CN110615842A - 一种包含共刺激受体的嵌合抗原受体及应用 - Google Patents
一种包含共刺激受体的嵌合抗原受体及应用 Download PDFInfo
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Abstract
本发明涉及一种包含共刺激受体的嵌合抗原受体,该嵌合抗原受体的结构为scFv(X)‑(Y)CD3zeta‑2A‑(Z);其中,X包括肿瘤靶向抗体或能与肿瘤特异结合的配体、受体;Y为共刺激受体的胞内区,Z为共刺激受体,所述共刺激受体选自ICOS、CD28、CD27、HVEM、LIGHT、CD40L、4‑1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2、CD226。本发明还涉及一种由上述嵌合抗原受体的重组表达载体构建的CAR‑T细胞及其制备方法和应用。本发明所述的CAR‑T细胞显著提高了肿瘤杀伤能力和扩增能力,将共刺激受体信号整合在CAR‑T中,具有潜在的增强效应的功能,且只对CAR‑T细胞有作用,降低了造成免疫副作用的风险。
Description
技术领域
本发明涉及细胞免疫治疗技术领域,尤其涉及一种包含共刺激受体的嵌合抗原受体及其应用。
背景技术
利用免疫学治疗手段来攻克肿瘤,一直是免疫学在转化医学方面应用的重要方向。随着各种组学(基因组学,蛋白组学等)的发展,肿瘤细胞由于突变产生的免疫原性得到了广泛的认可,这为肿瘤免疫治疗奠定了理论的基础。同时,随着肿瘤免疫学研究自身的积累,肿瘤免疫治疗近期取得了巨大的进步,一系列新的免疫治疗手段逐步进入临床。当前的肿瘤免疫学研究,奠定了T细胞杀伤在肿瘤免疫治疗中的中心地位,而嵌和抗原受体T细胞(CAR-T细胞)就是结合了抗体的靶向识别和T细胞的肿瘤杀伤功能,人工修饰生成的肿瘤杀伤细胞。
嵌和抗原受体T细胞的概念最早在1989年被Gross,Waks和Eshhar提出,他们将识别TNP的抗体表达在T细胞上,实现了抗原特异性的、非MHC限制的T细胞的活化和效应的增强,并提出了CAR-T技术在肿瘤治疗中的应用的概念。根据这一原理,将具有肿瘤特异性的抗体嵌入T细胞,将赋予T细胞新的杀瘤能力。之后,CAR-T技术被引入到抗肿瘤临床试验中,但早期的CAR-T细胞由于其胞内信号传递域仅含有第一信号,而且选择的肿瘤类型为实体瘤,最终的临床结果都不太理想。在2008年,Fred Hutchison肿瘤研究所等机构使用CAR-T对B细胞淋巴瘤来进行治疗,虽然治疗结果不太理想,但这一临床实验的关键在于证实了以表达CD20的B细胞作为靶点的CAR-T治疗是相对安全的。随后,在2010年NCI报道了一例B细胞淋巴瘤治疗成功的病例,利用针对CD19的CAR-T,病人的淋巴瘤得到控制,正常B细胞也被清除,血清Ig显著降低,为CAR-T治疗B细胞来源的淋巴瘤的有效性提供了理论和实际的支持。在2011年,美国宾夕法尼亚大学的的Carl June博士领导的团队将特异性识别CD19的CAR-T用于B细胞来源的慢性淋巴细胞白血病的治疗,显示了“治愈”的疗效,随后在复发难治性急性淋巴细胞白血病展开临床实验,也取得了良好的疗效。由于这一突破性的进展以及其他免疫调控手段的发展,Science杂志将肿瘤免疫治疗评为了2013年科技突破进展的第一名。这一成功在世界各国引起了广泛的影响,各国开始大量开展基于CAR-T的科学研究和肿瘤治疗的临床试验。
CAR的结构由胞外抗原识别结构域,胞外铰链区,跨膜区和胞内的信号传导结构域组成。胞外的抗原识别域通常是由单链抗体组成,特异性识别肿瘤细胞膜表面分子,也可以是某些肿瘤特异抗原的配体或受体等。胞外铰链区是一段用于隔开抗原识别域和跨膜区的空间结构,其目的是为了提供合适的空间位置,使得胞外抗原识别域能够在识别抗原前后维持正确的结构并传导胞内信号。跨膜区是为了保证CAR分子在膜表面定位的结构域。胞内信号传导结构域是介导CAR信号传导的关键部分,通常是一个或几个第一信号(TCR和MHC-I-peptide复合物识别),第二信号(共刺激受体和共刺激配体识别)的组合。第一代CAR只含有第一信号,第二代CAR有一个第一信号和一个第二信号,第三代CAR有一个第一信号和两个第二信号结构域。虽然CAR-T在针对B细胞来源的白血病治疗中获得了巨大的成功,但是其相对较高的复发率以及对实体瘤的低有效率是当前的重要挑战。因此发展新一代的高效CAR-T是目前临床所急需的。除了第三代CAR-T,目前还有其他新的CAR-T设计策略,即在第二代CAR-T的基础上引入了新的独立于CAR的调节分子,以进一步增强CAR-T的功能。
利用病人自体血液细胞制备的针对B细胞表面靶向分子CD19、CD20的CAR-T在B细胞白血病治疗中的应用已相对成熟,但虽然响应率高,但是存在大量的复发现象,此外对实体淋巴瘤的治疗效率相对较低,这与实体肿瘤中的免疫抑制微环境有关。
在实体肿瘤中,存在多种免疫细胞、肿瘤细胞和基质细胞,共同组成肿瘤微环境。肿瘤微环境通常是免疫抑制的,能够对内源的抗肿瘤T细胞反应或过继性的T细胞(譬如CAR-T)在多种层次进行抑制,譬如,导致T细胞发生耗竭,失去杀伤肿瘤的功能,最终T细胞被清除。如何增强CAR-T在实体瘤中的活化能力,使其能够对抗肿瘤微环境中的免疫抑制,是扩增CAR-T到实体瘤治疗的重要思路和方向。
而当前临床使用的CAR-T结构域,在肿瘤杀伤能力和扩增能力上还存在不足,在控制实体肿瘤/转移肿瘤上疗效较差,部分CAR-T采用新型调控分子如IL-12,4-1BBL等,这些分子除了影响CAR-T,也会对其他非CAR-T细胞产生非特异的活化作用,有造成免疫副作用的潜在可能。
发明内容
本发明的目的在于克服现有技术中的缺陷,提供一种包含共刺激受体的嵌合抗原受体及其应用,并提供一种由如该嵌合抗原受体的重组表达载体构建的CAR-T细胞,例如OX40是一个重要的共刺激受体,主要表达在活化的CD4和CD8T细胞,在T细胞活化过程中表现出多种功能,能够促进T细胞的活化,表达更多的效应分子以及减少细胞凋亡相关的基因表达,将共刺激受体信号整合在CAR-T中,具有潜在的增强效应的功能。
为实现上述目的,本发明采用如下技术方案:
本发明的第一个目的是提供一种包含共刺激受体的嵌合抗原受体,所述嵌合抗原受体的结构为scFv(X)-(Y)CD3zeta-2A-(Z);其中,X包括肿瘤靶向抗体或能与肿瘤特异结合的配体、受体;Y为共刺激受体的胞内区,所述共刺激受体选自ICOS、CD28、CD27、HVEM、LIGHT、CD40L、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2、CD226;Z为共刺激受体,所述共刺激受体选自ICOS、CD28、CD27、HVEM、LIGHT、CD40L、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2、CD226。
为了进一步优化上述嵌合抗原受体,本发明采取的技术措施还包括:
进一步地,所述X选自anti-CD19抗体、anti-CD20抗体、EGFR抗体、HER2抗体、EGFRVIII抗体、anti-PSMA抗体、anti-BCMA抗体、anti-CD22抗体、anti-CD30抗体。可理解的是,X还可为能与肿瘤特异结合的其他蛋白。
进一步地,所述X为anti-CD20抗体,所述Y为4-1BB,所述Z选自OX40、HVEM、ICOS、CD27、4-1BB中的一种。
