CN115246887A - 活化的t细胞及其在治疗癌症中的应用 - Google Patents
活化的t细胞及其在治疗癌症中的应用 Download PDFInfo
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Abstract
本发明涉及活化的T细胞及其在治疗癌症中的应用。具体地,本发明涉及一种经胎盘来源的热休克蛋白gp96‑抗原复合物活化的T细胞,以及含有所述T细胞的药物组合物及其在抗肿瘤中的用途。
Description
技术领域
本发明涉及生物医药领域,具体涉及活化的T细胞及其在治疗癌症中的应用。
背景技术
细胞免疫疗法是采集人体自身免疫细胞,经过体外培养,使其数量成千倍增多,靶向性杀伤功能增强,然后再回输到人体来杀灭血液及组织中的病原体、癌细胞、突变的细胞的技术。
以活化的肿瘤特异性T细胞为工具进行的细胞治疗是目前癌症防治有前景的手段之一。通常情况下,体内表达某一特异性TCR的T细胞克隆仅占总T细胞库的1/104-1/105。数量极少的特异性T细胞仅在被抗原激活后,通过克隆扩增而产生大量效应细胞,才能有效发挥作用。在体外环境中,利用肿瘤抗原致敏的树突状细胞与受试者外周血分离的淋巴细胞共培养,在T细胞高效增殖培养体系下可在体外获得大量肿瘤抗原特异性T淋巴细胞。
发明内容
经过我们科研团队大量的科学研究及论证,研发了针对肝细胞癌、胰腺癌等多种癌症的特异性细胞治疗方法。本研究以胎盘来源热休克蛋白gp96-抗原复合物为抗原,通过活化DC细胞高效激活肿瘤特异性T细胞,最终回输特异性活化的T细胞作为新型细胞治疗方法治疗癌症。
热休克蛋白gp96-抗原复合物
在一个方面,本发明提供一种热休克蛋白gp96-抗原复合物,其可通过以下方法制备得到:
将离体动物组织的匀浆液依次经ConA-Sepharose凝胶柱层析、HiTrap Q离子交换层析以及CHT离子交换层析分离得到所述复合物。
在一些实施方案中,所述离体动物组织为人或非人哺乳动物的胎盘组织或肿瘤组织。
在一些实施方案中,所述离体动物组织的匀浆液经下述方法制备得到:将离体动物组织按质量(g)-体积(ml)比1:4~1:8的比例加入10~50mM、pH值为6~8的NaHCO3溶液中研磨,得所述组织匀浆液。
在一些实施方案中,所述NaHCO3溶液浓度例如为10~20mM,10~30mM,10~40mM,20~30mM,20~40mM,20~50mM,30~40mM,30~50mM,或40~50mM,优选为30mM。在一些实施方案中,所述NaHCO3溶液的pH例如6.2~8,6.4~8,6.6~8,6.8~8,7.0~8,7.2~8,7.4~8,7.6~8,7.8~8,6.2~7.8,6.4~7.8,6.6~7.8,6.8~7.8,7.0~7.8,7.2~7.8,7.4~7.8,7.6~7.8,6.2~7.6,6.4~7.6,6.6~7.6,6.8~7.6,7.0~7.6,7.2~7.6,7.4~7.6,6.2~7.4,6.4~7.4,6.6~7.4,6.8~7.4,7.0~7.4,7.2~7.4,6.2~7.2,6.4~7.2,6.6~7.2,6.8~7.2,7.0~7.2,6.2~7.0,6.4~7.0,6.6~7.0,6.8~7.0,6.2~6.8,6.4~6.8,6.6~6.8,6.2~6.6,6.4~6.6,或6.2~6.4。
在一些实施方案中,在进行上述的分离前,还包括将所述组织匀浆液按下述步骤初步提纯的操作:
步骤1-1:将所述组织匀浆液低温(例如,2~6℃)离心,取上清;
步骤1-2:采用硫酸铵分级沉淀法,将步骤1-1所得上清在低温条件下(例如,2~6℃)加入硫酸铵,收集硫酸铵浓度为50%~70%时所得沉淀,得初提物。在一些实施方案中,在步骤1-1中,将所述组织匀浆液在2~6℃,1000rpm~10000rpm离心0.5h~1h,收集上清,任选地,将收集到的上清在2~6℃,1000rpm~10000rpm再次离心0.5h~1h,取上清。
在一些实施方案中,在步骤1-2中,收集硫酸铵浓度大于50%,例如52%~70%、54%~70%、56%~70%、58%~70%、60%~70%、62%~70%、64%~70%、66%~70%、或68%~70%时所得沉淀。
在一些实施方案中,在步骤1-2中,按质量(g)-体积(ml)比1:(2~20)的比例用含50~200mM NaCl(优选200mM)的5~50mM Tris-HCl溶液溶解所得沉淀。
在一些实施方案中,在步骤1-2中,按质量(g)-体积(ml)比为1:(4~20)、1:(6~20)、1:(8~20)、1:(10~20)、1:(12~20)、1:(14~20)、1:(16~20)、1:(18~20)、1:(2~18)、1:(4~18)、1:(6~18)、1:(8~18)、1:(10~18)、1:(12~18)、1:(14~18)、1:(16~18)、1:(2~16)、1:(4~16)、1:(6~16)、1:(8~16)、1:(10~16)、1:(12~16)、1:(14~16)、1:(2~14)、1:(4~14)、1:(6~14)、1:(8~14)、1:(10~14)、1:(12~14)、1:(2~12)、1:(4~12)、1:(6~12)、1:(8~12)、1:(10~12)、1:(2~10)、1:(4~10)、1:(6~10)、1:(8~10)、1:(2~8)、1:(4~8)、1:(6~8)、1:(2~6)、1:(4~6)、或1:(2~4),优选为1:9的比例用5~50mM的Tris-HCl溶液溶解所述沉淀。在一些实施方案中,所述Tris-HCl的浓度例如为5~10mM、5~15mM、5~20mM、5~25mM、5~30mM、5~35mM、5~40mM、5~45mM、5~50mM、10~15mM、10~20mM、10~25mM、10~30mM、10~35mM、10~40mM、10~45mM、10~50mM、15~20mM、15~25mM、15~30mM、15~35mM、15~40mM、15~45mM、15~50mM、20~25mM、20~30mM、20~35mM、20~40mM、20~45mM、20~50mM、25~30mM、25~35mM、25~40mM、25~45mM、25~50mM、30~35mM、30~40mM、30~45mM、30~50mM、35~40mM、35~45mM、35~50mM、40~45mM、40~50mM、或45~50mM,优选20mM。在进一步优选的实施方案中,所述Tris-HCl溶液中NaCl浓度例如为50~100mM、50~150mM、50~200mM、100~150mM、100~200mM、或150~200mM,优选为200mM。
在一些实施方案中,所述ConA-Sepharose凝胶柱层析包括以下步骤:
步骤2-1:将所述初提物上样至ConA-Sepharose凝胶柱;
步骤2-2:用含50~200mM NaCl的5~50mM Tris-HCl溶液洗脱至检测波长为280nm时洗脱产物紫外吸收低于0.01;
步骤2-3:用含8%α-吡喃糖苷、200mM NaCl的20mM Tris-HCl溶液继续洗脱,收集洗脱液(优选地,收集第0~3个(例如,0.5~2个)柱体积的流穿液),得ConA-Sepharose分离物。
在一些实施方案中,在步骤2-2中,所述Tris-HCl的浓度例如为5~10mM、5~15mM、5~20mM、5~25mM、5~30mM、5~35mM、5~40mM、5~45mM、5~50mM、10~15mM、10~20mM、10~25mM、10~30mM、10~35mM、10~40mM、10~45mM、10~50mM、15~20mM、15~25mM、15~30mM、15~35mM、15~40mM、15~45mM、15~50mM、20~25mM、20~30mM、20~35mM、20~40mM、20~45mM、20~50mM、25~30mM、25~35mM、25~40mM、25~45mM、25~50mM、30~35mM、30~40mM、30~45mM、30~50mM、35~40mM、35~45mM、35~50mM、40~45mM、40~50mM、或45~50mM,优选20mM。在进一步优选的实施方案中,所述Tris-HCl溶液中NaCl浓度例如为50~100mM、50~150mM、50~200mM、100~150mM、100~200mM、或150~200mM,优选为200mM。
在一些实施方案中,所述HiTrap Q离子交换层析包括以下步骤:
步骤3-1:将所述ConA-Sepharose分离物上样至HiTrap Q离子交换柱;
步骤3-2:用5~50mM Tris-HCl清洗HiTrap Q离子交换柱;
步骤3-3:用含NaCl(300mM~1000mM)的5~50mM Tris-HCl洗脱,收集洗脱液至检测波长为280nm时洗脱产物吸光度值低于100mA;任选地,将收集到的洗脱液浓缩(例如,超滤浓缩)并用pH 6~8的20~100mM磷酸盐缓冲液稀释,得HiTrap Q分离物。
在一些实施方案中,在步骤3-2中,用5~10mM、5~15mM、5~20mM、5~25mM、5~30mM、5~35mM、5~40mM、5~45mM、5~50mM、10~15mM、10~20mM、10~25mM、10~30mM、10~35mM、10~40mM、10~45mM、10~50mM、15~20mM、15~25mM、15~30mM、15~35mM、15~40mM、15~45mM、15~50mM、20~25mM、20~30mM、20~35mM、20~40mM、20~45mM、20~50mM、25~30mM、25~35mM、25~40mM、25~45mM、25~50mM、30~35mM、30~40mM、30~45mM、30~50mM、35~40mM、35~45mM、35~50mM、40~45mM、40~50mM、或45~50mM,优选20mM的Tris-HCl清洗HiTrap Q离子交换柱。
