CN109134665A - 一种基于单域抗体的bcma嵌合抗原受体及应用 - Google Patents
一种基于单域抗体的bcma嵌合抗原受体及应用 Download PDFInfo
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Abstract
本申请涉及一种嵌合抗原受体(CAR)及应用,所述CAR包含:BCMA结合结构域、跨膜结构域、一个或多个共刺激结构域、以及胞内信号传导结构域;其中所述BCMA结合结构域包含重链互补决定区HCDR1‑3,所述HCDR1‑3的氨基酸序列依次如SEQ ID NO:1‑3所示。
Description
技术领域
本申请属于免疫细胞治疗领域,具体地,涉及一种基于单域抗体的BCMA嵌合抗原受体及应用。
背景技术
多发性骨髓瘤(MM)是一种发生于骨髓,以克隆性浆细胞的积累为特征的血液肿瘤。治疗方案主要聚焦在浆细胞凋亡及/或降低破骨细胞活性(例如化疗、沙利窦迈(thalidomide)、来那窦胺(lenalidomide)、双磷酸盐及/或蛋白酶体抑制剂,诸如硼替佐米或卡非佐米(carfilzomib))。多发性骨髓瘤目前还是一种难以治愈的疾病,只有大约45%的患者在确诊后能活过5年。许多患者暂停治疗之后病情还会反复复发,复发之后患者的5年内存活率不足20%。
近年来,嵌合抗原受体T细胞疗法(Chimeric antigen receptor T-cellimmunotherapy,CART)成为目前最有发展前景的肿瘤免疫疗法之一。嵌合抗原受体由一个肿瘤相关抗原结合结构域、跨膜结构域、共刺激结构域以及胞内信号传导结构域组成。CART细胞疗法一般通过基因转导技术,把识别肿瘤相关抗原的最小抗体结合片段(Singlechain fragment variable或,scFv)和T细胞活化序列的融合蛋白表达到T细胞表面。表达CAR分子的T细胞以抗原依赖、但非MHC限制的方式结合肿瘤抗原,特异性杀伤肿瘤细胞。
CART细胞疗法的有效性依赖识别肿瘤相关抗原的抗体的特异性以及抗原结合的亲和力高低等性质。目前CART细胞胞内信号传导结构域的设计已经趋于成熟,抗原结合结构域的设计成为新型CART技术开发的重点和关键。羊驼源重链抗体(Heavy chainantibody,HCAb)中最小的、能完整结合抗原的单个功能域抗体片段,即没有轻链的重链抗体的可变区(又称为VHH),结构简单,分子量约为普通抗体分子量的1/10,可在体外表达系统(如大肠杆菌、酵母、真核细胞和植物)中高效表达和纯化。高特异性、高亲和力,免疫原性低,渗透性好,在进行肿瘤治疗时,具有接触到不能被常规抗体接触的较为隐蔽靶点的可能性。基于这些优点,利用单域抗体作为CAR的抗原结合区进行CAR修饰是CART细胞疗法的发展趋势之一。
就B细胞谱系恶性肿瘤而言,细胞成熟抗原(BCMA,B-cell maturation antigen)作为一种极为重要的B细胞生物标志物,它的RNA几乎总是在多发性骨髓瘤细胞中发现,并且该蛋白也被发现存在于多发性骨髓瘤患者恶性浆细胞表面。BCMA由185个氨基酸残基组成的III型跨膜蛋白,属TNF受体超家族,其配体属于TNF超家族,如增殖诱导配体(APRIL)B淋巴细胞刺激因子(BAFF),BCMA与其配体结合后,可激活B细胞的增殖和存活。BCMA特异高表达于浆细胞和多发性骨髓瘤细胞表面,而在造血干细胞和其他正常组织细胞中均不表达,因此,BCMA可以作为MM的靶向性治疗的理想靶点。
发明内容
本申请利用基因工程手段设计了特异性单域抗体作为CAR的抗原结合区进行CAR修饰及CART细胞疗法,提出了一种基于单域抗体的特异性嵌合抗原受体(CAR),其包括靶点结合结构域、跨膜结构域、一个或多个共刺激结构域、以及胞内信号传导结构域,其中所述胞外结构域是能结合人BCMA(B细胞成熟抗原)的抗原结合片段。
一方面,本申请提供了一种嵌合抗原受体(CAR),所述CAR包含:BCMA结合结构域、跨膜结构域、一个或多个共刺激结构域、以及胞内信号传导结构域;其中所述BCMA结合结构域包含重链互补决定区1(HCDR1),重链互补决定区2(HCDR2)和重链互补决定区3(HCDR3),所述HCDR1的氨基酸序列如SEQ ID NO:1所示,所述HCDR2的氨基酸序列如SEQ ID NO:2所示且所述HCDR3的氨基酸序列如SEQ ID NO:3所示。
在某些实施方式中,所述BCMA结合结构域为单域抗体。
在某些实施方式中,所述BCMA结合结构域包含SEQ ID NO:4所示的氨基酸序列或其功能性变体。
在某些实施方式中,所述跨膜结构域包含来自选自下述蛋白的多肽:T细胞受体的α,β或ζ链,CD28,CD3e,CD45,CD4,CD5,CD8a,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137和CD154。
在某些实施方式中,所述跨膜结构域包含SEQ ID NO:5所示的氨基酸序列或其功能性变体。
在某些实施方式中,所述BCMA结合结构域通过铰链区与所述跨膜结构域相连接。
在某些实施方式中,所述铰链区包含SEQ ID NO:6所示的氨基酸序列或其功能性变体。
在某些实施方式中,所述一个或多个共刺激结构域来自选自下述的共刺激分子:CARD11、CD2、CD7、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD152(CTLA4)、CD223(LAG3)、CD270(HVEM)、CD273(PD-L2)、CD274(PD-L1)、CD278(ICOS)、DAP10、LAT、NKG2C、SLP76、TRIM以及ZAP70。
在某些实施方式中,所述共刺激结构域包含SEQ ID NO:7所示的氨基酸序列或其功能性变体。
在某些实施方式中,所述胞内信号传导结构域包含CD3ζ的信号传导结构域。
在某些实施方式中,所述胞内信号传导结构域包含SEQ ID NO:8所示的氨基酸序列或其功能性变体。
在某些实施方式中,所述的CAR还包含前导序列,所述前导序列包含SEQ ID NO:9所示的氨基酸序列或其功能性变体。
在某些实施方式中,所述的CAR包含SEQ ID NO:10-11所示的氨基酸序列或其功能性变体。
另一方面,本申请提供了分离的核酸分子,其编码所述的CAR。
在某些实施方式中,所述核酸分子包含SEQ ID NO:12-13所示的核酸序列或其功能性变体。
另一方面,本申请提供了一种载体,其包含所述的核酸分子。
在某些实施方式中,所述的载体选自DNA载体,RNA载体,质粒,慢病毒载体,腺病毒载体和逆转录病毒载体。
在某些实施方式中,所述的载体还包含EF1启动子,该启动子包含SEQ ID NO:14所示的序列。
另一方面,本申请提供了一种免疫效应细胞,其包含所述的CAR,所述的核酸分子,或所述的载体。
在某些实施方式中,所述的免疫效应细胞选自T淋巴细胞和自然杀伤(NK)细胞。
另一方面,本申请提供了一种制备免疫效应细胞的方法,其包括向免疫效应细胞中引入所述的载体。
在某些实施方式中,在所述的方法中,所述免疫效应细胞选自T淋巴细胞和自然杀伤(NK)细胞。
另一方面,本申请提供了一种组合物,其包含所述的免疫效应细胞。
另一方面,本申请提供了所述的CAR,所述的核酸分子,所述的载体,或所述的免疫效应细胞用于制备药物的用途,其中所述药物用于治疗与BCMA的表达相关的疾病或病症。
另一方面,本申请提供了所述的CAR,所述的核酸分子,所述的载体,或所述的免疫效应细胞,其治疗与BCMA的表达相关的疾病或病症。
另一方面,本申请提供了治疗与BCMA的表达相关的疾病或病症的方法,其包括以下的步骤:向受试者施用所述的CAR,所述的核酸分子,所述的载体,或所述的免疫效应细胞。
在某些实施方式中,所述与BCMA的表达相关的疾病或病症为癌症或恶性肿瘤。在某些实施方式中,所述与BCMA的表达相关的疾病或病症选自下组:B细胞急性淋巴性白血病,T细胞急性淋巴性白血病,急性淋巴性白血病,慢性髓性白血病,慢性淋巴细胞白血病,B细胞幼淋巴细胞白血病,母细胞性浆细胞样树突状细胞瘤,伯基特淋巴瘤,弥散性大B细胞淋巴瘤,滤泡性淋巴瘤,毛细胞白血病,小细胞或大细胞滤泡性淋巴瘤,恶性淋巴增殖状况,MALT淋巴瘤,外套细胞淋巴瘤,边缘区淋巴瘤,多发性骨髓瘤,脊髓发育不良和骨髓增生异常综合征,非霍奇金淋巴瘤,浆母细胞淋巴瘤,浆细胞样树突细胞瘤,瓦尔登斯特伦巨球蛋白血症,前列腺癌,胰腺癌,肺癌,骨髓瘤,MGUS,浆细胞瘤,系统性淀粉样蛋白轻链淀粉样变性和POEMS综合征。
本申请的创新性及产生的有益技术效果:
申请人利用基因工程手段设计了包含特异性氨基酸序列的单域抗体,并以此作为结合结构域(BCMA结合结构域)构建嵌合抗原受体(CAR)。研究发现,包含该嵌合抗原受体的免疫细胞(如CART细胞)对相关肿瘤杀伤力强、特异性强。具体而言,所述CAR在体外高效地转导了健康人T淋巴细胞,对于BCMA阳性的靶细胞产生了强力的杀伤效果;并且在体内实验中,同样显示了很强的杀伤效果:利用转染有荧光素酶的MM.1S细胞建立原位骨髓瘤荷瘤鼠模型进行检测,用药3天后,荧光绝大部分消失,CART细胞在体内有极好的治疗效果。
