CN117089523A - 一种滋养细胞制备方法及其用途 - Google Patents
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Abstract
本发明提供了一种滋养细胞制备方法及其用途。本发明的滋养层细胞,表达含有膜锚定的细胞因子IL‑15、IL‑21和NK细胞激活性CD137L、CD48的融合蛋白,可显著增强NK细胞的扩增能力,增加NK细胞的扩增倍数,提高扩增后NK细胞的纯度和肿瘤杀伤活性。
Description
技术领域
本发明涉及生物技术领域,更具体地涉及一种滋养细胞制备方法及其用途。
背景技术
自然杀伤细胞(natural killer cell,NK)是机体内一类重要的免疫细胞,是固有免疫系统(Innate immune system)的重要组成成分之一。NK细胞来源于骨髓中的淋巴前体细胞,分化成熟后主要分布于骨髓、外周血、淋巴结和肝、脾、肺等一些器官组织中。在免疫防线中,NK细胞主要清除体内的病毒感染细胞和肿瘤细胞,从而防止病原体入侵和肿瘤发生。NK细胞上表达了多种受体,包括激活、抑制、细胞因子和趋化因子受体。其中激活和抑制受体的组合是控制NK细胞识别和清除异常细胞的开关,细胞因子受体可以控制NK细胞的发育和增殖,趋化因子受体主要控制NK细胞的迁移和组织分布。
NK细胞抑制性和激活性受体信号传导的动态平衡可以调节NK细胞的激活和免疫监视功能。其中抑制性受体主要包括抑制性杀伤性免疫球蛋白受体(iKIR)、NKG2A/CD94、TIGIT等,正常细胞组织会表达相应的抑制性配体,从而建立NK细胞的自我耐受性。激活性受体主要包括激活性杀伤性免疫球蛋白受体(aKIR)、CD16、NKG2C、NKG2D、自然细胞毒性受体(Natural Cytotoxicity Receptors,NCRs,包括NKp30、NKp44、NKp46等)和一些共刺激激活受体(CD226/DNAM-1、CD244/2B4、CD2等)。
在正常人的外周血中,NK细胞约占循环淋巴细胞的5%-15%。因此,为使NK细胞治疗能够满足临床应用的需要,如何通过体外培养的方法来得到大量高纯度、高杀伤活性的NK细胞是重要的研究方向。目前,自然杀伤细胞细胞的扩增策略主要有两种,一种是通过细胞因子刺激,使用包括IL-2、IL-12、IL-15、IL-18、IL-21等细胞因子来刺激扩增。细胞因子价格较贵,扩增成本高,而且效率有限,扩增倍数有限。另一种是通过滋养细胞刺激自然杀伤细胞细胞增殖。目前最常用的滋养细胞是K562细胞。K562是人红白血病细胞系,是天然缺少主要组织相容性复合物HLA-I/II的肿瘤细胞,同时其表面表达有NKG2D的激活性配体MICA/B、ULBP。对于NK细胞来说,K562细胞的刺激能加速NK细胞的扩增和成熟,同时可以提高NK细胞激活受体的表达进而提高NK细胞的杀伤活性。但这种方法也存在一些缺点,包括扩增后的CD3+T细胞残留比例高,CD56+CD16+双阳性NK细胞比例低,总体NK细胞扩增倍数小,天然细胞残留不容易检测等缺陷。
在前期专利中,研究人员使用表达有自然杀伤细胞(natural killer cell,NK的K562作为滋养层细胞,可显著增强NK细胞的扩增能力,增加了NK细胞的扩增倍数。但NK细胞表面的激活性受体种类和功能较多,利用K562本身的激活性配体和外源表达的CD137L无法完全利用这些激活性受体。
因此,建立表达有多种NK细胞激活性配体组合的滋养层细胞可以更高效的刺激NK细胞的扩增和成熟,进一步提高扩增后NK细胞的杀伤活性。
发明内容
本发明的目的在于提供一种滋养细胞制备方法及其用途。
在本发明的第一方面,提供了一种工程化滋养细胞,所述细胞表达第一融合蛋白元件和第二融合蛋白元件;且
所述第一融合蛋白元件的结构如式I所示:L1-Z1-H1-TM1-P1-Z2(I);
所述第二融合蛋白元件的结构如式II所示:L2-Z3-H2-TM2-P2-Z4(II);
式中,
各“-”独立地为连接肽或肽键;
L1、L2各自独立地为无或信号肽序列;
Z1为IL15;
Z3为IL21;
H1、H2各自独立地为任选的铰链区;
TM1、TM2各自独立地为跨膜结构域;
Z2和Z4两者中的一个为CD137L元件,另一个为CD48元件;
P1、P2各自独立地为自剪切蛋白。
在另一优选例中,所述Z2为CD137L或其活性片段
在另一优选例中,所述Z4为CD48或其活性片段。
在另一优选例中,所述CD137L来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述CD137L包括野生型和突变型。
在另一优选例中,所述CD137L包括全长的、成熟形式的CD137L,或其活性片段。
在另一优选例中,所述CD137L还包括CD137L的衍生物。
在另一优选例中,所述Z2还包括CD137的其他激活性配体,如CD137的激活性抗体或多肽。
在另一优选例中,所述CD48来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述CD48包括野生型和突变型。
在另一优选例中,所述CD48包括全长的、成熟形式的CD48,或其活性片段。
在另一优选例中,所述CD48还包括CD48的衍生物。
在另一优选例中,所述Z4还包括CD48的受体CD2/CD244等的其他激活性配体,如CD2/CD244的激活性抗体或多肽。
在另一优选例中,所述IL15来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述IL15包括野生型IL15和突变型IL15、或其活性片段。
在另一优选例中,所述IL15的氨基酸序列如SEQ ID NO.1所示。
在另一优选例中,所述IL21来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述IL21包括野生型IL21和突变型IL21、或其活性片段。
在另一优选例中,所述IL21的氨基酸序列如SEQ ID NO.4所示。
在另一优选例中,所述CD137L来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述CD137L包括野生型和突变型。
在另一优选例中,所述CD137L包括全长的、成熟形式的CD137L,或其活性片段。
在另一优选例中,所述CD137L还包括CD137L的衍生物。
在另一优选例中,所述CD137L的衍生物包括经修饰的CD137L、氨基酸序列与天然CD137L同源且具有天然CD137L活性的蛋白分子、CD137L的二聚体或多聚体、含有CD137L氨基酸序列的融合蛋白。
在另一优选例中,所述“氨基酸序列与天然CD137L同源且具有天然CD137L活性的蛋白分子”是指其氨基酸序列与CD137L相比具有≥85%的同源性,较佳地≥90%的同源性,更佳地≥95%的同源性,最佳地≥98%同源性;并且具有CD137L活性的蛋白分子。
在另一优选例中,所述CD137L的氨基酸序列如SEQ ID NO.2所示。
