CN110358734A - 以Tcm为主要效应成分的CAR-T制备方法及其应用 - Google Patents
以Tcm为主要效应成分的CAR-T制备方法及其应用 Download PDFInfo
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Abstract
本发明提供一种提高CAR‑T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,包括,在CAR中加入人工抗原表位,以及通过所述人工抗原表位激活CAR‑T;其中所述人工抗原表位不存在于所述CAR的其他结构域或区段中。本发明还提供了一种CAR‑T细胞的制备方法,所述制备方法包括,(1)将所述CAR导入T细胞;(2)培养所述导入CAR的T细胞,在培养过程中进行特异性激活。该制备方法不仅可提高产品中CAR阳性T细胞的比例,还可实现Tcm亚群的体外的特异性扩增,显著提高Tcm在终产品中的比例。临床试验表明,本发明制备得到的CAR‑T细胞在体内的扩增能力显著优于现有技术,具有更好的临床安全性和有效性。
Description
技术领域
本发明涉及基因治疗与细胞治疗技术领域,具体涉及一种以Tcm为主要效应成分的CAR-T制备方法及其应用。
背景技术
中央记忆型T细胞(centrol memory T cell,Tcm)是一群以CD45RO+/CD197+为表面标记物的T细胞亚群。该亚群的T细胞由初始型T细胞经抗原或非抗原刺激后分化而来,在体内主要参与特异性记忆免疫反应。Tcm亚群在外周血分离获得的T细胞亚群中比例较低,在体外培养过程中,Tcm会在培养的初始阶段快速增殖,之后会随着培养时间的延长而降低。
过继性免疫细胞治疗是当前生物医药领域新型的抗肿瘤治疗手段。该方法主要通过将患者自体细胞提取后,经体外进行活化,修饰,培养和扩增后,再回输至患者体内,从而到达治疗肿瘤的目的。CAR-T,即嵌合抗原受体修饰性T细胞是一种具有靶向性的过继性免疫细胞治疗方法。该技术通过利用基因修饰的方法改造T细胞基因组,使其表达可识别肿瘤特异性抗原的CAR受体,进而突破原始T细胞抗肿瘤的MHC限制性,使T细胞直接杀伤肿瘤。例如CD19特异性CAR-T细胞已经在急性B淋巴细胞白血病和B细胞淋巴瘤的治疗方面取得了突破性进展,并实现了临床应用。但是目前的CAR-T治疗技术依然存在诸多临床瓶颈。
已有大量研究表明,现有CAR-T细胞在体内疗效的维持性不甚理想。接受治疗的患者在达到完全缓解后,1年内的复发率高达46%。通过对患者回输后的免疫细胞亚群和回输的CAR-T制品进行分析显示,产品中Tcm的比例以及回输后受试者体内Tcm的比例与缓解时间和CAR-T抗肿瘤活性的维持性呈现正相关性。患者输注的CAR-T制品中CAR阳性T细胞中Tcm的比例越高,患者获得长期缓解的可能性越大。临床前动物实验也表明,回输Tcm为主要亚群的CAR-T细胞可以显著延长小鼠的生存时间。
目前已知的Tcm制备方法是从外周血中分离原代初始型T细胞,先利用CD3单克隆抗体OKT-3和IL-2进行活化。活化24小时后,加入包括IL-7、IL-15和IL-21的培养基进行培养。培养至6-9天后收获细胞。此时终产品中的Tcm比例大约为50%左右,难以满足临床回输的要求。
由于Tcm细胞亚群的增殖特点,在体外培养中,随着培养时间的延长,Tcm细胞亚群的比例会迅速降低。因此,短期培养工艺无法保证获得足够数量的目的细胞,而增加初始种子细胞的培养数量,又会使制备成本急剧增加。目前CAR-T的制备工艺在必须保证受试者获得回输剂量充足的细胞前提下,无法保证回输产品中具有高纯度的Tcm细胞。因此,如何利用经济高效的方法获得以Tcm为主要效应成分的细胞制品是目前行业内的一个技术难题。
发明内容
为了解决上述技术问题,本发明提供一种以Tcm为主要效应成分的CAR-T制备方法及其应用。
为此,本发明提供一种提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其中,在CAR中加入人工抗原表位,以及通过所述人工抗原表位激活CAR-T;其中所述人工抗原表位不存在于所述CAR的其他结构域或区段中。
进一步,所述人工抗原表位对CAR的其它结构域或区段的功能不产生或基本不产生负面影响;当所述人工抗原表位被结合时能够激活CAR-T。
进一步,所述人工抗原表位位于CAR的胞外结构域中、胞外结构域与铰链区之间、或铰链区与跨膜结构之间。
进一步,所述人工抗原表位的长度为7-15aa,优选8-12aa。
进一步,所述人工抗原表位的氨基酸序列为SEQ ID NO:1、SEQ ID NO:2或SEQ IDNO:3。
进一步,采用特异性识别所述人工抗原表位的分子结合所述人工抗原表位激活CAR-T,其中特异性识别所述人工抗原表位的分子优选为抗体分子。
进一步,通过所述人工抗原表位激活CAR-T的步骤在将CAR导入T细胞的步骤之后。
进一步,通过所述人工抗原表位激活CAR-T的步骤包括将CAR-T在含有IL-7、IL-2和IL-15的培养基中进行培养。
其中IL-7、IL-2和IL-15的浓度分别为10-200ng/mL、20-1000IU/mL和1-50ng/mL。
本发明所述方法为体外方法,尽管所述方法制备的CAR-T具有良好的肿瘤治疗效果,但本发明所述方法的直接目的是为了提高离体CAR-T细胞中中央记忆型T细胞(Tcm)亚群的比例,所述方法本身也并不涉及任何体内操作的步骤。
具体地,第一方面,本发明提供了一种CAR-T细胞的制备方法,包括,
(1)将所述嵌合抗原受体(CAR)导入T细胞;
(2)培养所述导入CAR的T细胞,在培养过程中进行特异性激活;
所述CAR具有人工抗原表位;
所述特异性激活包括在培养过程中加入抗人工抗原表位的抗体,所述抗人工抗原表位的抗体可特异性识别所述人工抗原表位。
CAR的蛋白质结构依次包括以下结构域:胞外结构域、任选的铰链区、跨膜结构域和胞内结构域,所述胞外结构域包括任选的信号肽和抗原结合结构域,所述抗原结合结构域包括具有抗原结合活性的抗体或抗体片段,所述抗体或抗体片段至少包括重链可变区和轻链可变区。
进一步,所述人工抗原表位位于所述CAR的胞外结构域中、胞外结构域与铰链区之间、或铰链区与跨膜结构域之间。在一个具体的实施方式中,所述人工抗原表位位于所述CAR的胞外结构域中。在一个优选实施例中,所述人工抗原表位位于所述信号肽与抗原结合结构域之间。在另一个优选实施例中,所述人工抗原表位位于所述抗原结合结构域中。进一步,所述人工抗原表位位于所述重链可变区和轻链可变区之间。
进一步,所述人工抗原表位为以下(a1)-(a3)中的一种:
(a1)E-tag,其氨基酸序列为KPLPEVTDEY(SEQ ID NO:1);
(a2)Strep-tag,其氨基酸序列为WSHPQFEK(SEQ ID NO:2);
(a3)Strep-tag II,其氨基酸序列为NWSHPQFEK(SEQ ID NO:3)。
当所述人工抗原表位为所述E-tag时,所述抗人工抗原表位的抗体为抗E-tag抗体,所述抗E-tag抗体可特异性识别所述E-tag。在一个具体的实施方式中,所述抗E-tag抗体的氨基酸序列为SEQ ID NO:4。
当所述人工抗原表位为Strep-tag时,所述抗人工抗原表位的抗体为抗Strep-tag抗体,所述抗Strep-tag抗体可特异性识别所述Strep-tag。在一个具体的实施方式中,所述抗Strep-tag抗体购自Bio-Rad公司(货号:MCA2488)。
当所述人工抗原表位为Strep-tag II时,所述抗人工抗原表位的抗体为抗Strep-tag II抗体,所述抗Strep-tag II抗体可特异性识别所述Strep-tag II。在一个具体的实施方式中,所述抗Strep-tag II抗体购自Genscript公司(货号:A01732)。
进一步,步骤(1)中所述T细胞的制备方法包括:从外周血中分离T细胞,对分离得到的T细胞进行T细胞活化。
进一步,步骤(1)中,所述T细胞活化包括将所述分离得到的T细胞在第一培养基中进行培养,所述第一培养基包括OKT-3和IL-2。进一步,所述第一培养基中,OKT-3的浓度为5-200ng/mL,10-100ng/mL,更优选为50-80ng/mL,例如50ng/mL,60ng/mL,70ng/mL,80ng/mL;IL-2的浓度为20-1000IU/mL,优选为50-500IU/mL,更优选为200-500IU/mL,例如200IU/mL,300IU/mL,400IU/mL,500IU/mL。
所述第一培养基可通过本领域常用的培养基配制得到。在具体的实施方式中,所述第一培养基可通过以下培养基配制得到,包括但不限于:X-VIVO15培养基(Lonza公司)、KBM581无血清培养基(Corning公司)、含有10%FBS的RPMI1640培养基(Gbico公司)或含有10%人AB血清的RPMI1640培养基(Gbico公司)。
进一步,所述T细胞活化的培养时间为4-72h,优选为24-36h,例如24h、28h、32h、36h,在一个优选的实施例中为24h。