在一些实施方案中,在步骤3-3中,所述Tris-HCl浓度例如为5~10mM、5~15mM、5~20mM、5~25mM、5~30mM、5~35mM、5~40mM、5~45mM、5~50mM、10~15mM、10~20mM、10~25mM、10~30mM、10~35mM、10~40mM、10~45mM、10~50mM、15~20mM、15~25mM、15~30mM、15~35mM、15~40mM、15~45mM、15~50mM、20~25mM、20~30mM、20~35mM、20~40mM、20~45mM、20~50mM、25~30mM、25~35mM、25~40mM、25~45mM、25~50mM、30~35mM、30~40mM、30~45mM、30~50mM、35~40mM、35~45mM、35~50mM、40~45mM、40~50mM、或45~50mM,优选20mM。在进一步优选的实施方案中,所述Tris-HCl中NaCl浓度例如为300~350mM、300~400mM、300~450mM、300~500mM、300~550mM、300~600mM、300~650mM、300~700mM、300~750mM、300~800mM、300~850mM、300~900mM、300~950mM、300~1000mM、350~400mM、350~450mM、350~500mM、350~550mM、350~600mM、350~650mM、350~700mM、350~750mM、350~800mM、350~850mM、350~900mM、350~950mM、350~1000mM、400~450mM、400~500mM、400~550mM、400~600mM、400~650mM、400~700mM、400~750mM、400~800mM、400~850mM、400~900mM、400~950mM、400~1000mM、450~500mM、450~550mM、450~600mM、450~650mM、450~700mM、450~750mM、450~800mM、450~850mM、450~900mM、450~950mM、450~1000mM、500~550mM、500~600mM、500~650mM、500~700mM、500~750mM、500~800mM、500~850mM、500~900mM、500~950mM、500~1000mM、550~600mM、550~650mM、550~700mM、550~750mM、550~800mM、550~850mM、550~900mM、550~950mM、550~1000mM、600~650mM、600~700mM、600~750mM、600~800mM、600~850mM、600~900mM、600~950mM、600~1000mM、650~700mM、650~750mM、650~800mM、650~850mM、650~900mM、650~950mM、650~1000mM、700~750mM、700~800mM、700~850mM、700~900mM、700~950mM、700~1000mM、750~800mM、750~850mM、750~900mM、750~950mM、750~1000mM、800~850mM、800~900mM、800~950mM、800~1000mM、850~900mM、850~950mM、850~1000mM、900~950mM、900~1000mM、或950~1000mM。
在一些优选的实施方案中,在步骤3-3中,所述磷酸盐缓冲液的pH例如为6.2~8,6.4~8,6.6~8,6.8~8,7.0~8,7.2~8,7.4~8,7.6~8,7.8~8,6.2~7.8,6.4~7.8,6.6~7.8,6.8~7.8,7.0~7.8,7.2~7.8,7.4~7.8,7.6~7.8,6.2~7.6,6.4~7.6,6.6~7.6,6.8~7.6,7.0~7.6,7.2~7.6,7.4~7.6,6.2~7.4,6.4~7.4,6.6~7.4,6.8~7.4,7.0~7.4,7.2~7.4,6.2~7.2,6.4~7.2,6.6~7.2,6.8~7.2,7.0~7.2,6.2~7.0,6.4~7.0,6.6~7.0,6.8~7.0,6.2~6.8,6.4~6.8,6.6~6.8,6.2~6.6,6.4~6.6,或6.2~6.4,优选pH 6.8。
在一些优选的实施方案中,在步骤3-3中,所述磷酸盐缓冲液的浓度例如为20~30mM、20~40mM、20~50mM、20~60mM、20~70mM、20~80mM、20~90mM、30~40mM、30~50mM、30~60mM、30~70mM、30~80mM、30~90mM、30~100mM、40~50mM、40~60mM、40~70mM、40~80mM、40~90mM、40~100mM、50~60mM、50~70mM、50~80mM、50~90mM、50~100mM、60~70mM、60~80mM、60~90mM、60~100mM、70~80mM、70~90mM、70~100mM、80~90mM、80~100mM、或80~100mM,优选50mM。
在一些实施方案中,所述CHT离子交换层析包括以下步骤:
步骤4-1:将所述HiTrap分离物上样至CHT离子交换柱;
步骤4-2:用5~50mM Tris-HCl清洗CHT离子交换柱;
步骤4-3:用含300mM~1000mM NaCl的20mM Tris-HCl洗脱,收集洗脱液至吸光度值低于100mA;任选地,将收集到的洗脱液浓缩(例如,超滤浓缩)并用pH 6.8的50mM磷酸盐缓冲液稀释,得所述复合物。
在一些实施方案中,在步骤4-2中,所述Tris-HCl浓度例如为5~10mM、5~15mM、5~20mM、5~25mM、5~30mM、5~35mM、5~40mM、5~45mM、5~50mM、10~15mM、10~20mM、10~25mM、10~30mM、10~35mM、10~40mM、10~45mM、10~50mM、15~20mM、15~25mM、15~30mM、15~35mM、15~40mM、15~45mM、15~50mM、20~25mM、20~30mM、20~35mM、20~40mM、20~45mM、20~50mM、25~30mM、25~35mM、25~40mM、25~45mM、25~50mM、30~35mM、30~40mM、30~45mM、30~50mM、35~40mM、35~45mM、35~50mM、40~45mM、40~50mM、或45~50mM,优选20mM。
在一些实施方案中,在步骤4-3中,用浓度例如为300~350mM、300~400mM、300~450mM、300~500mM、300~550mM、300~600mM、300~650mM、300~700mM、300~750mM、300~800mM、300~850mM、300~900mM、300~950mM、300~1000mM、350~400mM、350~450mM、350~500mM、350~550mM、350~600mM、350~650mM、350~700mM、350~750mM、350~800mM、350~850mM、350~900mM、350~950mM、350~1000mM、400~450mM、400~500mM、400~550mM、400~600mM、400~650mM、400~700mM、400~750mM、400~800mM、400~850mM、400~900mM、400~950mM、400~1000mM、450~500mM、450~550mM、450~600mM、450~650mM、450~700mM、450~750mM、450~800mM、450~850mM、450~900mM、450~950mM、450~1000mM、500~550mM、500~600mM、500~650mM、500~700mM、500~750mM、500~800mM、500~850mM、500~900mM、500~950mM、500~1000mM、550~600mM、550~650mM、550~700mM、550~750mM、550~800mM、550~850mM、550~900mM、550~950mM、550~1000mM、600~650mM、600~700mM、600~750mM、600~800mM、600~850mM、600~900mM、600~950mM、600~1000mM、650~700mM、650~750mM、650~800mM、650~850mM、650~900mM、650~950mM、650~1000mM、700~750mM、700~800mM、700~850mM、700~900mM、700~950mM、700~1000mM、750~800mM、750~850mM、750~900mM、750~950mM、750~1000mM、800~850mM、800~900mM、800~950mM、800~1000mM、850~900mM、850~950mM、850~1000mM、900~950mM、900~1000mM、或950~1000mM,优选500mM的PB洗脱。
在一些实施方案中,在步骤4-3中,用浓度为5~10mM、5~15mM、5~20mM、5~25mM、5~30mM、5~35mM、5~40mM、5~45mM、5~50mM、10~15mM、10~20mM、10~25mM、10~30mM、10~35mM、10~40mM、10~45mM、10~50mM、15~20mM、15~25mM、15~30mM、15~35mM、15~40mM、15~45mM、15~50mM、20~25mM、20~30mM、20~35mM、20~40mM、20~45mM、20~50mM、25~30mM、25~35mM、25~40mM、25~45mM、25~50mM、30~35mM、30~40mM、30~45mM、30~50mM、35~40mM、35~45mM、35~50mM、40~45mM、40~50mM、或45~50mM,优选20mM的磷酸盐缓冲液稀释。在进一步优选的实施方案中,所述磷酸盐缓冲液的pH例如为6.2~8,6.4~8,6.6~8,6.8~8,7.0~8,7.2~8,7.4~8,7.6~8,7.8~8,6.2~7.8,6.4~7.8,6.6~7.8,6.8~7.8,7.0~7.8,7.2~7.8,7.4~7.8,7.6~7.8,6.2~7.6,6.4~7.6,6.6~7.6,6.8~7.6,7.0~7.6,7.2~7.6,7.4~7.6,6.2~7.4,6.4~7.4,6.6~7.4,6.8~7.4,7.0~7.4,7.2~7.4,6.2~7.2,6.4~7.2,6.6~7.2,6.8~7.2,7.0~7.2,6.2~7.0,6.4~7.0,6.6~7.0,6.8~7.0,6.2~6.8,6.4~6.8,6.6~6.8,6.2~6.6,6.4~6.6,或6.2~6.4,优选pH6.8。