在另一优选例中,所述CD48来源于人或非人哺乳动物,更佳地来源于啮齿动物(如小鼠、大鼠)、灵长动物和人。
在另一优选例中,所述CD48包括野生型和突变型。
在另一优选例中,所述CD48包括全长的、成熟形式的CD48,或其活性片段。
在另一优选例中,所述CD48还包括CD48的衍生物。
在另一优选例中,所述CD48的衍生物包括经修饰的CD48、氨基酸序列与天然CD48同源且具有天然CD48活性的蛋白分子、CD48的二聚体或多聚体、含有CD48氨基酸序列的融合蛋白。
在另一优选例中,所述“氨基酸序列与天然CD48同源且具有天然CD48活性的蛋白分子”是指其氨基酸序列与CD48相比具有≥85%的同源性,较佳地≥90%的同源性,更佳地≥95%的同源性,最佳地≥98%同源性;并且具有CD48活性的蛋白分子。
在另一优选例中,所述CD48的氨基酸序列如SEQ ID NO.5所示。
在另一优选例中,所述L1、L2各自独立地为选自下组的蛋白的信号肽:CD8,CD28,GM-CSF,GMCSFR,IL2,IL15,IL21。
在另一优选例中,L1、L2各自独立地为GM-CSF蛋白的信号肽。
在另一优选例中,所述的TM1、TM2各自独立地为选自下组的蛋白的跨膜区:CD28、CD8、41BB、CD3。
在另一优选例中,所述的TM1、TM2各自独立地为CD28来源的跨膜区。
在另一优选例中,所述的TM1、TM2是相同的,均为CD28来源的跨膜区。
在另一优选例中,所述的H1、H2各自独立地为CD8来源的铰链区。
在另一优选例中,所述的H1、H2是相同的,均为CD8胞外段。
在另一优选例中,所述自剪切蛋白选自下组:T2A、P2A、E2A、F2A、或其组合。
在另一优选例中,所述自剪切蛋白包括T2A或F2A。
在另一优选例中,所述第一融合蛋白元件的序列选自下组:
(A)具有SEQ ID NO.3所示氨基酸序列的多肽;
(B)具有与SEQ ID NO.3所示氨基酸序列≥80%同源性(优选地,≥90%的同源性;等优选地≥95%的同源性;最优选地,≥97%的同源性,如98%以上,99%以上)的多肽,且所述多肽具有激活NK并能刺激细胞增殖的活性;
(C)将SEQ ID NO:3所示氨基酸序列经过1-5个氨基酸残基的取代、缺失或添加而形成的,且保留有激活NK并能刺激细胞增殖活性的衍生多肽。
在另一优选例中,所述第一融合蛋白元件的氨基酸序列如SEQ ID NO.:3所示。
在另一优选例中,所述第二融合蛋白元件的序列选自下组:
(A)具有SEQ ID NO.6所示氨基酸序列的多肽;
(B)具有与SEQ ID NO.6所示氨基酸序列≥80%同源性(优选地,≥90%的同源性;等优选地≥95%的同源性;最优选地,≥97%的同源性,如98%以上,99%以上)的多肽,且所述多肽具有激活NK并能刺激细胞增殖的活性;
(C)将SEQ ID NO:3所示氨基酸序列经过1-5个氨基酸残基的取代、缺失或添加而形成的,且保留有激活NK并能刺激细胞增殖活性的衍生多肽。
在另一优选例中,所述第二融合蛋白元件的氨基酸序列如SEQ ID NO.:6所示。
在另一优选例中,所述滋养细胞选自下组:K562细胞、外周血单核细胞、Daudi细胞、THP1细胞、RPMI8226细胞、Raji细胞、Jurkat细胞、MOLT-4细胞、SupB15细胞、HEK293细胞、Hela细胞、或其组合。
在本发明的第二方面,提供了一种制备工程化滋养细胞的方法,包括以下步骤:
(A)提供一待改造的滋养细胞;和
(B)对所述的滋养细胞进行改造,使得所述的免疫细胞表达第一融合蛋白元件和第二融合蛋白元件,从而获得如本发明第一方面所述的工程化滋养细胞。
在另一优选例中,在步骤(B)中,包括
(B1)将用于表达第一融合蛋白元件的第一表达盒导入到所述滋养细胞;和(B2)将用于表达第二融合蛋白元件的第二表达盒导入到所述滋养细胞,其中,所述步骤(B2)可在步骤(B1)之前、之后、同时或交替进行;
(B3)经过筛选获得如本发明第一方面所述的工程化滋养细胞。
在另一优选例中,所述第一表达盒和/或第二表达盒中还各自独立地包括筛选标记基因。
在另一优选例中,所述筛选标记基因选自下组:Puromycin基因、Blasticidin基因、和潮霉素抗性基因(Hyg)、卡那霉素抗性基因(NptII)、GFP基因、Amp抗性基因或草丁膦抗性基因(Bar)。
在另一优选例中,所述第一表达盒和/或第二表达盒中还各自独立地包括编码内部核糖体进入位点序列(IRES)的基因。
在另一优选例中,步骤(B3)中,所述筛选包括抗性筛选、加压筛选。
在另一优选例中,所述滋养细胞选自下组:K562细胞、外周血单核细胞、Daudi细胞、THP1细胞、RPMI8226细胞、Raji细胞、Jurkat细胞、MOLT-4细胞、SupB15细胞、HEK293细胞、Hela细胞、或其组合。
在另一优选例中,所述的第一表达盒和第二表达盒位于相同或不同的载体上。
在另一优选例中,所述的第一表达盒和第二表达盒位于同一载体。
在另一优选例中,所述载体包括质粒、病毒载体。
在另一优选例中,所述的载体包括PiggyBac质粒系统。
在另一优选例中,所述载体包括表达载体、穿梭载体、整合载体。
在另一优选例中,所述的载体选自下组:DNA、RNA、质粒、慢病毒载体、腺病毒载体、逆转录病毒载体、转座子、其他基因转移系统、或其组合。
在另一优选例中,所述的方法还包括对获得的工程化的滋养细胞进行功能和有效性检测的步骤。
在本发明的第三方面,提供了一种药物组合物,所述药物组合物含有本发明的第一方面所述的工程化滋养细胞,以及药学上可接受的载体、稀释剂或赋形剂。
在另一优选例中,所述药物组合物中,所述细胞的浓度为1×103-1×108个细胞/ml,较佳地1×104-1×107个细胞/ml。
在另一优选例中,所述药物组合物还含有其他增强自然杀伤细胞增殖能力的组分,如IL2,IL7,IL12,地西他滨。
在另一优选例中,所述自然杀伤细胞包括T细胞、NK细胞、巨噬细胞。
在另一优选例中,所述自然杀伤细胞为NK细胞。
在本发明的第四方面,提供了一种本发明的第一方面所述的工程化滋养细胞、本发明的第三方面所述的药物组合物的用途,用于制备增强自然杀伤细胞增殖能力的药物或制剂。
在另一优选例中,所述自然杀伤细胞包括T细胞、NK细胞、巨噬细胞。
在另一优选例中,所述自然杀伤细胞为NK细胞。
在本发明的第五方面,提供了一种用于增强自然杀伤细胞增殖能力的试剂盒,所述试剂盒含有容器,以及位于容器内的本发明的第一方面所述的工程化滋养细胞或本发明的第三方面所述的药物组合物。
在另一优选例中,所述试剂盒还含有标签或使用说明书。
在本发明的第六方面,提供了一种增强自然杀伤细胞增殖能力的方法,包括:
在本发明的第一方面所述的工程化滋养细胞的存在下,培养自然杀伤细胞,从而增强自然杀伤细胞增殖能力。
在另一优选例中,所述方法为体外的方法。
在另一优选例中,所述自然杀伤细胞包括T细胞、NK细胞、巨噬细胞。
在另一优选例中,所述自然杀伤细胞为NK细胞。
在另一优选例中,所述细胞为体外培养的细胞。