此外,本申请包含所述嵌合抗原受体所述免疫细胞在体外表现出很好的靶向性,其对BCMA阳性表达的细胞有极强的杀伤能力,而对不表达BCMA的细胞几乎没有任何杀伤作用;并且其在体内实验中,同样显示出很好的肿瘤靶向性。
附图说明
图1为本申请所述包含所述嵌合抗原受体的免疫细胞表达所述嵌合抗原受体的流式检测结果。
图2为多发性骨髓瘤MM.1S细胞(左图)、骨髓性白血病K562细胞(右图)表面的BCMA表达丰度的流式检测结果。
图3A-3B为肿瘤细胞和本申请所述包含所述嵌合抗原受体的免疫细胞共孵育后靶细胞杀伤率的结果。
图4A-4B肿瘤细胞和本申请所述包含所述嵌合抗原受体的免疫细胞共孵育后,ELISA方法检测上清中的细胞因子含量的结果。
图5为本申请所述包含所述嵌合抗原受体的免疫细胞治疗荷瘤小鼠的检测结果。
图6为本申请所述包含所述嵌合抗原受体的免疫细胞治疗荷瘤小鼠的检测结果。
具体实施方式
申请人利用基因工程手段设计了特异性单域抗体作为CAR的抗原结合区进行CAR修饰及CART细胞疗法,提出了一种基于单域抗体的特异性嵌合抗原受体(CAR),其包括胞外结构域、跨膜结构域和胞内结构域,其中所述胞外结构域是能结合人BCMA(B细胞成熟抗原)的抗原结合片段,选自羊驼单结构域抗体(sdAb,纳米抗体)。
本申请中,术语“CDR”通常是指互补决定区,CDR主要负责与抗原表位结合。重链的CDR通常被称作HCDR1、HCDR2和HCDR3,从N-端开始顺序编号。在本申请中,可以通过常规方法来限定或鉴定CDR。例如,根据Kabat等人(Wu,TT和Kabat,E.A.,J Exp Med.132(2):211-50,(1970);Borden,P.和Kabat E.A.,PNAS,84:2440-2443(1987)的方法,或者通过Chothia等人(Chothia,C.和Lesk,A.M.,J Mol.Biol.,196(4):901-917(1987)的方法。
本申请中,术语“单域抗体(sdAb)”通常是指由抗体重链的可变区(VH结构域)或抗体轻链的可变区(VL结构域)组成的抗体片段(Holt,L.等人,Trends in Biotechnology,21(11):484-490)也称为纳体抗体(Nanobody)。单域抗体大约只有12-15kDa。第一个单域抗体是从羊驼的重链抗体中人造工程制作出来的,又称为“VHH区段”。在本申请中,所述单域抗体可以为羊驼的单域抗体。例如,所述VHH区段可以指重链抗体的最小的已知抗原结合单元(Koch-Nolte等人,FASEB J.,21:3490-3498(2007))。
本申请中,术语“跨膜结构域”可以与“跨膜区(简称TM)”互换使用,指的是CAR的一部分,其使胞外结合部分和胞内信号转导结构域融合,并且使CAR锚定至免疫效应细胞的质膜上。跨膜区可以从天然蛋白质中获得,也可以合成、半合成或重组获得。TM结构域可以至少包括下述蛋白质的跨膜结构域:T细胞受体的α链、β链或ζ链、CD3ε、CD3ζ、CD4、CD5、CD8α、CD9、CD16、CD22、CD27、CD28、CD33、CD37、CD45、CD64、CD80、CD86、CD134、CD137、CD152、CD154和PD1。在本申请中,所述跨膜结构域可以包含来自选自下述蛋白的多肽:T细胞受体的α,β或ζ链,CD28,CD3e,CD45,CD4,CD5,CD8a,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137和CD154。
本申请中,术语“胞内信号传导结构域”通常是CAR的一部分,其参与将有效的抗BCMA CAR结合人BCMA多肽的信息转导进免疫效应细胞的内部,以引发效应细胞的功能,例如活化、细胞因子的产生、增殖和细胞毒活性,包括细胞毒性因子至CAR结合的靶细胞的释放或者用与胞外CAR结构域结合的抗原引发的其它细胞应答。在本申请中,所述胞内信号传导结构域可以包含CD3ζ的信号传导结构域。
本申请中,术语“BCMA”通常是指细胞成熟抗原,其属于肿瘤坏死因子受体超家族成员(参见Thompson等,J.Exp.Medicine,192(1):129-135,2000)。BCMA能结合B细胞活化因子(BAFF)和增殖诱导配体(APRIL)(参见Kalled等,Immunological Reviews,204:43-54,2005)。在非恶性细胞中,已报道BCMA主要在浆细胞以及成熟B细胞中亚集中表达(参见Laabi等,EMBO J.,77(1):3897-3904,1992;Laabi等,Nucleic Acids Res.,22(7):1147-1154,1994;Kalled等,2005;O'Connor等,J.Exp.Medicine,199(1):91-97,2004;以及Ng等,J.Immunol.,73(2):807-817,2004)。BCMA RNA在多发性骨髓瘤细胞和其它淋巴瘤中普遍被检测到,并且一些研究者在来自多发性骨髓瘤患者的浆细胞表面上检测到了BCMA蛋白(参见Novak等,Blood,103(2):689-694,2004;Neri等,Clinical Cancer Research,73(19):5903-5909,2007;Bellucci等,Blood,105(10):3945-3950,2005;以及Moreaux等,Blood,703(8):3148-3157,2004),因此BCMA可以作为恶性肿瘤(如多发性骨髓瘤)的潜在治疗靶点。
本申请中,术语“BCMA结合结构域”通常是指包含能特异性结合B细胞上表达的BCMA多肽的人源化的抗BCMA抗体或者其抗原结合片段。在本申请中,所述结合结构域可以源自天然来源、合成来源、半合成来源或者重组来源。在本申请中,所述胞外结合结构域可以包含针对BCMA的抗体或其抗原结合片段。其中,所述“抗体”可以为至少包含轻链或重链免疫球蛋白可变区的多肽,所述免疫球蛋白可变区特异性识别并结合抗原(例如BCMA)的表位,所述抗原如含有抗原决定簇(如由免疫细胞所识别的那些)的肽、脂质、多糖或核酸。
本申请中,术语“共刺激结构域”通常是指共刺激分子的胞内信号转导结构域。例如,共刺激分子可以是抗原受体或Fc受体之外的细胞表面分子,其在抗原结合时可提供T淋巴细胞的高效活化和功能所需的第二信号。例如,所述共刺激结构域可以选自以下组:CARD11、CD2、CD7、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD152(CTLA4)、CD223(LAG3)、CD270(HVEM)、CD273(PD-L2)、CD274(PD-L1)、CD278(ICOS)、DAP10、LAT、NKD2CSLP76、TRIM和ZAP70。
本申请中,术语“铰链区”通常是指在嵌合抗原受体中,将所述结合结构域定位于远离效应细胞表面以能够进行适当的细胞/细胞接触、抗原结合和活化方面发挥作用的结合域。在本申请中,所述铰链区可以位于所述结合结构域和所述跨膜结构域之间。所述铰链区可以源自天然来源、合成来源、半合成来源或重组来源。铰链结构域可以包含天然存在的免疫球蛋白铰链区或人工修饰(包括缺失、替换或插入)的免疫球蛋白铰链区的氨基酸序列。
本申请中,术语“前导序列”通常是指能够被转录但不能被翻译的、位于结构基因编码区之前的一段序列。在本申请中,所述前导序列可以自5’端起至编码所述嵌合抗原受体的基因的第一编码子为止。在本申请中,所述前导序列包含SEQ ID NO:9所示的氨基酸序列或其功能性变体。
本申请中,术语“功能性变体”通常是指包括与其具有基本上相同的功能(例如,可以具备所述嵌合抗原受体的性质),且与其具有至少85%(例如,至少85%,至少90%,至少91%,至少92%,至少93%,至少94%,至少95%,至少96%,至少97%,至少98%,至少99%,或至少100%)序列同一性的氨基酸序列。在某些实施方式中,所述氨基酸序列的变体为与其具有基本上相同的功能(例如,可以具备所述嵌合抗原受体的性质),且在其基础上包含一个或多个(例如,1-2个、1-3个、1-4个、1-5个、1-6个、1-7个、1-8个、1-9个、1-10个或更多)氨基酸的取代、缺失或添加的氨基酸序列。
本申请中,术语“慢病毒载体”通常是指以病毒为基础发展起来的基因治疗载体。在本申请中,所述病毒可以为人类免疫缺陷病毒(HIV)、猴免疫缺陷病毒(SIV)、马传染性贫血(EIA)或猫免疫缺陷病毒(FIV)。所述慢病毒载体对分裂细胞和非分裂细胞均具有感染能力,可以有效地感染包括神经元细胞、肝细胞、心肌细胞、肿瘤细胞、内皮细胞、干细胞等几乎所有的哺乳动物细胞,并且感染效率高。
本申请中,术语“EF1启动子”通常是指一种能够持续地使所调控的目的基因的转录水平维持在一定的水平上的启动子。在本申请中,所述EF1启动子可包含SEQ ID NO:14所示的序列。在本申请中,所述EF1启动子所调控的所述嵌合抗原受体的表达水平可以上调或下调至多5%、至多4%、至多3%、至多2%、至多1%、至多0.5%、至多0.1%、至多0.01%或更少。在本申请中,所述EF1启动子可以位于编码所述嵌合抗原受体的核酸的上游。