进一步地,所述scFv(X)-(Y)CD3zeta为scFv-antihCD20-20BBZ,其序列如SEQ IDNo.1所示;所述OX40的序列如SEQ ID No.2所示;所述HVEM的序列如SEQ ID No.3所示;所述ICOS的序列如SEQ ID No.4所示;所述CD27的序列如SEQ ID No.5所示;所述4-1BB的序列如SEQ ID No.6所示;所述2A的序列如SEQ ID No.7、SEQ ID No.8、SEQ ID No.9或SEQ IDNo.10所示。
其中上述各序列具体如下:
SEQ ID No.1:
QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSAAAATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR;
SEQ ID No.2:
MCVGARRLGRGPCAALLLLGLGLSTVTGLHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCRCRAGTQPLDSYKPGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRDPPATQPQETQGPPARPITVQPTEAWPRTSQGPSTRPVEVPGGRAVAAILGLGLVLGLLGPLAILLALYLLRRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI;
SEQ ID No.3:
MEPPGDWGPPPWRSTPKTDVLRLVLYLTFLGAPCYAPALPSCKEDEYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGCSPGHFCIVQDGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFSPNGTLEECQHQTKCSWLVTKAGAGTSSSHWVWWFLSGSLVIVIVCSTVGLIICVKRRKPRGDVVKVIVSVQRKRQEAEGEATVIEALQAPPDVTTVAVEETIPSFTGRSPNH;
SEQ ID No.4:
MKSGLWYFFLFCLRIKVLTGEINGSANYEMFIFHNGGVQILCKYPDIVQQFKMQLLKGGQILCDLTKTKGSGNTVSIKSLKFCHSQLSNNSVSFFLYNLDHSHANYYFCNLSIFDPPPFKVTLTGGYLHIYESQLCCQLKFWLPIGCAAFVVVCILGCILICWLTKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL;
SEQ ID No.5:
MARPHPWWLCVLGTLVGLSATPAPKSCPERHYWAQGKLCCQMCEPGTFLVKDCDQHRKAAQCDPCIPGVSFSPDHHTRPHCESCRHCNSGLLVRNCTITANAECACRNGWQCRDKECTECDPLPNPSLTARSSQALSPHPQPTHLPYVSEMLEARTAGHMQTLADFRQLPARTLSTHWPPQRSLCSSDFIRILVIFSGMFLVFTLAGALFLHQRRKYRSNKGESPVEPAEPCRYSCPREEEGSTIPIQEDYRKPEPACSP;
SEQ ID No.6:
MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL;
SEQ ID No.7:GSGATNFSLLKQAGDVEENPGP;
SEQ ID No.8:GSGEGRGSLLTCGDVEENPGP;
SEQ ID No.9:GSGQCTNYALLKLAGDVESNPGP;
SEQ ID No.10:GSGVKQTLNFDLLKLAGDVESNPGP。
进一步地,所述嵌合抗原受体的胞外铰链区选自CD8a或IgG的一段区域;所述嵌合抗原受体的跨膜区选自CD8a、CD28、CD137或CD3中的一个。
本发明的第二个目的是提供一种任一上述的嵌合抗原受体的重组表达载体。
本发明的第三个目的是提供一种由任一上述的嵌合抗原受体的重组表达载体构建的CAR-T细胞。
本发明的第四个目的是提供一种上述CAR-T细胞的制备方法,其包括以下步骤:
步骤一、慢病毒载体的构建及病毒生产;
将scFv(X)-(Y)CD3zeta,Z的中间加入2A形成融合蛋白,两端加入慢病毒载体,并和慢病毒包装质粒共同转染,获得scFv(X)-(Y)CD3zeta-2A-(Z)病毒;
步骤二、scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞的制备;
分离纯化后的人PBMC经过培养后,感染步骤一获得的scFv(X)-(Y)CD3zeta-2A-(Z)病毒,在合适的条件下进行细胞扩增,制备scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞。
为了进一步优化上述CAR-T细胞的制备方法,本发明所采用的技术措施还包括:
进一步地,所述慢病毒载体的构建及病毒生产的具体步骤包括:将scFv(X)-(Y)CD3zeta,Z通过overlap PCR在其中间加入2A形成融合蛋白,两端加入酶切位点克隆慢病毒载体;将测序正确的克隆无内毒素大提,和慢病毒包装质粒共同转染,预定时间收取上清,过滤、离心浓缩病毒,获得scFv(X)-(Y)CD3zeta-2A-(Z)病毒。
更进一步地,所述慢病毒载体的构建及病毒生产的具体步骤为:将scFv(X)-(Y)CD3zeta和OX40通过overlap PCR在其加入2A序列,两端加入EcoRI和SalI酶切位点克隆pCDH-MSCVEF载体,将测序正确的克隆无内毒素大提,和慢病毒包装质粒共同转染293X,48和72小时后收取上清,0.45uM过滤后,25000RPM离心2小时浓缩病毒,获得scFv(X)-(Y)CD3zeta-2A-(Z)病毒。
进一步地,所述scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞的制备的具体步骤包括:将人PBMC经过分离纯化后,接种到具有合适刺激条件的培养板,培养预定时间后,感染步骤一生产的scFv(X)-(Y)CD3zeta-2A-(Z)病毒,按照合适的刺激条件进行细胞扩增,经过2轮刺激扩增后,获得的细胞即为scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞。
进一步地,培养分离纯化后的人PBMC的刺激条件为anti-hCD3和anti-hCD28,扩增细胞的刺激条件为每6天使用人工抗原呈递细胞或anti-hCD3/28刺激。
更进一步地,所述scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞的制备的具体步骤为:将人PBMC经过Stemcell T细胞分离试剂盒纯化后,接种到anti-hCD3和anti-hCD28包被的96孔培养板,2天后,按照MOI=10-20感染scFv(X)-(Y)CD3zeta-2A-(Z)病毒,1天后换液继续细胞培养,按照每6天使用人工抗原呈递细胞或anti-hCD3/28刺激,经过2轮刺激后,所得细胞即为scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞。
