序列。
在某些实施方案中,在施用CAR至受试者后约28天,该CAR在受试者的血液中可以产生从约0.5e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约2e+07个拷贝/gDNA,从约5.0e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3e+07个拷贝/gDNA,从约5.0e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约2e+07个拷贝/gDNA,从约5.0e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.5e+07个拷贝/gDNA,从约5.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.0e+07个拷贝/gDNA,从约5.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3e+07个拷贝/gDNA,从约7.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.0e+07个拷贝/gDNA,从约8.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.0e+07个拷贝/gDNA,从约0.5e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约4e+06个拷贝/gDNA,从约0.5e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.5e+06个拷贝/gDNA,从约1e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.5e+06个拷贝/gDNA,从约1.2e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.2e+06个拷贝/gDNA,从约0.8e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.2e+06个拷贝/gDNA,从约1.6e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.2e+06个拷贝/gDNA,从约1e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约2e+06个拷贝/gDNA,从约0.6e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.8e+06个拷贝/gDNA,从约3e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.2e+06个拷贝/gDNA,从约0.5e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.7e+06个拷贝/gDNA,从约2e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.2e+06个拷贝/gDNA,从约1.5e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约2e+06个拷贝/gDNA,或从约1e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.2e+06个拷贝/gDNA范围的曲线下面积(AUC)。该AUC可以是中位值AUC。
在某些实施方案中,在施用CAR至受试者后,该CAR在受试者的血液中产生从约5x104个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3x106个拷贝/gDNA,从约5x104个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.5x106个拷贝/gDNA,从约5x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3x106个拷贝/gDNA,从约7.5x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1x106个拷贝/gDNA,从约7x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1x106个拷贝/gDNA,从约8x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1x106个拷贝/gDNA,从约7.5x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.5x106个拷贝/gDNA,从约7x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.5x106个拷贝/gDNA,从约8x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.5x106个拷贝/gDNA,从约0.8e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.5e+05个拷贝/gDNA,从约1e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.5e+05个拷贝/gDNA,从约1e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.6e+05个拷贝/gDNA,从约1e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.3e+05个拷贝/gDNA,从约0.8e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.5e+05个拷贝/gDNA,从约0.8e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约2e+05个拷贝/gDNA,从约1e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约2e+05个拷贝/gDNA,从约2e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约3e+05个拷贝/gDNA,从约2e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约3.5e+05个拷贝/gDNA,从约2e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约2.5e+05个拷贝/gDNA,或从约1e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约3e+05个拷贝/gDNA范围的最大血浆浓度(Cmax)。该Cmax可以是中位值Cmax。
在某些实施方案中,该CAR具有从约12天至约25天,从约14天至约20天,从约6天至约22天,从约3天至约20天,从约4天至约18天,从约5天至约17天,从约6天至约16天,从约7天至约15天,从约9天至约15天,从约10天至约15天,从约10天至约14天,从约8天至约12天,从约6天至约14天,从约12天至约14天,从约8天至约11天,从约8天至约15天,或从约10天至约14天范围的Tmax(CAR达到Cmax所需的时间)。该Tmax可以是中位值Tmax。
在某些实施方案中,该CAR具有从约30天至约200天,从约50天至约150天,从约50天至约100天,从约60天至约80天,从约60天至约150天,从约80天至约150天,从约50天至约200天,从约50天至约60天,从约50天至约80天,从约50天至约100天,从约60天至约100天,从约80天至约100天,从约60天至约200天,从约80天至约200天,从约50天至约140天,从约60天至约140天,或从约80天至约140天范围的Tlast(对应于最后可定量的CAR水平的时间)。该Tlast可以是中位值Tlast。
具体地,本公开的一个目的是提供靶向BCMA的嵌合抗原受体的序列及其修饰的T细胞(CART-BCMA)的制备方法和活性鉴定。
本公开提供了用于治疗BCMA阳性B细胞淋巴瘤的嵌合抗原受体结构。
在第一方面,本发明提供了嵌合抗原受体(CAR)(序列),并且其抗原结合结构域是靶向BCMA细胞外区的抗体单链可变区序列。
在另一个实施方案中,抗原结合结构域是靶向BCMA序列位置24至41位的氨基酸残基的抗体单链可变区序列。
在另一个实施方案中,BCMA序列的NCBI登录号为AY684975.1。
在另一个实施方案中,该抗原结合结构域的结构如下式I所示:
VL-VH(I)
其中VH是抗体重链可变区;VL是抗体轻链可变区;并且“-”是接头肽或肽键;
并且,VL的氨基酸序列如SEQ ID NO:1所示,且VH的氨基酸顺序如SEQ ID NO:2所示;
或者,VL的氨基酸序列如SEQ ID NO:3所示,且VH的氨基酸顺序如SEQ ID NO:4所示;
或者,VL的氨基酸序列如SEQ ID NO:5所示,且VH的氨基酸顺序如SEQ ID NO:6所示。
在另一个实施方案中,接头肽的氨基酸序列如SEQ ID NO:10或SEQ ID NO:11所示。
在另一个实施方案中,抗体单链可变区包含人抗体、小鼠抗体、人-小鼠嵌合抗体的单链可变区。
在另一个实施方案中,嵌合抗原受体的结构如下式II所示:
S-VL-VH-H-TM-C-CD3ζ (II)
其中,
S是任选的信号肽;
H是铰链区;
TM是跨膜结构域;
C是共刺激信号传导分子;
CD3ζ是衍生自CD3ζ的细胞质信号传导序列;
VH和VL如上所述。
在另一个实施方案中,S是选自CD8、CD28、GM-CSF、CD4、CD137的蛋白质的信号肽或其组合。
在另一个实施方案中,S是衍生自CD8的信号肽。
在另一个实施方案中,S的氨基酸序列如SEQ ID NO:9所示。
在另一个实施方案中,H是选自CD8、CD28、CD137的蛋白质的铰链区或其组合。
在另一个实施方案中,H是衍生自CD8的铰链区。
在另一个实施方案中,H的氨基酸序列如SEQ ID NO:12所示。
在另一个实施方案中,TM是选自CD28,CD3ε,CD45,CD4,CD5,CD8,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137,CD154的蛋白质的跨膜区,或其组合。
在另一个实施方案中,TM是衍生自CD8的跨膜区。
在另一个实施方案中,TM的序列如SEQ ID NO:13所示。
在另一个实施方案中,C是选自OX40,CD2,CD7,CD27,CD28,CD30,CD40,CD70,CD134,4-1BB(CD137),PD1,Dap10,CDS,ICAM-1,LFA-1(CD11a/CD18),ICOS(CD278),NKG2D,GITR,TLR2的蛋白质的共刺激信号传导分子或其组合。
在另一个实施方案中,C是衍生自4-1BB的共刺激信号传导分子。
在另一个实施方案中,C的氨基酸序列如SEQ ID NO:14所示。
在另一个实施方案中,CD3ζ的氨基酸序列如SEQ ID NO:15所示。
在第二方面,本发明提供了编码第一方面的嵌合抗原受体(CAR)的核酸分子。
在另一个实施方案中,所述核酸分子是分离的核酸分子。
在第三方面,本发明提供了包含第二方面的核酸分子的载体。
在另一个实施方案中,载体选自DNA、RNA、质粒、慢病毒载体、腺病毒载体、逆转录病毒载体、转座子或其组合。
在另一个实施方案中,所述载体是慢病毒载体。
在第四方面,本发明提供了宿主细胞,所述宿主细胞包含第三方面的载体或具有整合到染色体中的第二方面的外源核酸分子或表达第一方面的CAR。
在另一个实施方案中,细胞是分离的细胞,和/或细胞是基因工程化的细胞。
在另一个实施方案中,所述细胞是哺乳动物细胞。
在另一个实施方案中,所述细胞是T细胞。
在第五方面,本发明提供了制备表达第一方面的CAR的CAR-T细胞的方法,该方法包括以下步骤:将第二方面的核酸分子或第三方面的载体转导到T细胞中,从而获得CAR-T细胞。
在第六方面,本发明提供了一种制备物,其包含第一方面的嵌合抗原受体、第二方面的核酸分子、第三方面的载体或第四方面的细胞,以及可药用载体、稀释剂或赋形剂。
在另一个实施方案中,制备物是液体制备物。
在另一个实施方案中,制备物的剂型是注射剂。
在另一个实施方案中,制备物中CAR-T细胞的浓度为1×10 3-1×108个细胞/ml、或1×10 4-1×107个细胞/ml。
在第七方面,本发明提供了第一方面的嵌合抗原受体、第二方面的核酸分子、第三方面的载体或第四方面的细胞用于制备预防和/或治疗肿瘤或癌症的药物或制备物的用途。
在另一个实施方案中,肿瘤选自血液学肿瘤、实体瘤或其组合。
