CN113106068A - 一种自分泌IL-15与anti-PD1融合蛋白的免疫细胞 - Google Patents
一种自分泌IL-15与anti-PD1融合蛋白的免疫细胞 Download PDFInfo
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Abstract
本发明涉及生物细胞技术领域,特别涉及提供一种自分泌IL‑15与anti‑PD1融合蛋白的免疫细胞,使用经基因编辑过的免疫细胞分泌IL‑15与anti‑PD1融合蛋白,以提高免疫细胞的活性以及对肿瘤的杀伤效果,所述自分泌IL‑15与anti‑PD1融合蛋白的免疫细胞包括:按照anti‑PD1、G4S*4 Linker、IL‑15N72D、G4S*4 Linker和IL‑15RaSu顺序串联表达的融合蛋白,以及表达该融合蛋白并接受自分泌融合蛋白影响的接受基因编辑的细胞。结合了IL‑15和IL15Ra的超级动蛋白及anti‑PD1的融合蛋白,并使得CART细胞成功分泌该融合蛋白已达成增强CarT细胞增殖能力、抗凋亡能力和对于肿瘤的杀伤能力,杀伤效果精准,安全性更高,不易复发,提高患者的生存质量。
Description
技术领域
本发明涉及自分泌融合蛋白的免疫细胞技术领域,特别涉及表达嵌合抗原受体的免疫细胞,具体涉及一种自分泌IL-15与anti-PD1融合蛋白的免疫细胞。
背景技术
肿瘤(tumour)是指机体在各种致瘤因子作用下,局部组织细胞增生所形成的新生物(neogrowth),因为这种新生物多呈占位性块状突起,也称赘生物(neoplasm)。其中,恶性肿瘤因易发生转移,治疗后易复发以及其特殊的微环境导致极难治愈。
IL-15 在 T细胞、NK细胞和 NK细胞的发育、稳态和功能中起着至关重要的作用,并且还对B细胞、树突状细胞(DC)、巨噬细胞和肥大细胞具有各种功能。IL-15是细胞因子4-α-螺旋束家族的成员,分子量为14-15kDa,含有114个氨基酸。IL-15具有两种同种类型:①SSP:包含21个氨基酸组成的较短的信号肽(SSP,short signal peptide),SSP型IL-15被充分翻译但并不分泌,因此,它的活动范围被限制在细胞质和细胞核,可能在其转录调控中起着重要作用;②LSP:包含48个氨基酸组成的更长的信号肽(LSP,long signal peptide),LSP-IL-15是作为免疫调节剂被分泌至胞外的。IL-15以及IL-15Rα由抗原呈递细胞(单核细胞和树突细胞)协同表达。IL-15广泛表达于多种细胞中,细胞类型包括单核细胞,巨噬细胞,DC,成纤维细胞,上皮细胞和骨骼肌细胞,但T 细胞中并不表达IL-15。
IL-15与受体的结合方式为反式呈递方式:IL-15与表达在抗原提呈细胞上的高亲和力α受体结合,IL15Rα将IL-15递呈给IL-2/15Rβγ二聚体形成三元复合物。可激活JAK和STAT型号通路,并具有促进靶细胞增殖与活化、IFN-γ、TNF-α分泌水平提升等功能。
PD-1(程序性死亡受体1),也称为 CD279(分化簇 279),是一种重要的免疫抑制分子。通过向下调节免疫系统对人体细胞的反应,以及通过抑制T细胞炎症活动来调节免疫系统并促进自身耐受。这可以预防自身免疫性疾病,但它也可以防止免疫系统杀死癌细胞。PD-1是288个氨基酸的I型膜蛋白,其最初是从凋亡的小鼠T细胞杂交瘤2B4.11克隆出来,以PD-1为靶点的免疫调节对抗肿瘤、抗感染、抗自身免疫性疾病及器官移植存活等均有重要的意义。PD-1的配体PD-L1也可作为靶点,相应的抗体也可以起到相同的作用。PD-1和PD-L1结合启动T细胞的程序性死亡,使肿瘤细胞获得免疫逃逸。抗PD-1疗法通过结合PD-1并阻断PD-1与PD-L1和PD-L2的结合,解除免疫抑制效应,激活T细胞功能,增强T细胞对肿瘤的免疫监视能力和杀伤能力,产生肿瘤免疫应答。
发明内容
基于此,有必要针对上述问题,提供一种自分泌IL-15与anti-PD1融合蛋白的免疫细胞,结合了IL-15和IL15Ra的超级动蛋白及anti-PD1的融合蛋白,并使得CART细胞成功分泌该融合蛋白已达成增强CarT细胞增殖能力、抗凋亡能力和对于肿瘤的杀伤能力。