在另一优选例中,所述方法为非治疗性和非诊断性的。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1a显示了PB-mIL15-CD137L-Puromycin和PB-mIL21-CD48-Blasticidin的具体基因设计结构。
图1b显示了表达mIL15-CD137L和mIL21-CD48的K562细胞的稳转细胞株流式检测结果。
图2显示了表达mIL15、mIL21、CD137L、CD48的滋养层细胞(HyaMab Feeder 2.0)和表达mIL15、mIL21、CD137L的滋养层细胞(HyaMab Feeder 1.0)可以有效扩增外周血来源的NK细胞,
图3显示了流式检测不同滋养层细胞扩增的NK细胞的纯度和表型的结果。
图4显示了不同滋养层细胞扩增的NK细胞对多种肿瘤细胞的杀伤能力测定。
具体实施方式
本发明人经过广泛而深入地研究,首次意外发现一种新的滋养细胞,表达含有IL15、IL21、CD137L和CD48的融合蛋白,本发明的滋养细胞可显著增强自然杀伤细胞的扩增倍数,增强自然杀伤细胞的扩增能力。在此基础上,本发明人完成了本发明。
术语
为了可以更容易地理解本公开,首先定义某些术语。如本申请中所使用的,除非本文另有明确规定,否则以下术语中的每一个应具有下面给出的含义。在整个申请中阐述了其它定义。
术语“约”可以是指在本领域普通技术人员确定的特定值或组成的可接受误差范围内的值或组成,其将部分地取决于如何测量或测定值或组成。
IL15
人白细胞介素15(interleukin-15,IL-15)IL-15是一种多效性细胞因子,具有激活T细胞、B细胞和NK细胞,并可介导这些细胞的增殖和存活的功能。
IL21
人白细胞介素21(interleukin-21,IL-21)IL-21是一种多效性细胞因子,具有参与调节B细胞增殖,协同IL-15促进骨髓前体细胞增殖和NK细胞增殖、分化和细胞毒活性。
CD137L(CD137 ligand)
CD137L(CD137配体),又名4-1BBL,属于肿瘤坏死因子超家族成员,是一种Ⅱ型跨膜糖蛋白。它可以激活共刺激因子CD137,激活多种免疫细胞,如:DC细胞、单核细胞、B细胞、肥大细胞、NK细胞和中性粒细胞。4-1BBL,以同源三聚体存在,以延伸的三叶样螺旋结构为特征,发挥其生物学功能。它作为CD137的高亲和力配体,表达于活化的抗原递呈细胞(APC)表面,包括巨噬细胞、B细胞和树突状细胞及多种肿瘤细胞的表面等。作为一对重要的共刺激分子,CD137L与CD137通过在免疫细胞间传递活化、增殖或者凋亡信号来调节T细胞介导的免疫反应。
CD48
CD48为糖基磷脂酰肌醇连接的免疫球蛋白超家族成员,作为一个免疫共刺激分子和黏附分子,参与免疫性疾病的调控。CD48是NK细胞重要活化受体CD244的配体,可以激活NK细胞。
CD48也被称为B淋巴细胞激活标志物(BLAST-1)或信号淋巴细胞激活分子2(SLAMF2)。CD48是免疫球蛋白超家族(IgSF)的CD2亚家族的成员,该CD2亚家族包括SLAM(信号淋巴细胞激活分子)蛋白,如CD84、CD150、CD229以及CD244。CD48存在于淋巴细胞和其它免疫细胞以及树突状细胞的表面上,并且参与这些细胞中的激活和分化途径。
滋养细胞
滋养层细胞是一类具有不分裂不增殖但仍保持代谢活性的滋养层细胞。该类细胞通过基因工程技术进行改造,再经过射线辐照,细胞膜表面稳定表达多种细胞因子,在多种细胞因子协同作用下可定向刺激其他细胞的定向激活和增殖。
本发明提供了一种工程化滋养细胞,所述细胞表达第一融合蛋白元件和第二融合蛋白元件;且
所述第一融合蛋白元件的结构如式I所示:L1-Z1-H1-TM1-P1-Z2(I);
所述第二融合蛋白元件的结构如式II所示:L2-Z3-H2-TM2-P2-Z4(II);
式中,
各“-”独立地为连接肽或肽键;
L1、L2各自独立地为无或信号肽序列;
Z1为IL15;
Z3为IL21;
H1、H2各自独立地为铰链区;
TM1、TM2各自独立地为跨膜结构域;
Z2和Z4两者中的一个为CD137L或其活性片段,另一个为CD48或其活性片段;
P1、P2各自独立地为自剪切蛋白。
融合蛋白
如本文所用,术语“融合蛋白”还包括具有上述活性的融合蛋白(如SEQ ID NO.:3或6所示的序列)的变异形式。这些变异形式包括(但并不限于):1-3个(通常为1-2个,更佳地1个)氨基酸的缺失、插入和/或取代,以及在C末端和/或N末端添加或缺失一个或数个(通常为3个以内,较佳地为2个以内,更佳地为1个以内)氨基酸。例如,在本领域中,用性能相近或相似的氨基酸进行取代时,通常不会改变蛋白质的功能。又比如,在C末端和/或N末端添加或缺失一个或数个氨基酸通常也不会改变蛋白质的结构和功能。此外,所述术语还包括单体和多聚体形式的本发明多肽。该术语还包括线性以及非线性的多肽(如环肽)。
本发明还包括上述融合蛋白的活性片段、衍生物和类似物。如本文所用,术语“片段”、“衍生物”和“类似物”是指基本上保持本发明融合蛋白的功能或活性的多肽。本发明的多肽片段、衍生物或类似物可以是(i)有一个或几个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的多肽,或(ii)在一个或多个氨基酸残基中具有取代基团的多肽,或(iii)抗原肽与另一个化合物(比如延长多肽半衰期的化合物,例如聚乙二醇)融合所形成的多肽,或(iv)附加的氨基酸序列融合于此多肽序列而形成的多肽(与前导序列、分泌序列或6×His等标签序列融合而形成的融合蛋白)。根据本文的教导,这些片段、衍生物和类似物属于本领域熟练技术人员公知的范围。
一类优选的活性衍生物指与式I或式II的氨基酸序列相比,有至多3个,较佳地至多2个,更佳地至多1个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。这些保守性变异多肽最好根据表A进行氨基酸替换而产生。
表A
最初的残基 | 代表性的取代 | 优选的取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Lys;Arg | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser | Ser |
Gln(Q) | Asn | Asn |
Glu(E) | Asp | Asp |
Gly(G) | Pro;Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe | Leu |
Leu(L) | Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Leu;Val;Ile;Ala;Tyr | Leu |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala | Leu |