进一步地,所述X选自anti-CD19抗体、anti-CD20抗体、EGFR抗体、HER2抗体、EGFRVIII抗体。
进一步地,所述X为anti-CD20抗体,所述Y为4-1BB,所述Z选自OX40、HVEM、ICOS、CD27、4-1BB中的一种。
进一步地,所述scFv(X)-(Y)CD3zeta为scFv-antihCD20-20BBZ,其序列如SEQIDNo.1所示;所述OX40的序列如SEQID No.2所示;所述HVEM的序列如SEQID No.3所示;所述ICOS的序列如SEQID No.4所示;所述CD27的序列如SEQID No.5所示;所述4-1BB的序列如SEQID No.6所示;所述2A的序列如SEQID No.7所示。
进一步地,所述步骤一中慢病毒包装质粒包括VSV-g,pMD Gag/Pol,RSV-REV,离心使用贝克曼超速离心机和SW28转头。
本发明的第五个目的是提供一种含有上述CAR-T细胞或含有由上述制备方法制得的的CAR-T细胞的制剂;进一步地,所述制剂还包括药用的稀释剂或赋形剂。
本发明的第六个目的是提供一种上述嵌合抗原受体、上述CAR-T细胞或由上述制备方法制得的的CAR-T细胞在制备治疗或预防肿瘤药物中的应用。
进一步地,所述肿瘤为实体肿瘤,所述实体肿瘤的例子包括但不限于,淋巴瘤、肾脏肿瘤、神经母细胞瘤、生殖细胞瘤、骨肉瘤、软骨肉瘤、软组织肉瘤、肝脏肿瘤、胸腺瘤、肺母细胞瘤、胰母细胞瘤、血管瘤等。
与现有技术相比,本发明具有以下有益效果:
本发明所述的CAR-T细胞显著提高了肿瘤杀伤能力和扩增能力,显著提高的实体肿瘤/转移肿瘤的杀伤能力;本发明所述的CAR-T细胞,包含共刺激受体(ICOS、CD28、CD27、HVEM、LIGHT、CD40L、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2、CD226等)而不是常规所用的配体或分泌因子,只对CAR-T细胞有作用,降低了造成免疫副作用的风险。
本发明首次将共刺激受体用于CAR-T的构建,相对目前临床使用的CAR-T技术,其显著提高CAR-T细胞在肿瘤中的活化能力和存活能力,控制实体/转移肿瘤的能力,从而提高CAR-T细胞疗效,以具有更优异的抗肿瘤疗效。
附图说明
图1为本发明各实施例中含有第三信号受体的嵌合抗原受体(CAR)分子结构的说明示意图;
图2为本发明一实施例中BBZ-2A-OX40病毒感染293细胞后测得的病毒滴度的示意图;
图3为本发明一实施例中BBZ-2A-HVEM病毒感染293细胞后测得的病毒滴度的示意图;
图4为本发明一实施例中BBZ-2A-ICOS病毒感染293细胞后测得的病毒滴度的示意图;
图5为本发明一实施例中BBZ-2A-CD27病毒感染293细胞后测得的病毒滴度的示意图;
图6为本发明一实施例中BBZ-2A-4-1BB病毒感染293细胞后测得的病毒滴度的示意图;
图7为本发明一实施例中BBZ CAR-T细胞和BBZ-2A-OX40CAR-T细胞表型分析的结果示意图;
图8为本发明一实施例中BBZ CAR-T细胞和BBZ-2A-HVEM CAR-T细胞表型分析的结果示意图;
图9为本发明一实施例中BBZ CAR-T细胞和BBZ-2A-ICOS CAR-T细胞表型分析的结果示意图;
图10为本发明一实施例中BBZ CAR-T细胞和BBZ-2A-CD27CAR-T细胞表型分析的结果示意图;
图11为本发明一实施例中BBZ CAR-T细胞和BBZ-2A-4-1BB CAR-T细胞表型分析的结果示意图;
图12为本发明一实施例中BBZ CAR-T细胞和BBZ-2A-OX40CAR-T细胞的扩增能力的示意图;
图13为本发明一实施例BBZ CAR-T细胞和BBZ-2A-OX40CAR-T细胞的肿瘤杀伤能力的示意图;
图14为本发明一实施例中BBZ CAR-T细胞和BBZ-2A-OX40CAR-T细胞的抗肿瘤能力的示意图;
图15为本发明一实施例中BBZ CAR-T细胞和BBZ-2A-OX40CAR-T细胞的体内存活能力的示意图。
具体实施方式
本发明提供一种包含共刺激受体的嵌合抗原受体,所述嵌合抗原受体的结构为scFv(X)-(Y)CD3zeta-2A-(Z);其中,X为肿瘤靶向抗体或其他蛋白;Y为共刺激受体的胞内区,所述共刺激受体选自ICOS、CD28、CD27、HVEM、LIGHT、CD40L、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2、CD226;Z为共刺激受体,所述共刺激受体选自ICOS、CD28、CD27、HVEM、LIGHT、CD40L、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2、CD226。本发明还涉及一种由任一上述的嵌合抗原受体的重组表达载体构建的CAR-T细胞及其制备方法,含有该CAR-T细胞的制剂以及该CAR-T细胞的应用。
下面结合附图和实施例,对本发明的具体实施方式作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案,而不能以此来限制本发明的保护范围。
本发明下述实施例所涉及的含有共刺激受体的嵌合抗原受体(CAR)分子分别为BBZ-2A-OX40、BBZ-2A-HVEM、BBZ-2A-ICOS、BBZ-2A-CD27、BBZ-2A-4-1BB,其结构如图1所示。
实施例1-20BBZ-2A-OX40CAR-T细胞的制备
本实施例所述的20BBZ-2A-OX40CAR-T细胞的制备包括以下步骤:
1.慢病毒载体pCDH-MSCVEF-20BBZ-2A-OX40的构建及病毒生产
将scFv-antihCD20-20BBZ(SEQ ID No.1)和OX40(SEQ ID No.2)通过overlap PCR的中间加入2A(SEQ ID No.7)序列,两端加入EcoRI和SalI酶切位点克隆pCDH-MSCVEF载体。将测序正确的克隆无内毒素大提,和慢病毒包装质粒(VSV-g,pMD Gag/Pol,RSV-REV)共同转染293X,48和72小时后收取上清,0.45uM过滤后,使用贝克曼超速离心机和SW28转头,25000RPM离心2小时浓缩病毒,即为pCDH-MSCVEF-20BBZ-2A-OX40病毒(简称为20BBZ-2A-OX40病毒),用于后续CAR-T细胞生产。同时生产对照pCDH-MSCVEF-20BBZ病毒(简称20BBZ病毒),将所得病毒感染293细胞,测得病毒滴度,如图2所示。
2.20BBZ-2A-OX40CAR-T细胞和20BBZ CAR-T细胞的制备
将人PBMC经过Stemcell T细胞分离试剂盒纯化后,接种到anti-hCD3和anti-hCD28包被的96孔培养板,2天后,按照MOI=10-20感染20BBZ病毒和20BBZ-2A-OX40病毒,1天后换液继续细胞培养,按照每6天使用人工抗原呈递细胞或anti-hCD3/28刺激,经过2轮刺激后,所得细胞即为20BBZ CAR-T细胞和20BBZ-2A-OX40CAR-T细胞,用于后续实验和表型分析,其结果如图7所示。由图可知,所得细胞为CAR阳性。
实施例2-20BBZ-2A-HVEM CAR-T细胞的制备
本实施例所述的20BBZ-2A-HVEM CAR-T细胞的制备包括以下步骤:
1.慢病毒载体pCDH-MSCVEF-20BBZ-2A-HVEM的构建及病毒生产