进一步,步骤(2)中,所述培养所用的培养基为第二培养基,所述第二培养基包括IL-7、IL-2和IL-15。进一步,所述第二培养基中,IL-7的浓度为10-200ng/mL,优选为20-100ng/mL,更优选为80-100ng/mL,例如80ng/mL、90ng/mL、100ng/mL;IL-2的浓度为20-1000IU/mL,优选为50-500IU/mL,更优选为200-500IU/mL,例如200IU/mL,300IU/mL,400IU/mL,500IU/mL;IL-15的浓度为1-50ng/mL,优选为5-30ng/mL,更优选为10-20ng/mL,例如10ng/mL、12ng/mL、14ng/mL、16ng/mL、18ng/mL、20ng/mL。
所述第二培养基可通过本领域常用的培养基配制得到。在具体的实施方式中,所述第二培养基可通过以下培养基配制得到,包括但不限于:X-VIVO15培养基(Lonza公司)、KBM581无血清培养基(Corning公司)、含有10%FBS的RPMI1640培养基(Gbico公司)或含有10%人AB血清的RPMI1640培养基(Gbico公司)。
进一步,步骤(2)中,所述培养的时间为9-14天,优选9-12天,例如9天、10天、11天、12天;在一个优选的实施例中,为12天。
进一步,步骤(2)中,所述特异性激活包括,从培养过程中的第m天至培养结束,在所述第二培养基中加入起所述抗人工抗原表位的抗体,所述m选自6-9的整数,例如6、7、8、9,在一个优选的实施例中,所述m=6。
进一步,步骤(2)中,所述抗人工抗原表位的抗体的浓度为1-50μg/mL,优选为5-30μg/mL,更优选为10-25μg/mL,例如10μg/mL、15μg/mL、20μg/mL、25μg/mL;在一个优选的实施例中为20μg/mL。
进一步,步骤(2)中,所述抗人工抗原表位的抗体的加入方式选自下组:向培养基中直接加入所述抗人工抗原表位的抗体、将所述抗人工抗原表位的抗体包被于培养容器、或其组合。
进一步,步骤(1)将所述CAR导入T细胞的方法为通过病毒感染的方式导入T细胞或通过非病毒感染的方式导入T细胞;其中,所述病毒感染的方式中的病毒选自以下病毒:腺病毒、逆转录病毒、慢病毒、疱疹病毒和腺相关病毒;所述非病毒感染的方式为脂质体法、显微注射法、磷酸钙共沉淀法、电转法或DEAE-葡聚糖转染法。
进一步,所述步骤(1)为通过病毒感染将CAR导入T细胞。在优选的实施例中,所述步骤(1)具体包括以下步骤,
S1、构建CAR的病毒表达载体;
S2、将步骤S1制备得到的CAR病毒表达载体导入相应的包装细胞中进行病毒包装,得到编码CAR的病毒;
S3、从外周血中分离T细胞,对分离得到的T细胞进行T细胞活化;
S4、用步骤S2制备得到的编码CAR的病毒感染步骤S3制备得到的T细胞。
进一步,所述病毒表达载体为腺病毒表达载体、逆转录病毒表达载体、慢病毒表达载体、疱疹病毒表达载体或腺相关病毒表达载体。在一个优选的实施例中,为慢病毒表达载体。
第二方面,本发明提供了一种具有高比例中央记忆型T细胞(Tcm)亚群的CAR-T细胞,所述CAR-T细胞通过本发明所述的方法制备得到
第三方面,本发明提供了所述CAR-T细胞在制备预防和/或治疗癌症或肿瘤的药物或制剂中的应用。
进一步,所述肿瘤选自下组:血液肿瘤、实体瘤、或其组合。
进一步,所述血液肿瘤选自下组:急性髓细胞白血病(AML)、多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性淋巴白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、非霍奇金淋巴瘤(NHL)、或其组合。
进一步,所述实体瘤选自下组:胃癌、胃癌腹膜转移、肝癌、白血病、肾脏肿瘤、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、淋巴癌、鼻咽癌、肾上腺肿瘤、膀胱肿瘤、非小细胞肺癌(NSCLC)、脑胶质瘤、子宫内膜癌、间皮瘤、胰腺癌、多发性骨髓瘤、或其组合。
本发明的发明人在此前研究中,报道了一种具有人工抗原表位的CAR分子,可以通过二次分选的方法将表达CAR阳性的目的细胞进行高效分选,以提高终产品中阳性CAR-T细胞的比例(CN108017717A)。在此研究基础上,发明人意外地发现,在制备过程中,利用抗人工抗原表位的抗体对导入CAR的T细胞进行特异性激活,不仅可以提高终产品中CAR阳性T细胞的比例,还可以显著提高CAR阳性T细胞中Tcm的比例,带来意料不到的技术效果。
与现有技术相比,本发明具有以下优点:
1、本发明提供的制备方法无需对导入CAR的T细胞进行特异性分选,即可提高产品中CAR阳性T细胞的比例;
2、本发明提供的制备方法可以实现CAR阳性T细胞中Tcm亚群的体外的特异性扩增,显著提高Tcm在终产品中的比例;
3、本发明提供的制备方法克服了Tcm在体外无法长期培养的技术问题,实现了Tcm在体外的长期培养,有效提高了Tcm的产量;现有技术培养到第6天左右,Tcm比例开始下降,而本发明的技术方案培养至第12天时,Tcm比例依然可以维持较高水平;
4、与现有技术相比,本发明制备得到的CAR-T细胞在体外、体内环境中均具有良好的杀伤相关细胞因子释放活性,具有更好、更持久的抗肿瘤活性;
5、临床试验表明,本发明制备得到的CAR-T细胞产品在体内的扩增能力显著优于现有技术,具有更好的临床安全性和有效性。
附图说明
通过阅读下文优选实施方式的详细描述,各种其他的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的,而并不认为是对本发明的限制。在附图中:
图1-3分别为实施例3-5中各实验组制备得到的细胞产品中CAR阳性T细胞的比例;
图4-6分别为实施例3-5中各实验组制备得到的细胞产品中CAR阳性T细胞中Tcm的比例;
图7-9分别为实施例3-5中各实验组在制备细胞产品的过程中,随着培养时间的延长,培养体系中Tcm的比例变化;
图10为实施例3中各实验组制备得到的细胞产品的体外杀伤活性检测结果;
图11为实施例3中各实验组制备得到的细胞产品在体外的杀伤相关细胞因子(IL-2、IFN-γ、TNF-α)释放水平;
图12为实施例3中各实验组制备得到的细胞产品在体内的抗肿瘤活性评价结果,其中,纵轴为经注射细胞产品后,荷瘤小鼠的中位生存时间;
图13为实施例3中各实验组制备得到的细胞产品在体内的杀伤相关细胞因子(IL-2、IFN-γ、TNF-α)释放水平;
图14-18为不同CAR-T产品在患者体内的扩增水平检测,其中,图14-18依次分别为患者1-5的检测结果。
具体实施方式
下面将参照附图更详细地描述本公开的示例性实施方式。虽然附图中显示了本公开的示例性实施方式,然而应当理解,可以以各种形式实现本公开而不应被这里阐述的实施方式所限制。相反,提供这些实施方式是为了能够更透彻地理解本公开,并且能够将本公开的范围完整的传达给本领域的技术人员。
为了可以更容易地理解本公开,首先定义某些术语。如本公开所使用的,除非本文另有明确规定,否则以下每一个术语具有其下面给出的含义。
嵌合抗原受体(Chimeric antigen receptor,CAR)的蛋白质结构依次包括胞外结构域、任选的铰链区、跨膜结构域和胞内结构域。其中,胞外结构域包括任选的信号肽和抗原结合结构域,所述抗原结合结构域可直接识别肿瘤相关抗原(tumor associatedantigen,TAA),而不需要以MHC/抗原肽复合物的形式识别抗原。
本文所述的抗原结合结构域包括具有抗原结合活性的抗体或其片段,所述抗体或抗体片段至少包括重链可变区和轻链可变区。具体地,所述抗原结合结构域包括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抗体含有抗体重链可变区、轻链可变区,但没有恒定区,并具有全部抗原结合位点的最小抗体片段。一般地,Fv抗体还包含重链可变区和轻链可变区之间的多肽接头,且能够形成抗原结合所需的结构。抗原结合结构域通常是scFv(single-chain variable fragment)。
在本发明提供的嵌合抗原受体修饰性T细胞的制备方法中,所述CAR具有人工抗原表位,所述人工抗原表位具有以下特征:
(a)所述人工抗原表位不存在所述CAR的其他结构域或区段中;
(b)当所述人工抗原表位为游离态或存在于所述CAR时,所述人工抗原表位都能被抗人工抗原表位抗体识别;和
(c)不影响或基本不影响所述CAR与所述CAR靶向的抗原的结合。
所述人工抗原表位可位于CAR的胞外区,具体地,所述人工抗原表位可位于所述CAR的胞外结构域中、胞外结构域与铰链区之间、或铰链区与跨膜结构之间。在一个具体的实施方式中,所述人工抗原表位位于所述CAR的胞外结构域中。在一个优选实施例中,所述人工抗原表位位于信号肽与抗原结合结构域之间。在另一个优选实施例中,所述人工抗原表位位于所述抗原结合结构域中。进一步,所述人工抗原表位位于所述重链可变区和轻链可变区之间。
在本发明中,“特异性识别”,即“特异性结合”,抗人工抗原表位抗体可特异性识别所述人工抗原表位。当人工抗原表位为游离态或存在于所述CAR时,所述抗人工抗原表位抗体均可以特异性识别所述人工抗原表位,且所述抗人工抗原表位抗体不会与培养体系中的其他分子或CAR中除所述人工抗原表位以外的结构域发生识别或结合。