一种自分泌IL-15与anti-PD1融合蛋白的免疫细胞,使用经基因编辑过的免疫细胞分泌IL-15与anti-PD1融合蛋白,以提高免疫细胞的活性以及对肿瘤的杀伤效果,自分泌IL-15与anti-PD1融合蛋白的免疫细胞包括:按照anti-PD1、G4S*4 Linker、IL-15N72D、G4S*4 Linker和IL-15RaSu顺序串联表达的融合蛋白,以及表达该融合蛋白并接受自分泌融合蛋白影响的接受基因编辑的细胞。结合了IL-15和IL15Ra的超级动蛋白及anti-PD1的融合蛋白,并获得成功分泌该融合蛋白的嵌合抗原受体T细胞(Chimeric antigenreceptor CART)。
在其中一个实施例中,免疫细胞表达嵌合抗原受体(CAR)。
在其中一个实施例中,嵌合抗原受体的表达是靶向一个靶点的CAR,或是靶向两个靶点或者多个靶点的CAR。
在其中一个实施例中,嵌合抗原受体的靶点是抗CLDN18.2抗体的独特型。
在其中一个实施例中,嵌合抗原受体的靶点为独特型CLDN18.2、GPC3、HER2、TAA、GD2、MSLN、EGFR、NY-ESO-1、MUC1、PSMA和EBV中的一种或几种。
在其中一个实施例中,嵌合抗原受体和靶点的结合区域可以是scFv和/或Fab。
在其中一个实施例中,嵌合抗原受体结构中scFv区结构可由任意靶点的任意单链抗体、单链可变片段(scFv)及Fab片段取代。
在其中一个实施例中,嵌合抗原受体包含前导序列,识别肿瘤相关抗原的scFv,铰链区和跨膜结构域,胞内共刺激结构域以及胞内激活信号CD3ζ。
在其中一个实施例中,scFv为抗独特型抗体的scFv;铰链区和跨膜结构域为CD28或CD8铰链区和跨膜结构域;胞内共刺激结构域为CD28或CD137 (4-1BB)或者ICOS胞内共刺激结构域。
在其中一个实施例中,嵌合抗原受体和靶点的结合区域可以是结合一个靶点,也可以是结合两个靶点的双特异性抗体,也可以是两个或者多个嵌合抗原受体分别跨膜形成,并分别识别不同的靶点。
在其中一个实施例中,免疫细胞与自分泌IL-15与anti-PD1融合蛋白之间的分割方式为蛋白切割功能元件。
在其中一个实施例中,蛋白切割功能元件为T2A、P2A、E2A、F2A或IRES。
在其中一个实施例中,免疫细胞的基因转入方式为:慢病毒、逆转录病毒、普通质粒载体、附加体载体、纳米递送系统、电转导、转座子或其它递送系统。
在其中一个实施例中,免疫细胞为T细胞、NK细胞、NKT细胞、巨噬细胞、gamma-delta T细胞、TIL细胞、TCR-T细胞或其它肿瘤杀伤细胞。
与现有技术相比,本发明具有如下有益效果:
本发明的自分泌IL-15与anti-PD1融合蛋白的免疫细胞表达CAR,特异性识别抗自身抗体的独特型;另外本发明的免疫细胞可以特异性的杀伤分泌IL-15与anti-PD1融合蛋白;且杀伤效果精准,安全性更高,不易复发,提高患者的生存质量。
附图说明
图1 为序列结构设计图;
图2 为靶细胞表型流式检测结果;
图3 为分泌型CarT融合蛋白分泌情况;
图4 为分泌型CarT扩增情况;
图5为 CarT细胞阳性率及表型流式检测结果;
图6为 CarT细胞表型流式数据;
图7 为CarT细胞体外杀瘤功能评价;
图8为 动物实验方案;
图9为 CarT动物实验生存曲线。
具体实施方式
为了便于理解本发明,下面将对本发明进行更全面的描述。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
下面结合对本发明专利的技术方案进行清楚、完整的描述,显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域所属的技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明提供了一种自分泌IL-15与anti-PD1融合蛋白的免疫细胞,使用经基因编辑过的免疫细胞分泌IL-15与anti-PD1融合蛋白,以提高免疫细胞的活性以及对肿瘤的杀伤效果,自分泌IL-15与anti-PD1融合蛋白的免疫细胞包括:按照anti-PD1、G4S*4 Linker、IL-15N72D、G4S*4 Linker和IL-15RaSu顺序串联表达的融合蛋白,以及表达该融合蛋白并接受自分泌融合蛋白影响的接受基因编辑的细胞。