将scFv-antihCD20-20BBZ(SEQ ID No.1)和HVEM(SEQ ID No.3)通过overlap PCR的中间加入2A(SEQ ID No.8)序列,两端加入EcoRI和SalI酶切位点克隆pCDH-MSCVEF载体。将测序正确的克隆无内毒素大提,和慢病毒包装质粒(VSV-g,pMD Gag/Pol,RSV-REV)共同转染293X,48和72小时后收取上清,0.45uM过滤后,使用贝克曼超速离心机和SW28转头,25000RPM离心2小时浓缩病毒,即为pCDH-MSCVEF-20BBZ-2A-HVEM病毒(简称为20BBZ-2A-HVEM病毒),用于后续CAR-T细胞生产。同时生产对照pCDH-MSCVEF-20BBZ病毒(简称20BBZ病毒),将所得病毒感染293细胞,测得病毒滴度,如图3所示。
2.20BBZ-2A-HVEM CAR-T细胞和20BBZ CAR-T细胞的制备
将人PBMC经过Stemcell T细胞分离试剂盒纯化后,接种到anti-hCD3和anti-hCD28包被的96孔培养板,2天后,按照MOI=10-20感染20BBZ病毒和20BBZ-2A-HVEM病毒,1天后换液继续细胞培养,按照每6天使用人工抗原呈递细胞或anti-hCD3/28刺激,经过2轮刺激后,所得细胞即为20BBZ CAR-T细胞和20BBZ-2A-HVEM CAR-T细胞,用于后续实验和表型分析,其结果如图8所示。由图可知,所得细胞为CAR阳性。
实施例3-20BBZ-2A-ICOS CAR-T细胞的制备
本实施例所述的20BBZ-2A-ICOS CAR-T细胞的制备包括以下步骤:
1.慢病毒载体pCDH-MSCVEF-20BBZ-2A-ICOS的构建及病毒生产
将scFv-antihCD20-20BBZ(SEQ ID No.1)和ICOS(SEQ ID No.4)通过overlap PCR的中间加入2A(SEQ ID No.9)序列,两端加入EcoRI和SalI酶切位点克隆pCDH-MSCVEF载体。将测序正确的克隆无内毒素大提,和慢病毒包装质粒(VSV-g,pMD Gag/Pol,RSV-REV)共同转染293X,48和72小时后收取上清,0.45uM过滤后,使用贝克曼超速离心机和SW28转头,25000RPM离心2小时浓缩病毒,即为pCDH-MSCVEF-20BBZ-2A-ICOS病毒(简称为20BBZ-2A-ICOS病毒),用于后续CAR-T细胞生产。同时生产对照pCDH-MSCVEF-20BBZ病毒(简称20BBZ病毒),将所得病毒感染293细胞,测得病毒滴度,如图4所示。
2.20BBZ-2A-ICOS CAR-T细胞和20BBZ CAR-T细胞的制备
将人PBMC经过Stemcell T细胞分离试剂盒纯化后,接种到anti-hCD3和anti-hCD28包被的96孔培养板,2天后,按照MOI=10-20感染20BBZ病毒和20BBZ-2A-ICOS病毒,1天后换液继续细胞培养,按照每6天使用人工抗原呈递细胞或anti-hCD3/28刺激,经过2轮刺激后,所得细胞即为20BBZ CAR-T细胞和20BBZ-2A-ICOS CAR-T细胞,用于后续实验和表型分析,其结果如图9所示。由图可知,所得细胞为CAR阳性。
实施例4-20BBZ-2A-CD27CAR-T细胞的制备
本实施例所述的20BBZ-2A-CD27CAR-T细胞的制备包括以下步骤:
1.慢病毒载体pCDH-MSCVEF-20BBZ-2A-CD27的构建及病毒生产
将scFv-antihCD20-20BBZ(SEQ ID No.1)和CD27(SEQ ID No.5)通过overlap PCR的中间加入2A(SEQ ID No.10)序列,两端加入EcoRI和SalI酶切位点克隆pCDH-MSCVEF载体。将测序正确的克隆无内毒素大提,和慢病毒包装质粒(VSV-g,pMD Gag/Pol,RSV-REV)共同转染293X,48和72小时后收取上清,0.45uM过滤后,使用贝克曼超速离心机和SW28转头,25000RPM离心2小时浓缩病毒,即为pCDH-MSCVEF-20BBZ-2A-CD27病毒(简称为20BBZ-2A-CD27病毒),用于后续CAR-T细胞生产。同时生产对照pCDH-MSCVEF-20BBZ病毒(简称20BBZ病毒),将所得病毒感染293细胞,测得病毒滴度,如图5所示。
2.20BBZ-2A-CD27CAR-T细胞和20BBZ CAR-T细胞的制备
将人PBMC经过Stemcell T细胞分离试剂盒纯化后,接种到anti-hCD3和anti-hCD28包被的96孔培养板,2天后,按照MOI=10-20感染20BBZ病毒和20BBZ-2A-CD27病毒,1天后换液继续细胞培养,按照每6天使用人工抗原呈递细胞或anti-hCD3/28刺激,经过2轮刺激后,所得细胞即为20BBZ CAR-T细胞和20BBZ-2A-CD27CAR-T细胞,用于后续实验和表型分析,其结果如图10所示。由图可知,所得细胞为CAR阳性。
实施例5-20BBZ-2A-4-1BB CAR-T细胞的制备
本实施例所述的20BBZ-2A-4-1BB CAR-T细胞的制备包括以下步骤:
1.慢病毒载体pCDH-MSCVEF-20BBZ-2A-4-1BB的构建及病毒生产
将scFv-antihCD20-20BBZ(SEQ ID No.1)和4-1BB(SEQ ID No.6)通过overlapPCR的中间加入2A(SEQ ID No.7)序列,两端加入EcoRI和SalI酶切位点克隆pCDH-MSCVEF载体。将测序正确的克隆无内毒素大提,和慢病毒包装质粒(VSV-g,pMD Gag/Pol,RSV-REV)共同转染293X,48和72小时后收取上清,0.45uM过滤后,使用贝克曼超速离心机和SW28转头,25000RPM离心2小时浓缩病毒,即为pCDH-MSCVEF-20BBZ-2A-4-1BB病毒(简称为20BBZ-2A-4-1BB病毒),用于后续CAR-T细胞生产。同时生产对照pCDH-MSCVEF-20BBZ病毒(简称20BBZ病毒),将所得病毒感染293细胞,测得病毒滴度,如图6所示。
2.20BBZ-2A-4-1BB CAR-T细胞和20BBZ CAR-T细胞的制备
将人PBMC经过Stemcell T细胞分离试剂盒纯化后,接种到anti-hCD3和anti-hCD28包被的96孔培养板,2天后,按照MOI=10-20感染20BBZ病毒和20BBZ-2A-4-1BB病毒,1天后换液继续细胞培养,按照每6天使用人工抗原呈递细胞或anti-hCD3/28刺激,经过2轮刺激后,所得细胞即为20BBZCAR-T细胞和20BBZ-2A-4-1BB CAR-T细胞,用于后续实验和表型分析,其结果如图11所示。由图可知,所得细胞为CAR阳性。
实施例6-比较20BBZ CAR-T细胞和20BBZ-2A-OX40CAR-T细胞的扩增能力
将实施例1中步骤2制备所得的20BBZ CAR-T细胞和20BBZ-2A-OX40CAR-T细胞,连续培养14天,每隔6天用人工抗原呈递细胞刺激一次,细胞计数,其结果如图12所示。由图可知,20BBZ-2A-OX40CAR-T细胞相对20BBZ CAR-T细胞有更强的增殖能力。
实施例7-比较20BBZ CAR-T细胞和20BBZ-2A-OX40CAR-T细胞的肿瘤杀伤能力
将实施例1中步骤2制备所得的20BBZ CAR-T细胞和20BBZ-2A-OX40CAR-T细胞,实施例3步骤2制备所得的20BBZ-2A-ICOS CAR-T细胞,和实施例4步骤2制备所得的20BBZ-2A-CD27CAR-T细胞,接种到96孔板,按照CAR-T:肿瘤细胞比例1:1、1:2、1:4加入Raji肿瘤细胞,24、48小时后比较肿瘤细胞的存活比例,其结果如图13所示。由图可知,20BBZ-2A-OX40/ICOS/CD27CAR-T细胞相对20BBZ CAR-T细胞有相似的肿瘤杀伤能力,甚至部分含共刺激受体的CAR-T有更强的肿瘤杀伤能力。