本申请中,术语“T淋巴细胞”通常是指包括胸腺细胞、未成熟的T淋巴细胞、成熟的T淋巴细胞、静止的T淋巴细胞或活化的T淋巴细胞。T细胞可以是辅助性T(Th)细胞,例如辅助性T1(Th1)细胞或者辅助性T2(Th2)细胞。T细胞可以是辅助性T细胞(HTL;CD4+T细胞)CD4+T细胞、细胞毒性T细胞(CTL;CD8+T细胞)、CD4+CD8+T细胞或CD4-CD8-T细胞。或者,所述T淋巴细胞可以包括初始T细胞和记忆T细胞。
本申请中,术语“自然杀伤细胞”通常是指白细胞的一种亚型,它是先天免疫系统的组成部分。NK细胞在肿瘤和病毒感染细胞的宿主排斥中起主要作用。NK细胞具有细胞毒性,诱导细胞凋亡。NK细胞可用于抑制病毒感染,通过适应性免疫应答产生抗原特异性细胞毒性T细胞从而清除感染。
本申请中,术语“癌症”通常是指机体在各种致癌因素作用下,局部组织的某一个细胞在基因水平上失去对其生长的正常调控,导致其克隆性异常增生而形成的新生物,因为这种新生物多呈占位性块状突起,也称赘生物(neoplasm)。在本申请中,所述癌症可以包括鳞状细胞癌、肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞状细胞癌)、腹膜癌、肝细胞癌、胃癌或胃癌(包括胃肠癌)、胰腺癌、胶质母细胞瘤、子宫颈癌、卵巢癌、肝癌、膀胱癌、肝癌、乳腺癌、结肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾或肾癌、肝癌、前列腺癌、外阴癌、甲状腺癌、肝癌、头颈癌、B细胞淋巴瘤(包括低级别/滤泡性非霍奇金淋巴瘤NHL)、小淋巴细胞性(SL)NHL、中级/滤泡型NHL、中等级弥漫性NHL、高级免疫母细胞NHL、高级淋巴细胞性NHL、高级小型非切割细胞NHL、艾滋病相关淋巴瘤、Waldenstrom的巨球蛋白血症)、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(ALL)、毛细胞白血病慢性成髓细胞白血病和移植后淋巴增生性疾病(PTLD))。在本申请中,所述癌症可以包括与BCMA的表达相关的癌症或恶性肿瘤。例如,所述癌症可以选自下组:B细胞急性淋巴性白血病,T细胞急性淋巴性白血病,急性淋巴性白血病,慢性髓性白血病,慢性淋巴细胞白血病,B细胞幼淋巴细胞白血病,母细胞性浆细胞样树突状细胞瘤,伯基特淋巴瘤,弥散性大B细胞淋巴瘤,滤泡性淋巴瘤,毛细胞白血病,小细胞或大细胞滤泡性淋巴瘤,恶性淋巴增殖状况,MALT淋巴瘤,外套细胞淋巴瘤,边缘区淋巴瘤,多发性骨髓瘤,脊髓发育不良和骨髓增生异常综合征,非霍奇金淋巴瘤,浆母细胞淋巴瘤,浆细胞样树突细胞瘤,瓦尔登斯特伦巨球蛋白血症,前列腺癌,胰腺癌,肺癌,骨髓瘤,MGUS,浆细胞瘤,系统性淀粉样蛋白轻链淀粉样变性和POEMS综合征。
本申请提供了一种嵌合抗原受体(CAR),所述CAR可包含:BCMA结合结构域、跨膜结构域、一个或多个共刺激结构域、以及胞内信号传导结构域;其中所述BCMA结合结构域包含重链互补决定区1(HCDR1),重链互补决定区2(HCDR2)和重链互补决定区3(HCDR3),所述HCDR1的氨基酸序列如SEQ ID NO:1所示,所述HCDR2的氨基酸序列如SEQ ID NO:2所示且所述HCDR3的氨基酸序列如SEQ ID NO:3所示。
在本申请中,所述BCMA结合结构域可以大于或等于约105M-1(例如,大于或等于约105M-1、大于或等于约106M-1、大于或等于约107M-1、大于或等于约108M-1、大于或等于约109M-1、大于或等于约1010M-1、大于或等于约1011M-1、大于或等于约1012M-1、大于或等于约1013M-1或更高)的Ka(即结合相互作用的平衡缔合常数,数值为1/M);或者,以小于或等于约10-5M(例如,小于或等于约10-5M、小于或等于约10-6M、小于或等于约10-7M、小于或等于约10-8M、小于或等于约10-9M、小于或等于约10-10M、小于或等于约10-11M、小于或等于约10-12M、小于或等于约10-13M或更小)的平衡解离常数Kd与BCMA结合或缔合。
在本申请中,可以使用本领域的常规技术测定所述BCMA结合结构域和BCMA的亲和力,例如,通过竞争性ELISA(酶联免疫吸附分析),或通过结合缔合,或利用标记配体的位移分析(displacement assay),或者使用表面等离子共振装置(如BiacoreT100,其可获自Biacore,Inc.,Piscataway,NJ)或光学生物传感器技术来测定。
在本申请中,所述BCMA结合结构域可以为单域抗体。适于构建本申请所述嵌合抗原受体的所述BCMA结合结构域包含但不限于SEQ ID NO:4所示的氨基酸序列或其功能性变体。其中所述功能性变体选自以下组:在所述BCMA结合结构域中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和与所述BCMA结合结构域具有90%以上(例如,具有至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
在本申请中,所述跨膜结构域可以包含来自选自下述蛋白的多肽:T细胞受体的α,β或ζ链,CD28,CD3ζ,CD45,CD4,CD5,CD8α,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137和CD154。在本申请中,所述跨膜结构域可以源自CD8α的跨膜结构域。在本申请中,所述跨膜结构域可以包含SEQ ID NO:5所示的氨基酸序列或其功能性变体。其中所述功能性变体选自以下组:在所述跨膜结构域中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和与所述跨膜结构域具有90%以上(例如,具有至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
在本申请中,所述BCMA结合结构域可以通过铰链区与所述跨膜结构域相连接。在本申请中,所述CAR可以在所述BCMA结合结构域和所述跨膜结构域之间包含一个或多个所述铰链区。所述铰链区可以包含一些氨基酸的突变或替换,例如,可以包含脯氨酸残基被其他氨基酸残基(例如,丝氨酸残基)的突变或替换。在本申请中,所述铰链区可以包含SEQ IDNO:6所示的氨基酸序列或其功能性变体。其中所述功能性变体选自以下组:在所述铰链区中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和与所述铰链区具有90%以上(例如,具有至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
在本申请中,所述共刺激结构域可以以抗原非依赖(例如,BCMA非依赖)的方式起作用以提供次级或共刺激信号。在本申请中,所述CAR可以含有一个或多个所述共刺激结构域。多个所述共刺激结构域可以增强表达所述CAR的免疫细胞(如T细胞和NK细胞)的效力和增殖能力。例如,所述共刺激结构域可以连接至所述跨膜结构域的C端。在本申请中,所述一个或多个共刺激结构域可以来自选自下述的共刺激分子:CARD11、CD2、CD7、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD152(CTLA4)、CD223(LAG3)、CD270(HVEM)、CD273(PD-L2)、CD274(PD-L1)、CD278(ICOS)、DAP10、LAT、NKG2C、SLP76、TRIM以及ZAP70。在本申请中,所述共刺激结构域可以来自CD137。在本申请中,所述共刺激结构域可以包含SEQ ID NO:7所示的氨基酸序列或其功能性变体。其中所述功能性变体选自以下组:在所述共刺激结构域中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和与所述共刺激结构域具有90%以上(例如,具有至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
在本申请中,所述胞内信号转导结构域可以通过TCR(例如,TCR/CD3复合物)其实抗原依赖性的初级活化。在本申请中,所述胞内信号传导结构域可以源自TCRζ、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD22、CD79a、CD79b和CD66d。在本申请中,所述胞内信号传导结构域可以包含CD3ζ的信号传导结构域。例如,所述胞内信号传导结构域包含SEQ ID NO:8所示的氨基酸序列或其功能性变体。其中所述功能性变体选自以下组:在所述胞内信号转导结构域中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和与所述胞内信号转导结构域具有90%以上(例如,具有至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
