CN108884459A - 一种改善免疫应答细胞功能的方法 - Google Patents
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Abstract
Description
CD3+(个/μL) | CAR-T(个/μL) | |
Mock | 193.1453 | 0 |
GPC3-28Z | 375.802 | 232.2 |
GPC3-28Z-IFN | 1034.315 | 439.5 |
Claims (29)
- 一种免疫应答细胞,其特征在于,该细胞表达结合抗原的受体;和外源性I型干扰素。
- 如权利要求1所述的免疫应答细胞,其特征在于,所述的免疫应答细胞包括:T细胞、自然杀伤细胞、细胞毒性T淋巴细胞、自然杀伤T细胞、DNT细胞、和/或调节性T细胞。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述的抗原是肿瘤抗原或病原体抗原。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述的外源性I型干扰素是组成性表达或诱导性表达;较佳地,用于表达所述的I型干扰素的启动子包括:免疫细胞诱导型启动子;较佳地,所述的免疫细胞诱导型启动子是NFAT6启动子。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,该细胞表达内源性或重组的结合抗原的受体;较佳地,所述结合抗原的受体包括顺序连接的:特异性结合所述抗原的抗体,跨膜区和胞内信号区。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述免疫应答细胞的胞内信号区含有T细胞刺激信号分子或T细胞刺激信号分子与T细胞激活共刺激分子的组合;较佳地,所述T细胞刺激信号分子选自:CD3ζ或FcεRIγ;更佳地为CD3ζ;或所述的T细胞激活共刺激分子选自:CD27,CD28,CD137,CD134,ICOS蛋白的胞内信号区,或其组合。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述结合抗原的受体的氨基酸序列与以下序列中的一个具有至少90%的同一性:SEQ ID NO:49;SEQ ID NO:50;SEQ ID NO:51;SEQ ID NO:54;SEQ ID NO:55;SEQ ID NO:56;SEQ ID NO:61;SEQ ID NO:62;SEQ ID NO:63;SEQ ID NO: 64;SEQ ID NO:65;SEQ ID NO:66;SEQ ID NO:67;SEQ ID NO:68;SEQ ID NO:69;SEQ ID NO:70;SEQ ID NO:71;SEQ ID NO:72;SEQ ID NO:73;SEQ ID NO:74;SEQ ID NO:75;以及SEQ ID NO:77。
- 如权利要求7所述的免疫应答细胞,其特征在于,所述的特异性结合抗原的受体以及所述的外源性I型干扰素由与SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、SEQ ID NO:60或SEQ ID NO:76具有至少90%同一性的核苷酸序列编码。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述的免疫应答细胞不包含外源的共刺激配体。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述的I型干扰素包括:IFNα或IFNβ。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述的结合抗原的受体和/或I型干扰素组成性或诱导性表达在免疫应答细胞的表面。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述的免疫应答细胞中包含表达构建物,该表达构建物包括:所述结合抗原的受体的表达盒;和所述I型干扰素的表达盒。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述的结合抗原的受体和/或I型干扰素利用病毒载体表达;较佳地,所述的病毒载体是逆转录病毒载体;更佳地,所述的病毒载体包括:慢病毒载体,逆转录病毒载体或腺病毒载体。
- 如前述权利要求之一所述的免疫应答细胞,其中所述结合抗原的受体识别并结合病原微生物。