实施例8-比较20BBZ CAR-T细胞和20BBZ-2A-OX40CAR-T细胞的抗肿瘤能力和体内存活能力
将106Nalm-6肿瘤细胞通过静脉接种到B-NDG小鼠,6天后给予107 20BBZ CAR-T细胞和20BBZ-2A-OX40CAR-T细胞治疗,观察小鼠的存活率,部分小鼠在第7天检测其骨髓中的肿瘤细胞和CAR-T细胞的含量,其结果分别如图14和图15所示。由图可知,20BBZ-2A-OX40CAR-T细胞相对20BBZ CAR-T细胞显著延长了小鼠的生存,并在体内扩增更多。
由上述实施例可知,本发明通过构建新型含共刺激受体的CAR-T细胞,相对目前临床使用的CAR-T技术,其使CAR-T细胞在肿瘤中的活化能力、存活能力、扩增能力显著增强,具有更优异的抗肿瘤疗效。
以上对本发明的具体实施例进行了详细描述,但其只作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
序列表
<110> 上海隆耀生物科技有限公司
<120> 一种包含共刺激受体的嵌合抗原受体及其应用
<130> IPI181627
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 468
<212> PRT
<213> scFv-antihCD20-20BBZ序列(Artificial Sequence)
<400> 1
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
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His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
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Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
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Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
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Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
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Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly
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Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Pro
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Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys
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Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln
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Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn
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Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr
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Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr
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Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly
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Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val
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Ser Ala Ala Ala Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
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Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
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Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
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Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
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Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys
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Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
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Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
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Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
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Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