所述热休克蛋白gp96是细胞中表达丰度很高的一种分子伴侣蛋白,在多种新生蛋白折叠与受损蛋白降解、病毒与肿瘤抗原呈递和T细胞活化、损伤相关的分子模式(DAMPs)介导的天然免疫、引发抗肿瘤与抗病毒T细胞免疫,以及作为宿主因子调节病毒复制、驱动炎癌转化和肿瘤发生发展等方面均发挥重要功能。在一些实施方案中,所述gp96具有如SeqID No.1所示的氨基酸序列。
在一些实施方案中,本发明所述热休克蛋白gp96-抗原复合物中所述抗原选自如Seq ID No.2~72所示的多肽中的一种或多种(例如,1种以上、5种以上、10种以上、15种以上、20种以上、25种以上、30种以上、35种以上、40种以上、45种以上、50种以上、55种以上、60种以上、65种以上或70种以上),所述多肽为肿瘤相关抗原或肿瘤组织中高表达蛋白。
在一些实施方案中,经多肽芯片富集技术联合质谱鉴定,所述复合物中gp96与SeqID No.2~72所示的71条肿瘤相关抗原结合。在一些实施方案中,热休克蛋白gp96的多肽结合位点位于gp96高度保守的第624-630位氨基酸,可以非共价结合抗原多肽。
经本发明方法获得的复合物杂质含量更少,如核酸残留、杂蛋白残留等,大大提高了热休克蛋白gp96-抗原复合物的纯度,能够更好地活化免疫细胞。经SDS-PAGE胶分析显示,本发明所述复合物纯度为80%以上,例如85%以上,90%以上,91%以上,92%以上,93%以上,94%以上,95%以上,96%以上,97%以上,98%以上或99%以上。
T细胞群体
抗原递呈细胞(antigen presenting cell,APC),尤其是树突细胞(dendriticcell,DC),可处理并在其细胞表面上呈现肿瘤抗原。成熟之后,载有肿瘤抗原的DC可触发T细胞反应,该T细胞反应涉及细胞毒性T细胞、辅助T细胞和功能上不同的效应T细胞和记忆T细胞,其对抗表达肿瘤抗原的癌细胞。
在另一个方面,本发明提供一种T细胞群体,其通过以下方法制备得到:
用前文所述的热休克蛋白gp96-抗原复合物体外致敏DC细胞和T细胞,获得所述T细胞群体。
在一些实施方案中,所述T细胞群体的制备方法包括以下步骤:
(1)诱导单核细胞群体分化为树突细胞群体;
(2)将所述树突细胞群体与前文所述的热休克蛋白gp96-抗原复合物体接触,获得活化的树突细胞群体;
(3)将所述活化的树突细胞群体与非黏附PBMC群体共培养,获得所述T细胞群体;
所述单核细胞群体和所述非黏附PBMC群体来源于个体的PBMC群体,例如志愿者个体或者需要接受治疗的个体。
在一些实施方案中,所述制备方法进一步具有下述一种或多种特征:
1)在步骤(2)中,按10~100μg/1×107个树突细胞的比例加入所述热休克蛋白gp96-抗原复合物;
2)在步骤(3)中,进一步包括使所述T细胞群体与多种细胞因子接触的步骤,所述细胞因子包括IL-7和IL-15;优选地,IL-7和IL-15工作浓度独立地为1~20ng/ml,例如1ng/ml、2ng/ml、3ng/ml、4ng/ml、5ng/ml、6ng/ml、7ng/ml、8ng/ml、9ng/ml、10ng/ml、11ng/ml、12ng/ml、13ng/ml、14ng/ml、15ng/ml、16ng/ml、17ng/ml、18ng/ml、19ng/ml、或20ng/ml。
“单核细胞”是指具有分化成树突细胞能力的CD14+单核白细胞。单核细胞可以来自任何哺乳动物,但优选是人单核细胞。用于提供单核细胞的样品包括但不限于血液、血液级分(例如,白细胞(WBC)、血沉棕黄层、外周血单个核细胞(PBMC)、单核细胞白细胞去除术产物。在一些实施方案中,步骤(1)中所述单核细胞来源于外周血或脐带血,优选为外周血。在一些实施方案中,单核细胞与其他外周血单个核细胞(PBMC)一起提供,例如作为单核细胞单采血液成分分离术(apheresis)产物。从包括血液和骨髓在内的各种来源分离富集树突细胞前体如单核细胞和常规树突细胞的细胞群体的方法是本领域已知的。例如,单核细胞和常规树突细胞可以通过收集肝素化的血液、通过单采血液成分分离术或白细胞去除术、通过制备血沉棕黄层、玫瑰花环(rosetting)、离心、密度梯度离心、细胞的差异裂解、过滤、淘析、荧光激活细胞分选或免疫磁性分离来分离。在一些优选的实施方案中,单核细胞从单核细胞白细胞去除术中分离。白细胞去除术的方法是本领域已知的。白细胞去除术是从受试者的血液中去除白细胞,然后将其剩余部分输回受试者的程序。白细胞去除术产物通常是富含PBMC的血液级分,具有低水平的污染性红细胞、粒细胞和血小板。用于进行白细胞去除术的方法和设备是本领域众所周知的。单核细胞性树突细胞前体和/或分化的常规树突细胞可以从健康受试者或从需要免疫刺激的受试者分离,所述受试者例如是癌症患者或其他的细胞免疫刺激对其可以是有益的或期望的受试者(例如具有细菌或病毒感染的受试者等)。树突细胞前体和/或未成熟树突细胞也可以从与HLA匹配的健康个体中获得,以施用于需要免疫刺激的与HLA匹配的受试者。
在一些实施方案中,富集单核细胞的操作可以对单核细胞或PBMC等进行,包括例如离心、淘析、切向流过滤、Ficoll密度梯度、稀释的Ficoll密度梯度离心、稀释的Percoll密度梯度离心、抗体淘选、磁性细胞分选、阳性或阴性免疫磁性选择等。另外,一旦从受试者分离,单核细胞(例如,纯化的单核细胞,富集的单核细胞,包含单核细胞的PBMC等)可以任选地被温育,例如在1℃~34℃的温度下保持一段时间,例如从其自受试者分离的时间之后的大约1到96小时。成活的单核细胞是高度纯化的,例如纯度超过90%,95%甚至99%,如使用单核细胞标志物CD14和成活力染色通过流式细胞仪所确定。
在分离,纯化和/或富集单核细胞后,诱导其分化为树突细胞。因此,在一些实施方案中,本发明的方法包括培养和/或分化步骤以获得未成熟的DC。
在一些实施方案中,按1×105~1×108个/ml(例如,1×105个/ml,1×106个/ml,1×107个/ml,或1×108个/ml,优选2~4×106个/ml)的密度将所述单核细胞接种至DC细胞培养基。
在DC细胞培养过程中(例如在培养的第0天,1天,2天,3天,4天,5天,6天,7天,8天,9天或10天)加入PHA、IL-2、IL-4、GM-CSF和TNF-α中的一种或多种。在一些实施方案中,在至少粒细胞-巨噬细胞集落刺激因子(GM-CSF)和白细胞介素-4(IL-4)(称为分化培养基)存在下培养单核细胞,并且这持续约1至4天,例如1至3天或2至3天,甚至更特别地长达80、75、74、73、72、71、70小时或更短的小时,更特别地长达至少48小时和长达72小时。+/-4小时或+/-2小时的限度是可接受的。在一些实施方案中,在培养的第0天加入GM-CSF和IL-4,例如分别加入终浓度为50~100ng/ml的GM-CSF和IL-4。在一些实施方案中,使单核细胞与GM-CSF和IL-4接触约1至4天,例如1至3天或2至3天(以1天24小时计),在此期间DC前体分化为未成熟的树突细胞。GM-CSF和IL-4的浓度为50~100ng/ml,例如50ng/ml,60ng/ml,70ng/ml,80ng/ml,90ng/ml,或100ng/ml。
前体和/或未成熟树突细胞用(至少)以上因子的组合来培育。这可以通过将所述因子添加到培养基中来进行。所述培养基可以是任何合适的种类,即可以补充有或没有任何其他补充剂,例如蛋白质、氨基酸或抗生素。在一些实施方案中,所述培养基为RPMI1640。
在单核细胞分化成未成熟的树突细胞后,未成熟的树突细胞可以成熟为成熟的树突细胞。因此,在一些实施方案中,制备本文所述DC细胞群体的方法包括成熟步骤,例如向(分化的)未成熟的DC中加入TNF-α。DC细胞在TNF-α存在下的成熟时间为1至3天,优选为1至2天,更优选为约1天(24小时)。在一些实施方案中,在培养的第6天加入TNF-α,优选加入终浓度为10~50ng/ml的TNF-α,优选为20ng/ml。培养条件适合于未成熟的DC形成成熟的DC群体。特别地,在收获和/或刺激前的最后24小时±4小时(特别是±2小时)的细胞培养期间,将TNF-α加入到培养基中。在一些实施方案中,所述培养基为RPMI1640。
“活化的T细胞(activated T cell)”、“T细胞群体”等是指具有识别至少一种肿瘤抗原肽的T细胞受体的单克隆(例如,编码相同TCR)或多克隆(例如,具有编码不同TCR的殖株)T细胞群。活化T细胞可含有一种或多种T细胞亚型,其包括但不限于细胞毒性T细胞、辅助T细胞、天然杀伤性T细胞、γδT细胞、调节性T细胞、和记忆T细胞。
在一些实施方案中,在所述T细胞群体中,CD3+CD8+T细胞/CD3+T细胞比例大于80%,例如大于85%,大于90%,大于91%,大于92%,大于93%,大于94%,大于95%,大于96%,大于97%,大于98%或大于99%。
在一些实施方案中,在所述T细胞群体中,CCR7-CD45RA-CD8+T细胞/CD8+T细胞比例大于10%,例如大于15%,大于20%,大于25%,或者大于30%。
在一些实施方案中,所述T细胞群体对IFN-γ的细胞内表达呈阳性。在一些实施方案中,IFN-γ+ELISPOT检测斑点数大于500/103个T细胞。
药物组合物
在另一个方面,本发明提供一种药物组合物,其含有前文所述的T细胞群体,以及一种或多种药学上可接受的载体。
在一些实施方案中,所述药物组合物为注射剂(例如,注射液或者冻干粉针剂)。
在一些实施方案中,单位剂量T细胞含量不少于1×104个(例如不少于1×104个,不少于3×104个,不少于5×104个,不少于7×104个,不少于1×105个,不少于3×105个,不少于5×105个,不少于7×105个,不少于1×106个,不少于3×106个,不少于5×106个,不少于7×106个,不少于1×107个,不少于3×107个,不少于5×107个,不少于7×107个,不少于1×108个,不少于3×108个,不少于5×108个,不少于7×108个,不少于1×109个,不少于3×109个,不少于5×109个,不少于7×109个,不少于1×1010个,不少于3×1010个,不少于5×1010个或不少于7×1010个,又例如1×105~1×108个)。