本发明中的抗人工抗原表位抗体可以选自商业化抗体,也可以以所述人工抗原表位为抗原,按照抗体制备的常规技术方法制备得到。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件(例如参考J.萨姆布鲁克等著,贺福初等译的《分子克隆实验指南》,第四版,科学出版社;J.E.科利根等著,曹雪涛等译的《精编免疫学实验指南》,科学出版社等)或者按照产品说明书进行。
胎牛血清FBS、DMEM培养基、D-PBS培养基、RPMI1640培养基购自Gbico公司;
OKT-3购自Pepro Tech公司;
IL-2、IL-7、IL-15购自Thermo Fisher公司;
X-VIVO15购自LONZA公司;
SmAb(氨基酸序列为SEQ ID NO:4)委托北京义翘神州科技有限公司制备提供;
MCA2488购自Bio-Rad公司;
A01732购自Genscript公司;
人体肾脏细胞系HEK293T、人淋巴瘤细胞系raji购自美国ATCC;
NOD/SCID IL2Rγc-/-免疫缺陷小鼠购自北京维通达生物技术有限公司;
Raji-Luci细胞系购自北京维通达生物技术有限公司。
实施例1嵌合抗原受体(CD19sCAR-1)的表达载体的构建
本实施例以抗人CD19人源化单链抗体为例,构建靶向CD19的嵌合抗原分子CD19sCAR-1(氨基酸序列见SEQ ID NO:5),该CAR分子可靶向CD19抗原且包含人工抗原表位E-tag(氨基酸序列见SEQ ID NO:1)。
使用化学合成的方法将CD19sCAR-1的开放阅读框序列(核苷酸序列见SEQ ID NO:6)进行全序列合成,同时在其两端加入限制性酶切位点,将合成得到的序列利用基因克隆的方法插入含有CMV启动子的慢病毒表达载体pLenti6.4的CMV启动子下游。获得CD19sCAR-1的慢病毒表达载体。将所述的载体转化到Stbl3感受态工程菌种,进行保存及后续制备。
同时,构建CD19CAR作为对照用CAR分子,CD19CAR可靶向CD19抗原,其与CD19sCAR-1的区别在于,CD19CAR不包含人工抗原表位,其氨基酸序列如SEQ ID NO:7所示。
使用化学合成的方法将CD19CAR的开放阅读框序列(核苷酸序列见SEQ ID NO:8)进行全序列合成,同时在其两端加入限制性酶切位点,将合成得到的序列利用基因克隆的方法插入含有CMV启动子的慢病毒表达载体pLenti6.4的CMV启动子下游。获得CD19CAR的慢病毒表达载体。将所述的载体转化到Stbl3感受态工程菌种,进行保存及后续制备。
实施例2嵌合抗原受体(CD19sCAR-1)编码病毒的制备
本实施例制备了分别编码CD19sCAR-1、CD19CAR和EGFP的慢病毒。具体步骤如下:
利用HEK293T作为包装细胞进行嵌合抗原受体编码病毒的制备。将对数生长期的HEK293T细胞消化,800rpm离心5min,弃去培养基后用含有10%FBS的DMEM培养基重悬。进行细胞计数后,将细胞悬液的密度调整至3.6×106/ml,放置于37℃细胞培养箱中待用。
病毒包装质粒的转染使用Lipofectamine 3000试剂盒(Thermo Fisher公司),并按照试剂盒说明书进行操作。将慢病毒包装需要的三种质粒,包括慢病毒表达载体(分别使用实施例1制备得到的CD19sCAR-1慢病毒表达载体、CD19CAR慢病毒表达载体和含有EGFP编码基因的慢病毒载体pLenti6.4-CMV-EGFP)、编码病毒核衣壳蛋白Gag/Pol和Rev的质粒psPAX2和编码病毒包膜蛋白的质粒pVSVG,与Lipofectamine 3000按照说明书推荐比例混合配制成DNA脂质体复合物,室温下静置15min。静置结束后,取一块6孔培养板,将DNA-脂质体复合物加入到6孔板中,每孔1ml,再将之前制备的HEK293T细胞悬液轻柔混匀,加入到6孔板中,与脂质体复合物混匀。培养板放入培养箱继续培养,分别在培养24h和48h收集含有病毒的培养上清。在最后一次收集上清后,将上清2000g离心10min,用0.45μm的滤膜过滤,即制备得到了分别编码CD19sCAR-1、CD19CAR和EGFP的慢病毒,分装后冻存于-80℃保存待用。
实施例3嵌合抗原受体(CD19sCAR-1)修饰性T细胞的制备
用Ficol-Hypaque密度梯度离心法分离外周血中的单个核细胞(PBMC),将PMBC用D-PBS重悬后将密度调整为0.5×106/mL。按照T细胞绝对数与CD3/CD28分选磁珠1:1的比例,加入分选磁珠,室温轻柔混匀20min。混匀后的细胞-磁珠混合悬液利用分选磁力架进行CD3+T细胞的分选。将分选后的T细胞进行T细胞活化:用含有50ng/mL OKT-3和500IU/mLIL-2的X-VIVO15培养基按照1×106/mL重悬T细胞,接种至培养容器中进行培养,培养条件为放入37℃,5%CO2的饱和湿度培养箱中培养24h。T细胞活化后,将细胞收集到50mL离心管中,进行计数,将细胞密度调整至3×106/mL。
将收获的细胞按照表1的分组方式进行分组,进行体外培养。其中,SmAb为代表靶向人工抗原表位E-tag的单克隆抗体,阴性对照组是利用编码EGFP的慢病毒感染T细胞的处理组。
表1实验组分组(a)
序号 | 分组编号 | 处理及培养方法 |
1 | 实验组a1 | 感染CD19sCAR-1后利用SmAb进行特异性激活 |
2 | 实验组a2 | 感染CD19sCAR-1后不利用SmAb进行特异性激活 |
3 | 实验组a3 | 感染CD19CAR后利用SmAb进行特异性激活 |
4 | 实验组a4 | 感染CD19CAR后不利用SmAb进行特异性激活 |
5 | 实验组a5 | 阴性对照组 |
活化后的T细胞按照表1的分组方式分组后,分别感染实施例2制备得到的编码CD19sCAR-1、CD19CAR和EGFP的慢病毒。感染后24h,将各处理组的细胞转移至含有80ng/mLIL-7、500IU/mL IL-2和20ng/mL IL-15的X-VIVO15培养基中进行培养,培养条件为37℃,含有5%CO2的饱和湿度培养箱。在培养的第6天,根据实验分组的处理方式,将实验组1和实验组3进行特异性激活,处理方式为:将实验组1和实验组3的细胞转移至包被有20μg/mL SmAb抗体的培养容器,继续用含80ng/mL IL-7、500IU/mL IL-2和20ng/mL IL-15的X-VIVO15培养基以原相同的条件进行培养。
培养期间,每2-3天根据细胞生长情况对细胞进行补液。之后各组细胞继续培养至第12天,分别收获细胞制品。
实施例4嵌合抗原受体(CD19sCAR-2)修饰性T细胞的制备
本实施例构建了靶向CD19的嵌合抗原分子CD19sCAR-2(氨基酸序列见SEQ ID NO:9,开放阅读框的核苷酸序列见SEQ ID NO:10),该CAR分子可靶向CD19抗原且包含人工抗原表位Strep-tag(氨基酸序列见SEQ ID NO:2)。制备嵌合抗原受体(CD19sCAR-2)修饰性T细胞,具体步骤如下:
(1)构建CD19sCAR-2的表达载体
实验步骤同实施例1,区别在于,实施例1使用CD19sCAR-1的序列,而本步骤使用CD19sCAR-2的序列;
(2)制备CD19sCAR-2编码病毒
实验步骤同实施例2,区别在于,实施例2使用实施例1制备得到的CD19sCAR-1慢病毒表达载体,而本步骤使用步骤(1)制备得到的CD19sCAR-2慢病毒表达载体;
(3)制备CDsCAR-2修饰性T细胞
实验步骤同实施例3,区别在于,实施例3的分组采用表1,本步骤的分组采用表2,并按照表2进行制备。分别制备得到各组细胞制品。
表2实验组分组(b)
序号 | 分组编号 | 处理及培养方法 |
1 | 实验组b1 | 感染CD19sCAR-2后利用MCA2488进行特异性激活 |
2 | 实验组b2 | 感染CD19sCAR-2后不利用MCA2488进行特异性激活 |
3 | 实验组b3 | 感染CD19CAR后利用MCA2488进行特异性激活 |
4 | 实验组b4 | 同实验组a4 |
5 | 实验组b5 | 同实验组a5 |
实施例5嵌合抗原受体(CD19sCAR-3)修饰性T细胞的制备
本实施例构建了靶向CD19的嵌合抗原分子CD19sCAR-3(氨基酸序列见SEQ ID NO:11,开放阅读框的核苷酸序列见SEQ ID NO:12),该CAR分子可靶向CD19抗原且包含人工抗原表位Strep-tag II(氨基酸序列见SEQ ID NO:3)。制备嵌合抗原受体(CD19sCAR-3)修饰性T细胞,具体步骤如下:
(1)构建CD19sCAR-3的表达载体
实验步骤同实施例1,区别在于,实施例1使用CD19sCAR-1的序列,而本步骤使用CD19sCAR-3的序列;
(2)制备CD19sCAR-3编码病毒
实验步骤同实施例2,区别在于,实施例2使用实施例1制备得到的CD19sCAR-1慢病毒表达载体,而本步骤使用步骤(1)制备得到的CD19sCAR-3慢病毒表达载体;
(3)制备CDsCAR-3修饰性T细胞