在本申请中,所述的CAR还可以包含前导序列。例如,所述前导序列可以包含SEQID NO:9所示的氨基酸序列或其功能性变体。其中所述功能性变体选自以下组:在所述前导序列中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和与所述前导序列具有90%以上(例如,具有至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
在本申请中,所述的CAR在各结构域之间可以包含连接子。例如,为了各结构域之间的适当间隔和构象而添加的连接子。例如,所述连接子可以连接所述跨膜结构域和所述胞内信号转导结构域。在本申请中,所述连接子可以包含以下的氨基酸序列:GGG、(GGGGS)n和GGRRGGGS。
在本申请的所述CAR中,所述跨膜结构域可以来自CD8α,所述共刺激结构域可以来自CD137且所述胞内信号传导结构域可以来自CD3ζ。
在本申请中,所述CAR可包含含有如SEQ ID NO:1所示的氨基酸序列的HCDR1,如SEQ ID NO:2所示的氨基酸序列的HCDR2和如SEQ ID NO:3所示的氨基酸序列的HCDR3的BCMA结合结构域、含有如SEQ ID NO:5所示的氨基酸序列的跨膜结构域、含有如SEQ ID NO:6所示的氨基酸序列的铰链区、含有如SEQ ID NO:7所示的氨基酸序列的共刺激结构域、含有如SEQ IDNO:8所示的氨基酸序列的胞内信号转导结构域和含有如SEQ ID NO:9所示的氨基酸序列的前导序列。
在本申请中,所述CAR可包含含有如SEQ ID NO:4所示的氨基酸序列的BCMA结合结构域、含有如SEQ ID NO:5所示的氨基酸序列的跨膜结构域、含有如SEQ ID NO:6所示的氨基酸序列的铰链区、含有如SEQ ID NO:7所示的氨基酸序列的共刺激结构域、含有如SEQ IDNO:8所示的氨基酸序列的胞内信号转导结构域、含有如SEQ ID NO:9所示的氨基酸序列的前导序列。
在本申请中,所述CAR包含SEQ ID NO:10-11所示的氨基酸序列或其功能性变体。其中所述功能性变体选自以下组:在所述CAR中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和与CAR具有90%以上(例如,具有至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。
本申请提供了分离的核酸分子,其可以编码所述的CAR。
在本申请中,所述核酸分子可以包含SEQ ID NO:12-13所示的核酸序列或其功能性变体。例如,所述功能性变体可以包含与SEQ ID NO:12-13相比具有至少约50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%或100%的序列同一性的多核苷酸或变体,只要仍可以编码所述CAR即可。
本申请提供了一种载体,其可以包含所述的核酸分子。
在本申请中,所述载体可以包含复制起点、选择盒、启动子、增强子、翻译起始信号(Shine Dalgarno序列或Kozak序列)、内含子、聚腺苷酸化序列、5’和3’非翻译区中的一种或多种。例如,所述的载体可以包含EF1启动子,该启动子可以包含SEQ ID NO:14所示的序列。在本申请中,所述的载体可以选自质粒、噬菌体、人工染色体(例如酵母人工染色体YAC)和动物病毒。例如,所述载体可以选自DNA载体,RNA载体,质粒,慢病毒载体,腺病毒载体和逆转录病毒载体。
本申请提供了一种免疫效应细胞,其可以包含所述的CAR,所述的核酸分子,或所述的载体。
在本申请中,所述的免疫效应细胞可以选自T淋巴细胞和自然杀伤(NK)细胞。
在本申请中,
本申请提供了一种制备免疫效应细胞的方法,其可以包括向免疫效应细胞中引入所述的载体。例如,将所述的CAR引入所述免疫细胞,并在其中表达,以将其特异性地重新定向至靶标抗原(例如,BCMA)。在本申请中,在所述的方法中所述免疫效应细胞可以选自T淋巴细胞和自然杀伤(NK)细胞。在本申请中,所述方法可以包括从对象中获得所述免疫效应细胞的步骤。例如,可以从外周血单核细胞、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、胸腔积液、脾组织以及肿瘤获得所述T淋巴细胞。此外,所述方法可以进一步包括从所述免疫效应细胞中选择特定的细胞亚群的步骤。例如,可以通过CD3、CD28、CD4、CD8、CD45RA和CD45RO的特定表达的情况,选择特定的T细胞亚群。
本申请提供了一种组合物,其可以包含所述的免疫效应细胞。
在本申请中,所述组合物可以包含药学上可接受的载体。所述药学上可接受的载体可以选自以下组:赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等张剂、溶剂、表面活性剂和乳化剂。
在本申请中,所述组合物也可以进一步包含其他活性成分,如细胞因子、生长因子、激素、小分子化学药活性成分、前药和抗体中的一种或多种。
在本申请中,所述组合物中所述免疫效应细胞的量可以为有效量。所述有效量可以为达到有益的或期望的预防性或治疗性效果所需的最低的剂量。例如,所述有效量可以被受试者的疾病程度、年龄、体重、性别等因素所影响。
本申请提供了所述的CAR,所述的核酸分子,所述的载体,或所述的免疫效应细胞用于制备药物的用途,其中所述药物用于治疗与BCMA的表达相关的疾病或病症。
本申请提供了所述的CAR,所述的核酸分子,所述的载体,或所述的免疫效应细胞,其治疗与BCMA的表达相关的疾病或病症。
本申请提供了治疗与BCMA的表达相关的疾病或病症的方法,其包括以下的步骤:向受试者施用所述的CAR,所述的核酸分子,所述的载体,或所述的免疫效应细胞。
在本申请中,所述与BCMA的表达相关的疾病或病症为癌症或恶性肿瘤。在本申请中,所述与BCMA的表达相关的疾病或病症选自下组:B细胞急性淋巴性白血病,T细胞急性淋巴性白血病,急性淋巴性白血病,慢性髓性白血病,慢性淋巴细胞白血病,B细胞幼淋巴细胞白血病,母细胞性浆细胞样树突状细胞瘤,伯基特淋巴瘤,弥散性大B细胞淋巴瘤,滤泡性淋巴瘤,毛细胞白血病,小细胞或大细胞滤泡性淋巴瘤,恶性淋巴增殖状况,MALT淋巴瘤,外套细胞淋巴瘤,边缘区淋巴瘤,多发性骨髓瘤,脊髓发育不良和骨髓增生异常综合征,非霍奇金淋巴瘤,浆母细胞淋巴瘤,浆细胞样树突细胞瘤,瓦尔登斯特伦巨球蛋白血症,前列腺癌,胰腺癌,肺癌,骨髓瘤,MGUS,浆细胞瘤,系统性淀粉样蛋白轻链淀粉样变性和POEMS综合征。
在本申请中,所述药物的给药方式可以包括气雾剂吸入、注射、摄取、输注、植入或者移植。例如,所述注射可以包括血管内、静脉内、肌肉内、动脉内、鞘内、囊内、眶内、瘤内、心脏内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内注射,或者可以直接注射至肿瘤或淋巴结。
下面通过详细的实施例对本申请进行进一步的阐述,应该理解,下述实施例仅是为了用于说明本申请,并不对发明内容进行限定。
实施例
实施例1BCMA单域抗体VHH基因获取
1)BCMA单域抗体文库构建
利用购自北京义翘神州的BCMA抗原对成年健康的羊驼在颈背部皮下多点注射免疫。免疫时,加入抗原和等体积福氏佐剂,分4-6次免疫,跟踪观察注射部位包块吸收情况,以确认免疫正确。免疫间隔时间为7-15天,第4次免疫后,采血测定抗原免疫效价,当效价达到1万倍以上时(ELISA方法),采血100ml左右,分离淋巴细胞,提取RNA,并反转录成cDNA,通过两次PCR扩增羊驼重链抗体的可变区片段VHH。将VHH片段构建入噬菌体展示库中,并通过转化将携带有单域抗体的基因片段的产物转入感受态细胞中,从而获得单域抗体免疫文库。
2)BCMA单域抗体筛选
利用噬菌体展示技术将单域抗体分子展示于噬菌体表面,进而筛选出抗原特异性的单域抗体。通过噬菌体酶联免疫吸附ELISA方法,将抗原用100mMNaHCO3(pH8.0)稀释至终浓度为100μg/mL,包被100μL至96孔板中,4℃过夜。经过PBS冲洗、1%脱脂牛奶封闭后,加入噬菌体孵育1~2h,然后将抗原特异性的噬菌体洗脱并侵染TG1细胞,在含有氨苄青霉素的LB培养板上涂布培养,经过多轮筛选逐步达到富集。挑选大量阳性克隆进行ELISA检测并对阳性克隆进行测序,根据序列比对,确定独特的克隆并将其序列分为框架区FR和互补决定区CDR。
将测序正确的克隆接种在5mL含有氨苄青霉素的LB培养液中,37℃摇床培养过夜;接种1mL的菌液至300mL LB培养液中,37℃摇床培养至OD600nm=0.6~0.9时,加入1M IPTG,28℃摇床培养过夜;离心,收菌;利用渗透法,获得抗体粗提液;通过ProteinL标记并利用亲和层析法纯化出单域抗体,其产量均在10mg/L以上。利用SPR技术检测抗体的亲和力,进一步筛选出特异性高的单域抗体。通过以上实施方式,共获得6株BCMA单域抗体,选择亲和力较高的单域抗体。