用途或治疗方法
树突状细胞作为专职抗原呈递细胞(Antigen presenting Cells,APC),能摄取、加工及呈递抗原,处于启动、调控、并维持免疫应答的中心环节。体外诱导DC细胞是将人外周血单核细胞在体外用多种细胞因子如抗GM-CSF、IL-4等共同培养,再使用TNFα等因子激发DC细胞逐渐成熟,表达CD80\CD83\CD86分子,通过皮下、淋巴结注射进入病人体内,成熟DC细胞将gp96蛋白携带的肿瘤抗原信息呈递给T细胞。在某些实施方案中,本发明所述胎盘来源热休克蛋白gp96-抗原复合物活化的T细胞在体内和/或体外对肝癌细胞HEPG2具有杀伤作用。在另一些实施方案中,本发明所述胎盘来源热休克蛋白gp96-抗原复合物活化的T细胞在体内和/或体外对胰腺癌细胞PANC-1具有杀伤作用。
通过静脉回输所述T细胞在机体中发挥抗肿瘤功能主要有以下几个机制:
①诱导并激活特异性的抗肿瘤免疫反应:DC细胞将gp96制剂携带的肿瘤抗原信息通过MHC-I途径提呈给T细胞,引起细胞毒性T细胞(CTL)增殖、活化,T细胞可以通过不同的机制识别肿瘤细胞,释放颗粒酶/穿孔素等毒性颗粒,导致肿瘤细胞的裂解(CTL杀伤作用);
②诱导并激活Th细胞促进CTL杀伤作用:通过MHC-II途径提呈肿瘤抗原给CD4细胞,分泌大量细胞因子,促进CTL杀伤作用;
③刺激B细胞产生特异性抗体:引起B细胞增殖、活化,分泌产生大量抗肿瘤抗原特异性抗体杀灭肿瘤细胞。
④T细胞释放的大量炎性细胞因子具有抑瘤杀瘤作用:体外培养的T细胞可以分泌多种细胞因子,如IFN-γ、TNF-α、IL-2等,不仅对肿瘤细胞有直接抑制作用,还可通过调节机体免疫系统反应性间接杀伤肿瘤细胞。
此外,树突状细胞能够通过分泌IL-12I型干扰素等促进NK细胞,NKT细胞和γΔT细胞等固有免疫细胞的增殖进而杀伤肿瘤细胞,T细胞亦能够在培养过程中表达FasL(Ⅱ型跨膜糖蛋白)通过与肿瘤细胞膜表达的Fas(Ⅰ型跨膜糖蛋白)结合,诱导肿瘤细胞凋亡。
因此,在另一个方面,本发明提供前文所述的T细胞群体在制备抗肿瘤药物中的用途。
在一些实施方案中,所述药物可减缓或停止已建立的肿瘤病灶的生长。
在另一个方面,本发明提供前文所述的T细胞群体,其用于抗肿瘤。
在另一个方面,本发明提供一种抗肿瘤方法,其包括向有此需要的受试者施用有效量的前文所述的T细胞群体。
在一些实施方案中,所述T细胞群体可减缓或停止已建立的肿瘤病灶的生长。
在一些实施方案中,所述肿瘤选自肝癌和胰腺癌。
除非另有说明,本文使用的所有技术和科学术语具有本领域技术人员所通常理解的含义,本文中所涉及的免疫学、生物化学、化学、分子生物学、微生物学、细胞生物学、基因组学和重组DNA技术均为所属领域常规技术。参见例如Sambrook和Green,MolecularCloning:A LaboratoryMannual,第4版(2012);系列Current Protocols in MolecularBiology(F.M.Ausubel等人编辑);系列Methods In Enzymology(Academic Press,Inc.),PCR 2:A Practical Approach(M.J.MacPherson,B.D.Hames和G.R.Taylor编辑(1995));Harlow和Lane编辑(1988)Antibodies,A Laboratory Mannual;以及Culture of AnimalCells:A Mannual of Basic Technique and Specialized Applications,第6版(R.I.Freshney编辑(2010))。
除非有明确规定,否则本文中所使用的单数形式“一个/一种(a/an)”以及“所述(the)”包括复数形式的所指代物。
“约”或“大约”是指在如通过本领域普通技术人员所确定的特定值的可接受误差范围内,其部分取决于测量系统的局限性。例如,在一些实施方案中,“约”意指在1个或超过1个标准偏差内。可替代地,特别是关于生物系统或过程,“约”意指在所指代数值的一个数量级内、优选地在所指代数值的5倍内、更优选在所指代数值的2倍内。
“细胞”通常指生物细胞,其可以是活生物体的基本结构、功能和/或生物学单位。其可以来源于具有一个或多个细胞的任何生物体。一些非限制实例包括原核细胞、真核细胞、细菌细胞、古细菌细胞、单细胞真核生物体的细胞、原生动物细胞、来自植物的细胞、藻类细胞、真菌细胞、动物细胞(例如,无脊椎动物细胞、脊椎动物细胞、哺乳动物细胞)、等等。在一些实施方案中,所述细胞可以不是来源于天然生物体,例如,其为人造细胞。
“抗原”是指任何能够被选择性结合剂(例如,受体或者抗体)结合的分子或其片段。在一些实施方案中,抗原特指任何能够引起免疫反应的物质,其能够被用于动物中以产生能够于所述抗原结合的抗体的分子或其片段。
“肿瘤相关抗原”是指在肿瘤细胞中异常高表达、而在正常组织细胞中表达量较低的抗原。经多肽芯片富集技术联合质谱鉴定,本文中所述由离体动物组织提取获得的复合物中含多种肿瘤抗原,包括Seq ID No:2~72所示的71条肿瘤组织中高表达蛋白,是肿瘤相关抗原,部分抗原为脑胶质瘤和胆管癌的特异性表面抗原,涉及特异性免疫反应。
“肽”、“多肽”和“蛋白质”在本文中可互换使用,是指通过一个或多个肽键连接的至少两个氨基酸残基的聚合物。这一术语并不意味着聚合物的特定长度,也不旨在暗示或区分多肽是使用重组技术、化学或酶促合成产生还是天然存在的。
如本文所使用的,术语“特异性结合至(specifically bind to)”、“识别(recognizes)”、“特异性识别(specifically recognizes)”、“靶向(targets)”、或“对……具特异性(specific for)”是指可测量且可再现的相互作用,诸如目标与抗体之间、或受体与配体之间、或受体与表位/MHC复合物之间的结合,其判定在分子(包括生物分子)的异质群体存在下目标的存在。例如,结合至或特异性结合至目标(其可为表位)的抗体是以较大亲合性、结合性、更加容易地、和/或以更长持续时间结合此目标(相较于其结合至其他目标)的抗体。在一些实施方案中,如所测量(例如通过放射免疫测定法(RIA)),抗体与不相关目标的结合程度小于抗体与目标的结合的约10%。在某些实施方案中,特异性结合至抗原肽(或表位)的抗体具有≤1μM、≤100nM、≤10nM、≤1nM、或≤0.1nM的解离常数(Kd)。在某些实施方案中,抗体特异性结合至来自不同物种的蛋白质中保守的蛋白质上的表位。在另一实施方案中,特异性结合可包括但不需要排他性结合。
“受试者”是指健康个体、患有或者疑似患有某种疾病的个体,可以为人或者非人哺乳动物,优选为人。通常包括健康志愿者、患者、检测对象以及治疗对象等。
“治疗(treatment/treating)”通常是指获得所需的药理和/或生理效果,并且涵盖哺乳动物尤其是人中的任何疾病治疗,包括:
(1)防止疾病或症状发生于可能易患该疾病或症状但尚未被诊断为患有该疾病或症状的受试者中;
(2)抑制疾病症状,即阻止其发展;或
(3)减轻疾病症状,即引起疾病或症状的消退。
就完全或部分预防疾病或其症状而言,该效果可以是预防性的,和/或就部分或完全稳定或治愈疾病和/或归因于该疾病的副作用而言,该效果可以是治疗性的。此外,除了主要疗法或初始疗法外,还可将疫苗用作“辅助疗法”以使其在治疗环境中的有效性最大化,或在初始疗法后用作“维持”或“巩固(consolidative)”法以使疾病控制最大化并延迟疾病复发。
如本文中所使用的,术语“有效量”是指足以产生所需治疗结果(例如,降低癌的严重程度或持续时间、稳定癌的严重程度或消除癌的一种或多种症状)的量。对于治疗用途而言,有益或所需的结果包括例如:减轻由疾病引起的一种或多种症状(生化、组织学和/或行为),包括在疾病发展期间出现的其并发症和中间病理表型;提高罹患疾病的个体的生活质量;降低治疗疾病所需的其他药物的剂量;增强另一种药物的疗效;延迟疾病的进展;和/或延长患者的生存期。
“癌症”是指由恶性肿瘤引起的任何种类的疾病。
“肝癌”:2014年,世界卫生组织发布的《世界癌症报告2014》指出,2012年中国新增肝癌病例数和死亡病例数均占全球新增病例数和死亡病例数的一半以上。2012年我国新增肝癌病例394770例,占到了全球肝癌新增病例的50%。我国肝癌死亡病例依旧居高不下,死亡率仅次于肺癌,每年约有38.3万人死于肝癌,超过全球肝癌死亡病例数的一半。现有的肝癌主要治疗手段有外科治疗、局部射频消融等,但多数患者治疗后仍会复发和转移,这是导致死亡的主要因素。慢性肝炎、肝硬化、肝癌的渐进性发展被称为肝癌三部曲。据估算,我国乙肝病毒携带者约9000万人,其中约2800万人为慢性乙肝患者。庞大的高危人群基数导致了肝癌高发病率和高死亡率。越来越多的证据表明,肝癌的发生、发展、转移和复发与机体免疫系统有密切的关系。免疫治疗,特别是细胞免疫治疗,通过调节机体免疫功能,诱导特异性肿瘤免疫,达到治疗肝癌、减少肝癌复发和转移的目的,现已成为肝癌综合治疗的重要组成部分。
“胰腺癌”:是恶性程度极高的消化道肿瘤之一,其在全球的发病率和死亡率均在逐年升高。目前临床上治疗胰腺癌的方式主要包括手术切除、放化疗。由于胰腺癌发病隐匿、病情进展快、恶性程度高等特点,患者一经发现多处于癌症的中晚期,丧失手术机会,导致患者5年生存率不足6%。为延长患者生存时间,积极探索有效的治疗方法是目前胰腺癌治疗领域亟待解决的问题。
附图说明
图1显示SDS-PAGE电泳分析和Western blot检测gp96-抗原复合物分子量结果。
图2显示本发明制备得到的T细胞对肝癌细胞HEPG2特异性杀伤实验结果。
图3显示本发明制备得到的T细胞对人胰腺癌细胞PANC-1杀伤实验结果。
图4显示雌性裸鼠尾静脉回输本发明制备得到的T细胞对肝癌肿瘤体积变化的影响。
图5显示显示雌性裸鼠尾静脉回输本发明制备得到的T细胞对胰腺癌肿瘤体积变化的影响。
具体实施方式