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Leu Pro Pro Arg
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<210> 2
<211> 277
<212> PRT
<213> OX40的序列(Artificial Sequence)
<400> 2
Met Cys Val Gly Ala Arg Arg Leu Gly Arg Gly Pro Cys Ala Ala Leu
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Leu Leu Leu Gly Leu Gly Leu Ser Thr Val Thr Gly Leu His Cys Val
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Gly Asp Thr Tyr Pro Ser Asn Asp Arg Cys Cys His Glu Cys Arg Pro
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Pro Pro Gly His Phe Ser Pro Gly Asp Asn Gln Ala Cys Lys Pro Trp
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Thr Asn Cys Thr Leu Ala Gly Lys His Thr Leu Gln Pro Ala Ser Asn
145 150 155 160
Ser Ser Asp Ala Ile Cys Glu Asp Arg Asp Pro Pro Ala Thr Gln Pro
165 170 175
Gln Glu Thr Gln Gly Pro Pro Ala Arg Pro Ile Thr Val Gln Pro Thr
180 185 190
Glu Ala Trp Pro Arg Thr Ser Gln Gly Pro Ser Thr Arg Pro Val Glu
195 200 205
Val Pro Gly Gly Arg Ala Val Ala Ala Ile Leu Gly Leu Gly Leu Val
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Leu Gly Leu Leu Gly Pro Leu Ala Ile Leu Leu Ala Leu Tyr Leu Leu
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Arg Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly
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Gly Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser
260 265 270
Thr Leu Ala Lys Ile
275
<210> 3
<211> 283
<212> PRT
<213> HVEM的序列(Artificial Sequence)
<400> 3
Met Glu Pro Pro Gly Asp Trp Gly Pro Pro Pro Trp Arg Ser Thr Pro
1 5 10 15
Lys Thr Asp Val Leu Arg Leu Val Leu Tyr Leu Thr Phe Leu Gly Ala
20 25 30
Pro Cys Tyr Ala Pro Ala Leu Pro Ser Cys Lys Glu Asp Glu Tyr Pro
35 40 45
Val Gly Ser Glu Cys Cys Pro Lys Cys Ser Pro Gly Tyr Arg Val Lys
50 55 60
Glu Ala Cys Gly Glu Leu Thr Gly Thr Val Cys Glu Pro Cys Pro Pro
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Gly Thr Tyr Ile Ala His Leu Asn Gly Leu Ser Lys Cys Leu Gln Cys
85 90 95
Gln Met Cys Asp Pro Ala Met Gly Leu Arg Ala Ser Arg Asn Cys Ser
100 105 110
Arg Thr Glu Asn Ala Val Cys Gly Cys Ser Pro Gly His Phe Cys Ile
115 120 125
Val Gln Asp Gly Asp His Cys Ala Ala Cys Arg Ala Tyr Ala Thr Ser
130 135 140
Ser Pro Gly Gln Arg Val Gln Lys Gly Gly Thr Glu Ser Gln Asp Thr
145 150 155 160
Leu Cys Gln Asn Cys Pro Pro Gly Thr Phe Ser Pro Asn Gly Thr Leu
165 170 175
Glu Glu Cys Gln His Gln Thr Lys Cys Ser Trp Leu Val Thr Lys Ala
180 185 190
Gly Ala Gly Thr Ser Ser Ser His Trp Val Trp Trp Phe Leu Ser Gly
195 200 205
Ser Leu Val Ile Val Ile Val Cys Ser Thr Val Gly Leu Ile Ile Cys
210 215 220
Val Lys Arg Arg Lys Pro Arg Gly Asp Val Val Lys Val Ile Val Ser
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Val Gln Arg Lys Arg Gln Glu Ala Glu Gly Glu Ala Thr Val Ile Glu
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Ala Leu Gln Ala Pro Pro Asp Val Thr Thr Val Ala Val Glu Glu Thr
260 265 270
Ile Pro Ser Phe Thr Gly Arg Ser Pro Asn His
275 280
<210> 4
<211> 199
<212> PRT
<213> ICOS的序列(Artificial Sequence)
<400> 4
Met Lys Ser Gly Leu Trp Tyr Phe Phe Leu Phe Cys Leu Arg Ile Lys
1 5 10 15
Val Leu Thr Gly Glu Ile Asn Gly Ser Ala Asn Tyr Glu Met Phe Ile
20 25 30
Phe His Asn Gly Gly Val Gln Ile Leu Cys Lys Tyr Pro Asp Ile Val
35 40 45