本发明还提供本发明融合蛋白的类似物。这些类似物与SEQ ID NO.:3或6所示的多肽的差别可以是氨基酸序列上的差异,也可以是不影响序列的修饰形式上的差异,或者兼而有之。类似物还包括具有不同于天然L-氨基酸的残基(如D-氨基酸)的类似物,以及具有非天然存在的或合成的氨基酸(如β、γ-氨基酸)的类似物。应理解,本发明的多肽并不限于上述例举的代表性的多肽。
修饰(通常不改变一级结构)形式包括:体内或体外的多肽的化学衍生形式如乙酰化或羧基化。修饰还包括糖基化,如那些在多肽的合成和加工中或进一步加工步骤中进行糖基化修饰而产生的多肽。这种修饰可以通过将多肽暴露于进行糖基化的酶(如哺乳动物的糖基化酶或去糖基化酶)而完成。修饰形式还包括具有磷酸化氨基酸残基(如磷酸酪氨酸,磷酸丝氨酸,磷酸苏氨酸)的序列。还包括被修饰从而提高了其抗蛋白水解性能或优化了溶解性能的多肽。
表达载体和宿主细胞
本发明也涉及包含本发明的多核苷酸的载体,以及用本发明的载体或本发明融合蛋白编码序列经基因工程产生的宿主细胞,以及经重组技术产生本发明所述多肽的方法。
通过常规的重组DNA技术,可利用本发明的多聚核苷酸序列可用来表达或生产重组的融合蛋白。一般来说有以下步骤:
(1).用本发明的编码本发明融合蛋白的多核苷酸(或变异体),或用含有该多核苷酸的重组表达载体转化或转导合适的宿主细胞;
(2).在合适的培养基中培养的宿主细胞;
(3).从培养基或细胞中分离、纯化蛋白质。
本发明中,编码融合蛋白的多核苷酸序列可插入到重组表达载体中。术语“重组表达载体”指本领域熟知的细菌质粒、噬菌体、酵母质粒、植物细胞病毒、哺乳动物细胞病毒如腺病毒、逆转录病毒或其他载体。只要能在宿主体内复制和稳定,任何质粒和载体都可以用。表达载体的一个重要特征是通常含有复制起点、启动子、标记基因和翻译控制元件。
本领域的技术人员熟知的方法能用于构建含本发明融合蛋白编码DNA序列和合适的转录/翻译控制信号的表达载体。这些方法包括体外重组DNA技术、DNA合成技术、体内重组技术等。所述的DNA序列可有效连接到表达载体中的适当启动子上,以指导mRNA合成。这些启动子的代表性例子有:大肠杆菌的lac或trp启动子;λ噬菌体PL启动子;真核启动子包括CMV立即早期启动子、HSV胸苷激酶启动子、早期和晚期SV40启动子、反转录病毒的LTRs和其他一些已知的可控制基因在原核或真核细胞或其病毒中表达的启动子。表达载体还包括翻译起始用的核糖体结合位点和转录终止子。
此外,表达载体优选地包含一个或多个选择性标记基因,以提供用于选择转化的宿主细胞的表型性状,如真核细胞培养用的二氢叶酸还原酶、新霉素抗性以及绿色荧光蛋白(GFP),或用于大肠杆菌的四环素或氨苄青霉素抗性。
包含上述的适当DNA序列以及适当启动子或者控制序列的载体,可以用于转化适当的宿主细胞,以使其能够表达蛋白质。
宿主细胞可以是原核细胞(如大肠杆菌),或是低等真核细胞,或是高等真核细胞,如酵母细胞、植物细胞或哺乳动物细胞(包括人和非人哺乳动物)。代表性例子有:大肠杆菌、麦胚细胞,昆虫细胞,SF9、Hela、HEK293、CHO、酵母细胞等。在本发明的一个优选实施方式中,选择酵母细胞(如毕氏酵母、克鲁维酵母、或其组合;较佳地,所述的酵母细胞包括:克鲁维酵母,更佳地为马克斯克鲁维酵母、和/或乳酸克鲁维酵母)为宿主细胞。
本发明的多核苷酸在高等真核细胞中表达时,如果在载体中插入增强子序列时将会使转录得到增强。增强子是DNA的顺式作用因子,通常大约有10到300个碱基对,作用于启动子以增强基因的转录。可举的例子包括在复制起始点晚期一侧的100到270个碱基对的SV40增强子、在复制起始点晚期一侧的多瘤增强子以及腺病毒增强子等。
本领域一般技术人员都清楚如何选择适当的载体、启动子、增强子和宿主细胞。
用重组DNA转化宿主细胞可用本领域技术人员熟知的常规技术进行。当宿主为原核生物如大肠杆菌时,能吸收DNA的感受态细胞可在指数生长期后收获,用CaCl2法处理,所用的步骤在本领域众所周知。另一种方法是使用MgCl2。如果需要,转化也可用电穿孔的方法进行。当宿主是真核生物,可选用如下的DNA转染方法:磷酸钙共沉淀法,常规机械方法如显微注射、电穿孔、脂质体包装等。
获得的转化子可以用常规方法培养,表达本发明的基因所编码的多肽。根据所用的宿主细胞,培养中所用的培养基可选自各种常规培养基。在适于宿主细胞生长的条件下进行培养。当宿主细胞生长到适当的细胞密度后,用合适的方法(如温度转换或化学诱导)诱导选择的启动子,将细胞再培养一段时间。
在上面的方法中的重组多肽可在细胞内、或在细胞膜上表达、或分泌到细胞外。如果需要,可利用其物理的、化学的和其它特性通过各种分离方法分离和纯化重组的蛋白。这些方法是本领域技术人员所熟知的。这些方法的例子包括但并不限于:常规的复性处理、用蛋白沉淀剂处理(盐析方法)、离心、渗透破菌、超处理、超离心、分子筛层析(凝胶过滤)、吸附层析、离子交换层析、高效液相层析(HPLC)和其它各种液相层析技术及这些方法的结合。
本发明的主要优点包括
(1)本发明首次发现一种新的滋养层细胞,表达含有膜锚定的细胞因子IL-15、IL-21和NK细胞激活性CD137L、CD48的融合蛋白,本发明的滋养层细胞可显著增强NK细胞的扩增能力,增加NK细胞的扩增倍数,提高扩增后NK细胞的纯度和肿瘤杀伤活性。
(2)本发明首次设计了一种新型的滋养层细胞,为了增强K562对NK细胞的刺激扩增能力,本发明改造了天然的IL-15和IL-21细胞因子结构,使得这些细胞因子可以表达在细胞膜表面,同时表达两个NK细胞的激活性配体CD137L和CD48,这样进一步增强K562的扩增能力。对表达的蛋白质的基因序列做优化,保证没有同源的人源基因干扰,后续可以高灵敏度的用定量PCR检测,监测滋养细胞在培养后的残留。
(3)本发明首次设计了一种新的滋养细胞,通过同时表达膜表面展示的IL15、IL21和CD137L、CD48,自然杀伤细胞的扩增倍数更高,CD3+阳性细胞的残留比例更低。
(4)本发明通过优化过表达的基因的序列,可以利用qPCR实现对残余滋养层细胞的高灵敏度、高特异性及快速检测。
下面结合具体实施例,进一步陈述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明详细条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1.利用非病毒载体PiggyBac设计mIL15-CD137L-Puromycin和mIL21-CD48-Blasticidin的基因转座稳定表达载体
使用PCR和同源重组方法分别构建PB-mIL15-CD137L-Puromycin和PB-mIL21-CD48-Blasticidin,其中IL-15和CD137L、IL-21和CD48基因之间使用自剪切短肽T2A或F2A连接,真核细胞筛选抗生素Puromycin和Blasticidin的基因使用内部核糖体进入位点序列(IRES)连接。IL-15和IL-21的分泌信号肽均使用GM-CSF的信号肽序列,IL-15和IL-21的膜锚定序列均使用CD8胞外段和CD28的跨膜结构区域。具体基因设计结构见图1a所示。