实验步骤同实施例3,区别在于,实施例3的分组采用表1,本步骤的分组采用表3,并按照表3进行制备。分别制备得到各组细胞制品。
表2实验组分组(c)
序号 | 分组编号 | 处理及培养方法 |
1 | 实验组c1 | 感染CD19sCAR-3后利用A01732进行特异性激活 |
2 | 实验组c2 | 感染CD19sCAR-3后不利用A01732进行特异性激活 |
3 | 实验组c3 | 感染CD19CAR后利用A01732进行特异性激活 |
4 | 实验组c4 | 同实验组a4 |
5 | 实验组c5 | 同实验组a5 |
实施例6细胞制品中CAR阳性T细胞、Tcm比例
统计3个独立批次实验,分别对实施例3-5制备得到的各实验组的终产品进行流式检测分析,流式检测分析结果见图1-6。由图1-3可知,实验组a1、b1、c1的终产品中CAR阳性T细胞比例显著高于其他实验组,说明根据本发明提供的制备方法,可促进CAR阳性T细胞的扩增,提高其在终产品中的比例;由图4-6可知,实验组a1、b1、c1的CAR阳性T细胞中Tcm的比例约为80%,显著高于其他实验组。
对培养过程中Tcm亚群的增殖情况进行分析,分析结果见图7-9所示。由图7-9可知,实验组a1、b1、c1的CAR阳性T细胞中Tcm亚群比例在培养初期显著升高,且随着培养时间的延长,扩增比例未发生显著变化;而其他实验组培养体系中的Tcm比例,在培养初期有所升高,但是随着培养时间的延长,比例逐渐下降。这表明,本发明提供的制备方法有效克服了Tcm在体外无法长期培养的限制,延长了其体外培养的时间,保证了终产品收获时的细胞数量和Tcm亚群的比例。
实施例7体外杀伤活性
以人淋巴瘤细胞系raji为靶细胞,按照5×104/mL接种至U型底96孔板,将实施例3制备得到的各实验组CAR-T细胞,按照效靶比(E/T)比例25:1、12.5:1、6.25:1和1:1的比例进行共培养,培养基为不含血清的RPMI1640培养基,培养条件为37℃,5%CO2,饱和湿度培养箱,培养12h后,利用乳酸脱氢酶释放法(LDH法)检测不同实验组的CAR-T细胞对靶细胞的杀伤活性,检测结果见图10。由图10的实验结果可知,在相同效靶比的条件下,本发明的制备方法获得的CAR-T细胞产品的杀伤活性显著优于其他实验组,同时也说明Tcm比例较高的CAR-T细胞制品具有更好的靶细胞杀伤活性。
实施例8杀伤相关细胞因子释放能力的检测
按照实施例7的方法,将实施例3制备得到的各实验组CAR-T细胞与Raji靶细胞按照25:1的比例混合,共培养12h后,收集培养上清,利用ELISA方法检测CAR-T杀伤相关细胞因子(IL-2、IFN-γ、TNF-α)的释放水平。如图11显示的实验结果所示,本发明的制备方法获得的CAR-T细胞与其他实验组制备的CAR-T细胞相比,在杀伤过程中具有更好的细胞因子释放活性。
实施例9体内抗肿瘤活性评价
选择6-8周龄的NOD/SCID IL2Rγc-/-免疫缺陷小鼠,将稳定表达荧光素酶蛋白的人Raji细胞系(Raji-Luci)以1×106/100μL/只的剂量,经过尾静脉注射的方式建立荷瘤小鼠模型。注射肿瘤细胞3天后,按照实施例3的实验分组,每组实验动物通过尾静脉按照1×106/100μL/只注射实施例3制备得到的CAR-T细胞。注射后每周利用小动物成像系统观测实验动物的体内肿瘤进展,直至全部实验动物死亡。对实验数据的统计分析结果见图12所示,与其他实验组相比,本发明的制备方法获得的CAR-T细胞可以有效的延长荷瘤小鼠的中位生存时间,延缓肿瘤体内的进展,具有更持久的体内抗肿瘤活性。
实施例10体内杀伤细胞因子释放活性的评价
利用ELISA方法检测实施例9中不同实验组动物血清中CAR-T相关抗肿瘤细胞因子的水平,包括IFN-γ、TNF-α、IL-2。检测结果见图13所示,与其他实验组相比,接受本发明技术方案制备的CAR-T的实验动物,体内的杀伤相关细胞因子的水平显著更高,提示其在体内具有更好的抗肿瘤活性。
实施例11临床安全性及有效性评估
实施例3实验组a1制备得到的CD9sCAR-T细胞产品,通过I期临床试验(注册号:ChiCTR1800017439,ChiCTR1800014761)对其临床安全性和有效性进行了验证。
5名前期接受过鼠源性CD19CAR-T治疗后又再次复发的急性B淋巴细胞白血病患者接受了本发明实施例3实验组a1制备的CD9sCAR-T产品,每名患者均为单次输注,回输剂量范围为0.3×106/kg-3×106/kg。所有患者均在回输后每周接受安全性评估,在第15天和第30天接受了疗效评估。研究结果见表4所示,5名患者中有4名患者在第30天评估为达到完全缓解,总体缓解率为80%。5名患者均未出现3级以上的毒副反应。
通过与患者前期接受CD19CAR-T治疗后监测的CAR-T体内扩增数据对比,本发明技术方案制备的CD9sCAR-T的体内扩增水平显著高于前期CD19CAR-T(图14-18)。本实施例的研究结果表明,本发明的技术方案制备的CD19sCAR-T在临床应用中具有良好的安全性和有效性,且具有优异的体内扩增能力。
表4受试者基本信息及临床疗效评估
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以所述权利要求的保护范围为准。
序列表
<110> 首都医科大学宣武医院
<120> 以Tcm为主要效应成分的CAR-T制备方法及其应用
<160> 12
<170> PatentIn version 3.5
<210> 1
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Lys Pro Leu Pro Glu Val Thr Asp Glu Tyr
1 5 10
<210> 2
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Trp Ser His Pro Gln Phe Glu Lys
1 5
<210> 3
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Asn Trp Ser His Pro Gln Phe Glu Lys
1 5
<210> 4
<211> 577
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Asp Ile Val Leu Thr Gln Thr Thr Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Pro Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Glu Glu Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser
130 135 140
Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr His Tyr Tyr
145 150 155 160
Ile Tyr Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
165 170 175
Gly Val Asn Pro Ser Asn Gly Gly Thr His Phe Asn Glu Lys Phe Lys
180 185 190
Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met
195 200 205
Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Thr
210 215 220
Arg Ser Glu Tyr Asp Tyr Gly Leu Gly Phe Ala Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
245 250 255
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
260 265 270
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
275 280 285
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
290 295 300
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
305 310 315 320
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
325 330 335
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
340 345 350
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
355 360 365
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