在一个实施例中,癌症是B细胞淋巴瘤。
在另一个实施方案中,血液肿瘤选自急性髓性白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性淋巴母细胞性白血病(ALL)、弥散性大B细胞淋巴瘤(DLBCL)或其组合。
在另一个实施方案中,实体瘤选自胃癌、胃癌的腹膜转移、肝癌、白血病、肾癌、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、宫颈癌、卵巢癌、淋巴瘤、鼻咽癌、肾上腺肿瘤、膀胱肿瘤、非小细胞肺癌(NSCLC)、胶质瘤、子宫内膜癌或其组合。
在另一个实施方案中,肿瘤是BCMA阳性肿瘤,例如BCMA阳性B细胞淋巴瘤、多发性骨髓瘤或浆细胞白血病。
在第八方面,本发明提供了用于制备第四方面的细胞的试剂盒,该试剂盒包含容器,且第二方面的核酸分子或第三方面的载体位于容器中。
在第九方面,本发明提供了第四方面的细胞或第六方面的制备物用于预防和/或治疗癌症或肿瘤的用途。
在第十方面,本发明提供了治疗疾病的方法,包括向需要治疗的受试者施用合适量的第四方面的细胞或第六方面的制备物。
在另一实施方案中,该疾病是癌症或肿瘤。
应当理解,上述本公开的各个技术特征和下文(如在实施例中)具体描述的各个技术特征可以在本公开的范围内相互组合,以构成新的或优选的技术方案,由于篇幅的限制,无需在此逐一描述。
附图简述
图1A、图1B和图1C显示了CART-BCMA比较例的筛选结果。图1A显示了用靶向BCMA的嵌合抗原受体对工程化T细胞的转染效率的检测。培养第6天的CAR-BCMA细胞中,通过重组人BCMA蛋白的Fc片段染色法鉴定CAR基因编码的蛋白在T细胞膜表面的表达水平。培养第10天的1*105个CART-BCMA细胞分别与BCMA阳性K562-BCMA-B9肿瘤细胞系、天然表达BCMA的MM.1S肿瘤细胞系和RPMI8226肿瘤细胞系、以及BCMA阴性K562肿瘤细胞系、或没有肿瘤细胞,在200μl GT-551培养基中以1:1的比例培养18h。然后分别检测T细胞膜表面CD137的表达水平(图1B)和培养上清液中IFNγ的分泌水平(图1C)。
图2显示了靶向BCMA的嵌合抗原受体的结构。CAR的结构包括前导序列、抗原识别序列、接头区、跨膜区、共刺激因子信号区和CD3ζ信号传导区。
图3A、图3B和图3C显示了用靶向BCMA的嵌合抗原受体对工程化T细胞的转染效率的检测。通过重组人BCMA蛋白的Fc片段染色法鉴定在第7天(图3A)、第21天(图3B)和第29天(图3C)培养的CAR-BCMA细胞中CAR基因编码的蛋白在T细胞膜表面上的表达水平。
图4A和图4B显示了T细胞膜表面CD137的表达水平(图4A)和培养上清液中IFNγ的分泌水平(图4B)。具体而言,将第7天培养的1×105个CART-BCMA细胞分别与BCMA阳性K562-BCMA-E7肿瘤细胞系和BCMA阴性K562肿瘤细胞系或没有肿瘤细胞在200μlGT-551培养基中以1:1的比例培养18h。然后分别检测T细胞膜表面CD137的表达水平和培养上清液中IFNγ的分泌水平。
图5显示了CART-BCMA诱导的肿瘤细胞晚期凋亡水平(advanced apoptosislevel)的检测。具体而言,将1×104个CFSE标记的BCMA阴性(NH929)或BCMA阳性(NH929-BCMA)肿瘤细胞系分别与相应的T细胞在100μl GT-551培养基中以如图所示的比例共培养4小时。在用100μl 25% PI染料染色15分钟后,通过流式细胞术分析CFSE阳性细胞中PI阳性细胞的比例。该图显示了相应的共培养样品中PI阳性细胞的统计学分析。
图6A和图6B显示了CART-BCMA诱导的肿瘤细胞晚期凋亡水平的检测。图6A显示了分析样品中CART阳性细胞的比例,其中NT和BCMA-MO6以60%计算。将1x 104个CFSE标记的BCMA阴性(NH929)或BCMA阳性(NH929-BCMA,MM.1S)肿瘤细胞系分别与相应的T细胞在100μlGT-551培养基中按图所示比例共培养4小时。用100μl 25% PI染料染色15分钟后,通过流式细胞术分析CFSE阳性细胞中PI阳性细胞的比例。图6B显示了在相应的共培养样品中PI阳性细胞的统计学分析。
图7A和图7B显示了在B-NDG小鼠中,CART-BCMA对骨髓瘤细胞系RPMI-8226的体内增殖的抑制作用。收集对数生长期的RPMI-8226细胞,并在小鼠右背部皮下接种4.0×106个肿瘤细胞。当肿瘤体积达到约120mm3时,根据肿瘤体积将动物随机分为4组。然后通过尾静脉分别注射溶剂对照、7.5×106个NT(仅T细胞)和7.5×10 6个CART-BCMA细胞。图7A显示通过尾静脉单次注射CART-BCMA-1和CART-BCMA-20可以有效抑制人骨髓瘤RPMI-8226细胞的生长。图7B显示CART-BCMA-1和CART-BCMA-20可以显著延长具有人骨髓瘤RPMI-8226细胞的荷瘤小鼠的存活时间。
图8显示了转染相关质粒后,通过流式细胞术测定的293T细胞中BCMA、CR2、CXADR、DDR2和MAG的表达结果。
图9A、图9B和图9C显示了细胞因子检测结果。
图10显示了每种细胞对靶细胞的杀伤能力。三角形:BCMA-20(C-CAR088);正方形:阳性对照;圆圈:NT对照(未转染的(NT)T细胞)。
图11显示了可溶性BCMA对细胞杀伤活性的影响。
图12显示了各组小鼠的存活率。
图13显示了I期临床研究的实验过程。
图14显示了I期临床研究的临床应答。
图15显示了ID为Z0203-00801C008的患者的治疗情况。
图16A和16B显示了ID为Z0203-00701C001的患者的治疗情况。
图17显示了血液中C-CAR088的扩增和M-蛋白/sFLC水平的降低。
图18A-图18C显示了评估C-CAR088的scFv结合特异性的结果。图18A显示了实验方案。图18B显示了抗BCMA CAR和scFv rabFc的结构。图18C显示了实验结果。
图19A-图19B显示了组织交叉反应性IHC GLP研究和验证。HAdCC:人原代肾上腺皮质细胞。HPTEC:人原代甲状腺上皮细胞。A549 BCMA OE:过量表达BCMA的稳定株。
图20显示了CAR(C-CAR088)制造工艺的一个实例。该工艺包括使用无血清培养基、封闭的模块化集成的半自动化系统和数字监测。星号表示改善的工艺。静脉到静脉的中位时间为约17天(范围:13至83天)。中位制造时间为约7天(范围:5至10天)。
图21显示了C-CAR088 I期临床研究设计(在治疗复发或难治性多发性骨髓瘤中)。在四个医疗中心进行了I期、开放标签、剂量递增和扩大研究。C-CAR088是本发明CAR的一个实施方案,其基于BCMA-20抗体。
图22显示了C-CAR088的临床应答,包括SD,MR,PR,CR,VGPR,MRD和PD。SD:稳定的疾病;PR:部分应答;CR:完全应答;PD:进展性疾病;MR:最小应答;VGPR:非常好的部分应答;MRD:最小残留疾病。
图23显示了C-CAR088的临床应答,包括CR/sCR、VGPR和PR。
图24显示了中剂量组和高剂量组无进展生存(PFS)的Kaplan Meyer评估。
图25A显示了CAR施用后患者血液中C-CAR088的扩增。图25B显示了至最近一次就诊时患者血液中C-CAR088的扩增。图25C显示了CAR施用后患者血液中的Cmax水平。图25D显示了CAR施用后患者血液中的AUC水平。图25E显示了CAR施用后患者血液中的Tmax水平。图25F显示了CAR施用后患者血液中的Tlast水平。
详细描述
本公开提供了靶向BCMA的嵌合抗原受体(CAR)。在某些实施方案中,所述CAR基于四种单克隆抗体:BCMA-1、BCMA-20、BCMA-CA8和BCMA-MO6。本公开还提供了原代T细胞中CAR的表达水平、这些嵌合抗原受体的体外激活能力和肿瘤细胞杀伤功效的分析和鉴定。研究表明,本公开的嵌合抗原受体靶向BCMA阳性细胞,并可用于治疗BCMA阳性B细胞淋巴瘤、多发性骨髓瘤、浆细胞白血病或其他疾病。
具体而言,本公开确定了病毒感染后细胞膜表面上不同CAR结构的表达时间和表达强度之间的相关性,并进一步确定了不同CAR结构蛋白表达的差异。这一发现表明,不同的CAR结构在相同的感染条件下,膜表面CAR蛋白的表达水平和CART体内活性的持久性存在差异。经过广泛筛选,获得了本公开的CAR结构。结果显示,由本公开的CAR结构编码的蛋白质可以充分表达和膜定位。
在本公开中,改进了靶向BCMA抗原的CAR修饰的T细胞的制备方法。在一个实施方案中,补充有1%人白蛋白的GT-551无血清培养基用于体外培养淋巴细胞。
术语
术语“约”可以指本领域技术人员确定的特定值或组成在可接受误差范围内的值或组成,这部分取决于如何测量或确定该值或组成。提及数值时,术语“约”可指所述数值的±10%。换句话说,数值可以在所述值的90%到所述值110%的范围内。
术语“施用”是指使用本领域技术人员已知的各种方法和递送系统中的任何一种将本公开的产品物理引入受试者,包括但不限于静脉内、肌内、皮下、腹膜内、脊髓或其他肠胃外施用,例如通过注射或输注。
术语“抗体”(Ab)可以包括但不限于特异性结合抗原的免疫球蛋白,并且含有通过二硫键连接的至少两条重(H)链和两条轻(L)链,或其抗原结合部分。每条H链包含一个重链可变区(本文缩写为VH)和一个重链恒定区。该重链恒定区包含三个恒定结构域,即CH1、CH2和CH3。每条轻链含有一个轻链可变区(本文缩写为VL)和一个轻链恒定区。该轻链恒定区含有恒定结构域CL。VH区和VL区可以进一步细分为称为互补决定区(CDR)的高变区,所述CDR散布在称为构架区(FR)的较保守的区域内。每个VH和VL包含三个CDR和四个FR,它们从氨基端到羧基端按以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重链和轻链的可变区包含与抗原相互作用的结合结构域。
嵌合抗原受体(CAR)
本公开的嵌合抗原受体(CAR)可以包含细胞外结构域、跨膜结构域和细胞内结构域。细胞外结构域包含靶特异性结合元件(也称为抗原结合结构域)。细胞内结构域包括共刺激信号传导区和ζ链。共刺激信号传导区是指包括共刺激分子的细胞内结构域的一部分。共刺激分子是淋巴细胞对抗原有效应答所需的细胞表面分子,而不是抗原受体或其配体。
接头可以掺入在CAR的细胞外结构域和跨膜结构域之间,或者掺入在CAR的细胞质结构域和跨膜结构域之间。如本文所用,术语“接头”通常指在多肽链中起到将跨膜结构域连接至细胞外结构域或细胞质结构域的作用的任何寡肽或多肽。接头可以包含0-300个氨基酸、2-100个氨基酸或3-50个氨基酸。
在一个实施方案中,CAR的细胞外结构域包含靶向BCMA的抗原结合结构域。当本公开的CAR在T细胞中表达时,可以基于抗原结合特异性进行抗原识别。当CAR与其相关抗原结合时,它影响肿瘤细胞,引起肿瘤细胞无法生长、死亡或受到其他影响,导致患者的肿瘤负荷缩小或消除。抗原结合结构域可以与来自一个或多个共刺激分子和ζ链的细胞内结构域融合。抗原结合结构域可以与这样的细胞内结构域融合,所述细胞内结构域是4-1BB信号传导结构域和CD3ζ信号传导结构域的组合。
如本文所用,“抗原结合结构域”和“单链抗体片段”可以指具有抗原结合活性的Fab片段、Fab’片段、F(ab’)2片段或单一Fv片段。Fv抗体包含抗体的重链可变区和轻链可变区,但没有恒定区。Fv抗体具有最小的抗体片段,其具有所有抗原结合位点。通常,Fv抗体也包括VH和VL结构域之间的多肽接头,并且可以形成抗原结合所需的结构。抗原结合结构域通常是scFv(单链可变片段)。scFv的大小通常是完整抗体的1/6。单链抗体可以是由核苷酸链编码的氨基酸链序列。在某些实施方案中,scFv可以包含特异性识别BCMA的细胞外区的抗体,所述BCMA的细胞外区例如BCMA序列第24至41位的氨基酸残基。抗体可以是单链抗体。
关于铰链区和跨膜区(跨膜结构域),可以设计CAR为包含与CAR的细胞外结构域融合的跨膜结构域。在一个实施方案中,使用与CAR中的结构域之一天然连接的跨膜结构域。在一些实施方案中,可以选择或通过氨基酸替代来修饰跨膜结构域,以避免将这类结构域与相同或不同的表面膜蛋白的跨膜结构域结合,从而使与受体复合物的其他成员的相互作用最小化。
CAR中的细胞内结构域包含4-1BB的信号传导结构域和CD3ζ的信号转导结构域。
在某些实施方案中,本公开的CAR结构包含信号肽、抗原识别序列(抗原结合结构域)、接头区、跨膜区、共刺激因子信号区和CD3ζ信号传导区(ζ链部分)。连接顺序如下:
[CD8 S]-[VL-接头-VH]-[铰链-CD8TM]-[4-1BB]-[CD3ζ]
在某些实施方案中,本公开中选择的序列如下:
(1)信号肽是衍生自CD8的信号肽:
MALPVTALLLPLALLLHAARP(SEQ ID NO:9)
(2)衍生自BCMA-1抗体的单链可变区的轻链(VL)序列:
DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK(SEQ ID NO:7)
(3)衍生自BCMA-1抗体的单链可变区的重链(VH)序列:
QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVSS(SEQ ID NO:8)
其中,BCMA-1是包含在公开的Car-T序列中的抗体序列,并且在本申请中用作对照。
(4)衍生自BCMA-20抗体的单链可变区的轻链(VL)序列:
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLNWYQQKPGKAPKPLIYYTSNLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCMGQTISSYTFGQGTKLEI(SEQ ID NO:1)
(5)衍生自BCMA-20抗体的单链可变区的重链(VH)序列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFDMAWVRQAPGKGLVWVSSITTGADHAIYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCVRHGYYDGYHLFDYWGQGTLVTVSS(SEQ ID NO:2)
(6)衍生自BCMA-CA8抗体的单链可变区的轻链(VL)序列:
DIQLTQTTSSLSASLGDRVTISCSASTTTSNYLNWYQQKPDGTVELVIYYTSNLHGGGPSRFSGSGSGTDYSLTIGYLEPEDVATYYCQQYRKLPWTFGGGSKLEIKR(SEQ ID NO:3)
(7)衍生自BCMA-CA8抗体的单链可变区的重链(VH)序列:
EVQLQQSGAVLARPGASVKMSCKGSGYTFTNYWMHWVKQRPGQGLEWIGATYRGHSDTYYNQKFKGKAKLTAVTSTSTAYMELSSLTNEDSAVYYCTRGAIYNGYDVLDNWGQGTLVTVSS(SEQ ID NO:4)
(8)衍生自BCMA-MO6抗体的单链可变区的轻链(VL)序列:
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR(SEQ ID NO:5)
(9)衍生自BCMA-MO6抗体的单链可变区的重链(VH)序列:
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS(SEQ ID NO:6)
(10)BCMA-1单链可变区的重链和轻链之间的接头序列为:
GSTSGSGKPGSGEGSTKG(SEQ ID NO:10)
(11)BCMA-20、BCMA-CA8和BCMA-MO6单链可变区的重链和轻链之间的接头序列为:
GGGGSGGGGSGGGGS(SEQ ID NO:11)
(12)铰链区和接头区的序列:
FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD(SEQ ID NO:12)
(13)跨膜区是CD8抗原的跨膜区序列(CD8TM):
IYIWAPLAGTCGVLLLSLVITLYC(SEQ ID NO:13)
(14)共刺激因子信号区是衍生自4-1BB细胞质信号传导基序的序列:
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL(SEQ ID NO:14)
(15)CD3ζ的信号传导区是衍生自TCR复合物中CD3ζ的免疫受体基于酪氨酸的激活基序(immunorecceptor tyrosine-based activation motif,ITAM)的序列:
RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:15)
在某些实施方案中,编码CAR(衍生自BCMA-20抗体)的核酸可以具有以下序列(SEQID NO:58):
atggccttaccagtgaccgccttgctcctgccgctggccttgctgctccacgccgccaggccggacatccagatgacccagtccccctcctccctgtccgcctccgtgggcgaccgggtgaccatcacctgccgggcctcccagggcatctccaactacctgaactggtaccagcagaagcccggcaaggcccccaagcccctgatctactacacctccaacctgcagtccggcgtgccctcccggttctccggctccggctccggcaccgactacaccctgaccatctcctccctgcagcccgaggacttcgccacctactactgcatgggccagaccatctcctcctacaccttcggccagggcaccaagctggagatcaagggtggcggtggctcgggcggtggtgggtcgggtggcggcggatctgaggtgcagctggtggagtccggcggcggcctggtgcagcccggcggctccctgcggctgtcctgcgccgcctccggcttcaccttctccaacttcgacatggcctgggtgcggcaggcccccggcaagggcctggtgtgggtgtcctccatcaccaccggcgccgaccacgccatctacgccgactccgtgaagggccggttcaccatctcccgggacaacgccaagaacaccctgtacctgcagatgaactccctgcgggccgaggacaccgccgtgtactactgcgtgcggcacggctactacgacggctaccacctgttcgactactggggccagggcaccctggtgaccgtgtcctccttcgtgccggtcttcctgccagcgaagcccaccacgacgccagcgccgcgaccaccaacaccggcgcccaccatcgcgtcgcagcccctgtccctgcgcccagaggcgtgccggccagcggcggggggcgcagtgcacacgagggggctggacttcgcctgtgatatctacatctgggcgcccttggccgggacttgtggggtccttctcctgtcactggttatcaccctttactgcaaacggggcagaaagaaactcctgtatatattcaaacaaccatttatgagaccagtacaaactactcaagaggaagatggctgtagctgccgatttccagaagaagaagaaggaggatgtgaactgagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgccccctcgctaa
在某些实施方案中,CAR(衍生自BCMA-20抗体)可以具有以下氨基酸序列(SEQ IDNO:59):
MALPVTALLLPLALLLHAARPDIQMTQSPSSLSASVGDRVTITCRASQGISNYLNWYQQKPGKAPKPLIYYTSNLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCMGQTISSYTFGQGTKLEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSNFDMAWVRQAPGKGLVWVSSITTGADHAIYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCVRHGYYDGYHLFDYWGQGTLVTVSSFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
在某些实施方案中,编码CAR(衍生自BCMA-CA8抗体)的核酸可以具有以下序列(SEQ ID NO:60):
atggccttaccagtgaccgccttgctcctgccgctggccttgctgctccacgccgccaggccggatatccagctgacccagaccacaagcagcctgagcgcctccctgggcgacagggtgaccattagctgcagcgccagccaggacatcagcaactacctgaactggtaccagcagaagcccgacggcaccgtggagctcgtgatctactacacctccaacctgcacagcggcgtgcccagcaggttctctggcagcggcagcggcaccgactacagcctgaccatcggctatctggagcccgaggacgtcgccacctactactgccagcagtacaggaagctgccctggaccttcggcggaggctctaagctggagattaagcgtggtggcggtggctcgggcggtggtgggtcgggtggcggcggatctgaggtgcagctgcagcagagcggcgccgtgctggccaggcccggagctagcgtgaagatgagctgcaagggcagcggctacaccttcaccaactactggatgcactgggtgaaacagaggcccggccagggactggagtggatcggcgccacctacaggggccacagcgacacctactacaaccagaagttcaagggcaaggccaagctgaccgccgtgacctcaaccagcaccgcctacatggaactgagcagcctgaccaacgaggacagcgccgtctattactgcaccaggggcgccatctacaacggctacgacgtgctggacaattggggccagggaacactagtgaccgtgtccagcttcgtgccggtcttcctgccagcgaagcccaccacgacgccagcgccgcgaccaccaacaccggcgcccaccatcgcgtcgcagcccctgtccctgcgcccagaggcgtgccggccagcggcggggggcgcagtgcacacgagggggctggacttcgcctgtgatatctacatctgggcgcccttggccgggacttgtggggtccttctcctgtcactggttatcaccctttactgcaaacggggcagaaagaaactcctgtatatattcaaacaaccatttatgagaccagtacaaactactcaagaggaagatggctgtagctgccgatttccagaagaagaagaaggaggatgtgaactgagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgccccctcgctaa
在某些实施方案中,CAR(衍生自BCMA-CA8抗体)可以具有以下氨基酸序列(SEQ IDNO:61):
MALPVTALLLPLALLLHAARPDIQLTQTTSSLSASLGDRVTISCSASQDISNYLNWYQQKPDGTVELVIYYTSNLHSGVPSRFSGSGSGTDYSLTIGYLEPEDVATYYCQQYRKLPWTFGGGSKLEIKRGGGGSGGGGSGGGGSEVQLQQSGAVLARPGASVKMSCKGSGYTFTNYWMHWVKQRPGQGLEWIGATYRGHSDTYYNQKFKGKAKLTAVTSTSTAYMELSSLTNEDSAVYYCTRGAIYNGYDVLDNWGQGTLVTVSSFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
在某些实施方案中,编码CAR(衍生自BCMA-MO6抗体)的核酸可以具有以下序列(SEQ ID NO:62):
atggccttaccagtgaccgccttgctcctgccgctggccttgctgctccacgccgccaggccggacatccagatgacccagagccctagctcactgagcgccagcgtgggcgacagggtgaccattacctgctccgccagccaggacatcagcaactacctgaactggtaccagcagaagcccggcaaggcccccaagctgctgatctactacacctccaacctgcactccggcgtgcccagcaggttcagcggaagcggcagcggcaccgatttcaccctgaccatctccagcctgcagcccgaggacttcgccacctactactgccagcagtacaggaagctcccctggactttcggccagggcaccaaactggagatcaagcgtggtggcggtggctcgggcggtggtgggtcgggtggcggcggatctcaggtgcagctggtccagagcggcgccgaagtgaagaagcccggcagctccgtgaaagtgagctgcaaggccagcggcggcaccttcagcaactactggatgcactgggtgaggcaggcccccggacagggcctggagtggatgggcgccacctacaggggccacagcgacacctactacaaccagaagttcaagggccgggtgaccatcaccgccgacaagagcaccagcaccgcctacatggaactgagcagcctcaggagcgaggacaccgctgtgtattactgcgccaggggcgccatctacgacggctacgacgtgctggacaactggggccagggcacactagtgaccgtgtccagcttcgtgccggtcttcctgccagcgaagcccaccacgacgccagcgccgcgaccaccaacaccggcgcccaccatcgcgtcgcagcccctgtccctgcgcccagaggcgtgccggccagcggcggggggcgcagtgcacacgagggggctggacttcgcctgtgatatctacatctgggcgcccttggccgggacttgtggggtccttctcctgtcactggttatcaccctttactgcaaacggggcagaaagaaactcctgtatatattcaaacaaccatttatgagaccagtacaaactactcaagaggaagatggctgtagctgccgatttccagaagaagaagaaggaggatgtgaactgagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgccccctcgctaa
在某些实施方案中,CAR(衍生自BCMA-BCMA-MO6抗体)可以具有以下氨基酸序列(SEQ ID NO:63):
MALPVTALLLPLALLLHAARPDIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKRGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSSFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
嵌合抗原受体T细胞(CAR-T细胞)
如本文所用,术语“CAR-T细胞”、“CAR-T”和“CART”可以互换使用。
本公开涉及靶向BCMA的嵌合抗原受体结构的构建、靶向BCMA的嵌合抗原受体工程化T细胞的制备方法及其活性鉴定。
载体
编码目的分子的核酸序列可以使用本领域已知的重组方法获得,例如,通过从表达该基因的细胞中筛选文库,通过从已知包含该基因的载体中衍生该基因,或者通过使用标准技术从含有该基因的细胞和组织中直接分离来获得。备选地,可以合成产生目的基因。
本公开还提供了其中插入了本公开的表达盒的载体。衍生自逆转录病毒(如慢病毒)的载体是实现长期基因转移的合适工具,因为它们允许转基因的长期、稳定整合及其在子细胞中的繁殖。与衍生自肿瘤逆转录病毒(如鼠白血病病毒)的载体相比,慢病毒载体具有优势,因为它们可以转导非增殖细胞,如肝细胞。它们还具有低免疫原性的优点。
简要总结为,表达盒或核酸序列通常可操作地连接到启动子,并掺入表达载体中。所述载体可以适用于在真核生物中的复制和整合。典型的克隆载体包含可用于调节目的核酸序列表达的转录和翻译终止子、起始序列和启动子。
本公开的表达构建体也可以使用标准基因递送方案用于核酸免疫和基因治疗。基因递送的方法是本领域已知的。参见例如美国专利号5,399,346、5,580,859、5,589,466,通过引用将其全部并入本文作为参考。在另一个实施方案中,本公开提供了一种基因治疗载体。
可以将核酸克隆到多种类型的载体中。例如,可以将核酸克隆到载体中,该载体包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。特别感兴趣的载体包括表达载体、复制载体、探针生成载体和测序载体。
此外,表达载体可以以病毒载体的形式提供给细胞。病毒载体技术在本领域是众所周知的,并且在例如Sambrook等人(2001,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratorie,New York)以及其他病毒学和分子生物学手册中进行了描述。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。通常,合适的载体包含在至少一种生物体中具有功能的复制起点、启动子序列、方便的限制性内切核酸酶位点和一种或多种选择性标记(例如,WO 01/96584;WO 01/29058;和美国专利号6326193)。
已经开发了许多基于病毒的系统用于将基因转移到哺乳动物细胞中。例如,逆转录病毒为基因递送系统提供了一个方便的平台。可以使用本领域已知的技术将选定的基因插入载体并包装入逆转录病毒颗粒中。然后可以在体内或离体(ex vivo)分离重组病毒并将其递送到受试者的细胞中。本领域已知许多逆转录病毒系统。在一些实施方案中,使用腺病毒载体。本领域已知许多腺病毒载体。在一个实施方案中,使用慢病毒载体。
额外的启动子元件,例如增强子,调节转录起始的频率。通常,它们位于起始位点上游30-110bp的区域,尽管最近已经显示许多启动子也包含起始位点下游的功能元件。启动子元件之间的间隔通常是灵活的,因此当元件相对于彼此倒置或移动时,启动子功能得以保留。在胸苷激酶(tk)启动子中,在活性开始下降之前,启动子元件之间的间隔可以增加到50bp。根据启动子的不同,似乎各个元件可以协同或独立地发挥作用来激活转录。
合适的启动子的一个例子是立即早期巨细胞病毒(CMV)启动子序列。该启动子序列是强组成型启动子序列,能够驱动与其有效连接的任何多核苷酸序列的高水平表达。合适的启动子的另一个例子是延伸生长因子-1α(EF-1α)。但是,也可以使用其他组成型启动子序列,包括但不限于猿猴病毒40(SV40)早期启动子、小鼠乳腺肿瘤病毒(MMTV)、人免疫缺陷病毒(HIV)长末端重复(LTR)启动子、MoMuLV启动子、禽白血病病毒启动子、爱泼斯坦-巴尔病毒立即早期启动子、劳斯肉瘤病毒启动子,以及人基因启动子,例如但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。此外,可以使用组成型启动子或诱导型启动子。诱导型启动子的使用提供了一种分子开关,该分子开关能够在需要这种表达时开启其有效连接的多核苷酸序列的表达,或者在不需要表达时关闭表达。诱导型启动子的实例包括但不限于金属硫蛋白启动子、糖皮质激素启动子、黄体酮启动子和四环素启动子。
为了评估CAR多肽或其部分的表达,待引入细胞中的表达载体也可以含有选择标记基因或报告基因,或含有这两者,以便于从寻求通过病毒载体转染或感染的细胞群中鉴定和选择表达细胞。在其他方面,选择性标记可以携带在分别的DNA片段上,并用于共转染程序。适当的调控序列可以在选择性标记和报告基因的侧翼,以使其能够在宿主细胞中表达。有用的选择性标记包括例如抗生素抗性基因,例如neo等。
报告基因用于鉴定潜在转染的细胞并用于评估调节序列的功能性。一般来说,报告基因是一种不存在于受体生物体(recipient organism)或组织中或不由其表达的基因,并且报告基因编码多肽,该多肽的表达通过一些容易检测的特性例如酶活性来表现。在将DNA引入受体细胞(recipient cell)后的适当时间测定报告基因的表达。合适的报告基因可以包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌型碱性磷酸酶的基因或绿色荧光蛋白基因(例如,Ui-Tei等人,2000FEBS Letters 479:79-82)。合适的表达系统是众所周知的,并且可以使用已知技术制备或商业获得。通常,将具有最小5'侧翼区的、显示出最高水平报告基因表达的构建体鉴定为启动子。这类启动子区可以与报告基因连接,并用于评估试剂调节启动子驱动的转录的能力。
将基因引入到细胞中并表达的方法是本领域已知的。在表达载体的上下文中,可以通过本领域的任何方法将载体容易地引入宿主细胞,例如哺乳动物、细菌、酵母或昆虫细胞。例如,可以通过物理、化学或生物学手段将表达载体转移到宿主细胞中。
将多核苷酸引入宿主细胞的物理方法包括磷酸钙沉淀、脂转染、粒子轰击、显微注射、电穿孔等。产生包含载体和/或外源核酸的细胞的方法在本领域是众所周知的。参见例如Sambrook等人(2001,Molecular Cloning:A Laboratory Manual,Cold Spring HarborLaboratory,New York)。将多核苷酸引入宿主细胞的一种方法是磷酸钙转染。
将目的多核苷酸引入宿主细胞的生物学方法包括使用DNA和RNA载体。病毒载体,尤其是逆转录病毒载体,已经成为将基因插入哺乳动物(例如人细胞)中最广泛使用的方法。其他病毒载体可以衍生自慢病毒、痘病毒、单纯疱疹病毒I、腺病毒和腺相关病毒等。参见例如,美国专利号5,350,674和5,585,362。
将多核苷酸引入宿主细胞的化学手段包括胶体分散系统,如大分子复合物、纳米胶囊、微球、珠、以及基于脂质的系统,包括水包油乳液、胶束、混合胶束和脂质体。在体外和体内用作递送运载体的示例性胶体系统是脂质体(例如,人工膜泡)。
在使用非病毒递送系统的情况下,示例性递送运载体是脂质体。考虑使用脂质制剂,用于将核酸(体外、离体或体内)引入宿主细胞。在另一方面,核酸可以与脂质相关联。与脂质相关联的核酸可以是将核酸包封在脂质体的水性内部,散布在脂质体的脂双层内,通过与脂质体和寡核苷酸这两者均缔合的连接分子连接到脂质体,包埋在脂质体中,与脂质体复合,分散在含有脂质的溶液中,与脂类混合,与脂质组合,以悬浮液的形式包含在脂质中,包含胶束或与胶束复合,或以其他方式与脂质缔合。脂质、脂质/DNA或脂质/表达载体相关的组合物不限于溶液中的任何特定结构。例如,它们可能以双层结构、胶束或“塌陷的”结构存在。它们也可以简单地分散在溶液中,可能形成大小或形状不均匀的聚集体。脂质是脂肪物质,可能是天然存在的或是合成的脂质。例如,脂质包括天然存在于细胞质中的脂肪小滴,以及含有长链脂族烃及其衍生物的一类化合物,如脂肪酸、醇、胺、氨基醇和醛。
在一个实施方案中,所述载体是慢病毒载体。
组合物
本公开提供了包含免疫细胞(例如CAR-T细胞)和可药用载体、稀释剂和/或赋形剂的组合物。在一个实施方案中,所述组合物是液体组合物。例如,该组合物是可注射的组合物。在某些实施方案中,组合物中CAR-T细胞的浓度为1×103-1×108个细胞/ml,或1×104-1×107个细胞/ml。
在一个实施方案中,所述组合物可以包含缓冲剂,例如中性缓冲盐水、磷酸盐缓冲盐水等;碳水化合物,如葡萄糖、甘露糖、蔗糖或右旋糖酐、甘露醇;蛋白质;多肽或氨基酸,例如甘氨酸;抗氧化剂;螯合剂,例如EDTA或谷胱甘肽;佐剂(例如氢氧化铝);和防腐剂。该组合物可以配制用于静脉内施用。
治疗应用
本公开包括使用细胞(例如T细胞)的治疗应用,其中所述细胞(例如T细胞)用编码本公开的表达盒的慢病毒载体(LV)转导。经转导的T细胞可以靶向肿瘤细胞标志物BCMA,协同激活T细胞,并引起T细胞免疫反应,从而显著提高对肿瘤细胞的杀伤效率。
因此,本公开还提供了一种用于刺激T细胞介导的对哺乳动物中的靶细胞群体或组织的免疫应答的方法,包括向哺乳动物施用本公开的CAR-T细胞的步骤。
在一个实施方案中,本公开包括一类细胞疗法,其中分离来自自体患者(或异源供者)的T细胞、活化和基因修饰以产生CAR-T细胞,然后注射到同一患者中。以这种方式发生移植物抗宿主疾病的概率极低,并且抗原以非MHC限制的方式被T细胞识别。此外,一种CAR-T可以治疗所有表达抗原的癌症。与抗体疗法不同,CAR-T细胞能够在体内复制,产生长期持久性,从而导致持续控制肿瘤。
在一个实施方案中,本公开的CAR-T细胞可以经历强有力的体内T细胞扩增,并且可以持续较长的时间。此外,CAR介导的免疫应答可以是过继免疫疗法方法的一部分,在过继免疫疗法中,CAR修饰的T细胞诱导对CAR中的抗原结合部分特异的免疫应答。例如,抗BCMA CAR-T细胞引发针对表达BCMA的细胞特异的免疫应答。
尽管本文公开的数据特别公开了慢病毒载体,其包含BCMA scFv、铰链和跨膜结构域以及4-1BB和CD3ζ信号传导结构域,但本公开应被解释为包括本文其他地方所述的构建体的每个组分的任何数量的变异。
可以治疗的癌症包括未血管化或大部分未血管化的肿瘤,以及血管化的肿瘤。癌症可能包括非实体瘤(如血液学肿瘤,例如白血病和淋巴瘤)或实体瘤。待用CAR治疗的癌症类型包括但不限于癌(carcinoma)、母细胞瘤和肉瘤,以及某些白血病或淋巴系统恶性肿瘤、良性和恶性肿瘤,以及恶性肿瘤,例如肉瘤、癌和黑素瘤。成人肿瘤/癌症和儿童肿瘤/癌症也包括在内。
血液学癌是血液或骨髓的癌症。血液学癌(或血源性癌)的例子包括白血病,白血病包括急性白血病(如急性淋巴细胞白血病、急性髓细胞白血病(acute myelocyticleukemia)、急性粒细胞白血病(acute myelogenous leukemia)和成髓细胞、早幼细胞白血病、粒单核细胞白血病、单核细胞和红细胞白血病)、慢性白血病(如慢性髓细胞(粒细胞)白血病、慢性粒细胞白血病和慢性淋巴细胞白血病),真性红细胞增多症,淋巴瘤,霍奇金病,非霍奇金淋巴瘤(惰性和高分级型),多发性骨髓瘤,Waldenstrom巨球蛋白血症,重链疾病,骨髓增生异常综合征,毛细胞白血病和骨髓发育不良。