Gln Gln Phe Lys Met Gln Leu Leu Lys Gly Gly Gln Ile Leu Cys Asp
50 55 60
Leu Thr Lys Thr Lys Gly Ser Gly Asn Thr Val Ser Ile Lys Ser Leu
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Lys Phe Cys His Ser Gln Leu Ser Asn Asn Ser Val Ser Phe Phe Leu
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Tyr Asn Leu Asp His Ser His Ala Asn Tyr Tyr Phe Cys Asn Leu Ser
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His Ile Tyr Glu Ser Gln Leu Cys Cys Gln Leu Lys Phe Trp Leu Pro
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Ile Cys Trp Leu Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro
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Asn Gly Glu Tyr Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser
180 185 190
Arg Leu Thr Asp Val Thr Leu
195
<210> 5
<211> 260
<212> PRT
<213> CD27的序列(Artificial Sequence)
<400> 5
Met Ala Arg Pro His Pro Trp Trp Leu Cys Val Leu Gly Thr Leu Val
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Gly Leu Ser Ala Thr Pro Ala Pro Lys Ser Cys Pro Glu Arg His Tyr
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Trp Ala Gln Gly Lys Leu Cys Cys Gln Met Cys Glu Pro Gly Thr Phe
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Leu Val Lys Asp Cys Asp Gln His Arg Lys Ala Ala Gln Cys Asp Pro
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Cys Ile Pro Gly Val Ser Phe Ser Pro Asp His His Thr Arg Pro His
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Cys Glu Ser Cys Arg His Cys Asn Ser Gly Leu Leu Val Arg Asn Cys
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Thr Ile Thr Ala Asn Ala Glu Cys Ala Cys Arg Asn Gly Trp Gln Cys
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Arg Asp Lys Glu Cys Thr Glu Cys Asp Pro Leu Pro Asn Pro Ser Leu
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Thr Ala Arg Ser Ser Gln Ala Leu Ser Pro His Pro Gln Pro Thr His
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Leu Pro Tyr Val Ser Glu Met Leu Glu Ala Arg Thr Ala Gly His Met
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Gln Thr Leu Ala Asp Phe Arg Gln Leu Pro Ala Arg Thr Leu Ser Thr
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His Trp Pro Pro Gln Arg Ser Leu Cys Ser Ser Asp Phe Ile Arg Ile
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Leu Val Ile Phe Ser Gly Met Phe Leu Val Phe Thr Leu Ala Gly Ala
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Leu Phe Leu His Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser
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Pro Val Glu Pro Ala Glu Pro Cys Arg Tyr Ser Cys Pro Arg Glu Glu
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Glu Gly Ser Thr Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro
245 250 255
Ala Cys Ser Pro
260
<210> 6
<211> 255
<212> PRT
<213> 4-1BB的序列(Artificial Sequence)
<400> 6
Met Gly Asn Ser Cys Tyr Asn Ile Val Ala Thr Leu Leu Leu Val Leu
1 5 10 15
Asn Phe Glu Arg Thr Arg Ser Leu Gln Asp Pro Cys Ser Asn Cys Pro
20 25 30
Ala Gly Thr Phe Cys Asp Asn Asn Arg Asn Gln Ile Cys Ser Pro Cys
35 40 45
Pro Pro Asn Ser Phe Ser Ser Ala Gly Gly Gln Arg Thr Cys Asp Ile
50 55 60
Cys Arg Gln Cys Lys Gly Val Phe Arg Thr Arg Lys Glu Cys Ser Ser
65 70 75 80
Thr Ser Asn Ala Glu Cys Asp Cys Thr Pro Gly Phe His Cys Leu Gly
85 90 95