其中一株BCMA单域抗体命名为BCMA sdAb I。测序发现,BCMA sdAbI的HCDR1-3的氨基酸序列依次如SEQ ID NO:1-3所示。
实施例2嵌合抗原受体基因载体构建
由中美泰和公司合成2段基因,一段实施例1制备的BCMA sdAb I包含的核苷酸序列SEQ ID NO:15;一段为设计的2代CAR结构基因(CD8a铰链区、跨膜结构域+4-1BB共刺激结构域+CD3ζ胞内信号传导结构域,编码包含这些结构域的2代CAR结构基因的核苷酸序列如SEQ ID NO:16所示)。得到合成基因后,进行分子克隆,进行BCMA CAR的构建,通过PCR得到SEQ ID NO:15和SEQ ID NO:16的PCR产物,进行重叠PCR,得到两个片段连接在一起的BCMACAR基因(其核苷酸序列如SEQ ID NO:12所示);酶切慢病毒Pre载体和BCMA CAR基因,连接,转化,挑克隆,提质粒,测序,得到序列正确慢病毒载体Pre-Lenti-EF1-BCMA
1)SEQ ID NO:15:
atggccttaccagtgaccgccttgctcctgccgctggccttgctgctccacgccgccaggccggaagtccaactccaggcttccggtggcggtctggcacagcctggagggtccctgcggctctcctgcgcagcaagtggcaggactttcagtacctactttatggcctggttcagacagccacctggcaaaggcctcgaatacgtcggagggattaggtggtctgacggtgtccctcactacgctgacagtgtgaagggtcggttcaccattagcagagacaacgctaagaatacagtgtacctgcaaatgaactcactgagagctgaggatactgctgtgtacttctgcgcatctcgcggaatcgctgacgggtcagactttggctcctatggacagggcacccaggtgactgtgagttcc
2)SEQ ID NO:16:
ccagcgaagcccaccacgacgccagcgccgcgaccaccaacaccggcgcccaccatcgcgtcgcagcccctgtccctgcgcccagaggcgtgccggccagcggcggggggcgcagtgcacacgagggggctggacttcgcctgtgatatctacatctgggcgcccttggccgggacttgtggggtccttctcctgtcactggttatcaccctttactgcaaacggggcagaaagaaactcctgtatatattcaaacaaccatttatgagaccagtacaaactactcaagaggaagatggctgtagctgccgatttccagaagaagaagaaggaggatgtgaactgagagtgaagttcagcaggagcgcagacgcccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgcagagaaggaagaaccctcaggaaggcctgtacaatgaactgcagaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagggtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgccccc tcgctaa
实施例3BCMA嵌合抗原受体慢病毒制备
包装病毒前一天,胰酶消化293T细胞(购自ATCC),1×107个细胞/皿种植10cm培养皿。转染细胞时,除了实施例2制备的Pre-Lenti-EF1-BCMA质粒外,每种质粒需和包装质粒psPAX2、pMD2.0G共转染。其中Pre-Lenti-EF1-BCMA使用5μg,psPAX2质粒使用3.75μg,pMD2.0G质粒使用1.25μg。转染时,将以上三种质粒的混合物加入500μl MEM培养基内,在另一个微型离心管内将25μl Lipofectamine(脂质体)2000试剂加入500μl MEM培养基内,然后,将稀释的转染试剂逐滴加入稀释的质粒上方,混匀,离心,室温静置20分钟,最后将质粒和转染试剂形成的混合物加入10cm培养皿内,轻晃10次、混匀,放入孵箱。细胞转染3天后,收获病毒,将10ml含病毒培养上清转入50ml离心管内,4℃,1250rpm,5分钟,去除死亡的293T细胞,然后,将含病毒上清过滤,浓缩,分装,-80℃保存备用。
实施例4BCMA特异性嵌合抗原受体修饰的T细胞的制备
1)T淋巴细胞的制备
在无菌环境,抽取志愿者静脉血10ml。在50ml离心管中加入10ml人淋巴细胞分离液(达科为生物工程有限公司)。用电动移液枪将血液贴壁缓慢加入离心管中。放入离心机中,700g,22℃离心25分钟。离心结束后,PBMC在上层血浆层和分离液之间的白膜层中。用巴氏吸管尽量将白膜层吸到另一支离心管中(加入30ml 1640培养基),注意不要吸到分离液。250g,22℃,10分钟。弃掉上层液体,用3ml 1640培养基重悬计数,用于T细胞纯化。
取1×107个细胞于微型离心管中。250g,22℃,10分钟离心。弃掉上层液体,80μL磁珠分离缓冲液重悬细胞沉淀,加入20μl的CD3 MicroBeads(美天旎)。冰箱4℃区放置1小时,保证充分结合。1小时后,在微型离心管中加入1mL的磁珠分离缓冲液,250g,4℃离心10分钟。期间准备过滤柱子,将过滤柱安放在磁铁上,用500μl的缓冲液润洗(缓冲液随着重力留下)。离心后细胞弃上清,500μl的缓冲液重悬,加入柱子,缓冲液随着重力向下,细胞悬液流出后,柱子用500μl的缓冲液洗四次。将柱子从磁铁上卸掉,用1mL缓冲液将T细胞冲出,至1.5ml微型离心管。250g,4℃离心10分钟。含IL2的X-vivo 15培养基(Lonza)重悬,计数后按照2×106个T细胞/孔(6孔板)种植。
2)慢病毒感染T细胞
培养过夜后,加入MOI为2的实施例3制备的Pre-Lenti-EF1-BCMA病毒液,感染过夜。第二天,补加1ml新鲜培养基。第三天,T细胞已充分活化,增殖旺盛,此时将T细胞转入25cm2培养瓶。感染5天后,使用生物素标记的BCMA Fc蛋白测定BCMA CAR分子在T细胞表面表达效率,产生定BCMACART细胞。利用流式细胞仪检测细胞膜表面CAR的表达,BCMA CART细胞表面BCMA CAR分子表达的流式检测结果见图1。图1的结果显示,实施例4制备的BCMACART细胞中,CAR表达效率在50%以上。
实施例5BCMA嵌合抗原受体修饰T细胞功能评价
1)体外功能评价
对多发性骨髓瘤MM.1S细胞、骨髓性白血病K562细胞(购自ATCC进行流式细胞术检测,结果参见图2。图2的结果显示,BCMA分子在MM.1S细胞中高效表达,在K562细胞中不表达。
体外细胞杀伤实验采用LDH检测试剂盒(Promega)进行检测。将实施例4制备的BCMA CART细胞和靶细胞(如MM.1S细胞或K562细胞)按照两者的个数比(即效靶比)为0.5:1、1:1、2:1、4:1设置四个梯度。其中靶细胞3×104个/孔,用含X-VIVO培养基/1640培养基将其余所有孔的体系补足200μL。将96孔板放置于37℃,5%CO2培养箱中培养。17小时后,在最大释放的孔内加入20μL的裂解液,混匀使细胞完全破裂,将96孔板放入CO2培养箱中孵育2小时。2小时后,观察最大释放的孔,靶细胞全部裂解后从每个孔吸出50μL上清液到平底96孔板中,再在各个孔中加入50μL底物液,避光显色30min。30min之后观察颜色变化,其中最大释放MM.1S孔和含有BCMA CART细胞的孔的颜色比较深。酶标仪进行测量,测量波长为490nm。用LDH检测试剂盒获得杀伤力的检测结果。
结果如图3所示,其中对K562细胞的杀伤作用参见图3A;对MM.1S细胞的杀伤作用参见图3B。图3的结果说明,实施例4制备的BCMA CART细胞可以特异性杀伤BCMA阳性的细胞,且杀伤活性很高,均在40%以上;同时这些BCMA CART细胞对BCMA阴性的细胞不具杀伤效应。
将MM.1S肿瘤细胞和实施例4制备的BCMA CART细胞共孵育,ELISA方法检测上清中的IFN-γ、TNFα含量。结果如图4所示,其中IFN-γ的含量如图4A所示,TNFα的含量如图4B所示。图4的结果说明,不同的效靶比都能够上调具备肿瘤杀伤作用的细胞因子IFN-γ、TNFα的表达量。这从另一个角度验证了BCMA CART细胞的特异性杀伤作用。
2)动物实验
将人多发性骨髓瘤MM.1S细胞株转导表达荧光素酶报告基因(荧光素酶(luciferase),得到MM.1S-luc。用含10%胎牛血清(FBS)的1640培养基,置于5%二氧化碳,37℃培养箱中常规培养。MM.1S-luc细胞系以1.5×106个细胞/200μl PBS尾静脉注射(50只小鼠,雌雄各半)NSG小鼠17天后,对所有动物进行成像,荷瘤均一小鼠进入实验组,随机分为5组(雌雄各半,每组8只小鼠),分别作为细胞外液组,Mock T组,BCMA CART低中高剂量组。其中,细胞外液组尾静脉注射细胞外液,Mock T组尾静脉注射Mock T细胞,BCMA CART低中高剂量组尾静脉注射实施例4制备的BCMA CART细胞。