mIL15的氨基酸序列如SEQ ID NO.1所示:
NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTSGYPYDVPDYAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRP
CD137L的氨基酸序列如SEQ ID NO.2所示:
MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSEmIL15-CD137L融合蛋白的氨基酸序列如SEQ IDNO.3所示:
mIL21的氨基酸序列如SEQ ID NO.4所示:
HKSSSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDSALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEASRPAAGGAVHTRGLDKPFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRP
CD48的氨基酸序列如SEQ ID NO.5所示:
MCSRGWDSCLALELLLLPLSLLVTSIQGHLVHMTVVSGSNVTLNISESLPENYKQLTWFYTFDQKIVEWDSRKSKYFESKFKGRVRLDPQSGALYISKVQKEDNSTYIMRVLKKTGNEQEWKIKLQVLDPVPKPVIKIEKIEDMDDNCYLKLSCVIPGESVNYTWYGDKRPFPKELQNSVLETTLMPHNYSRCYTCQVSNSVSSKNGTVCLSPPCTLARSFGVEWIASWLVVTVPTILGLLLT
mIL21-CD48融合蛋白的氨基酸序列如SEQ ID NO.6所示:
实施例2.稳定表达mIL15-CD137L和mIL21-CD48的K562细胞的构建与鉴定
使用无内毒素质粒抽提试剂盒制备PB-mIL15-CD137L-Puromycin、PB-mIL21-CD48-Blasticidin和PB200(表达转座酶Transposase)的细胞转染级质粒。使用BIORAD的细胞电转仪将三个质粒按2:2:1的质量比例转染K562细胞,48小时后加入抗生素Puromycin(2μg/mL)和Blasticidin(5μg/mL),培养一周后流式检测细胞表面mIL15、mIL21、CD137L、CD48的表达量,并分选四个蛋白表达都为阳性的细胞群。分选后细胞继续培养一周,流式分选四个蛋白表达都为阳性的单克隆细胞,获得稳转的细胞株,进行扩增培养。最终获得的稳转细胞株表达四个蛋白的流式检测结果如图1b所示。
实施例3.使用表达不同刺激因子的滋养层细胞扩增外周血来源的NK细胞滋养层细胞的制备:
表达mIL15、mIL21、CD137L、CD48的K562细胞(HyaMab Feeder 2.0)为实验组,表达mIL15、mIL21、CD137L的K562细胞(HyaMab Feeder 1.0)为对照组1,K562野生型细胞为对照组2,仅表达CD48的K562细胞为对照组3。各组细胞在扩大培养后收集,检测无菌无支原体合格后,经100Gy的X射线辐照灭活后冻存。
外周血单核细胞(PBMC)的获取:在50毫升的离心管中加入15毫升的淋巴细胞分离液;向离心管中缓缓加入30毫升的新鲜血;室温2000转/分钟快升慢降离心20分钟;将白膜层细胞转移到一个新的离心管中,用生理盐水补充到50毫升,1800转/分钟,快升快降离心8分钟;弃去上清,用1ml生理盐水将细胞悬起,再用生理盐水补充到50毫升,1200转/分钟快升快降离心8分钟,细胞沉淀即为获得的白膜层外周血单核细胞。
使用NK细胞扩增完全培养基(含有100IU/ml IL-2的X-VIVO15无血清培养基)将PBMC细胞密度调整为1E6/mL,然后按比例加入辐照后的各组滋养层细胞在T75培养瓶中进行共培养,滋养层细胞和PBMC细胞的细胞数量比例为2:1。每隔2-3天观察细胞情况,当细胞密度较高的时候,补充完全培养基至细胞密度在1E6/mL左右;共培养第7天,细胞计数,再加入各组滋养细胞进行第2轮刺激,滋养层细胞和PBMC细胞的数量比例为1:1,细胞转入T175培养瓶中进行培养,期间视细胞生长情况添加培养基。培养14天后统计细胞扩增结果。
如图2所示,表达mIL15、mIL21、CD137L、CD48的滋养层细胞(HyaMab Feeder 2.0)和表达mIL15、mIL21、CD137L的滋养层细胞(HyaMab Feeder 1.0)可以有效扩增外周血来源的NK细胞,对照组的K562野生型细胞和仅表达CD48的K562细胞扩增NK细胞的效果明显较差。
实施例4.流式检测不同滋养层细胞扩增的NK细胞的纯度和表型
由于K562和K562-CD48滋养层细胞扩增出的NK细胞数量和活力较低,本实施例仅对比检测表达mIL15、mIL21、CD137L、CD48的滋养层细胞(HyaMab Feeder 2.0)和表达mIL15、mIL21、CD137L的滋养层细胞(HyaMab Feeder 1.0)两组扩增出来的NK细胞的纯度和表型。
如图3所示,HyaMab Feeder 2.0扩增出的细胞中CD3-CD56+和CD56+CD16+的细胞群比例分别为95.3%,77.3%。HyaMab Feeder 1.0扩增出的细胞中CD3-CD56+和CD56+CD16+的细胞群比例分别为83.6%,59.6%。
结果表明使用HyaMab Feeder 2.0的滋养层细胞扩增出的NK细胞的纯度和CD16阳性的细胞比例均优于HyaMab Feeder 1.0的滋养层细胞。
实施例5.不同滋养层细胞扩增的NK细胞对多种肿瘤细胞的杀伤能力测定
利用荧光素酶报告基因方法检测NK细胞对肿瘤细胞系的杀伤效果,肿瘤细胞包括:K562、Raji、U87-MG和高表达EGFRvIII的U87-MG细胞。实验操作方法如下:
1)在白色不透底96孔板中加入100uL肿瘤细胞悬液(5×103个/孔)。将培养板在培养箱预培养12h。
2)弃去96孔板的培养上清,每孔加入100uL效应细胞,效应细胞与靶细胞数目的比例分别为1:1、5:1和10:1。空白对照孔只加100ul培养基,每个实验置三个复孔。效应细胞与靶细胞共孵育24小时。
3)每孔加入100ul Steady-Glo荧光素酶底物溶液,将培养板在水平振荡仪上振荡5分钟后使用酶标仪测定冷光的相对光强度(RLU)。
4)计算肿瘤细胞杀伤效果,杀伤率=(1-(Sample-control))/(Tumor cell-control)*100%
结果如图4所示。在各组肿瘤细胞的杀伤实验中,当效靶比为1:1时,使用HyaMabFeeder 2.0的滋养层细胞扩增出的NK细胞对靶细胞的裂解效率均高于使用HyaMab Feeder1.0的滋养层细胞扩增出的NK细胞;特别地,在对NK细胞杀伤有抵抗的Raji细胞组中,在不同的效靶比下,差异均更加明显。