下面进一步结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。若未特别指明,实施例均按照常规实验条件,如Sambrook等分子克隆实验手册(Sambrook J&Russell DW,MolecularCloning:a Laboratory Manual,2001),或按照制造厂商说明书建议的条件。
以下实施例中的定量试验,均设置三次重复实验,结果取平均值。
雌性裸鼠源自北京维通利华实验动物有限责任公司产品;在实施例中简称小鼠。
HepG2细胞(人肝癌细胞)购自ATCC(美国菌种保藏中心),产品目录号为HB-8065TM。
PANC-1(人胰腺癌细胞)购自中国医学科学院基础医学研究所基础医学细胞中心,细胞株资源编号为3111C0001CCC000023。
gp96单克隆抗体为Santa Cruz公司产品,产品目录号为sc-56399。
辣根过氧化物酶标记的山羊抗大鼠的单克隆抗体为北京中杉金桥生物技术有限公司产品,产品目录号为ZB-2307。
人重组细胞因子IL-7和IL-15购自Peprotech公司,货号分别为AF-200-07-10,AF-200-15-10。
HRP标记的IgG抗体为SEROTEC公司产品,产品目录号为STAR117P。
HiTrap-Q Sepharose离子交换层析柱为GE公司产品,产品目录号为17-5053-01。
Superdex 200 10/300GL分子筛层析柱为GE公司产品,产品目录号为17517501。
ConA琼脂糖凝胶柱为GE公司产品,产品目录号为17-0440-01,填充介质为Con A-Sepharose 4B。
Hitrap Q阴离子交换柱为GE公司产品,产品目录号为17-1153-01,该柱的规格为0.7×2.5cm。
1×洗涤液为含0.1%(体积百分比)Triton-X100的pH7.4、0.01mol/L PBS缓冲液。
50kD与3kD超滤管为Merck Millipore公司产品,产品目录号分别为UFC905096、UFC500324。
研磨缓冲液:溶质及其浓度为30mM NaHCO3;溶剂为蒸馏水;pH值为7.4。
溶液A:溶质及其浓度为20mM Tris-HCl;溶剂为蒸馏水;pH值为7.4。
溶液B:溶质及其浓度为20mM Tris-HCl;1000mM NaCl;溶剂为蒸馏水;pH值为7.4。
溶液C:溶质及其浓度为20mM Tris-HCl;200mM NaCl;溶剂为蒸馏水;pH值为7.4。
BSA、PMSF、NaHCO3、MnCl2、CaCl2、NaCl2、Tris、甲基α-D-吡喃甘露糖苷均为Sigma-Aldrich公司产品,产品目录号分别为V900933、P7626、792519、V900197、793639、746398、T1378、M6882。
序列信息简表
热休克蛋白gp96的氨基酸序列:
MRALWVLGLCCVLLTFGSVRADDEVDVDGTVEEDLGKSREGSRTDDEVVQREEEAIQLDGLNASQIRELREKSEKFAFQAEVNRMMKLIINSLYKNKEIFLRELISNASDALDKIRLISLTDENALSGNEELTVKIKCDKEKNLLHVTDTGVGMTREELVKNLGTIAKSGTSEFLNKMTEAQEDGQSTSELIGQFGVGFYSAFLVADKVIVTSKHNNDTQHIWESDSNEFSVIADPRGNTLGRGTTITLVLKEEASDYLELDTIKNLVKKYSQFINFPIYVWSSKTETVEEPMEEEEAAKEEKEESDDEAAVEEEEEEKKPKTKKVEKTVWDWELMNDIKPIWQRPSKEVEEDEYKAFYKSFSKESDDPMAYIHFTAEGEVTFKSILFVPTSAPRGLFDEYGSKKSDYIKLYVRRVFITDDFHDMMPKYLNFVKGVVDSDDLPLNVSRETLQQHKLLKVIRKKLVRKTLDMIKKIADDKYNDTFWKEFGTNIKLGVIEDHSNRTRLAKLLRFQSSHHPTDITSLDQYVERMKEKQDKIYFMAGSSRKEAESSPFVERLLKKGYEVIYLTEPVDEYCIQALPEFDGKRFQNVAKEGVKFDESEKTKESREAVEKEFEPLLNWMKDKALKDKIEKAVVSQRLTESPCALVASQYGWSGNMERIMKAQAYQTGKDISTNYYASQKKTFEINPRHPLIRDMLRRIKEDEDDKTVLDLAVVLFETATLRSGYLLPDTKAYGDRIERMLRLSLNIDPDAKVEEEPEEEPEETAEDTTEDTEQDEDEEMDVGTDEEEETAKESTAEKDEL
实施例1胎盘组织gp96蛋白的提取
组织中热休克蛋白gp96(以下简称pgp96)的提取步骤如下:
(1)收集分娩后人体胎盘组织,剪碎,按质量体积比1g:4mL加入研磨缓冲液,然后用组织匀浆机制备组织匀浆;
(2)完成步骤(1)后,7000rpm离心1h,得到上清液甲。
(3)完成步骤(2)后,取上清液甲,7000rpm离心50min,得到上清液乙。
(4)完成步骤(3)后,取上清液乙,硫酸铵粗沉淀后收沉淀,按质量比1:9(g:ml)加入溶液C,混匀后得到上样液。具体操作如下:
a.上清杂蛋白去除
量取匀浆上清总体积,4℃中按29.1g硫酸铵/100ml的比例(即50%饱和硫酸铵比例)缓慢加入硫酸铵粉末,以磁力搅拌器混匀液体,确保硫酸铵迅速溶解,然后将该溶液4℃静置过夜,于4℃,7000rpm离心30min,弃去沉淀。
b.上清目的蛋白收集
量取上清体积,再按12.5g硫酸铵/100ml的比例(即70%饱和硫酸铵比例)补加硫酸铵粉末。同样缓慢加入,利用磁力搅拌器,确保硫酸铵加入后迅速溶解,于4℃静置3小时以上,7000rpm离心30分钟,收集沉淀,按沉淀:溶液C=1:9(g/ml)的比例加入溶液C溶解沉淀。
(5)完成步骤(4)后,将上样液上样至ConA琼脂糖凝胶柱。
(6)完成步骤(5)后,用溶液C冲洗所述ConA琼脂糖凝胶柱,洗脱过程中实时监测紫外吸收值,检测波长为280nm,直至洗脱产物的紫外吸收值低于0.01。
(7)完成步骤(6)后,用含α吡喃糖的溶液C洗脱所述ConA琼脂糖凝胶柱,弃去前0.5个柱体积流穿液,再收集过柱后溶液2个柱体积,此即为ConA洗脱液。
(8)完成步骤(7)后,将ConA洗脱液上样至Hitrap Q阴离子交换柱。
(9)完成步骤(8)后,用A、B液进行线性梯度洗脱,流速为1mL/min。梯度洗脱程序:线性梯度洗脱20个柱体积。洗脱过程中实时监测紫外吸收值,检测波长为280nm,收集洗脱峰,获得洗脱液甲。
(10)完成步骤(9)后,取洗脱液甲,用超滤管进行超滤浓缩,然后用PH 6.8的50mMPB缓冲液进行换液为置换液乙,将置换液乙以1ml/min~2ml/min上样CHT离子层析柱。利用A、B液进行梯度洗脱:冲洗洗脱5-10个柱体积,目的梯度洗脱收集洗脱液丙;
(11)完成步骤(10)后,取洗脱液丙进行超滤浓缩并置换至保护缓冲液中得到高纯度的gp96-抗原复合物溶液。BCA法测定gp96-抗原复合物的溶液中gp96-抗原复合物浓度为5mg/mL。
将gp96-抗原复合物的溶液进行SDS-PAGE电泳分析和Western blot(以gp96单克隆抗体作为一抗,HRP标记的IgG抗体作为二抗),实验结果见图1(泳道1为分子量标记,泳道2为gp96-抗原复合物考马斯亮蓝染色检测结果,泳道3为gp96-抗原复合物Western blot检测结果,箭头所指为gp96-抗原复合物)。结果表明,gp96-抗原复合物的溶液显示单一分子量条带,对应的分子量为96kDa,蛋白纯度大于95%。
将gp96-抗原复合物经0.3%三氟乙酸冰浴处理30分钟,促进gp96与胎盘来源抗原肽的解离。再用5kDa超滤管浓缩收集洗脱下来的多肽抗原,滴加至多肽富集芯片表面,质谱鉴定多肽序列。
经多肽芯片富集技术联合质谱鉴定,在胎盘提取的热休克蛋白gp96-抗原复合物分子鉴定出71条肿瘤抗原,氨基酸序列见Seq ID No.2~72。胎盘gp96氨基酸序列见Seq IDNo.1。
实施例2gp96-抗原复合物活化的特异性CTL
a.采集健康志愿者外周血150-200ml左右,将采集的血样转入50ml离心管,2000rpm离心5min,吸取血浆分装于50ml离心管中,将血浆放入56℃水浴锅中灭活30min,供培养DC时使用;
b.预先将淋巴细胞分离液Ficoll-Hypaque(密度1.077),加入50ml无菌离心管,20ml/管(分离单个核细胞);
c.用生理盐水将吸取血浆后的标本还原至一定体积,混匀,按体积比为1~1.5:1缓慢加在Ficoll-Hypaque上(方法:将离心管倾斜45°,在Ficoll液面以上1cm处,缓慢注入稀释血,不要打乱液面界面),2000rpm室温离心20min(注意调整离心机升降速过程为最低);
d.用平口巴氏滴管轻轻插入到单个核细胞层,沿着管壁小心吸取该层细胞转移到另一支50ml离心管中。每管加生理盐水至50ml,轻轻吹匀细胞,离心洗涤2次(第1次,室温1500r/min,7min;第2次,室温1200r/min,10min),除去血小板和分离介质;
e.将获得的外周血单个核细胞(PBMC)进行培养;
f.取一份PBMC,按浓度为2~4x106/ml铺入175cm2 Flask中,每瓶40ml,置于37℃、5%CO2培养箱中。可根据细胞数量,适当调整细胞浓度及瓶数;
g.孵育2小时后,轻晃T175培养瓶,收集悬浮细胞用于培养T细胞。再用PBS洗瓶1~2次,加入DC培养液40ml后继续置于37℃、5%CO2培养箱中。
h.第3天补加40ml/瓶DC培养基;
i.第6天加入终浓度20ng/ml的TNF-α,并取样做细菌/真菌检测;
j.第6天收集1×107DC,加入50μg gp96-抗原复合物或缓冲液作为对照,置于37℃、5%CO2培养箱中共刺激24h。将致敏得到的DC细胞连同培养基一起转入T细胞培养袋中进行联合培养,T细胞培养基补加人重组细胞因子IL-7,IL-15,工作浓度分别为10ng/ml,5ng/ml。
k.每2~3天取样计数,用含IL-7,IL-15的T细胞完全培养基补液或传代,以维持细胞浓度为2~3×106/ml;