- 如权利要求14所述的免疫应答细胞,其中所述病原微生物包括病毒、细菌、真菌、原生动物或寄生虫;更佳地,所述病原微生物为病毒;或者更佳地,所 述病原体微生物选自巨细胞病毒、爱泼斯坦-巴尔病毒、人类免疫缺陷病毒及流感病毒。
- 如前述权利要求之一所述的免疫应答细胞,其特征在于,所述的抗原包括:前列腺特异性膜抗原(PSMA)、癌胚抗原(CEA)、IL13Ralpha、HER-2、CD19、NY-ESO-1、HIV-1Gag、Lewis Y、MART-1、gp100、酪氨酸酶、WT-I、hTERT、间皮素、EGFR、EGFRvIII、磷脂酰肌醇蛋白聚糖3、EphA2、HER3、EpCAM、MUC1、MUC16、CLDN18.2、叶酸受体、CLDN6、CD30、CD138、ASGPR1、CDH16、GD2、5T4、8H9、αvβ6整合素、B细胞成熟抗原(BCMA)、B7-H3、B7-H6、CAIX、CA9、CD20、CD22、κ轻链(kappa light chain)、CD33、CD38、CD44、CD44v6、CD44v7/8、CD70、CD123、CD171、CSPG4、EGP2、EGP40、ERBB3、ERBB4、ErbB3/4、FAP、FAR、FBP、胚胎型AchR、GD2、GD3、HLA-AI MAGE A1、MAGE3、HLA-A2、IL11Ra、KDR、Lambda、MCSP、NCAM、NKG2D配体、PRAME、PSCA、PSC1、ROR1、Sp17、SURVIVIN、TAG72、TEM1、TEM8、VEGRR2、HMW-MAA、VEGF受体、和/或纤连蛋白、腱生蛋白或肿瘤坏死区的癌胚变体。
- 一种表达构建物,其特征在于,该表达构建物包括顺序连接的:结合抗原的受体的表达盒;和I型干扰素的表达盒;其中所述结合抗原的受体和I型干扰素如前述权利要求之一所定义。
- 一种提高向个体给予的免疫应答细胞活力的方法,其特征在于,所述免疫应答细胞表达如权利要求1至16之一所述的结合抗原的受体,并且其中所述方法包括向所述个体给予所述免疫应答细胞以及有效量的外源性I型干扰素。
- 如权利要求18所述的方法,其中所述外源性I型干扰素与所述表达结合抗原的受体的免疫应答细胞顺序给予或者同时给予。
- 如权利要求18或19所述的方法,其中所述外源性I型干扰素通过在免疫应答细胞中共表达,与所述免疫应答细胞同时向患者给予。
- 如权利要求18至20之一所述的方法,其中所述免疫应答细胞包括T细胞、 自然杀伤细胞、细胞毒性T淋巴细胞、自然杀伤T细胞、DNT细胞、和/或调节性T细胞。
- 如权利要求18至21之一所述的方法,其中所述方法使得在向所述个体给予所述免疫应答细胞后,与不存在所述外源性I型干扰素的情况相比,所述个体外周血中细胞毒性T细胞和辅助T细胞的数量之和提高至少50%。
- 如权利要求18至22之一所述的方法,其中所述方法使得在向所述个体给予所述免疫应答细胞约5天后,所述个体外周血中细胞毒性T细胞和辅助T细胞的数量之和大于15,000个/μL;给予所述免疫应答细胞约7天后,所述个体外周血中细胞毒性T细胞和辅助T细胞的数量之和大于500个/μL;或者给予所述免疫应答细胞约10天后,所述个体外周血中细胞毒性T细胞和辅助T细胞的数量之和大于50个/μL。
- 权利要求1-16之一所述的免疫应答细胞在制备用于治疗有此需要的个体的肿瘤、病原体感染、或增强个体免疫耐受能力的药物组合物中的用途。
- 如权利要求24所述的用途,其特征在于,所述的肿瘤包括:胰腺癌、肝癌、肺癌、胃癌、头颈部鳞状细胞癌、前列腺癌、结肠癌、乳腺癌、淋巴瘤、胆囊癌、肾癌、白血病、骨髓瘤、卵巢癌、宫颈癌、卵巢癌、宫颈癌或胶质瘤;或所述的病原体包括:病毒、细菌、真菌、原生动物或寄生虫;较佳地,所述的病毒包括:巨细胞病毒、爱泼斯坦-巴尔病毒、人类免疫缺陷病毒或流感病毒。
- 如权利要求24或25所述的用途,其中根据计算机断层扫描测量,所述药物使得肿瘤减小至少30%。
- 如权利要求24或25所述的用途,其中根据计算机断层扫描测量,所述药物使得肿瘤完全消失。
- 药物组合物,其特征在于,所述的药物组合物包括:权利要求1-16之一所述的免疫应答细胞;以及药学上可接受的载体或赋形剂。
- 试剂盒,其包含:如权利要求1-16之一所述的免疫应答细胞;以及指导如何向个体给予所述免疫应答细胞的说明书。
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