免疫细胞本身并不会表达上述提及的融合蛋白,为了使免疫细胞分泌该融合蛋白需经过基因编辑,另外如CarT/CarNK/TCR-T/IPS等用于肿瘤治疗的细胞本身已是经过基因编辑了,再使其分泌融合蛋白仍是经过编辑的免疫细胞,所以在此统称为经过基因编辑的免疫细胞。本发明自分泌IL-15与anti-PD1融合蛋白的免疫细胞结合了IL-15和IL15Ra的超级动蛋白及anti-PD1的融合蛋白,并获得成功分泌该融合蛋白的嵌合抗原受体T细胞(Chimeric antigen receptor CART)。
anti-PD1为anti-PD1 VL和/或anti-PD1 VH。
一个实施例中,免疫细胞表达嵌合抗原受体(CAR)。嵌合抗原受体的表达可以是靶向一个靶点的CAR,或是靶向两个靶点或者多个靶点的CAR。
一个实施例中,嵌合抗原受体的靶点可以是抗CLDN18.2抗体的独特型。
嵌合抗原受体的靶点还可以为独特型CLDN18.2、GPC3、HER2、TAA、GD2、MSLN、EGFR、NY-ESO-1、MUC1、PSMA和EBV中的一种或几种。
嵌合抗原受体和靶点的结合区域可以是scFv和/或Fab。一个实施例中,嵌合抗原受体结构中scFv区结构可由任意靶点的任意单链抗体、单链可变片段(scFv)及Fab片段取代。
嵌合抗原受体包含前导序列,识别肿瘤相关抗原的scFv,铰链区和跨膜结构域,胞内共刺激结构域以及胞内激活信号CD3ζ。
scFv为抗独特型抗体的scFv;铰链区和跨膜结构域为CD28或CD8铰链区和跨膜结构域;胞内共刺激结构域为CD28或CD137 (4-1BB)或者ICOS胞内共刺激结构域。
嵌合抗原受体和靶点的结合区域可以是结合一个靶点,也可以是结合两个靶点的双特异性抗体,也可以是两个或者多个嵌合抗原受体分别跨膜形成,并分别识别不同的靶点。
免疫细胞与自分泌IL-15与anti-PD1融合蛋白之间的分割方式为蛋白切割功能元件。蛋白切割功能元件可以为T2A、P2A、E2A、F2A或IRES。
一个实施例中,免疫细胞的基因转入方式为:慢病毒、逆转录病毒、普通质粒载体、附加体载体、纳米递送系统、电转导、转座子或其它递送系统。
一个实施例中,免疫细胞为T细胞、NK细胞、NKT细胞、巨噬细胞、gamma-delta T细胞、TIL细胞、TCR-T细胞或其它肿瘤杀伤细胞。
自分泌IL-15与anti-PD1融合蛋白的免疫细胞可制成制剂,制剂为药学上可接受的载体、稀释剂或赋形剂。本发明的制剂的施用可以以任何方便的方式进行,包括通过喷雾法、注射、吞咽、输液、植入或移植。该制剂可用于预防和/或治疗实体肿瘤。
本发明的自分泌IL-15与anti-PD1融合蛋白的免疫细胞表达CAR,特异性识别抗自身抗体的独特型;结合了IL-15和IL15Ra的超级动蛋白及anti-PD1的融合蛋白,并使得CART细胞成功分泌该融合蛋白已达成增强CarT细胞增殖能力、抗凋亡能力和对于肿瘤的杀伤能力;另外本发明的免疫细胞可以特异性的杀伤分泌IL-15与anti-PD1融合蛋白;且杀伤效果精准,安全性更高,不易复发,提高患者的生存质量。
以下为具体实施例说明。
下列实施例中以外周血中T细胞制备CarT并分泌IL-15与anti-PD1融合蛋白为例,免疫细胞的制备方法及功能验证包括以下步骤:
1)融合蛋白的结构设计;
2)构建分泌型CART细胞并进行体外功能试验;
3)分泌融合蛋白型CART细胞体内功能试验。
1)融合蛋白的结构设计
根据hIL15、hIL15Ra、anti-PD1的序列,按照图1中结构设计如下A#~D#中的融合蛋白结构,并将其设计到CarT-CLDN18.2中,其中,1#为对照CarT,2#~4#为分泌型CarT。