l.收集细胞前48h取样进行无菌检测(细菌、真菌、支原体、内毒素);利用流式细胞检测CD8+T细胞的比例(CD3+CD8+T细胞/CD3+T细胞)大于90%,记忆性T细胞(CCR7-CD45RA-CD8+T细胞/CD8+T)细胞的比例大于20%。
流式细胞检测:
(1)取适量需要染色的外周血单个核细胞(不超过106个细胞),将细胞放入到1.5mL的EP管中,加入含有10%BSA的PBS封闭至少10分钟。
(2)细胞中加入1mL的PBS,1500rmp离心五分钟,弃去上清。再加入1mL的PBS将细胞重悬起来,再1500rmp离心五分钟,弃去上清。
(3)将细胞用100uL含有10%BSA的PBS重悬起来,加入CD3、CD8、CCR7和CD45RA表面染色抗体,每种抗体5μL,4℃孵育30分钟以上。
(4)细胞中加入1mL的PBS,1500rmp离心五分钟,弃去上清。再加入1mL的PBS将细胞重悬起来,再1500rmp离心五分钟,弃去上清。
(5)细胞用500μL的PBS重悬,直接上流式仪检测。
m.第14天左右收集不少于1×107的T细胞作为效应T细胞,用于体外肿瘤细胞杀伤实验。
实施例3肝癌细胞杀伤效应的检测
1、以HEPG2细胞作为靶细胞,接种靶细胞数目为5×103/孔,按照效靶比20:1,10:1,5:1的比例加入上述效应T细胞和靶细胞,效应细胞以50μ1/孔接种于96孔培养板中,终体积100μ1;
此外另设效应细胞自发LDH释放组,用来校准效应细胞自发释放出来的LDH(各组效应细胞以50μ1/孔加入96孔板,补充50μ1含5%胎牛血清的RPMI-1640培养基至终体积100μ1)。靶细胞自发LDH释放组,用来校正靶细胞自发释放出来的LDH(各组靶细胞以50μ1/孔加入96孔板,补充50μ1含5%胎牛血清的RPMI-1640培养基至终浓度100μ1)。靶细胞最大LDH释放组,用来计算时作为确定100%的LDH释放的参照(细胞上样同靶细胞自发释放组)。体积校正对照组,用来校正由于加入裂解液引起的体积变化(加入含5%胎牛血清的RPMI-1640培养基100μ1)。培养基背景对照组,用来校正由培养基中血清产生的LDH活性以及酚红造成的背景吸收(加入含5%胎牛血清的RPMI-1640培养基100μ1)。
2、细胞接种后,使用250g离心4min,接着于37℃培养箱中孵育4h;在收获上清前45min,向靶细胞最大LDH释放组中加入裂解液(10×),10μ1/孔;接着使用250g离心4min,收获上清;
3、转移50μ1上清至酶标板中,用检测缓冲液配制底物,将配好的底物50μ1/孔加到酶标板中,盖好平板,室温避光反应30min,向每孔加入50μ1终止液,1h内于酶标仪检测490nm吸光值OD。
4、计算细胞杀伤率
杀伤率(%)=[(实验组OD值-效应细胞自发释放组OD值-靶细胞自发释放组OD值)/(靶细胞最大释放组OD值-靶细胞自发释放组OD值)]×100%
细胞杀伤结果见图2。
实施例4人胰腺癌细胞杀伤效应
1、以PANC-1细胞作为靶细胞,接种靶细胞数目为5×103/孔,按照效靶比20:1,10:1,5:1的比例加入上述效应细胞,效应细胞以50μ1/孔接种于96孔培养板中,终体积100μ1;
此外另设效应细胞自发LDH释放组,用来校准效应细胞自发释放出来的LDH(各组效应细胞以50μ1/孔加入96孔板,补充50μ1含5%胎牛血清的RPMI-1640培养基至终体积100μ1)。靶细胞自发LDH释放组,用来校正靶细胞自发释放出来的LDH(各组靶细胞以50μ1/孔加入96孔板,补充50μ1含5%胎牛血清的RPMI-1640培养基至终浓度100μ1)。靶细胞最大LDH释放组,用来计算时作为确定100%的LDH释放的参照(细胞上样同靶细胞自发释放组;)。体积校正对照组,用来校正由于加入裂解液引起的体积变化(加入含5%胎牛血清的RPMI-1640培养基100μ1)。培养基背景对照组,用来校正由培养基中血清产生的LDH活性以及酚红造成的背景吸收(加入含5%胎牛血清的RPMI-1640培养基100μ1)。
2、细胞接种后,使用250g离心4min,接着于37℃培养箱中孵育4h;在收获上清前45min,向靶细胞最大LDH释放组中加入裂解液(10×),10μ1/孔;接着使用250g离心4min,收获上清;
3、转移50μ1上清至酶标板中,用检测缓冲液配制底物,将配好的底物50μ1/孔加到酶标板中,盖好平板,室温避光反应30min,向每孔加入50μ1终止液,1h内于酶标仪检测490nm吸光值OD。
4、计算细胞杀伤率
杀伤率(%)=[(实验组OD值-效应细胞自发释放组OD值-靶细胞自发释放组OD值)/(靶细胞最大释放组OD值-靶细胞自发释放组OD值)]×100%
细胞杀伤结果见图3。
实施例5对肝癌的治疗作用
取20只6-8周的雌性裸鼠,每只尾静脉回输107个实施例2制备得到的T细胞(0.5ml);回输后3天,所有小鼠皮下分别接种5×106HEPG2肝癌细胞;肿瘤接种后第2天将小鼠分成两组,每组10只,分别进行如下处理:
第一组:尾静脉回输gp96-抗原复合物活化的人T淋巴细胞,免疫三次(每次0.5ml),单次回输剂量为107/只;
第二组:尾静脉回输未刺激的人源T细胞,免疫三次(每次0.5ml),单次免疫剂量为单次回输剂量为107/只;
以上两组中:接种肿瘤细胞后第2,3,4天分别回输3次。从第一天回输开始,每天观察肿瘤生长情况,记录肿瘤大小,按以下公式计算肿瘤体积:V=ab2/2(V—体积,a—肿瘤长径,b—肿瘤短径)。肿瘤体积变化见图4。
实施例6对胰腺癌的治疗作用
取20只6-8周的雌性裸鼠,每只尾静脉回输107个实施例2制备得到的T细胞(0.5ml);回输后3天,所有小鼠皮下分别接种2×106PANC-1胰腺癌细胞;肿瘤接种后第2天将小鼠分成两组,每组10只,分别进行如下处理:
第一组:尾静脉回输gp96-抗原复合物活化的人T淋巴细胞,免疫三次(每次0.5ml),单次回输剂量为107/只;
第二组:尾静脉回输未经gp96-抗原复合物活化的人T淋巴细胞,免疫三次(每次0.5ml),单次免疫剂量为单次回输剂量为107/只;
以上两组中:接种肿瘤细胞后第2,3,4天分别回输3次。从第一天回输开始,每天观察肿瘤生长情况,记录肿瘤大小,按以下公式计算肿瘤体积:V=ab2/2(V—体积,a—肿瘤长径,b—肿瘤短径)。肿瘤体积变化见图5。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
SEQUENCE LISTING
<110> 佛山热休生物技术有限公司
<120> 活化的T细胞及其在治疗癌症中的应用
<130> IDC200472
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<170> PatentIn version 3.5
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Asn Tyr Asp Ile Pro Asn Leu Ala Lys Lys Leu Glu Glu Ile Lys Lys
1 5 10 15
Asp Leu Asp Ala Lys Lys Lys Pro Pro Ser Ala
20 25
<210> 37
<211> 23
<212> PRT
<213> artificial
<220>
<223> 抗原36
<400> 37
Ala Val Pro Met Gln His Asn Asn Arg Pro Thr Gln Pro Leu Lys Gly
1 5 10 15
Arg Thr Val Arg Ala Ser Phe
20
<210> 38
<211> 18
<212> PRT
<213> artificial
<220>
<223> 抗原37
<400> 38
Ala Ala Ile Pro Lys Asp Lys Ala Ile Leu Asp Ile Glu Arg Pro Asp
1 5 10 15
Leu Met
<210> 39
<211> 15
<212> PRT
<213> artificial
<220>
<223> 抗原38
<400> 39
Ile Arg Glu Val Ala Asn Lys Val Lys Val Pro Leu Gln Asp Leu
1 5 10 15
<210> 40
<211> 18
<212> PRT
<213> artificial
<220>
<223> 抗原39
<400> 40
Thr Lys Leu Ala Asn Pro His Tyr Gln Pro Glu Leu Gln Ala Gln Ala
1 5 10 15
Thr Leu
<210> 41
<211> 56
<212> PRT
<213> artificial
<220>
<223> 抗原40
<400> 41
Thr Pro Ala Val Pro Val Glu Ser Lys Pro Asp Lys Pro Ser Gly Lys
1 5 10 15
Ser Gly Met Asp Ala Ala Leu Asp Asp Leu Ile Asp Thr Leu Gly Gly
20 25 30
Pro Glu Glu Thr Glu Glu Glu Asn Thr Thr Tyr Thr Gly Pro Glu Val
35 40 45
Ser Asp Pro Met Ser Ser Thr Tyr
50 55
<210> 42
<211> 38
<212> PRT
<213> artificial
<220>
<223> 抗原41
<400> 42
Gly Ile Leu Gly Tyr Thr Glu His Gln Val Val Ser Ser Asp Phe Asn
1 5 10 15
Ser Asp Thr His Ser Ser Thr Phe Asp Ala Gly Ala Gly Ile Ala Leu
20 25 30
Asn Asp His Phe Val Lys
35
<210> 43
<211> 38
<212> PRT
<213> artificial
<220>
<223> 抗原42
<400> 43
Glu Pro Val Arg Thr Ser Arg Glu His Pro Val Pro Leu Leu Pro Ile