370 375 380
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
385 390 395 400
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
405 410 415
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
420 425 430
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
435 440 445
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
450 455 460
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
465 470 475 480
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
485 490 495
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
500 505 510
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
515 520 525
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
530 535 540
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
545 550 555 560
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570 575
Lys
<210> 5
<211> 499
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
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 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Val Arg Pro Gly Ser Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ala Phe Ser Ser Tyr Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn
65 70 75 80
Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser
100 105 110
Ala Val Tyr Phe Cys Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr
115 120 125
Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
130 135 140
Ser Gly Gly Gly Gly Ser Lys Pro Leu Pro Glu Val Thr Asp Glu Tyr
145 150 155 160
Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu
165 170 175
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln
180 185 190
Ser Val Asp Tyr Asp Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile
195 200 205
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val
210 215 220
Ser Gly Ile Pro Pro Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
225 230 235 240
Thr Leu Asn Ile His Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His
245 250 255
Cys Gln Gln Ser Thr Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys
260 265 270
Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 6
<211> 1500
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
atggctctgc cagtgacagc tctgctgctg cctctggctc tgctgctgca cgcagctaga 60
ccccaggtgc agctgcagca gtcaggagca gaactcgtga gaccaggcag cagcgtgaag 120
atctcttgca aggccagcgg ctacgccttc tctagctatt ggatgaattg ggtgaagcag 180
cggccaggac agggactgga gtggattgga cagatttggc ccggcgacgg cgataccaac 240
tacaacggca agttcaaggg caaggccacc ctgacagccg acgagtctag cagcacagcc 300
tacatgcagc tgagctctct ggccagcgag gatagcgccg tgtacttttg cgccagaagg 360
gagaccacaa cagtgggccg gtactactac gccatggact attggggcca gggcacaacc 420
gtgacagtgt ctagcggagg aggcggctct aagcctctgc cagaagtgac agacgagtac 480
ggcggaggag gaagcgacat ccagctgacc cagagcccag cttctctggc agtgtctctg 540
ggacagaggg ctaccatctc ttgcaaggcc agccagagcg tggattacga cggcgacagc 600
tacctgaatt ggtatcagca gatccccggc cagcctccta agctgctgat ctacgacgcc 660
tccaacctgg tgtccggcat ccctcccaga ttcagcggaa gcggcagcgg cacagacttc 720
accctgaaca tccaccccgt ggagaaggtg gacgccgcca cataccattg ccagcagagc 780
acagaggacc cctggacctt tggcggcgga acaaagctgg agatcaagac aaccacccca 840
gcccctagac ctcctacacc agcccctaca atcgcctctc agcctctgag cctgaggcca 900
gaagcttgta gacccgcagc aggaggagca gtgcatacaa ggggcctgga cttcgcttgc 960
gacatctaca tttgggcccc tctggcagga acttgcggag tgctgctgct gtctctggtc 1020
atcaccctgt attgcaagcg gggccggaag aagctgctgt acatcttcaa gcagcccttc 1080
atgcggccag tgcagacaac acaggaggag gacggttgca gctgcagatt cccagaggag 1140
gaggaaggcg gctgcgagct gagagtgaag ttcagcagga gcgccgacgc tccagcctat 1200
aaacagggac agaaccagct gtacaacgag ctgaacctgg gcagaagaga ggagtacgac 1260
gtgctggaca agaggagagg cagagaccca gagatgggcg gcaagcctag aaggaagaac 1320
ccccaggagg gcctgtacaa cgagctgcag aaggacaaga tggccgaggc ttacagcgag 1380
atcggcatga agggcgagag gagaagaggc aaaggccacg acggactgta tcagggactg 1440
agcacagcca ccaaggacac ctacgacgct ctgcacatgc aggctctgcc tcctagataa 1500
<210> 7
<211> 486