其中,hIL15氨基酸序列为:METDTLLLWVLLLWVPGSTGNWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANDSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS。
hIL15Ra氨基酸序列为:ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIR。
Anti-PD1 VH氨基酸序列为:QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS。
Anti-PD1 VL氨基酸序列为:EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK。
Linker氨基酸序列为:GSSSSGSSSSGSSSSGSSSS。
2)构建分泌型CART细胞并进行体外功能试验
构建分泌型CART细胞并进行体外功能试验包括以下步骤:
S100:细胞系培养
将表达CLDN18.2的碱基序列克隆至PHBLV慢病毒载体骨架中,置于EF1α(EF-1α)的启动子下,形成PHBLV-EF1α-CLDN18.2,将PHBLV-EF1α-CLDN18.2、慢病毒包膜质粒pMD2 .G(Addgene,Plasmid#12259)和慢病毒包装质粒psPAX2(Addgene Plasmid#12260)三个质粒使用Lipofectamine3000转入293T中制备慢病毒完整表达载体;
在48h和72h收集病毒上清,超离进行浓缩(Merck Millipore);浓缩后的病毒即可用于感染HGC-27,最终得到过表达CLDN18.2的HGC-27细胞系,命名为HGC-27-CLDN18.2,HGC-27-CLDN18.2细胞表达CLDN18.2的检测结果如图2所示。
S200:外周血PBMC的分离和T细胞的扩增
从供体外周血中分离单个核细胞,使用ficol进行密度梯度离心,并用T细胞分选试剂盒富集T细胞(CD3 MicroBeads, human - lyophilized,130-097-043),使用偶联anti-CD3/anti-CD28的磁珠激活培养和扩增T细胞;
培养基使用TexMACS GMP Medium(Miltenyi Biotec,170-076-309),含10%FBS,2mM L-glutamine,100IU/ml rhIL2,所有细胞均置于37℃,5%CO2恒温培养箱中培养。
将1)融合蛋白的结构设计中B#~D#序列中蛋白通过CHO蛋白表达系统表达纯化后作为ELISA检测1#~4#中蛋白分泌的阳性对照标准品,收集CarT培养上清,检测细胞培养上清中蛋白分泌数据如图3所示,CarT-CLDN18.2-IL15/Ra、CarT-CLDN18.2-antiPD1、CarT-CLDN18.2-15&PD1可以正常分泌蛋白,并且具有基本相同的蛋白分泌效率。
通过慢病毒包装制备CarT,阳性率及表型结果见图5和图6。所获得的CarT增殖情况如图4所示,CarT-CLDN18.2-15&PD1具有更优异的细胞增殖能力。
S300:细胞体外杀伤实验
使用HGC-27-CLDN18.2和HGC-27细胞分别作为阳性和阴性靶细胞,使用流式检测方法对CarT体外杀瘤功能进行验证。结果如图7显示,相比之下分泌融合蛋白的CarT-CLDN18.2-15&PD1对HGC-27-CLDN18.2阳性靶细胞具有最强的杀伤效果。
3)CART细胞体内功能评价
取6-8周龄NSG小鼠(体重18-22g)24只,适应饲养一周后,皮下接种HGC-27-CLDN18.2阳性的肿瘤细胞株,每只小鼠接种1*107个肿瘤细胞,密切观察动物状态,每三天使用游标卡尺测量小鼠肿瘤体积,当肿瘤体积达到100mm3,根据小鼠体重和肿瘤大小随机分组后,经尾静脉输注CAR-T细胞或对照T细胞。详细的给药方法、给药剂量和给药途径见图8。通过生存曲线图9结果显示,CarT-CLDN18.2-15&PD1分泌型CarT可以大幅延长小鼠生存期。