1 5 10 15
Arg Gln Thr Leu Pro Glu Asp Asn Glu Glu Pro Pro Ala Leu Pro Pro
20 25 30
Arg Thr Leu Glu Gly Leu
35
<210> 44
<211> 18
<212> PRT
<213> artificial
<220>
<223> 抗原43
<400> 44
Trp Thr Ala Asn Val Gly Lys Gly Gln Pro Ser Val Leu Gln Val Val
1 5 10 15
Asn Leu
<210> 45
<211> 20
<212> PRT
<213> artificial
<220>
<223> 抗原44
<400> 45
Pro Glu Lys Arg Pro Phe Glu Arg Leu Pro Ala Asp Val Ser Pro Ile
1 5 10 15
Asn Tyr Ser Leu
20
<210> 46
<211> 32
<212> PRT
<213> artificial
<220>
<223> 抗原45
<400> 46
Lys Pro Ala Ala Ala Ala Ala Pro Gly Thr Ala Glu Lys Leu Ser Pro
1 5 10 15
Lys Ala Ala Thr Leu Ala Glu Arg Ser Ala Gly Leu Ala Phe Ser Leu
20 25 30
<210> 47
<211> 22
<212> PRT
<213> artificial
<220>
<223> 抗原46
<400> 47
Thr Ser Trp Glu Arg Val Ser Thr Glu Val Arg Asp Tyr Val Tyr Arg
1 5 10 15
Gln Glu Ala Arg Leu Glu
20
<210> 48
<211> 32
<212> PRT
<213> artificial
<220>
<223> 抗原47
<400> 48
Ser Asp Gly Val Pro Ser Asp Ser Val Glu Ala Ala Lys Asn Ala Ser
1 5 10 15
Asn Thr Glu Lys Leu Thr Asp Gln Val Met Gln Asn Pro Arg Val Leu
20 25 30
<210> 49
<211> 21
<212> PRT
<213> artificial
<220>
<223> 抗原48
<400> 49
Met Ile Glu Gln Asn Thr Lys Ser Pro Leu Phe Met Gly Lys Val Val
1 5 10 15
Asn Pro Thr Gln Lys
20
<210> 50
<211> 25
<212> PRT
<213> artificial
<220>
<223> 抗原49
<400> 50
Lys Thr Asp Thr Ser His His Asp Gln Asp His Pro Thr Phe Asn Lys
1 5 10 15
Ile Thr Pro Asn Leu Ala Glu Phe Ala
20 25
<210> 51
<211> 30
<212> PRT
<213> artificial
<220>
<223> 抗原50
<400> 51
Glu Ala Asp Glu Arg Glu Pro Thr Glu Ser Thr Gln Gln Leu Asn Lys
1 5 10 15
Pro Glu Val Leu Glu Val Thr Leu Asn Arg Pro Phe Leu Phe
20 25 30
<210> 52
<211> 25
<212> PRT
<213> artificial
<220>
<223> 抗原51
<400> 52
Ala Leu Ala Gly Asn Gln Asp Lys Arg Lys Glu Val Leu Lys Ser Leu
1 5 10 15
Asn Glu Glu Ala Val Lys Lys Asp Asn
20 25
<210> 53
<211> 25
<212> PRT
<213> artificial
<220>
<223> 抗原52
<400> 53
Glu His Leu Ser Thr Leu Ser Glu Lys Ala Lys Pro Ala Leu Glu Asp
1 5 10 15
Leu Arg Gln Gly Leu Leu Pro Val Leu
20 25
<210> 54
<211> 38
<212> PRT
<213> artificial
<220>
<223> 抗原53
<400> 54
Gly Gly Ala Arg Leu Ala Glu Tyr His Ala Lys Ala Thr Glu His Leu
1 5 10 15
Ser Thr Leu Ser Glu Lys Ala Lys Pro Ala Leu Glu Asp Leu Arg Gln
20 25 30
Gly Leu Leu Pro Val Leu
35
<210> 55
<211> 27
<212> PRT
<213> artificial
<220>
<223> 抗原54
<400> 55
Gln Arg Gln Trp Ala Gly Leu Val Glu Lys Val Gln Ala Ala Val Gly
1 5 10 15
Thr Ser Ala Ala Pro Val Pro Ser Asp Asn His
20 25
<210> 56
<211> 21
<212> PRT
<213> artificial
<220>
<223> 抗原55
<400> 56
Ile Thr Val Lys His Arg Lys Gln Gln Val Leu Glu Thr Val Ala Gly
1 5 10 15
Lys Arg Ser Tyr Arg
20
<210> 57
<211> 35
<212> PRT
<213> artificial
<220>
<223> 抗原56
<400> 57
Glu Pro Ser Pro Gly Thr Leu Pro Arg Lys Ala Gly Val Phe Ser Asp
1 5 10 15
Leu Ser Asn Gln Glu Leu Lys Ala Val His Ser Phe Leu Trp Ser Lys
20 25 30
Lys Glu Leu
35
<210> 58
<211> 24
<212> PRT
<213> artificial
<220>
<223> 抗原57
<400> 58
Leu Glu Tyr Arg Glu Val Val Asp Gly Leu Glu Lys Ala Ile Tyr Lys
1 5 10 15
Gly Pro Gly Ser Glu Ala Gly Pro
20
<210> 59
<211> 24
<212> PRT
<213> artificial
<220>
<223> 抗原58
<400> 59
Lys Leu Ser Asn Asn Ala Leu Ser Gly Leu Pro Gln Gly Val Phe Gly
1 5 10 15
Lys Leu Gly Ser Leu Gln Glu Leu
20
<210> 60
<211> 20
<212> PRT
<213> artificial
<220>
<223> 抗原59
<400> 60
Pro Ala Leu Gln Gly Ala Gln Thr Lys Met Ser Ala Ser Asp Pro Asn
1 5 10 15
Ser Ser Ile Phe
20
<210> 61
<211> 28
<212> PRT
<213> artificial
<220>
<223> 抗原60
<400> 61
Thr Glu Glu Asp Lys Ala Thr Ile Thr Ser Leu Trp Gly Lys Val Asn
1 5 10 15
Val Glu Asp Ala Gly Gly Glu Thr Leu Gly Arg Leu
20 25
<210> 62
<211> 27
<212> PRT
<213> artificial
<220>
<223> 抗原61
<400> 62
Val Leu Ser Pro Ala Asp Lys Thr Asn Val Lys Ala Ala Trp Gly Lys
1 5 10 15
Val Gly Ala His Ala Gly Glu Tyr Gly Ala Glu
20 25
<210> 63
<211> 29
<212> PRT
<213> artificial
<220>
<223> 抗原62
<400> 63
Val Gly Asn Lys Ser Asp Leu Arg His Leu Arg Ala Val Pro Thr Asp
1 5 10 15
Glu Ala Arg Ala Phe Ala Glu Lys Asn Asn Leu Ser Phe
20 25
<210> 64
<211> 19
<212> PRT
<213> artificial
<220>
<223> 抗原63
<400> 64
Ile Lys Gln Leu Ala Lys Ser Val Arg Asp Arg Tyr Ala Arg Ser Pro
1 5 10 15
Lys Glu Lys
<210> 65
<211> 21
<212> PRT
<213> artificial
<220>
<223> 抗原64
<400> 65
Ala Ala Pro Ser Glu Pro Ser Glu Pro Ser Arg Pro Ser Pro Gln Pro
1 5 10 15
Lys Pro Arg Thr Pro
20
<210> 66
<211> 42
<212> PRT
<213> artificial
<220>
<223> 抗原65
<400> 66
Arg Ser Trp Ser Pro Thr Gly Glu Arg Leu Gly Glu Asp Pro Tyr Tyr