Ala Gly Cys Ser Met Cys Glu Gln Asp Cys Lys Gln Gly Gln Glu Leu
100 105 110
Thr Lys Lys Gly Cys Lys Asp Cys Cys Phe Gly Thr Phe Asn Asp Gln
115 120 125
Lys Arg Gly Ile Cys Arg Pro Trp Thr Asn Cys Ser Leu Asp Gly Lys
130 135 140
Ser Val Leu Val Asn Gly Thr Lys Glu Arg Asp Val Val Cys Gly Pro
145 150 155 160
Ser Pro Ala Asp Leu Ser Pro Gly Ala Ser Ser Val Thr Pro Pro Ala
165 170 175
Pro Ala Arg Glu Pro Gly His Ser Pro Gln Ile Ile Ser Phe Phe Leu
180 185 190
Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu Leu Phe Phe Leu Thr Leu
195 200 205
Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
210 215 220
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
225 230 235 240
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
245 250 255
<210> 7
<211> 22
<212> PRT
<213> 2A的序列(Artificial Sequence)
<400> 7
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
1 5 10 15
Glu Glu Asn Pro Gly Pro
20
<210> 8
<211> 21
<212> PRT
<213> 2A的序列(Artificial Sequence)
<400> 8
Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu
1 5 10 15
Glu Asn Pro Gly Pro
20
<210> 9
<211> 23
<212> PRT
<213> 2A的序列(Artificial Sequence)
<400> 9
Gly Ser Gly Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp
1 5 10 15
Val Glu Ser Asn Pro Gly Pro
20
<210> 10
<211> 25
<212> PRT
<213> 2A的序列(Artificial Sequence)
<400> 10
Gly Ser Gly Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala
1 5 10 15
Gly Asp Val Glu Ser Asn Pro Gly Pro
20 25
Claims (10)
1.一种包含共刺激受体的嵌合抗原受体,其特征在于,所述嵌合抗原受体的结构为scFv(X)-(Y)CD3zeta-2A-(Z);
其中,X包括肿瘤靶向抗体或能与肿瘤特异结合的配体、受体;
Y为共刺激受体的胞内区,所述共刺激受体选自ICOS、CD28、CD27、HVEM、LIGHT、CD40L、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2、CD226;
Z为共刺激受体,所述共刺激受体选自ICOS、CD28、CD27、HVEM、LIGHT、CD40L、4-1BB、OX40、DR3、GITR、CD30、TIM1、SLAM、CD2、CD226。
2.根据权利要求1所述的一种包含共刺激受体的嵌合抗原受体,其特征在于,所述X选自anti-CD19抗体、anti-CD20抗体、EGFR抗体、HER2抗体、EGFRVIII抗体、anti-PSMA抗体、anti-BCMA抗体、anti-CD22抗体、anti-CD30抗体。
3.根据权利要求1所述的一种包含共刺激受体的嵌合抗原受体,其特征在于,所述X为anti-CD20抗体,所述Y为4-1BB,所述Z选自OX40、HVEM、ICOS、CD27、4-1BB中的一种。
4.根据权利要求3所述的一种包含共刺激受体的嵌合抗原受体,其特征在于,所述scFv(X)-(Y)CD3zeta为scFv-antihCD20-20BBZ,其序列如SEQ ID No.1所示;所述OX40的序列如SEQ ID No.2所示;所述HVEM的序列如SEQ ID No.3所示;所述ICOS的序列如SEQ ID No.4所示;所述CD27的序列如SEQ ID No.5所示;所述4-1BB的序列如SEQ ID No.6所示;所述2A的序列如SEQ ID No.7、SEQ ID No.8、SEQ ID No.9或SEQ ID No.10所示。
5.一种由如权利要求1~4中任一项所述的嵌合抗原受体的重组表达载体构建的CAR-T细胞。
6.根据权利要求5所述的CAR-T细胞的制备方法,其特征在于,包括如下步骤:
步骤一、慢病毒载体的构建及病毒生产;
将scFv(X)-(Y)CD3zeta,Z的中间加入2A形成融合蛋白,两端加入慢病毒载体,并和慢病毒包装质粒共同转染,获得scFv(X)-(Y)CD3zeta-2A-(Z)病毒;
步骤二、scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞的制备;
分离纯化后的人PBMC经过培养后,感染步骤一获得的scFv(X)-(Y)CD3zeta-2A-(Z)病毒,在合适的条件下进行细胞扩增,制备scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞。
7.根据权利要求6所述的CAR-T细胞的制备方法,其特征在于,所述慢病毒载体的构建及病毒生产的具体步骤包括:
将scFv(X)-(Y)CD3zeta,Z通过overlap PCR在其中间加入2A形成融合蛋白,两端加入酶切位点克隆慢病毒载体;将测序正确的克隆无内毒素大提,和慢病毒包装质粒共同转染,预定时间收取上清,过滤、离心浓缩病毒,获得scFv(X)-(Y)CD3zeta-2A-(Z)病毒。
8.根据权利要求6所述的CAR-T细胞的制备方法,其特征在于,所述scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞的制备的具体步骤包括:将人PBMC经过分离纯化后,接种到具有合适刺激条件的培养板,培养预定时间后,感染步骤一生产的scFv(X)-(Y)CD3zeta-2A-(Z)病毒,按照合适的刺激条件进行细胞扩增,经过2轮刺激扩增后,获得的细胞即为scFv(X)-(Y)CD3zeta-2A-(Z)CAR-T细胞。
9.一种含有如权利要求5所述的CAR-T细胞的制剂。
10.如权利要求1~4中任一项所述的嵌合抗原受体,如权利要求5所述的CAR-T细胞在制备治疗或预防肿瘤药物中的应用。
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