实体瘤是指通常不包含囊肿或液体区域的异常组织块。实体瘤可以是良性的,也可以是恶性的。不同类型的实体瘤是根据形成它们的细胞类型命名的(如肉瘤、癌(carcinoma)和淋巴瘤)。实体瘤如肉瘤和癌的例子包括纤维肉瘤、黏液肉瘤、脂肪肉瘤、间皮瘤、恶性淋巴瘤、胰腺癌和卵巢癌。
CAR修饰的T细胞也可以用作哺乳动物的离体免疫和/或体内治疗的一种疫苗。优选地,哺乳动物是人。
关于离体免疫(ex vivo immunization),在将细胞施与哺乳动物之前,在体外发生以下至少一种:i)扩增细胞,ii)将编码CAR的核酸引入细胞,和/或iii)冷冻保存细胞。
离体程序在本领域中是众所周知的,并且将在下面更全面地讨论。简言之,从哺乳动物(如人)中分离细胞,并用表达本文公开的CAR的载体进行基因修饰(即,体外转导或转染)。CAR修饰的细胞可以施与哺乳动物受者以提供治疗益处。哺乳动物受者可以是人,并且CAR修饰的细胞可以是相对于该受者是自体的。备选地,相对于该受者,细胞可以是同种异体(异基因)的(allogeneic)、同基因的(syngeneic)或异种的(xenogeneic)。
除了在离体免疫方面使用基于细胞的疫苗外,本公开还提供了用于体内免疫的组合物和方法,以在患者中引发针对抗原的免疫应答。
本公开提供了治疗肿瘤的方法,包括给有需要的受试者施用治疗有效量的CAR修饰的T细胞。
本公开的CAR修饰的T细胞可以单独施用,或作为药物组合物与稀释剂和/或与其他成分如IL-2、IL-17或其他细胞因子或细胞群组合施用。简言之,本公开的药物组合物可以包含本文所述的靶细胞群(target cell population)与一种或多种药学或生理学可接受的载体、稀释剂或赋形剂的组合。这类组合物可以包含缓冲剂,例如中性缓冲盐水、磷酸盐缓冲盐水等;碳水化合物,如葡萄糖、甘露糖、蔗糖或右旋糖酐、甘露醇;蛋白质;多肽或氨基酸,例如甘氨酸;抗氧化剂;螯合剂,例如EDTA或谷胱甘肽;佐剂(例如氢氧化铝);和防腐剂。本公开的组合物可以配制用于静脉内施用。
本公开的药物组合物可以以适合于待治疗(或预防)的疾病的方式施用。施用的数量和频率将由患者的病情、患者疾病的类型和严重程度等因素决定,尽管临床试验可能确定适当的剂量。
当谈及“免疫有效量”、“抗肿瘤有效量”,“肿瘤抑制有效量”或“治疗量”时,医生可以考虑年龄、体重、肿瘤大小、感染或转移程度的个体差异、以及患者(受试者)的状况来确定待施用的本公开的组合物的精确量。通常可以说,包含本文所述T细胞的药物组合物可以以104至109个细胞/kg体重或105至106个细胞/kg体重的剂量施用,包括这些范围内的所有整数值。T细胞组合物也可以以这些剂量多次施用。这些细胞可以通过使用免疫疗法中常见的输注技术来施用(参见例如,Rosenberg等人,New Eng.J.of Med.319:1676,1988)。医学领域的技术人员可以通过监测患者的疾病迹象并相应地调整治疗来容易地确定特定患者的最佳剂量和治疗方案。
可以以任何方便的方式进行主题组合物的施用,包括通过气溶胶吸入、注射、摄入、转输、植入或移植。本文所述的组合物可通过皮下、皮内、瘤内、结节内、髓内、肌内、静脉注射或腹膜内施用于患者。在一个实施方案中,本公开的T细胞组合物通过皮内或皮下注射施与患者。在另一个实施方案中,本公开的T细胞组合物可以通过静脉注射施用。T细胞的组合物可以直接注射入肿瘤、淋巴结或感染部位。
在本公开的某些实施方案中,使用本文所述方法或本领域已知的将T细胞扩增到治疗水平的其他方法来活化和扩增的细胞施与患者,(例如,在此之前、同时或之后)组合任何数量的相关治疗模式,包括但不限于使用试剂治疗,诸如抗病毒治疗、西多福韦(cidofovir)和白细胞介素-2、阿糖胞苷(也称为ARA-C)或用于MS患者的那他珠单抗(natalizumab)治疗、或者用于银屑病患者的依法珠单抗(efalizumab)治疗或用于PML患者的其他治疗。在进一步的实施方案中,本公开的T细胞可以与化疗、放射、免疫抑制剂如环孢菌素、硫唑嘌呤、甲氨蝶呤、霉酚酸酯和FK506、抗体或其他免疫治疗剂组合使用。在进一步的实施方案中,将本公开的细胞组合物与骨髓移植相关联地(例如,在骨髓移植之前、同时或之后)施与患者,或者使用化疗剂如氟达拉滨、外束放射治疗(external-beam radiationtherapy,XRT)、环磷酰胺。例如,在一个实施方案中,受试者可以接受高剂量化疗、然后进行外周血干细胞移植的标准治疗。在某些实施方案中,在移植之后,受试者接受本公开的经扩增免疫细胞的输注。在一个额外的实施方案中,在手术之前或之后施与经扩增的细胞。
待施与患者的上述治疗的剂量将随着被治疗的疾病的确切性质和治疗的接受者而变化。可以根据本领域公认的实践进行用于患者施用的剂量缩放。通常,可以通过例如每次治疗或每个疗程的静脉输注的方式将本公开的1×106至1×1010个经修饰的T细胞(例如,CAR-T-BCMA细胞)应用于患者。
本公开的主要优点包括:
(a)关于本公开的嵌合抗原受体,细胞外抗原结合结构域是特异性抗BCMA scFv;CAR已经显示出以低细胞毒性和低副作用杀死肿瘤细胞的强大能力。
(b)本公开提供的嵌合抗原受体可以在T细胞被携带该CAR基因的病毒载体(例如慢病毒)感染后实现CAR蛋白的稳定表达和膜定位。
(c)本公开的CAR修饰的T细胞具有较长的体内存活时间和强的抗肿瘤作用。本公开中使用的scFv可以是人源化或人衍生的抗体,并且不太可能产生特异性免疫排斥反应。
以下将参考具体实施例进一步说明本公开内容。应当理解,这些实施例仅用于说明目的,并不旨在限制本发明的范围。对于以下实施例中的实验方法,其具体条件没有具体指出,它们是在常规条件下进行的,例如Sambrook等人,Molecule Clone:A LaboratoryManual,New York:Cold Spring Harbor Laboratory Press,1989所描述的那些条件,或者按照制造商的指示实施,除非另有规定。除非另有说明,否则百分数和份数(parts)均按重量计算。
实施例1慢病毒表达载体的构建
委托上海博益生物科技有限公司(Shanghai Boyi Biotechnology Co.,Ltd)进行全长DNA合成和克隆,以实现编码质粒的构建。选择pWPT慢病毒载体作为克隆载体,且克隆位点为BamH I和Sal I位点。具体序列如上所述。
实施例2CAR-T细胞的制备
(1)通过密度梯度离心从健康人的静脉血中分离出单个核细胞(PBMC)。
(2)在第0天,将PBMC接种在细胞培养烧瓶中,所述细胞培养烧瓶预先用终浓度为5μg/mL的CD3单克隆抗体(OKT3)和终浓度为10μg/mL的Retronectin(购自TAKARA)包被。培养基为含有1%人白蛋白的GT-551细胞培养基。将重组人白细胞介素2(IL-2)以1000U/mL的最终浓度加入培养基中。细胞在37℃、饱和湿度为5%的CO2培养箱中培养。
(3)在第1天,缓慢吸出并丢弃培养的PBMC的上清液。添加含有1%人白蛋白的新GT-551细胞培养基,并将重组人白细胞介素2(IL-2)以1000U/mL的最终浓度添加到培养基中。细胞在37℃、饱和湿度为5%的CO2培养箱中继续培养。
(4)在第3天,加入新鲜培养基、浓缩和纯化的CAR BCMA慢病毒溶液、鱼精蛋白硫酸盐(12ug/ml)和IL-2(终浓度为1000U/ml)。在37℃ 5% CO2培养箱中感染12小时后,丢弃培养基,加入新鲜培养基,并在37℃ 5% CO2培养箱中继续培养。
(5)从第6天开始,可以取CAR BCMA细胞进行相应的活性测定。
实施例3检测CAR基因在T细胞基因组中的整合率及其编码的蛋白在膜表面的表达水平
分别取实施例2中第7天(图3A)、第21天(图3B)和第29天(图3C)培养的0.5×106个CART-BCMA细胞样品。重组人BCMA蛋白Fc片段染色后,通过流式细胞术分析CAR-BCMA蛋白在T细胞膜表面的表达水平。
结果如图3A、图3B和图3C所示,本公开设计的四种CAR结构可以在它们相应的经修饰T细胞中表达,并完成细胞膜表面定位。
实施例4CAR BCMA体外激活能力的检测
使用实施例2中第7天培养的CART-BCMA细胞检测细胞活化水平指示蛋白CD137和IFNγ。第7天培养的1×105个CART-BCMA细胞分别与BCMA阳性K562-BCMA+E7肿瘤细胞系和BCMA阴性K562肿瘤细胞系或不与肿瘤细胞在200μl GT-551培养基中以1:1的比例培养18h。然后通过流式细胞术检测T细胞膜表面CD137的表达水平,并通过ELISA检测培养上清液中IFNγ的分泌水平。
结果如图4A和图4B所示,在四种CART细胞的表面检测到CD137的表达,并在培养上清液中检测到IFNγ的表达。其中CAR-BCMA-20显示最佳的CD137激活水平和IFNγ释放水平。基于人源化MO6抗体序列构建的CART-BCMA-MO6显示出比基于小鼠抗体序列构建的CART-BSCMA-CA8弱的CD137激活水平,但更高水平的IFNγ释放。
此外,与基于BCMA-1、BCMA-CA8和BCMA-MO6的CAR相比,C-CAR088诱导了BCMA阳性肿瘤细胞中的更高水平的IFN-γ释放(图4B)和CD137表达(图4A)。
与CART-BCMA-1(阳性对照)、CART-BCMA-MO6和CART-BCMA-CA8相比,CART-BCMA-20诱导的BCMA阳性肿瘤细胞凋亡更大(图5)。
实施例5由CART-BCMA细胞诱导的肿瘤细胞的晚期凋亡活性的检测
(1)将实施例2中第17天培养的CART-BCMA细胞分别与1×104个CFSE标记的BCMA阴性细胞(NH929)或BCMA阳性自建细胞(NH929-BCMA过量表达的肿瘤细胞系)以1:1、2.5:1、5:1、10:1、20:1的比例混合(如图5所示)。将混合的细胞在100μl GT-551培养基中共培养4小时,然后用100μl 25% PI染料染色15分钟。通过流式细胞术分析CFSE阳性细胞中PI阳性细胞的比例。
(2)将实施例2中第22天培养的CART-BCMA细胞分别与1×104个CFSE标记的BCMA阴性细胞(NH929)、BCMA阳性自构建细胞(NH929-BCMA过量表达的肿瘤细胞系)或天然表达BCMA的MM.1S细胞系以1:1,5:1,10:1,10:1,40:1的比例混合(如图6B所示)。将混合的细胞在100μl GT-551培养基中共培养4小时,然后用100μl 25% PI染料染色15分钟。通过流式细胞术分析CFSE阳性细胞中PI阳性细胞的比例。
结果如图5和图6A和图6B所示,所有四个CART细胞都可以诱导BCMA阳性肿瘤细胞凋亡。其中,CART-BCMA-20比CART-BCMA-1更能诱导BCMA阳性肿瘤细胞的晚期凋亡(advanced apoptosis)。CART-BCMA-MO6和CART-BCMA-CA8诱导BCMA阳性肿瘤细胞晚期凋亡的能力相似。
实施例6CART-BCMA对RPMI-8226骨髓瘤异种移植模型的抑制
收集对数生长期的RPMI-8226细胞,并在6-8周龄B-NDG小鼠的右背部皮下接种4.0×106个肿瘤细胞。当肿瘤体积达到约120mm3时,根据肿瘤体积将动物随机分为4组,使每组的肿瘤体积差异小于平均值的10%。然后通过尾静脉分别注射溶剂对照、7.5×10 6NT和7.5×106个CART-BCMA细胞。
结果如图7A和图7B所示,与对照组相比,尾静脉单次注射CART-BCMA-1和CART-BCMA-20可以有效抑制人骨髓瘤RPMI-8226细胞的生长(相对肿瘤增殖率%T/CRTV≤40%,P<0.05%),并能显著延长人骨髓瘤荷瘤小鼠的生存时间(对照组的中位生存期为23天,CART-BCMA治疗组的中位生存期>33天)。在用CART-BCMA-1和CART-BCMA-20处理的小鼠之间,肿瘤增殖率和中位生存期没有显著性差异。
对于体内研究,将B-NDG小鼠用人骨髓瘤RPMI-8226细胞异种移植。当肿瘤体积达到约120mm3时,通过小鼠尾静脉注射溶剂对照、未转染的(NT)T细胞(阴性对照)或CART-BCMA细胞。
与对照组相比,单次注射CART-BCMA-1和CART-BCMA-20有效抑制骨髓瘤细胞的生长,并显著延长了人骨髓瘤荷瘤小鼠的生存时间:CART-BCMA处理组的中位生存期>33天,而对照组的中位生存期为23天。用CART-BCMA-1处理的小鼠和用CART-BCMA-20处理的小鼠之间的肿瘤增殖率和中位生存期没有显著性差异(图7A和图7B)。
这些结果表明,BCMA-20(C-CAR088)具有高的体内抗肿瘤功效。
比较例
在本申请的嵌合抗原受体的筛选过程中,本发明人测试了大量的候选序列,这些候选序列在下面用实例说明。
待筛选的抗体包括:BCMA-1,BCMA-2,BCMA-69,BCMA-72,BCMA-2A1,BCMA-1E1,BCMA-J22.9,BCMA-20,BCMA-CA8和BCMA-MO6。以上述抗体为基础构建了靶向BCMA的嵌合抗原受体的结构。其中,BCMA-1和BCMA-2是已发表的Car-T序列,且用作筛选的阳性对照。以与实施例2相同的方式制备CAR-T细胞,并以与实施例3和4相同的方式检测CAR-T细胞。