1 5 10 15
Thr Glu Asn Gly Gly Gly Gln Gly Tyr Ser Ser Gly Pro Gly Thr Ser
20 25 30
Pro Glu Ala Gln Gly Lys Ala Ser Val Asn
35 40
<210> 67
<211> 35
<212> PRT
<213> artificial
<220>
<223> 抗原66
<400> 67
Ser Asn Glu Asn His Gly Ile Ala Gln Arg Ile Tyr Gly Asn Gln Asp
1 5 10 15
Thr Ser Ser Gln Leu Lys Lys Phe Tyr Asn Gln Val Ser Thr Pro Leu
20 25 30
Leu Arg Asn
35
<210> 68
<211> 27
<212> PRT
<213> artificial
<220>
<223> 抗原67
<400> 68
Leu Ser Ser Trp Leu Gln Ser Asp Asp Glu Pro Glu Lys Glu Arg Leu
1 5 10 15
Arg Gln Arg Ala Gln Ala Leu Ala Val Ser Tyr
20 25
<210> 69
<211> 23
<212> PRT
<213> artificial
<220>
<223> 抗原68
<400> 69
Ile Ala Asn Met Pro Glu Ser Gly Pro Ser Tyr Glu Phe His Leu Thr
1 5 10 15
Arg Gln Glu Ile Val Ser Leu
20
<210> 70
<211> 34
<212> PRT
<213> artificial
<220>
<223> 抗原69
<400> 70
Phe Ser Glu Thr Gly Ala Gly Lys His Val Pro Arg Ala Val Phe Val
1 5 10 15
Asp Leu Glu Pro Thr Val Ile Asp Glu Val Arg Thr Gly Thr Tyr Arg
20 25 30
Gln Leu
<210> 71
<211> 47
<212> PRT
<213> artificial
<220>
<223> 抗原70
<400> 71
Thr Val Thr Asp Tyr Gly Lys Asp Leu Met Glu Lys Val Lys Ser Pro
1 5 10 15
Glu Leu Gln Ala Glu Ala Lys Ser Tyr Phe Glu Lys Ser Lys Glu Gln
20 25 30
Leu Thr Pro Leu Ile Lys Lys Ala Gly Thr Glu Leu Val Asn Phe
35 40 45
<210> 72
<211> 32
<212> PRT
<213> artificial
<220>
<223> 抗原71
<400> 72
Val Lys Ser Pro Glu Leu Gln Ala Glu Ala Lys Ser Tyr Phe Glu Lys
1 5 10 15
Ser Lys Glu Gln Leu Thr Pro Leu Ile Lys Lys Ala Gly Thr Glu Leu
20 25 30
Claims (10)
1.一种热休克蛋白gp96-抗原复合物,其通过以下方法制备得到:
将离体动物组织(例如,人或非人哺乳动物的胎盘组织或肿瘤组织)的匀浆液依次经ConA-Sepharose凝胶柱层析、HiTrap Q离子交换层析以及CHT离子交换层析分离得到所述热休克蛋白gp96-抗原复合物。
2.权利要求1所述的热休克蛋白gp96-抗原复合物,其制备方法特征在于下述的一项或多项:
(1)所述离体动物组织的匀浆液经下述方法制备得到:将离体动物组织按质量(g)-体积(ml)比1:4~1:8的比例加入10~50mM、pH值为6~8的NaHCO3溶液中研磨,得所述组织匀浆液;
(2)在分离前,还包括将所述组织匀浆液按下述步骤初步提纯的操作:
步骤1-1:将所述组织匀浆液低温(例如,2~6℃)离心,取上清;
优选地,将所述组织匀浆液在2~6℃,1000rpm~10000rpm离心0.5h~1h,收集上清,任选地,将收集到的上清在2~6℃,1000rpm~10000rpm再次离心0.5h~1h,取上清;
步骤1-2:采用硫酸铵分级沉淀法,将步骤1-1所得上清在低温条件下(例如,2~6℃)加入硫酸铵,收集硫酸铵浓度为50%~70%时所得沉淀,得初提物;优选地,按质量(g)-体积(ml)比1:(2~20)的比例用含50~200mM NaCl的5~50mM Tris-HCl溶液溶解所得沉淀;
(3)所述ConA-Sepharose凝胶柱层析包括以下步骤:
步骤2-1:将所述初提物上样至ConA-Sepharose凝胶柱;
步骤2-2:用含50~200mM NaCl的5~50mM Tris-HCl溶液洗脱至检测波长为280nm时洗脱产物紫外吸收低于0.01;
步骤2-3:用含8%α-吡喃糖苷、50~200mM NaCl的5~50mM Tris-HCl溶液继续洗脱,收集洗脱液(优选地,收集第0~3个(例如,0.5~2个)柱体积的流穿液),得ConA-Sepharose分离物;
(4)所述HiTrap Q离子交换层析包括以下步骤:
步骤3-1:将所述ConA-Sepharose分离物上样至HiTrap Q离子交换柱;
步骤3-2:用5~50mM Tris-HCl清洗HiTrap Q离子交换柱;
步骤3-3:用含NaCl(300mM~1000mM)的5~50mM Tris-HCl洗脱,收集洗脱液至检测波长为280nm时洗脱产物吸光度值低于100mA;任选地,将收集到的洗脱液浓缩(例如,超滤浓缩)并用pH 6~8的20~100mM磷酸盐缓冲液稀释,得HiTrap Q分离物;
(5)所述CHT离子交换层析包括以下步骤:
步骤4-1:将所述HiTrap分离物上样至CHT离子交换柱;
步骤4-2:用5~50mM PB清洗CHT离子交换柱;
步骤4-3:用含300mM~1000mMPB洗脱,收集洗脱液至吸光度值低于100mA;任选地,将收集到的洗脱液浓缩(例如,超滤浓缩)并用pH 6~8的5~50mM磷酸盐缓冲液稀释,得所述热休克蛋白gp96-抗原复合物。
3.权利要求1或2的热休克蛋白gp96-抗原复合物,其中所述抗原选自如Seq ID No.2~72所示的多肽中的一种或多种(例如,1种以上、5种以上、10种以上、15种以上、20种以上、25种以上、30种以上、35种以上、40种以上、45种以上、50种以上、55种以上、60种以上、65种以上或70种以上),所述多肽为肿瘤相关抗原或肿瘤组织中高表达蛋白;
优选地,所述复合物纯度为80%以上,例如85%以上,90%以上,91%以上,92%以上,93%以上,94%以上,95%以上,96%以上,97%以上,98%以上或99%以上。
4.一种T细胞群体,其通过以下方法制备得到:
用权利要求1-3任一项所述的热休克蛋白gp96-抗原复合物体外致敏DC细胞和T细胞,获得所述T细胞群体。
5.权利要求4所述的T细胞群体,其制备方法包括以下步骤:
(1)诱导单核细胞群体分化为树突细胞群体;
(2)将所述树突细胞群体与权利要求1-3任一项所述的热休克蛋白gp96-抗原复合物体接触,获得活化的树突细胞群体;
(3)将所述活化的树突细胞群体与非黏附PBMC群体共培养,获得所述T细胞群体;
所述单核细胞群体和所述非黏附PBMC群体来源于个体的PBMC群体,例如志愿者个体或者需要接受治疗的个体。
6.权利要求5所述的T细胞群体,其制备方法进一步具有下述一种或多种特征:
1)在步骤(2)中,按10~100μg/1×107个树突细胞的比例加入所述热休克蛋白gp96-抗原复合物;
2)在步骤(3)中,进一步包括使所述T细胞群体与多种细胞因子接触的步骤,所述细胞因子包括IL-7和IL-15;优选地,IL-7和IL-15工作浓度独立地为1~20ng/ml,例如1ng/ml、2ng/ml、3ng/ml、4ng/ml、5ng/ml、6ng/ml、7ng/ml、8ng/ml、9ng/ml、10ng/ml、11ng/ml、12ng/ml、13ng/ml、14ng/ml、15ng/ml、16ng/ml、17ng/ml、18ng/ml、19ng/ml、或20ng/ml。
7.权利要求4-6任一项所述的T细胞群体,其中CD3+CD8+T细胞/CD3+T细胞比例大于80%,例如大于85%,大于90%,大于91%,大于92%,大于93%,大于94%,大于95%,大于96%,大于97%,大于98%或大于99%;
优选地,CCR7-CD45RA-CD8+T细胞/CD8+T细胞比例大于10%,例如大于15%,大于20%,大于25%,或者大于30%;
优选地,所述T细胞群体对IFN-γ的细胞内表达呈阳性。
8.一种药物组合物,其含有权利要求4-7任一项所述的T细胞群体,以及一种或多种药学上可接受的载体。
9.权利要求8所述的药物组合物,其为注射剂(例如,注射液或者冻干粉针剂);
优选地,单位剂量T细胞含量不少于1×104个(例如不少于1×104个,不少于3×104个,不少于5×104个,不少于7×104个,不少于1×105个,不少于3×105个,不少于5×105个,不少于7×105个,不少于1×106个,不少于3×106个,不少于5×106个,不少于7×106个,不少于1×107个,不少于3×107个,不少于5×107个,不少于7×107个,不少于1×108个,不少于3×108个,不少于5×108个,不少于7×108个,不少于1×109个,不少于3×109个,不少于5×109个,不少于7×109个,不少于1×1010个,不少于3×1010个,不少于5×1010个或不少于7×1010个,又例如1×105~1×108个)。
10.权利要求4-7任一项所述的T细胞群体在制备抗肿瘤药物中的用途;
优选地,所述药物可减缓或停止已建立的肿瘤病灶的生长;
优选地,所述肿瘤选自肝癌和胰腺癌。
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