图4的表格数据如下表1所示。
表1
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 上海怀越生物科技有限公司
<120> 一种滋养细胞制备方法及其用途
<130> P2022-0526
<160> 6
<170> PatentIn version 3.5
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145 150 155 160
Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly Ala
165 170 175
Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu Ala
180 185 190
Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser Ala
195 200 205
Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg His
210 215 220
Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg Val
225 230 235 240
Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu
245 250
<210> 3
<211> 511
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
1 5 10 15
Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu
20 25 30
Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val
35 40 45
His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu
50 55 60
Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val
65 70 75 80
Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn
85 90 95
Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn
100 105 110
Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile
115 120 125
Asn Thr Ser Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ala Leu Ser
130 135 140
Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val Phe Leu Pro Ala
145 150 155 160
Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
165 170 175
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Ser Arg Pro Ala
180 185 190
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Lys Pro Phe Trp Val
195 200 205
Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr
210 215 220
Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Pro Glu
225 230 235 240
Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly
245 250 255
Pro Met Glu Tyr Ala Ser Asp Ala Ser Leu Asp Pro Glu Ala Pro Trp
260 265 270
Pro Pro Ala Pro Arg Ala Arg Ala Cys Arg Val Leu Pro Trp Ala Leu
275 280 285
Val Ala Gly Leu Leu Leu Leu Leu Leu Leu Ala Ala Ala Cys Ala Val
290 295 300
Phe Leu Ala Cys Pro Trp Ala Val Ser Gly Ala Arg Ala Ser Pro Gly
305 310 315 320
Ser Ala Ala Ser Pro Arg Leu Arg Glu Gly Pro Glu Leu Ser Pro Asp
325 330 335
Asp Pro Ala Gly Leu Leu Asp Leu Arg Gln Gly Met Phe Ala Gln Leu
340 345 350
Val Ala Gln Asn Val Leu Leu Ile Asp Gly Pro Leu Ser Trp Tyr Ser
355 360 365
Asp Pro Gly Leu Ala Gly Val Ser Leu Thr Gly Gly Leu Ser Tyr Lys
370 375 380
Glu Asp Thr Lys Glu Leu Val Val Ala Lys Ala Gly Val Tyr Tyr Val
385 390 395 400
Phe Phe Gln Leu Glu Leu Arg Arg Val Val Ala Gly Glu Gly Ser Gly
405 410 415
Ser Val Ser Leu Ala Leu His Leu Gln Pro Leu Arg Ser Ala Ala Gly
420 425 430
Ala Ala Ala Leu Ala Leu Thr Val Asp Leu Pro Pro Ala Ser Ser Glu
435 440 445
Ala Arg Asn Ser Ala Phe Gly Phe Gln Gly Arg Leu Leu His Leu Ser
450 455 460
Ala Gly Gln Arg Leu Gly Val His Leu His Thr Glu Ala Arg Ala Arg
465 470 475 480
His Ala Trp Gln Leu Thr Gln Gly Ala Thr Val Leu Gly Leu Phe Arg
485 490 495