3天后,麻醉小鼠,腹腔注射Luciferase底物,使用小动物体内成像系统观察对照组(细胞外液组和Mock T组)小鼠和BCMA CART治疗组的肿瘤负荷情况,治疗后第3天和第7天的结果分别如图5和图6所示。
图5的结果可知,BCMA CART高中剂量治疗组中几乎无肿瘤细胞成像,而对照组小鼠肿瘤负荷严重,表明BCMA CART能够有效清除BCMA阳性的肿瘤细胞。BCMA CART细胞静脉回输后,第3天小鼠体内的荧光信号强度相对于细胞外液组、MOCK T组开始降低,表明肿瘤负荷在降低。由图6可知,第7天小鼠体内的荧光信号强度基本检测不到,可见BCMA CART在动物体内实验中也表现出强大的针对BCMA表达相关疾病的治疗效果。
至此,本领域技术人员应认识到,虽然本文已详尽示出和描述了本申请的多个示例性实施例,但是,在不脱离本申请精神和范围的情况下,仍可根据本申请公开的内容直接确定或推导出符合本申请原理的许多其他变型或修改。因此,本申请的范围应被理解和认定为覆盖了所有这些其他变型或修改。
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Gly Ser Tyr Gly Gln Gly Thr Gln Val Thr Val Ser Ser Pro Ala Lys
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Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
145 150 155 160
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
165 170 175
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
180 185 190
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
195 200 205
Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
210 215 220
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
225 230 235 240
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
245 250 255
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
260 265 270
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
275 280 285
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
290 295 300
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
305 310 315 320
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
325 330 335
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
340 345 350
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
355 360 365
Arg
<210> 11
<211> 348
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Glu Val Gln Leu Gln Ala Ser Gly Gly Gly Leu Ala Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Thr Tyr
20 25 30
Phe Met Ala Trp Phe Arg Gln Pro Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Gly Gly Ile Arg Trp Ser Asp Gly Val Pro His Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Arg Gly Ile Ala Asp Gly Ser Asp Phe Gly Ser Tyr Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser Pro Ala Lys Pro Thr Thr Thr Pro
115 120 125
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
130 135 140
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
145 150 155 160
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
165 170 175
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
180 185 190
Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
195 200 205
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
210 215 220
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
225 230 235 240
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
245 250 255
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
260 265 270
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys
275 280 285
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
290 295 300
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
305 310 315 320
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
325 330 335
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
340 345
<210> 12
<211> 1110
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggaagtcc aactccaggc ttccggtggc ggtctggcac agcctggagg gtccctgcgg 120
ctctcctgcg cagcaagtgg caggactttc agtacctact ttatggcctg gttcagacag 180
ccacctggca aaggcctcga atacgtcgga gggattaggt ggtctgacgg tgtccctcac 240
tacgctgaca gtgtgaaggg tcggttcacc attagcagag acaacgctaa gaatacagtg 300
tacctgcaaa tgaactcact gagagctgag gatactgctg tgtacttctg cgcatctcgc 360
ggaatcgctg acgggtcaga ctttggctcc tatggacagg gcacccaggt gactgtgagt 420
tccccagcga agcccaccac gacgccagcg ccgcgaccac caacaccggc gcccaccatc 480
gcgtcgcagc ccctgtccct gcgcccagag gcgtgccggc cagcggcggg gggcgcagtg 540
cacacgaggg ggctggactt cgcctgtgat atctacatct gggcgccctt ggccgggact 600
tgtggggtcc ttctcctgtc actggttatc accctttact gcaaacgggg cagaaagaaa 660