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
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 Thr Thr Ser Ser Leu
20 25 30
Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
35 40 45
Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
50 55 60
Val Lys Leu Leu Ile Tyr His Thr Ser Arg 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
Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
100 105 110
Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
130 135 140
Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
145 150 155 160
Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
165 170 175
Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
180 185 190
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
195 200 205
Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
210 215 220
Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
225 230 235 240
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
260 265 270
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
275 280 285
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
290 295 300
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
305 310 315 320
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
325 330 335
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
340 345 350
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
355 360 365
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
370 375 380
Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
385 390 395 400
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
405 410 415
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
420 425 430
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
435 440 445
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
450 455 460
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
465 470 475 480
Gln Ala Leu Pro Pro Arg
485
<210> 8
<211> 1461
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atggctctgc cagtgacagc tctgctgctg cctctggctc tgctgctgca cgcagctaga 60
cccgacatcc agatgaccca gaccaccagc tctctgagcg cttctctggg cgacagagtg 120
accatctctt gcagggccag ccaggacatc agcaagtacc tgaattggta tcagcagaag 180
cccgacggca cagtgaagct gctgatctac cacacaagca gactgcacag cggagtgcct 240
agcagattca gcggcagcgg aagcggaacc gactacagcc tgaccatcag caacctggag 300
caggaggaca tcgccaccta cttctgccag cagggcaaca ccctgcctta cacattcggc 360
ggcggcacaa agctggagat cacaggagga ggaggaagcg gaggaggagg aagcggagga 420
ggaggaagcg aagtgaagct gcaggagagc ggaccaggac tggtggctcc ttcacagtct 480
ctgagcgtga cttgcaccgt gtcaggagtg tccctgccag actacggcgt gtcttggatc 540
aggcagcctc ctagaaaggg actggagtgg ctgggagtga tttggggaag cgagaccacc 600
tactacaaca gcgccctgaa gagccggctg accatcatca aggacaacag caagagccag 660
gtgttcctga agatgaacag cctgcagacc gacgacaccg ccatctacta ctgcgccaag 720
cactactact acggcggcag ctacgccatg gactattggg gacagggcac cagcgtgaca 780
gtgtctagca caaccacccc agcccctaga cctcctacac cagcccctac aatcgcctct 840
cagcctctga gcctgaggcc agaagcttgt agacccgcag caggaggagc agtgcataca 900
aggggcctgg acttcgcttg cgacatctac atttgggccc ctctggcagg aacttgcgga 960
gtgctgctgc tgtctctggt catcaccctg tattgcaagc ggggccggaa gaagctgctg 1020
tacatcttca agcagccctt catgcggcca gtgcagacaa cacaggagga ggacggttgc 1080
agctgcagat tcccagagga ggaggaaggc ggctgcgagc tgagagtgaa gttcagcagg 1140
agcgccgacg ctccagccta taaacaggga cagaaccagc tgtacaacga gctgaacctg 1200
ggcagaagag aggagtacga cgtgctggac aagaggagag gcagagaccc agagatgggc 1260
ggcaagccta gaaggaagaa cccccaggag ggcctgtaca acgagctgca gaaggacaag 1320
atggccgagg cttacagcga gatcggcatg aagggcgaga ggagaagagg caaaggccac 1380
gacggactgt atcagggact gagcacagcc accaaggaca cctacgacgc tctgcacatg 1440
caggctctgc ctcctagata a 1461
<210> 9
<211> 497
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Val Arg Pro Gly Ser Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ala Phe Ser Ser Tyr Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn
65 70 75 80
Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser
100 105 110