结果如图1A、图1B和图1C所示,它们是两批CAR-T细胞的实验结果。用BCMA-Fc融合蛋白检测Car-T的表达。可以看出,在原代T细胞中有高表达,如图1A所示。在图1B中,可以看出BCMA抗原可以激活BCMA-1,BCMA-20,BCMA-1E1,BCMA-CA8,BCMA-MO6和BCMA-J22.9。图1C显示,活化的BCMA-1,BCMA-20,BCMA-1E1,BCMA-CA8,BCMA-MO6和BCMA-J22.9 CAR-T可以产生更高水平的IFN-γ。这些结果表明,BCMA-1、BCMA-20、CA8和MO6获得的CAR-T功能相似,因此对BCMA-20、CA8和MO6 CAR-T进行了进一步的分析和研究。
实施例7膜蛋白阵列实验
使用SEQ ID NO:1的轻链可变区和SEQ ID NO:2的重链可变区制备单链抗体B20-scFv-rabFc,并进行膜蛋白阵列实验。
将20ug/mL B20-scFv-rabFc分别添加到用5344种膜蛋白瞬时转染的HEK293T细胞阵列。流式细胞术发现,在这种测试条件下,B20-scFv-rabFc可以用TNFRSF17(Q02223),MAG(P20916),CR2(P20023),CXADR(P78310)和DDR2(Q16832)交叉识别,其中TNFRSF17,即BCMA,是B20-scFv的特异性靶,而MAG,CR2,CXADR和DDR2是可疑的非特异性靶。
为了进一步证实可疑的靶是否能引起CAR-T的激活,将CBM.BCMA CAR-T与分别用BCMA、CR2、CXADR、DDR2和MAG转染的293T细胞共培养。检测共培养上清液中的IFNγ、TNF、IL-2和其他细胞因子。用空载体转染的293T细胞用作阴性对照,且用BCMA转染的293T细胞用作阳性对照。
图8显示了通过流式细胞术检测转染相关质粒后,293T细胞中BCMA、CR2、CXADR、DDR2和MAG的表达。
图9A、图9B和图9C显示了细胞因子检测结果。只有在293T细胞上表达的BCMA才能诱导CBM.BCMA CAR-T细胞产生大量IFNγ/TNF/IL-2,而其他四种非特异性表面标志物不能激活CBM.BCMA CAR-T细胞。
图8和图9A-图9C显示了全基因组膜蛋白质组阵列和验证。鉴定了TNFRSF17、MAG、CR2、CXADR和DDR2在浓度20.0μg/mL与B-20scFv rabFc中度结合。只有表达TNFRSF17(BCMA)的细胞才能诱导BCMA-CAR-T细胞产生大量细胞因子(IFNγ/TNF/IL-2)。
在胸腺、脾脏、淋巴结、骨髓中的人淋巴细胞以及甲状腺、肾上腺中的散在淋巴细胞上观察到20.0μg/mL浓度时的特异性膜染色(表1和图19A-图19B)。
表1
a)3名供者的阳性染色数量。
b)阳性细胞的染色强度和同类型细胞中阳性细胞的百分比。
“-”无染色的细胞,
“+”弱阳性染色,﹤10%的细胞被染色,
“++”中等阳性染色,11%-50%的细胞被染色。
实施例8C-CAR088细胞的体外抗肿瘤活性
选择嵌合抗原受体BCMA-20(以下称为C-CAR088)用于随后的实验。将C-CAR088细胞、NT细胞(未转染的T细胞,用作阴性对照)和阳性对照细胞(蓝鸟bb2121)与BCMA阴性细胞(NH929)或BCMA阳性细胞(NH929-BCMA)以不同的效靶比共同培养,分析各细胞对靶细胞的杀伤能力。
结果如图10所示。C-CAR088细胞和阳性对照细胞仅对NH929-BCMA细胞具有强的杀伤作用,而对阴性靶细胞NH929没有显著的杀伤作用。未转染组(NT)对靶细胞也没有显著的杀伤作用。
将具有C-CAR088的T细胞、未转染的(NT)T细胞(阴性对照)和阳性对照细胞(蓝鸟bb2121)与BCMA阴性细胞(NH929)或BCMA阳性细胞(NH929-BCMA)以不同的效/靶比共同培养。然后测定细胞毒性。
图10显示,C-CAR088 T细胞和阳性对照对NH929-BCMA细胞表现出强的细胞毒性,但对NH929细胞没有。
实施例9可溶性BCMA对细胞杀伤活性的影响
在C-CAR088细胞与BCMA阴性靶细胞A549和BCMA阳性靶细胞A549-BCMA-2E9的共培养系统中,分别加入100ng/ml和500ng/ml可溶性BCMA蛋白以检测其对CD137表达的影响。
结果如图11所示。可溶性BCMA蛋白对CD137表达的上调没有影响,表明可溶性BCMA不阻断CAR和靶抗原的特异性识别。在体外细胞杀伤能力测试和IFN-γ释放的ELISA中,500ng/ml可溶性BCMA蛋白减少了C-CAR088细胞对靶细胞的杀伤作用和IFN-γ的释放,但没有显著性差异。上述结果表明,可溶性BCMA基本上不影响C-CAR088细胞的细胞杀伤活性。
实施例10C-CAR088细胞的剂量依赖性效应
选择6周龄的B-NDG小鼠(一半雄性,一半雌性),并腹膜内注射2.5×106个人多发性骨髓瘤细胞RPMI-8226。选择肿瘤负荷相似的小鼠,分为5组,分别注射2.5×106个C-CAR088细胞(低剂量组)、5×106个C-CAR088细胞(中剂量组)、1×107个C-CAR088细胞(高剂量组)、T细胞和载剂(以冷冻保护剂(CBMG C-CFMC)作为载剂)。实验持续了54天。在实验过程中,每5天对小鼠的肿瘤负荷进行评估。在实验结束时,计算小鼠的存活率。
结果如图12所示。单次施用5×106个细胞/小鼠和1×107个细胞/小鼠剂量的C-CAR088细胞可以有效抑制人骨髓瘤RPMI-8226细胞的B-NDG小鼠异种移植肿瘤的生长。相对肿瘤增殖率分别为6.12%和0.75%(p<0.05)。实验结束时,中剂量组荷瘤小鼠的存活率为91.7%(11/12)。高剂量组荷瘤小鼠无死亡,存活率为100.0%(12/12),与载剂组(存活率58.3%)相比有显著性差异(p<0.05)。上述结果表明,C-CAR088显示剂量依赖性的体内抗肿瘤活性。
实施例11C-CAR088的I期临床研究
经伦理委员会批准,共有15名志愿者进行了I期临床试验。志愿者的主要资格标准如下:18-75岁的多发性骨髓瘤患者,MM细胞表达BCMA,具有可测量的MM,曾接受过2种MM治疗,并接受过PI和IMiD治疗,具有足够的肝、肾、心脏和造血功能。
实验过程如图13所示。
治疗结果如图14和表2所示。两名患者在第2周进行评估,一名SD和一名CR。其余13名患者在第4周进行评估。客观应答率ORR达到100%。在所有患者中,有3例CR,5例VGPR(包括1例Daratumumab耐药患者)和6例PR。
表2临床应答
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治疗中出现的不良事件如表3所示。在15名患者中,只有一名患者出现3级细胞因子释放综合征。在剂量递增中未观察到神经毒性事件和剂量限制毒性(DLT)。血细胞减少主要与Cy/Flu淋巴细胞耗竭有关。需要注意的是,治疗后出现某种程度的细胞因子释放综合征也从侧面说明了CART治疗的有效性。15名患者中没有一人有特别严重的细胞因子,C-CAR088具有较好的安全性。
表3治疗出现的不良事件
治疗出现的不良事件 | n(%)总体 | n(%)等级3/4 |
细胞因子释放综合征 | 14(93) | 1(7) |
中性粒细胞减少症 | 15(100) | 15(100) |
血小板减少症 | 13(87) | 11(73) |
贫血 | 12(80) | 6(40) |
增加的AST | 5(33) | 3(20) |
感染 | 3(20) | 3(20) |
图15显示了ID为Z0203-00801C008的患者的治疗情况。图16显示了ID为Z0203-00701C001的患者的治疗情况。一名患者的癌症病变的PET-CT图像显示,C-CAR088治疗后骨髓中的异常浆细胞显著减少(图15)。图16A和图16B显示,在实验开始时(基线),大多数PC是异常的(>90%是CD45lo/-),是BCMA+和κ轻链的克隆。图16B显示,BCMA CAR-T治疗14或28天后,BM中的异常PC显著降低,尤其是κ+PC从85.2%的基线水平降至0%。
图17显示了血液中C-CAR088的扩增和M-蛋白/sFLC水平的降低。结果表明,注射后C-CAR088细胞有效扩增,M-蛋白/sFLC标志物水平持续下降。一名患者的M-标志物水平在第14天降至0。
C-CAR088的观测结果总结如下。
·在临床前研究中,C-CAR088在体外和体内均显示出抗肿瘤活性。
·在患有r/r MM患者中的早期C-CAR088试验结果支持临床前发现,显示出有前景的功效和可管理的安全特性。
·低的次优剂量的早期临床功效信号是令人鼓舞的。
·与KarMMa数据相比,我们目前来自输注患者的剂量水平远低于bb2121的最佳剂量。53%(8/15)最近施用(约4周)。
·基于PK曲线观察剂量依赖性。患者中C-CAR088是良好耐受的。
实施例12抗BCMA CAR T细胞疗法(C-CAR088)在治疗复发性或难治性多发性骨髓瘤(r/r MM)中显示出有希望的安全性和功效特性
我们的研究表明,与其他抗BCMA CAR相比,C-CAR088在体外和体内对肿瘤细胞具有显著更高的细胞毒性。
我们进行了一项抗BCMA CAR(BCMA-20,也称为“C-CAR088”)治疗复发/难治性多发性骨髓瘤(R/R MM)患者的临床试验。
临床试验是根据许多不同的标准进行评估的。两个关键指标是总应答率(ORR)和完全应答率(CR)。与其他抗BCMA CAR相比,所要求保护的方法的CAR在临床试验中提供更好的治疗效果,这反映在治疗复发/难治性多发性骨髓瘤(R/R MM)的高应答率(95%的总应答率或ORR,以及67%的完全应答率或CR)上。即使与JNJ-4528(CARTITUDE-1)相比,C-CAR088中的不良事件(如神经毒性)的百分数也显著较低。具体而言,对于C-CAR088,只有4%的患者经历1级神经毒性,并自行缓解。因此,所要求保护的方法的CAR-T细胞提供了有利的安全性。
C-CAR088展示了可管理的安全特性。
·大多数CRS病例为等级1/2,中位发病时间为6天。
·神经毒性(ICANS)不常见,且一般为低等级,具有1级1事件。
剂量依赖性应答早期出现并加深。
·ORR:95.7%,在至CR的中位时间1.6个月处是43.5% CR率(范围:0.5-9.5)。至应答的中位时间:0.5个月。
·在中位值为6.2个月的随访中,65.1%的患者在6个月时没有进展
在临床前研究中,C-CAR088显示出非常好的体外和体内抗肿瘤活性和靶特异性。24例r/r MM患者的临床试验结果显示,强的治疗指数,具有有前景的疗效和可管理的安全特性。
我们进行了一项抗BCMA CAR(BCMA-20,也称为“C-CAR088”)治疗复发/难治性多发性骨髓瘤(R/R MM)患者的临床试验。在我们的抗BCMA CAR治疗开始之前,患者的基线人口统计和临床特征如表4所示。
施用患者的中位年龄为60岁(范围:45-74岁)。既往治疗线的中位数为4个(范围为2-12个既往治疗)。所有患者之前都接受过IMiDs(免疫调节药物)和蛋白酶体抑制剂的治疗。25%的患者以前用抗CD38单克隆抗体治疗过,而25%的患者接受过自体造血干细胞移植。
表4患者的基线临床特征汇总
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*包括1q21增益,del(17p),t(4;14)和t(14;16)。
临床方案以及关键纳入标准如图21所示。具体而言,招募合格的受试者,并使用收集的外周血白细胞产生CAR-T细胞(C-CAR088)。然后将CAR-T细胞冷冻并储存在-135℃以下直至使用。对于CAR-T治疗,将CAR-T细胞解冻,并在30-45分钟内完成施用。
在CAR-T输注前-5天和-3天,患者接受淋巴耗竭预处理,包括氟达拉滨(fludarabine)(30mg/m2/d,静脉内注射,每天一次,持续三天)和环磷酰胺(300mg/m2/d、静脉内注射,每天一次,连续三天)。
淋巴耗竭后约72小时,患者在第0天施用1.0-6.0x 106个CAR-T细胞/kg,作为3+3剂量递增。从第1天开始输注后到第24个月对患者进行随访。
主要目标包括安全性:剂量限制毒性评级;治疗突发不良事件的发生率和严重性(CTCAEV5.0)。次要目标包括疗效:IMWG 2016ORR;DOR;PFS;OS。探索性目标包括CAR-T的扩增和持久性。
如图22所示,我们的抗BCMA CAR-T试验的总应答率(ORR,包括CR和PR)为96%。最佳总应答(BOR)包括12个严格完全应答(sCR)、2个完全应答(CR)、8个非常好的部分应答(VGPR)和1个部分应答(PR)。完全应答(CR)为67%。(SD:稳定的疾病;PR:部分应答;CR:完全应答;PD:进行性疾病;MR:最小应答;VGPR:非常好的部分应答;MRD:最小残留疾病。)
总剂量组和每个剂量组的CR/sCR、VGPR和PR如表5和图23所示。在3.0-6.0x106个CAR-T细胞/kg剂量组中,在10-4 -10-6时通过流式细胞术可见,14/21(66.7%)患者实现了CR/sCR,且所有(14/14)患者实现MRD阴性。
表5
*1名患者接受4.5x 106/kg和1名患者接受5.0x 106/kg.