ctcctgtata tattcaaaca accatttatg agaccagtac aaactactca agaggaagat 720
ggctgtagct gccgatttcc agaagaagaa gaaggaggat gtgaactgag agtgaagttc 780
agcaggagcg cagacgcccc cgcgtaccag cagggccaga accagctcta taacgagctc 840
aatctaggac gaagagagga gtacgatgtt ttggacaaga gacgtggccg ggaccctgag 900
atggggggaa agccgcagag aaggaagaac cctcaggaag gcctgtacaa tgaactgcag 960
aaagataaga tggcggaggc ctacagtgag attgggatga aaggcgagcg ccggaggggc 1020
aaggggcacg atggccttta ccagggtctc agtacagcca ccaaggacac ctacgacgcc 1080
cttcacatgc aggccctgcc ccctcgctaa 1110
<210> 13
<211> 1047
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
gaagtccaac tccaggcttc cggtggcggt ctggcacagc ctggagggtc cctgcggctc 60
tcctgcgcag caagtggcag gactttcagt acctacttta tggcctggtt cagacagcca 120
cctggcaaag gcctcgaata cgtcggaggg attaggtggt ctgacggtgt ccctcactac 180
gctgacagtg tgaagggtcg gttcaccatt agcagagaca acgctaagaa tacagtgtac 240
ctgcaaatga actcactgag agctgaggat actgctgtgt acttctgcgc atctcgcgga 300
atcgctgacg ggtcagactt tggctcctat ggacagggca cccaggtgac tgtgagttcc 360
ccagcgaagc ccaccacgac gccagcgccg cgaccaccaa caccggcgcc caccatcgcg 420
tcgcagcccc tgtccctgcg cccagaggcg tgccggccag cggcgggggg cgcagtgcac 480
acgagggggc tggacttcgc ctgtgatatc tacatctggg cgcccttggc cgggacttgt 540
ggggtccttc tcctgtcact ggttatcacc ctttactgca aacggggcag aaagaaactc 600
ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 660
tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 720
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 780
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 840
gggggaaagc cgcagagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa 900
gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag 960
gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta cgacgccctt 1020
cacatgcagg ccctgccccc tcgctaa 1047
<210> 14
<211> 553
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
aaggatctgc gatcgctccg gtgcccgtca gtgggcagag cgcacatcgc ccacagtccc 60
cgagaagttg gggggagggg tcggcaattg aacgggtgcc tagagaaggt ggcgcggggt 120
aaactgggaa agtgatgtcg tgtactggct ccgccttttt cccgagggtg ggggagaacc 180
gtatataagt gcagtagtcg ccgtgaacgt tctttttcgc aacgggtttg ccgccagaac 240
acagctgaag cttcgagggg ctcgcatctc tccttcacgc gcccgccgcc ctacctgagg 300
ccgccatcca cgccggttga gtcgcgttct gccgcctccc gcctgtggtg cctcctgaac 360
tgcgtccgcc gtctaggtaa gtttaaagct caggtcgaga ccgggccttt gtccggcgct 420
cccttggagc ctacctagac tcagccggct ctccacgctt tgcctgaccc tgcttgctca 480
actctacgtc tttgtttcgt tttctgttct gcgccgttac agatccaagc tgtgaccggc 540
gcctacgcta gac 553
<210> 15
<211> 423
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60
ccggaagtcc aactccaggc ttccggtggc ggtctggcac agcctggagg gtccctgcgg 120
ctctcctgcg cagcaagtgg caggactttc agtacctact ttatggcctg gttcagacag 180
ccacctggca aaggcctcga atacgtcgga gggattaggt ggtctgacgg tgtccctcac 240
tacgctgaca gtgtgaaggg tcggttcacc attagcagag acaacgctaa gaatacagtg 300
tacctgcaaa tgaactcact gagagctgag gatactgctg tgtacttctg cgcatctcgc 360
ggaatcgctg acgggtcaga ctttggctcc tatggacagg gcacccaggt gactgtgagt 420
tcc 423
<210> 16
<211> 687
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
ccagcgaagc ccaccacgac gccagcgccg cgaccaccaa caccggcgcc caccatcgcg 60
tcgcagcccc tgtccctgcg cccagaggcg tgccggccag cggcgggggg cgcagtgcac 120
acgagggggc tggacttcgc ctgtgatatc tacatctggg cgcccttggc cgggacttgt 180
ggggtccttc tcctgtcact ggttatcacc ctttactgca aacggggcag aaagaaactc 240
ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 300
tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 360
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 420
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 480
gggggaaagc cgcagagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa 540
gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag 600
gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta cgacgccctt 660
cacatgcagg ccctgccccc tcgctaa 687
Claims (26)