Ala Val Tyr Phe Cys Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr
115 120 125
Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
130 135 140
Ser Gly Gly Gly Gly Ser Trp Ser His Pro Gln Phe Glu Lys Gly Gly
145 150 155 160
Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala Val
165 170 175
Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val
180 185 190
Asp Tyr Asp Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly
195 200 205
Gln Pro Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly
210 215 220
Ile Pro Pro Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
225 230 235 240
Asn Ile His Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln
245 250 255
Gln Ser Thr Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu
260 265 270
Ile Lys 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 Lys 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> 10
<211> 1494
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atggcgctgc cggtgaccgc gctgctgctg ccgctggcgc tgctgctgca tgcggcgcgt 60
ccgcaggtgc agctgcagca gagcggcgcg gaactggtgc gtccgggcag cagcgtgaaa 120
attagctgca aagcgagcgg ctatgcgttt agcagctatt ggatgaactg ggtgaaacag 180
cgtccgggcc agggcctgga atggattggc cagatttggc cgggcgatgg cgataccaac 240
tataacggca aatttaaagg caaagcgacc ctgaccgcgg atgaaagcag cagcaccgcg 300
tatatgcagc tgagcagcct ggcgagcgaa gatagcgcgg tgtatttttg cgcgcgtcgt 360
gaaaccacca ccgtgggccg ttattattat gcgatggatt attggggcca gggcaccacc 420
gtgaccgtga gcagcggcgg cggcggcagc tggagccatc cgcagtttga aaaaggcggc 480
ggcggcagcg atattcagct gacccagagc ccggcgagcc tggcggtgag cctgggccag 540
cgtgcgacca ttagctgcaa agcgagccag agcgtggatt atgatggcga tagctatctg 600
aactggtatc agcagattcc gggccagccg ccgaaactgc tgatttatga tgcgagcaac 660
ctggtgagcg gcattccgcc gcgttttagc ggcagcggca gcggcaccga ttttaccctg 720
aacattcatc cggtggaaaa agtggatgcg gcgacctatc attgccagca gagcaccgaa 780
gatccgtgga cctttggcgg cggcaccaaa ctggaaatta aaaccaccac cccggcgccg 840
cgtccgccga ccccggcgcc gaccattgcg agccagccgc tgagcctgcg tccggaagcg 900
tgccgtccgg cggcgggcgg cgcggtgcat acccgtggcc tggattttgc gtgcgatatt 960
tatatttggg cgccgctggc gggcacctgc ggcgtgctgc tgctgagcct ggtgattacc 1020
ctgtattgca aacgtggccg taaaaaactg ctgtatattt ttaaacagcc gtttatgcgt 1080
ccggtgcaga ccacccagga agaagatggc tgcagctgcc gttttccgga agaagaagaa 1140
ggcggctgcg aactgcgtgt gaaatttagc cgtagcgcgg atgcgccggc gtataaacag 1200
ggccagaacc agctgtataa cgaactgaac ctgggccgtc gtgaagaata tgatgtgctg 1260
gataaacgtc gtggccgtga tccggaaatg ggcggcaaac cgcgtcgtaa aaacccgcag 1320
gaaggcctgt ataacgaact gcagaaagat aaaatggcgg aagcgtatag cgaaattggc 1380
atgaaaggcg aacgtcgtcg tggcaaaggc catgatggcc tgtatcaggg cctgagcacc 1440
gcgaccaaag atacctatga tgcgctgcat atgcaggcgc tgccgccgcg ttaa 1494
<210> 11
<211> 498
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
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 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu
20 25 30
Val Arg Pro Gly Ser Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ala Phe Ser Ser Tyr Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln
50 55 60
Gly Leu Glu Trp Ile Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn
65 70 75 80
Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser
85 90 95
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser
100 105 110
Ala Val Tyr Phe Cys Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr
115 120 125
Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
130 135 140
Ser Gly Gly Gly Gly Ser Asn Trp Ser His Pro Gln Phe Glu Lys Gly
145 150 155 160
Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ala
165 170 175
Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser
180 185 190
Val Asp Tyr Asp Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro
195 200 205
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser
210 215 220
Gly Ile Pro Pro Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Asn Ile His Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys
245 250 255
Gln Gln Ser Thr Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
260 265 270
Glu Ile Lys 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 Lys
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> 12
<211> 1497
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atggcgctgc cggtgaccgc gctgctgctg ccgctggcgc tgctgctgca tgcggcgcgt 60
ccgcaggtgc agctgcagca gagcggcgcg gaactggtgc gtccgggcag cagcgtgaaa 120
attagctgca aagcgagcgg ctatgcgttt agcagctatt ggatgaactg ggtgaaacag 180
cgtccgggcc agggcctgga atggattggc cagatttggc cgggcgatgg cgataccaac 240
tataacggca aatttaaagg caaagcgacc ctgaccgcgg atgaaagcag cagcaccgcg 300
tatatgcagc tgagcagcct ggcgagcgaa gatagcgcgg tgtatttttg cgcgcgtcgt 360
gaaaccacca ccgtgggccg ttattattat gcgatggatt attggggcca gggcaccacc 420
gtgaccgtga gcagcggcgg cggcggcagc aattggagcc atccgcagtt tgaaaaaggc 480
ggcggcggca gcgatattca gctgacccag agcccggcga gcctggcggt gagcctgggc 540
cagcgtgcga ccattagctg caaagcgagc cagagcgtgg attatgatgg cgatagctat 600
ctgaactggt atcagcagat tccgggccag ccgccgaaac tgctgattta tgatgcgagc 660
aacctggtga gcggcattcc gccgcgtttt agcggcagcg gcagcggcac cgattttacc 720
ctgaacattc atccggtgga aaaagtggat gcggcgacct atcattgcca gcagagcacc 780
gaagatccgt ggacctttgg cggcggcacc aaactggaaa ttaaaaccac caccccggcg 840
ccgcgtccgc cgaccccggc gccgaccatt gcgagccagc cgctgagcct gcgtccggaa 900
gcgtgccgtc cggcggcggg cggcgcggtg catacccgtg gcctggattt tgcgtgcgat 960
atttatattt gggcgccgct ggcgggcacc tgcggcgtgc tgctgctgag cctggtgatt 1020
accctgtatt gcaaacgtgg ccgtaaaaaa ctgctgtata tttttaaaca gccgtttatg 1080
cgtccggtgc agaccaccca ggaagaagat ggctgcagct gccgttttcc ggaagaagaa 1140
gaaggcggct gcgaactgcg tgtgaaattt agccgtagcg cggatgcgcc ggcgtataaa 1200
cagggccaga accagctgta taacgaactg aacctgggcc gtcgtgaaga atatgatgtg 1260
ctggataaac gtcgtggccg tgatccggaa atgggcggca aaccgcgtcg taaaaacccg 1320
caggaaggcc tgtataacga actgcagaaa gataaaatgg cggaagcgta tagcgaaatt 1380
ggcatgaaag gcgaacgtcg tcgtggcaaa ggccatgatg gcctgtatca gggcctgagc 1440
accgcgacca aagataccta tgatgcgctg catatgcagg cgctgccgcc gcgttaa 1497
Claims (10)
1.一种提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其特征在于,在CAR中加入人工抗原表位,以及通过所述人工抗原表位激活CAR-T;其中所述人工抗原表位不存在于所述CAR的其他结构域或区段中。
2.如权利要求1所述提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其特征在于,所述人工抗原表位对CAR的其它结构域或区段的功能不产生或基本不产生负面影响;当所述人工抗原表位被结合时能够激活CAR-T。
3.如权利要求1所述提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其特征在于,所述人工抗原表位位于CAR的胞外结构域中、胞外结构域与铰链区之间、或铰链区与跨膜结构之间。
4.如权利要求1所述提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其特征在于,所述人工抗原表位的长度为7-15aa,优选8-12aa。
5.如权利要求1所述提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其特征在于,所述人工抗原表位的氨基酸序列为SEQ ID NO:1、SEQ ID NO:2或SEQ ID NO:3。
6.如权利要求1-5任一所述提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其特征在于,采用特异性识别所述人工抗原表位的分子结合所述人工抗原表位激活CAR-T,其中特异性识别所述人工抗原表位的分子优选为抗体分子。
7.如权利要求1所述提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其特征在于,通过所述人工抗原表位激活CAR-T的步骤在将CAR导入T细胞的步骤之后。
8.如权利要求1所述提高CAR-T细胞制品中中央记忆型T细胞(Tcm)亚群比例的方法,其特征在于,通过所述人工抗原表位激活CAR-T的步骤包括将CAR-T在含有IL-7、IL-2和IL-15的培养基中进行培养。
9.一种具有高比例中央记忆型T细胞(Tcm)亚群的CAR-T细胞,其特征在于,所述CAR-T细胞通过权利要求1-8任一项所述的方法制备得到。
10.如权利要求9所述的CAR-T细胞在制备预防和/或治疗癌症或肿瘤的药物或制剂中的应用。
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EP19932402.1A EP3988648A4 (en) | 2019-06-13 | 2019-11-11 | METHOD FOR PREPARING DECAR-T USING TCM AS PRINCIPAL ACTIVE INGREDIENT AND CORRESPONDING USE |
PCT/CN2019/117100 WO2020248486A1 (zh) | 2019-06-13 | 2019-11-11 | 以Tcm为主要效应成分的CAR-T制备方法及其应用 |
US17/061,558 US11857572B2 (en) | 2019-06-13 | 2020-10-01 | Method for preparing CAR-T cell with TCM as main active component and use thereof |
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CN115322968A (zh) * | 2022-09-21 | 2022-11-11 | 东莞市东南部中心医院 | 一种car-t细胞的培养体系及应用和培养方法 |
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US11857572B2 (en) | 2024-01-02 |
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US20210077531A1 (en) | 2021-03-18 |
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