Val Thr Pro Glu Ile Pro Ala Gly Leu Pro Ser Pro Arg Ser Glu
500 505 510
<210> 4
<211> 236
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
His Lys Ser Ser Ser Gln Gly Gln Asp Arg His Met Ile Arg Met Arg
1 5 10 15
Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp Leu
20 25 30
Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys Glu
35 40 45
Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala Asn
50 55 60
Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu Lys
65 70 75 80
Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg Leu
85 90 95
Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu Phe
100 105 110
Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His Leu
115 120 125
Ser Ser Arg Thr His Gly Ser Glu Asp Ser Ala Leu Ser Asn Ser Ile
130 135 140
Met Tyr Phe Ser His Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr
145 150 155 160
Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser
165 170 175
Gln Pro Leu Ser Leu Arg Pro Glu Ala Ser Arg Pro Ala Ala Gly Gly
180 185 190
Ala Val His Thr Arg Gly Leu Asp Lys Pro Phe Trp Val Leu Val Val
195 200 205
Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe
210 215 220
Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Pro
225 230 235
<210> 5
<211> 243
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Met Cys Ser Arg Gly Trp Asp Ser Cys Leu Ala Leu Glu Leu Leu Leu
1 5 10 15
Leu Pro Leu Ser Leu Leu Val Thr Ser Ile Gln Gly His Leu Val His
20 25 30
Met Thr Val Val Ser Gly Ser Asn Val Thr Leu Asn Ile Ser Glu Ser
35 40 45
Leu Pro Glu Asn Tyr Lys Gln Leu Thr Trp Phe Tyr Thr Phe Asp Gln
50 55 60
Lys Ile Val Glu Trp Asp Ser Arg Lys Ser Lys Tyr Phe Glu Ser Lys
65 70 75 80
Phe Lys Gly Arg Val Arg Leu Asp Pro Gln Ser Gly Ala Leu Tyr Ile
85 90 95
Ser Lys Val Gln Lys Glu Asp Asn Ser Thr Tyr Ile Met Arg Val Leu
100 105 110
Lys Lys Thr Gly Asn Glu Gln Glu Trp Lys Ile Lys Leu Gln Val Leu
115 120 125
Asp Pro Val Pro Lys Pro Val Ile Lys Ile Glu Lys Ile Glu Asp Met
130 135 140
Asp Asp Asn Cys Tyr Leu Lys Leu Ser Cys Val Ile Pro Gly Glu Ser
145 150 155 160
Val Asn Tyr Thr Trp Tyr Gly Asp Lys Arg Pro Phe Pro Lys Glu Leu
165 170 175
Gln Asn Ser Val Leu Glu Thr Thr Leu Met Pro His Asn Tyr Ser Arg
180 185 190
Cys Tyr Thr Cys Gln Val Ser Asn Ser Val Ser Ser Lys Asn Gly Thr
195 200 205
Val Cys Leu Ser Pro Pro Cys Thr Leu Ala Arg Ser Phe Gly Val Glu
210 215 220
Trp Ile Ala Ser Trp Leu Val Val Thr Val Pro Thr Ile Leu Gly Leu
225 230 235 240
Leu Leu Thr
<210> 6
<211> 518
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Met Trp Leu Gln Ser Leu Leu Leu Leu Gly Thr Val Ala Cys Ser Ile
1 5 10 15
Ser His Lys Ser Ser Ser Gln Gly Gln Asp Arg His Met Ile Arg Met
20 25 30
Arg Gln Leu Ile Asp Ile Val Asp Gln Leu Lys Asn Tyr Val Asn Asp
35 40 45
Leu Val Pro Glu Phe Leu Pro Ala Pro Glu Asp Val Glu Thr Asn Cys
50 55 60
Glu Trp Ser Ala Phe Ser Cys Phe Gln Lys Ala Gln Leu Lys Ser Ala
65 70 75 80
Asn Thr Gly Asn Asn Glu Arg Ile Ile Asn Val Ser Ile Lys Lys Leu
85 90 95
Lys Arg Lys Pro Pro Ser Thr Asn Ala Gly Arg Arg Gln Lys His Arg