1.嵌合抗原受体(CAR),所述CAR包含:BCMA结合结构域、跨膜结构域、一个或多个共刺激结构域、以及胞内信号传导结构域;其中所述BCMA结合结构域包含重链互补决定区1(HCDR1),重链互补决定区2(HCDR2)和重链互补决定区3(HCDR3),所述HCDR1的氨基酸序列如SEQ ID NO:1所示,所述HCDR2的氨基酸序列如SEQ ID NO:2所示且所述HCDR3的氨基酸序列如SEQ ID NO:3所示。
2.根据权利要求1所述的CAR,其中所述BCMA结合结构域为单域抗体。
3.根据权利要求1-2中任一项所述的CAR,其中所述BCMA结合结构域包含SEQ ID NO:4所示的氨基酸序列或其功能性变体。
4.根据权利要求1-3中任一项所述的CAR,其中所述跨膜结构域包含来自选自下述蛋白的多肽:T细胞受体的α,β或ζ链,CD28,CD3e,CD45,CD4,CD5,CD8a,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137和CD154。
5.根据权利要求1-4中任一项所述的CAR,其中所述跨膜结构域包含SEQ ID NO:5所示的氨基酸序列或其功能性变体。
6.根据权利要求1-5中任一项所述的CAR,其中所述BCMA结合结构域通过铰链区与所述跨膜结构域相连接。
7.根据权利要求6所述的CAR,其中所述铰链区包含SEQ ID NO:6所示的氨基酸序列或其功能性变体。
8.根据权利要求1-7中任一项所述的CAR,其中所述一个或多个共刺激结构域来自选自下述的共刺激分子:CARD11、CD2、CD7、CD27、CD28、CD30、CD40、CD54(ICAM)、CD83、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD152(CTLA4)、CD223(LAG3)、CD270(HVEM)、CD273(PD-L2)、CD274(PD-L1)、CD278(ICOS)、DAP10、LAT、NKG2C、SLP76、TRIM以及ZAP70。
9.根据权利要求1-8中任一项所述的CAR,其中所述共刺激结构域包含SEQ ID NO:7所示的氨基酸序列或其功能性变体。
10.根据权利要求1-9中任一项所述的CAR,其中所述胞内信号传导结构域包含CD3ζ的信号传导结构域。
11.根据权利要求1-10中任一项所述的CAR,其中所述胞内信号传导结构域包含SEQ IDNO:8所示的氨基酸序列或其功能性变体。
12.根据权利要求1-11中任一项所述的CAR,其还包含前导序列,所述前导序列包含SEQID NO:9所示的氨基酸序列或其功能性变体。
13.根据权利要求1-12中任一项所述的CAR,其包含SEQ ID NO:10-11所示的氨基酸序列或其功能性变体。
14.分离的核酸分子,其编码权利要求1-13中任一项所述的CAR。
15.编码CAR的分离的核酸分子,其包含SEQ ID NO:12-13所示的核酸序列或其功能性变体。
16.一种载体,其包含权利要求14-15中任一项所述的核酸分子。
17.根据权利要求16所述的载体,其选自DNA载体,RNA载体,质粒,慢病毒载体,腺病毒载体和逆转录病毒载体。
18.根据权利要求16-17中任一项所述的载体,其还包含EF1启动子,该启动子包含SEQID NO:14所示的序列。
19.一种免疫效应细胞,其包含权利要求1-13中任一项所述的CAR,权利要求14-15中任一项所述的核酸分子,或权利要求16-18中任一项所述的载体。
20.根据权利要求19所述的免疫效应细胞,其选自T淋巴细胞和自然杀伤(NK)细胞。
21.一种制备免疫效应细胞的方法,其包括向免疫效应细胞中引入权利要求16-18中任一项所述的载体。
22.根据权利要求21所述的方法,其中所述免疫效应细胞选自T淋巴细胞和自然杀伤(NK)细胞。
23.组合物,其包含权利要求19-20中任一项所述的免疫效应细胞。
24.权利要求1-13中任一项所述的CAR,权利要求14-15中任一项所述的核酸分子,权利要求16-18中任一项所述的载体,或权利要求19-20中任一项所述的免疫效应细胞用于制备药物的用途,其中所述药物用于治疗与BCMA的表达相关的疾病或病症。
25.根据权利要求24所述的用途,其中所述与BCMA的表达相关的疾病或病症为癌症或恶性肿瘤。
26.根据权利要求24-25中任一项所述的用途,其中所述与BCMA的表达相关的疾病或病症选自下组:B细胞急性淋巴性白血病,T细胞急性淋巴性白血病,急性淋巴性白血病,慢性髓性白血病,慢性淋巴细胞白血病,B细胞幼淋巴细胞白血病,母细胞性浆细胞样树突状细胞瘤,伯基特淋巴瘤,弥散性大B细胞淋巴瘤,滤泡性淋巴瘤,毛细胞白血病,小细胞或大细胞滤泡性淋巴瘤,恶性淋巴增殖状况,MALT淋巴瘤,外套细胞淋巴瘤,边缘区淋巴瘤,多发性骨髓瘤,脊髓发育不良和骨髓增生异常综合征,非霍奇金淋巴瘤,浆母细胞淋巴瘤,浆细胞样树突细胞瘤,瓦尔登斯特伦巨球蛋白血症,前列腺癌,胰腺癌,肺癌,骨髓瘤,MGUS,浆细胞瘤,系统性淀粉样蛋白轻链淀粉样变性和POEMS综合征。
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KR1020190039819A KR102223873B1 (ko) | 2018-08-24 | 2019-04-04 | 단일 도메인 항체에 기반한 bcma 키메라 항원 수용체 및 응용 |
EA202190607A EA202190607A1 (ru) | 2018-08-24 | 2019-07-10 | Химерный антигенный рецептор для bcma на основе однодоменного антитела и его применение |
EP19852889.5A EP3842462A4 (en) | 2018-08-24 | 2019-07-10 | BCMA SINGLE-DOMAIN ANTIBODY-BASED CHEMICAL ANTIGEN RECEPTOR AND USE THEREOF |
PCT/CN2019/095505 WO2020038146A1 (zh) | 2018-08-24 | 2019-07-10 | 一种基于单域抗体的bcma嵌合抗原受体及应用 |
SG11202101685XA SG11202101685XA (en) | 2018-08-24 | 2019-07-10 | Bcma chimeric antigen receptor based on single domain antibody and use thereof |
JP2021534411A JP7237287B2 (ja) | 2018-08-24 | 2019-07-10 | 単一ドメイン抗体に基づくbcmaキメラ抗原受容体及びその使用 |
BR112021003408-0A BR112021003408A2 (pt) | 2018-08-24 | 2019-07-10 | receptor de antígeno químico bcma com base em anticorpo de domínio único e uso do mesmo |
US17/270,775 US20220218746A1 (en) | 2018-08-24 | 2019-07-10 | Bcma chimeric antigen receptor based on single domain antibody and use thereof |
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CN109678961A (zh) * | 2019-01-15 | 2019-04-26 | 深圳市南科生物工程有限公司 | 一种基于bmca纳米抗体序列的嵌合抗原受体的构建方法及其应用 |
CN109942708A (zh) * | 2019-03-28 | 2019-06-28 | 上海科棋药业科技有限公司 | 一种抗bcma的单域抗体及其应用 |
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KR20200023165A (ko) | 2020-03-04 |
KR102223873B1 (ko) | 2021-03-08 |
AU2019325036B2 (en) | 2023-10-05 |
JP2021535756A (ja) | 2021-12-23 |
CA3109320C (en) | 2023-10-31 |
EA202190607A1 (ru) | 2021-05-28 |
BR112021003408A2 (pt) | 2021-05-18 |
JP7237287B2 (ja) | 2023-03-13 |
WO2020038146A1 (zh) | 2020-02-27 |
EP3842462A1 (en) | 2021-06-30 |
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