以上实施例证明自分泌IL-15与anti-PD1融合蛋白的CarT具有更胜不分泌其他细胞因子的CarT或只分泌一种细胞因子的CarT的增殖能力和对肿瘤的体内体外杀瘤活性。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的一种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
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Claims (10)
1.一种自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,使用经基因编辑过的免疫细胞分泌IL-15与anti-PD1融合蛋白,以提高免疫细胞的活性以及对肿瘤的杀伤效果,所述自分泌IL-15与anti-PD1融合蛋白的免疫细胞包括:按照anti-PD1、G4S*4 Linker、IL-15N72D、G4S*4 Linker和IL-15RaSu顺序串联表达的融合蛋白,以及表达该融合蛋白并接受自分泌融合蛋白影响的接受基因编辑的细胞。
2.根据权利要求1所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述自分泌IL-15与anti-PD1融合蛋白的免疫细胞表达嵌合抗原受体。
3.根据权利要求2所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述嵌合抗原受体的表达是靶向一个靶点的嵌合抗原受体,或是靶向两个靶点的嵌合抗原受体或者多个靶点的嵌合抗原受体。
4.根据权利要求3所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述嵌合抗原受体的靶点为独特型CLDN18.2、GPC3、HER2、TAA、GD2、MSLN、EGFR、NY-ESO-1、MUC1、PSMA和EBV中的一种或几种。
5.根据权利要求3所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述嵌合抗原受体和靶点的结合区域为scFv、Fab和任意靶点的任意单链抗体中的一种或两种;和/或,
所述嵌合抗原受体和靶点的结合区域为结合一个靶点或者结合两个靶点的双特异性抗体,或者由两个或者多个嵌合抗原受体分别跨膜形成,并分别识别不同的靶点。
6.根据权利要求2所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述嵌合抗原受体的结构中的功能元件为信号肽CD8SP、跨膜结构域CD8Hinger、CD8TM、胞内激活元件4-1BB或CD3Zeta。
7.根据权利要求2所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述免疫细胞与自分泌IL-15与anti-PD1融合蛋白之间的分割方式为蛋白切割功能元件。
8.根据权利要求7所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述蛋白切割功能元件为T2A、P2A、E2A、F2A或IRES。
9.根据权利要求1所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述免疫细胞的基因转入方式为慢病毒、逆转录病毒、普通质粒载体、附加体载体、纳米递送系统、电转导或转座子。
10.根据权利要求1或2所述的自分泌IL-15与anti-PD1融合蛋白的免疫细胞,其特征在于,所述免疫细胞为T细胞、NK细胞、NKT细胞、巨噬细胞、gamma-delta T细胞、TIL细胞、TCR-T细胞、IPS细胞或其它肿瘤杀伤细胞。
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WO2022199125A1 (zh) * | 2021-03-26 | 2022-09-29 | 深圳市先康达生命科学有限公司 | 一种自分泌IL-15与anti-PD1融合蛋白的免疫细胞 |
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