下表6将C-CAR088试验与Munshi等人(KarMMa:Idecabtagene Vicleucel),Mailankody等人(EVOLVE:Orvacabtagene Autoleucel)和Madduri等人(CARTITUDE-1:JNJ-4528)的试验进行了比较。
表6C-CAR088临床试验与其他BCMA特异性CAR的比较
*包括+1q21。+PFS在最低剂量队列中(300x 106个细胞)。#在3-6x 106个CAR-T细胞/kg剂量队列中的结果。
ICANS:免疫效应细胞相关的神经毒性综合征。
参见Munshi等人,Idecabtagene vicleucel(ide-cel;bb2121),在复发和难治性多发性骨髓瘤(RRMM)患者中的一种靶向BCMA的CAR T细胞疗法:初步KarMMa结果,Journalof Clinical Oncology,2020,38(15)增刊,摘要8503;Mailankody等人,Orvacabtageneautoleucel(orva-cel),用于复发的/难治性多发性骨髓瘤(RRMM)患者(pts)的针对B细胞成熟抗原(BCMA)的CAR T细胞疗法:1/2期EVOLVE研究(NCT03430011)的更新,Journal ofClinical Oncology,2020,38(15)增刊,摘要8504;Madduri等人,CARTITUDE-1:在复发/难治性多发性骨髓瘤中针对B细胞成熟抗原的嵌合抗原受体T细胞疗法,西达基奥仑赛(Ciltacabtagene Autoleucel)的1b/2期研究,第62届ASH年会和博览会(62nd ASH AnnualMeeting and Exposition),2020年12月5-8日,摘要177。
对于我们的C-CAR088临床试验,Kaplan Meier无进展生存期(PFS)估计包括中和高剂量组的6个月PFS为78.7%,95%置信区间(CI)为62.1%-99.7%。未达到中位应答持续时间(DOR)。见表7和图24。
表7
患者血液中CAR拷贝的时程如图25A和图25B所示。因此,施用后血液中的CAR水平得以维持。
C-CAR088治疗耐受性良好。记录患者的不良反应(不良事件,AE)(表8和表9)。只有1个(4.2%)级别≥3细胞因子释放综合征(CRS)。仅在一名患者(4.2%)中观察到神经毒性,该患者自发消退,无等级≥3的神经毒性。细胞减少症(Cytopenia),如中性粒细胞减少症和血小板减少症,主要与氟达拉滨/环磷酰胺(Cy/Flu)淋巴耗竭有关。未观察到剂量限制毒性(dose-limiting toxicities),所有不良事件都是可逆的。这些表明我们的抗BCMA CAR具有极好的安全特性。
表8
表9
*2019年与免疫效应细胞相关的细胞因子释放综合征和神经毒性的ASTCT共识分级。
CRS:细胞因子释放综合征
本发明的范围不受上文具体示出和描述的内容的限制。本领域技术人员将认识到,对于所描述的材料、配置、构建和尺寸的实例,存在合适的备选方案。在本发明的说明书中引用并讨论了许多参考文献,包括专利和各种出版物。提供这些参考文献的引用和讨论仅仅是为了使本发明的描述清楚,而不是承认任何参考文献都是本文所述发明的现有技术。本说明书中引用和讨论的所有参考文献通过引用的方式全部并入本文。在不脱离本发明的精神和范围的情况下,本领域的普通技术人员将对本文所描述的内容进行变化、修改和其他实践。虽然已经示出和描述了本发明的某些实施方案,但是对于本领域技术人员而言显而易见的是,可以在不脱离本发明的精神和范围的情况下进行改变和修改。上述描述和所附附图中示出的事项仅以说明的方式提供,而不是作为限制。
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<110> 上海赛比曼生物科技有限公司
<120> 靶向BCMA的嵌合抗原受体
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Lys Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 6
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> BCMA-MO6重链可变区
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 7
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> BCMA-1轻链可变区
<400> 7
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu
20 25 30
Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 8
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> BCMA-1重链可变区
<400> 8
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe
50 55 60
Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 9
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> CD8信号肽
<400> 9
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 10
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 10
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 11
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 11
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 12
<211> 55
<212> PRT
<213> 人工序列
<220>
<223> 铰链
<400> 12
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
1 5 10 15
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
20 25 30
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
35 40 45
Gly Leu Asp Phe Ala Cys Asp
50 55
<210> 13
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> CD8跨膜结构域
<400> 13
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 14
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 4-1BB共刺激序列
<400> 14
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 15
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> CD3ζ
<400> 15
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 16
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 16
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 17
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 17
Arg Ala Ser Gln Gly Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 18
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 18
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Leu Ile Tyr
1 5 10 15
<210> 19
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 19
Tyr Thr Ser Asn Leu Gln Ser
1 5
<210> 20
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 20
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 21
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 21
Met Gly Gln Thr Ile Ser Ser Tyr Thr
1 5
<210> 22
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 22
Phe Gly Gln Gly Thr Lys Leu Glu Ile
1 5
<210> 23
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 23
Glu 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
20 25 30
<210> 24
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 24
Asn Phe Asp Met Ala
1 5
<210> 25
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 25
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val Ser
1 5 10
<210> 26
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 26
Ser Ile Thr Thr Gly Ala Asp His Ala Ile Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 27
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 27
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
20 25 30
<210> 28
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 28
His Gly Tyr Tyr Asp Gly Tyr His Leu Phe Asp Tyr
1 5 10
<210> 29
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 29
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 30
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 30
Asp Ile Gln Leu Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys
20
<210> 31
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 31
Ser Ala Ser Thr Thr Thr Ser Asn Tyr Leu Asn
1 5 10
<210> 32
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 32
Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Glu Leu Val Ile Tyr
1 5 10 15
<210> 33
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 33
Tyr Thr Ser Asn Leu His Gly
1 5
<210> 34
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 34
Gly Gly Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser
1 5 10 15
Leu Thr Ile Gly Tyr Leu Glu Pro Glu Asp Val Ala Thr Tyr Tyr Cys
20 25 30
<210> 35
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 35
Gln Gln Tyr Arg Lys Leu Pro Trp Thr
1 5
<210> 36
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 36
Phe Gly Gly Gly Ser Lys Leu Glu Ile Lys Arg
1 5 10
<210> 37
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 37
Glu Val Gln Leu Gln Gln Ser Gly Ala Val Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 38
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 38
Asn Tyr Trp Met His
1 5
<210> 39
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 39
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 40
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 40
Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 41
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 41
Lys Ala Lys Leu Thr Ala Val Thr Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys Thr Arg
20 25 30
<210> 42
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 42
Gly Ala Ile Tyr Asn Gly Tyr Asp Val Leu Asp Asn
1 5 10
<210> 43
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 43
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 44
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 45
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 45
Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 46
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 46
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 47
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 47
Tyr Thr Ser Asn Leu His Ser
1 5
<210> 48
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 48
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 49
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 49
Gln Gln Tyr Arg Lys Leu Pro Trp Thr
1 5
<210> 50
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 50
Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
1 5 10
<210> 51
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 51
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser
20 25 30
<210> 52
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 52
Asn Tyr Trp Met His
1 5
<210> 53
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 53
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 54
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 54
Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 55
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 55
Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 56
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 56
Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn
1 5 10
<210> 57
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 57
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 58
<211> 1494
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 58
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgaccca gtccccctcc tccctgtccg cctccgtggg cgaccgggtg 120
accatcacct gccgggcctc ccagggcatc tccaactacc tgaactggta ccagcagaag 180
cccggcaagg cccccaagcc cctgatctac tacacctcca acctgcagtc cggcgtgccc 240
tcccggttct ccggctccgg ctccggcacc gactacaccc tgaccatctc ctccctgcag 300
cccgaggact tcgccaccta ctactgcatg ggccagacca tctcctccta caccttcggc 360
cagggcacca agctggagat caagggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420
ggcggatctg aggtgcagct ggtggagtcc ggcggcggcc tggtgcagcc cggcggctcc 480
ctgcggctgt cctgcgccgc ctccggcttc accttctcca acttcgacat ggcctgggtg 540
cggcaggccc ccggcaaggg cctggtgtgg gtgtcctcca tcaccaccgg cgccgaccac 600
gccatctacg ccgactccgt gaagggccgg ttcaccatct cccgggacaa cgccaagaac 660
accctgtacc tgcagatgaa ctccctgcgg gccgaggaca ccgccgtgta ctactgcgtg 720
cggcacggct actacgacgg ctaccacctg ttcgactact ggggccaggg caccctggtg 780
accgtgtcct ccttcgtgcc ggtcttcctg ccagcgaagc ccaccacgac gccagcgccg 840
cgaccaccaa caccggcgcc caccatcgcg tcgcagcccc tgtccctgcg cccagaggcg 900
tgccggccag cggcgggggg cgcagtgcac acgagggggc tggacttcgc ctgtgatatc 960
tacatctggg cgcccttggc cgggacttgt ggggtccttc tcctgtcact ggttatcacc 1020
ctttactgca aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 1080
ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1140
ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1200
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1260
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1320
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1380
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1440
gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1494
<210> 59
<211> 497
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 59
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
20 25 30
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
35 40 45
Gly Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala
50 55 60
Pro Lys Pro Leu Ile Tyr Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
85 90 95
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Met Gly Gln
100 105 110
Thr Ile Ser Ser Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
145 150 155 160
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe Asp
165 170 175
Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val Ser
180 185 190
Ser Ile Thr Thr Gly Ala Asp His Ala Ile Tyr Ala Asp Ser Val Lys
195 200 205
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
210 215 220
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Val
225 230 235 240
Arg His Gly Tyr Tyr Asp Gly Tyr His Leu Phe Asp Tyr Trp Gly Gln
245 250 255
Gly Thr Leu Val Thr Val Ser Ser Phe Val Pro Val Phe Leu Pro Ala
260 265 270
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
275 280 285
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
290 295 300
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
305 310 315 320
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
325 330 335
Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr
340 345 350
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
355 360 365
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
370 375 380
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
385 390 395 400
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
405 410 415
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
420 425 430
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
435 440 445
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
450 455 460
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
465 470 475 480
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
485 490 495
Arg
<210> 60
<211> 1497
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 60
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggatatcc agctgaccca gaccacaagc agcctgagcg cctccctggg cgacagggtg 120
accattagct gcagcgccag ccaggacatc agcaactacc tgaactggta ccagcagaag 180
cccgacggca ccgtggagct cgtgatctac tacacctcca acctgcacag cggcgtgccc 240
agcaggttct ctggcagcgg cagcggcacc gactacagcc tgaccatcgg ctatctggag 300
cccgaggacg tcgccaccta ctactgccag cagtacagga agctgccctg gaccttcggc 360
ggaggctcta agctggagat taagcgtggt ggcggtggct cgggcggtgg tgggtcgggt 420
ggcggcggat ctgaggtgca gctgcagcag agcggcgccg tgctggccag gcccggagct 480
agcgtgaaga tgagctgcaa gggcagcggc tacaccttca ccaactactg gatgcactgg 540
gtgaaacaga ggcccggcca gggactggag tggatcggcg ccacctacag gggccacagc 600
gacacctact acaaccagaa gttcaagggc aaggccaagc tgaccgccgt gacctcaacc 660
agcaccgcct acatggaact gagcagcctg accaacgagg acagcgccgt ctattactgc 720
accaggggcg ccatctacaa cggctacgac gtgctggaca attggggcca gggaacacta 780
gtgaccgtgt ccagcttcgt gccggtcttc ctgccagcga agcccaccac gacgccagcg 840
ccgcgaccac caacaccggc gcccaccatc gcgtcgcagc ccctgtccct gcgcccagag 900
gcgtgccggc cagcggcggg gggcgcagtg cacacgaggg ggctggactt cgcctgtgat 960
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 1080
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1140
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1200
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1260
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1320
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1380
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1440
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1497
<210> 61
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 61
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Leu Thr Gln Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln
35 40 45
Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Glu Leu Val Ile Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
85 90 95
Gly Tyr Leu Glu Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr
100 105 110
Arg Lys Leu Pro Trp Thr Phe Gly Gly Gly Ser Lys Leu Glu Ile Lys
115 120 125
Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Glu Val Gln Leu Gln Gln Ser Gly Ala Val Leu Ala Arg Pro Gly Ala
145 150 155 160
Ser Val Lys Met Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr
165 170 175
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
180 185 190
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
195 200 205
Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Thr Ser Thr Ala Tyr
210 215 220
Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys
225 230 235 240
Thr Arg Gly Ala Ile Tyr Asn Gly Tyr Asp Val Leu Asp Asn Trp Gly
245 250 255
Gln Gly Thr Leu Val Thr Val Ser Ser Phe Val Pro Val Phe Leu Pro
260 265 270
Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
275 280 285
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
290 295 300
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
305 310 315 320
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
325 330 335
Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu
340 345 350
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
355 360 365
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
370 375 380
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
385 390 395 400
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
405 410 415
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
420 425 430
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
435 440 445
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
450 455 460
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
465 470 475 480
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
485 490 495
Pro Arg
<210> 62
<211> 1497
<212> DNA
<213> 人工序列
<220>
<223> 合成的
<400> 62
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggacatcc agatgaccca gagccctagc tcactgagcg ccagcgtggg cgacagggtg 120
accattacct gctccgccag ccaggacatc agcaactacc tgaactggta ccagcagaag 180
cccggcaagg cccccaagct gctgatctac tacacctcca acctgcactc cggcgtgccc 240
agcaggttca gcggaagcgg cagcggcacc gatttcaccc tgaccatctc cagcctgcag 300
cccgaggact tcgccaccta ctactgccag cagtacagga agctcccctg gactttcggc 360
cagggcacca aactggagat caagcgtggt ggcggtggct cgggcggtgg tgggtcgggt 420
ggcggcggat ctcaggtgca gctggtccag agcggcgccg aagtgaagaa gcccggcagc 480
tccgtgaaag tgagctgcaa ggccagcggc ggcaccttca gcaactactg gatgcactgg 540
gtgaggcagg cccccggaca gggcctggag tggatgggcg ccacctacag gggccacagc 600
gacacctact acaaccagaa gttcaagggc cgggtgacca tcaccgccga caagagcacc 660
agcaccgcct acatggaact gagcagcctc aggagcgagg acaccgctgt gtattactgc 720
gccaggggcg ccatctacga cggctacgac gtgctggaca actggggcca gggcacacta 780
gtgaccgtgt ccagcttcgt gccggtcttc ctgccagcga agcccaccac gacgccagcg 840
ccgcgaccac caacaccggc gcccaccatc gcgtcgcagc ccctgtccct gcgcccagag 900
gcgtgccggc cagcggcggg gggcgcagtg cacacgaggg ggctggactt cgcctgtgat 960
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 1020
accctttact gcaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 1080
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1140
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1200
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1260
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1320
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1380
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1440
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1497
<210> 63
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 63
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
20 25 30
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln
35 40 45
Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
85 90 95
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
100 105 110
Arg Lys Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
115 120 125
Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
145 150 155 160
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
165 170 175
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
180 185 190
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
195 200 205
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
210 215 220
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
225 230 235 240
Ala Arg Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn Trp Gly
245 250 255
Gln Gly Thr Leu Val Thr Val Ser Ser Phe Val Pro Val Phe Leu Pro
260 265 270
Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
275 280 285
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
290 295 300
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
305 310 315 320
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
325 330 335
Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu
340 345 350
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
355 360 365
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
370 375 380
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln
385 390 395 400
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
405 410 415
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
420 425 430
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
435 440 445
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
450 455 460
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
465 470 475 480
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
485 490 495
Pro Arg
Claims (34)
1.嵌合抗原受体(CAR),其包含:抗BCMA抗原结合区,所述抗BCMA抗原结合区包含轻链可变区(VL)和重链可变区(VH),VL包含三个互补性决定区(CDR),为LCDR1、LCDR2和LCDR3,VH包含三个CDR,为HCDR1、HCDR2和HCDR3,
(a)其中LCDR1、LCDR2和LCDR3分别具有与SEQ ID NO:17、SEQ ID NO:19、SEQ ID NO:21中所示的氨基酸序列约80%至约100%同一的氨基酸序列,其中HCDR1、HCDR2和HCDR3分别具有与SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:28中所示氨基酸序列约80%至约100%同一的氨基酸序列;
(b)其中LCDR1、LCDR2和LCDR3分别具有与SEQ ID NO:31、SEQ ID NO:33、SEQ ID NO:35中所示的氨基酸序列约80%至约100%同一的氨基酸序列,其中HCDR1、HCDR2和HCDR3分别具有与SEQ ID NO:38、SEQ ID NO:40、SEQ ID NO:42中所示氨基酸序列约80%至约100%同一的氨基酸序列;或
(c)其中LCDR1、LCDR2和LCDR3分别具有与SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49中所示的氨基酸序列约80%至约100%同一的氨基酸序列,其中HCDR1、HCDR2和HCDR3分别具有与SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:56中所示氨基酸序列约80%至约100%同一的氨基酸序列。
2.根据权利要求1所述的CAR,其中VL位于VH的N末端。
3.根据权利要求1所述的CAR,其中VL和VH具有(a)分别与SEQ ID NO:1和SEQ ID NO:2;(a)分别与SEQ ID NO:3和SEQ ID NO:4;或(a)分别与SEQ ID NO:5和SEQ ID NO:6,中所示的氨基酸序列约80%至约100%同一的氨基酸序列。
4.根据权利要求1所述的CAR,其中所述抗BCMA抗原结合区是特异性结合BCMA的单链可变片段(scFv)。
5.根据权利要求1所述的CAR,其中所述CAR还包含以下中的一个或多个:
(a)信号肽,
(b)铰链区,
(c)跨膜结构域,
(d)共刺激区,和
(e)胞质信号传导结构域。
6.根据权利要求5所述的CAR,其中所述共刺激区包含4-1BB(CD137)、CD28、OX40、CD2、CD7、CD27、CD30、CD40、CD70、CD134、PD1、Dap10、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、NKG2D、GITR、TLR2的共刺激区或它们的组合。
7.根据权利要求5所述的CAR,其中所述胞质信号传导结构域包含CD3ζ.的胞质信号传导结构域。
8.根据权利要求5所述的CAR,其中所述铰链区包含CD8、CD28、CD137、Ig4的铰链区或它们的组合。
9.根据权利要求5所述的CAR,其中所述跨膜结构域包含CD8、CD28、CD3ε、CD45、CD4、CD5、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154的跨膜结构域或它们的组合。
10.免疫细胞,其表达权利要求1所述的CAR。
11.根据权利要求10所述的免疫细胞,其中所述免疫细胞是T细胞或自然杀伤(NK)细胞。
12.核酸,其编码权利要求1所述的CAR。
13.载体,其包含权利要求12所述的核酸。
14.一种治疗癌症的方法,该方法包括将权利要求10所述的免疫细胞施与需要其的受试者。
15.根据权利要求14所述的方法,其中所述癌症是血液学癌症。
16.根据权利要求14所述的方法,其中所述癌症是浆细胞恶性肿瘤。
17.根据权利要求14所述的方法,其中所述癌症是BCMA阳性的恶性肿瘤。
18.根据权利要求14所述的方法,其中所述癌症是多发性骨髓瘤(MM)或浆细胞白血病。
19.根据权利要求14所述的方法,其中所述免疫细胞是通过输注、注射、转输、植入和/或移植来施用的。
20.根据权利要求14所述的方法,其中所述免疫细胞是静脉内、皮下、皮内、结节内、肿瘤内、髓内、肌内或腹膜内施用的。
21.根据权利要求14所述的方法,其中所述免疫细胞通过静脉内输注施用。
22.根据权利要求14所述的方法,其中所述免疫细胞是同种异体的或自体的。
23.根据权利要求14所述的方法,其中所述受试者是人。
24.一种治疗癌症的方法,所述方法包括将权利要求10所述的免疫细胞施与需要其的受试者,其中该嵌合抗原受体(CAR)在施用后约28天在受试者的血液中产生从约5.0e+05个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3e+07个拷贝/gDNA范围的曲线下面积(AUC)。
25.根据权利要求24所述的方法,其中在施用后约28天在受试者的血液中的所述AUC范围是从约5.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.0e+07个拷贝/gDNA。
26.根据权利要求24所述的方法,其中在施用后约28天在受试者的血液中的所述AUC范围是从约5.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3e+07个拷贝/gDNA。
27.根据权利要求24所述的方法,其中在施用后约28天在受试者的血液中的所述AUC范围是从约7.0e+06个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.0e+07个拷贝/gDNA。
28.一种治疗癌症的方法,所述方法包括将权利要求10所述的免疫细胞施与需要其的受试者,其中该嵌合抗原受体(CAR)在受试者的血液中产生从约5x104个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3x106个拷贝/gDNA范围的最大血浆浓度(Cmax)。
29.根据权利要求28所述的方法,其中在施用后约28天在受试者的血液中的所述Cmax范围是从约5x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1.3x106个拷贝/gDNA。
30.根据权利要求28所述的方法,其中在施用后约28天在受试者的血液中的所述Cmax范围是从约7.5x105个拷贝/μg基因组DNA(个拷贝/gDNA)至约1x106个拷贝/gDNA。
31.根据权利要求28所述的方法,其中所述CAR具有范围从约12天至约25天的Tmax。
32.根据权利要求28所述的方法,其中所述CAR具有范围从约14天至约20天的Tmax。
33.根据权利要求28所述的方法,其中所述CAR具有范围从约6天至约22天的Tmax。
34.根据权利要求1所述的CAR,其包含与SEQ ID NO:59、SEQ ID NO:61或SEQ ID NO:63中所示的氨基酸序列约80%至约100%同一的氨基酸序列。
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US17/476,661 US11498973B2 (en) | 2018-04-12 | 2021-09-16 | BCMA-targeted chimeric antigen receptor as well as preparation method therefor and application thereof |
PCT/US2021/061410 WO2022119923A1 (en) | 2020-12-02 | 2021-12-01 | Bcma-targeted chimeric antigen receptors |
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