100 105 110
Leu Thr Cys Pro Ser Cys Asp Ser Tyr Glu Lys Lys Pro Pro Lys Glu
115 120 125
Phe Leu Glu Arg Phe Lys Ser Leu Leu Gln Lys Met Ile His Gln His
130 135 140
Leu Ser Ser Arg Thr His Gly Ser Glu Asp Ser Ala Leu Ser Asn Ser
145 150 155 160
Ile Met Tyr Phe Ser His Phe Val Pro Val Phe Leu Pro Ala Lys Pro
165 170 175
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
180 185 190
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Ser Arg Pro Ala Ala Gly
195 200 205
Gly Ala Val His Thr Arg Gly Leu Asp Lys Pro Phe Trp Val Leu Val
210 215 220
Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala
225 230 235 240
Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Pro Val Lys Gln
245 250 255
Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val Glu Ser Asn
260 265 270
Pro Gly Pro Met Cys Ser Arg Gly Trp Asp Ser Cys Leu Ala Leu Glu
275 280 285
Leu Leu Leu Leu Pro Leu Ser Leu Leu Val Thr Ser Ile Gln Gly His
290 295 300
Leu Val His Met Thr Val Val Ser Gly Ser Asn Val Thr Leu Asn Ile
305 310 315 320
Ser Glu Ser Leu Pro Glu Asn Tyr Lys Gln Leu Thr Trp Phe Tyr Thr
325 330 335
Phe Asp Gln Lys Ile Val Glu Trp Asp Ser Arg Lys Ser Lys Tyr Phe
340 345 350
Glu Ser Lys Phe Lys Gly Arg Val Arg Leu Asp Pro Gln Ser Gly Ala
355 360 365
Leu Tyr Ile Ser Lys Val Gln Lys Glu Asp Asn Ser Thr Tyr Ile Met
370 375 380
Arg Val Leu Lys Lys Thr Gly Asn Glu Gln Glu Trp Lys Ile Lys Leu
385 390 395 400
Gln Val Leu Asp Pro Val Pro Lys Pro Val Ile Lys Ile Glu Lys Ile
405 410 415
Glu Asp Met Asp Asp Asn Cys Tyr Leu Lys Leu Ser Cys Val Ile Pro
420 425 430
Gly Glu Ser Val Asn Tyr Thr Trp Tyr Gly Asp Lys Arg Pro Phe Pro
435 440 445
Lys Glu Leu Gln Asn Ser Val Leu Glu Thr Thr Leu Met Pro His Asn
450 455 460
Tyr Ser Arg Cys Tyr Thr Cys Gln Val Ser Asn Ser Val Ser Ser Lys
465 470 475 480
Asn Gly Thr Val Cys Leu Ser Pro Pro Cys Thr Leu Ala Arg Ser Phe
485 490 495
Gly Val Glu Trp Ile Ala Ser Trp Leu Val Val Thr Val Pro Thr Ile
500 505 510
Leu Gly Leu Leu Leu Thr
515
Claims (10)
1.一种工程化滋养细胞,其特征在于,所述细胞表达第一融合蛋白元件和第二融合蛋白元件;且
所述第一融合蛋白元件的结构如式I所示:L1-Z1-H1-TM1-P1-Z2(I);
所述第二融合蛋白元件的结构如式II所示:L2-Z3-H2-TM2-P2-Z4(II);
式中,
各“-”独立地为连接肽或肽键;
L1、L2各自独立地为无或信号肽序列;
Z1为IL15;
Z3为IL21;
H1、H2各自独立地为任选的铰链区;
TM1、TM2各自独立地为跨膜结构域;
Z2和Z4两者中的一个为CD137L元件,另一个为CD48元件;
P1、P2各自独立地为自剪切蛋白。
2.如权利要求1所述的工程化滋养细胞,其特征在于,所述Z2为CD137L或其活性片段;和所述Z4为CD48或其活性片段。
3.如权利要求1所述的工程化滋养细胞,其特征在于,所述滋养细胞选自下组:K562细胞、外周血单核细胞、Daudi细胞、THP1细胞、RPMI8226细胞、Raji细胞、Jurkat细胞、MOLT-4细胞、SupB15细胞、HEK293细胞、Hela细胞、或其组合。
4.一种制备工程化滋养细胞的方法,其特征在于,包括以下步骤:
(A)提供一待改造的滋养细胞;和
(B)对所述的滋养细胞进行改造,使得所述的免疫细胞表达第一融合蛋白元件和第二融合蛋白元件,从而获得如权利要求1所述的工程化滋养细胞。
5.一种药物组合物,其特征在于,所述药物组合物含有权利要求1所述的工程化滋养细胞,以及药学上可接受的载体、稀释剂或赋形剂。
6.一种权利要求1所述的工程化滋养细胞、或权利要求5所述的药物组合物的用途,其特征在于,用于制备增强自然杀伤细胞增殖能力的药物或制剂。
7.如权利要求6所述的用途,其特征在于,所述自然杀伤细胞包括T细胞、NK细胞或巨噬细胞。
8.一种用于增强自然杀伤细胞增殖能力的试剂盒,其特征在于,所述试剂盒含有容器,以及位于容器内的权利要求1所述的工程化滋养细胞或权利要求3所述的药物组合物。
9.一种增强自然杀伤细胞增殖能力的方法,其特征在于,包括:
在权利要求1所述的工程化滋养细胞的存在下,培养自然杀伤细胞,从而增强自然杀伤细胞增殖能力。
10.如权利要求9所述的方法,其特征在于,所述自然杀伤细胞包括T细胞、NK细胞或巨噬细胞。
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