混合活化杀伤免疫细胞临床前毒性伴随生物分布研究  

Pre-Clinical Toxicity Evaluation Accompanied with Biodistribution of Mixed Activated Killer Immune Cells

作　　者：赵曼曼 姜丽君 王超[1] 霍桂桃[1] 姜华[1] 贲亮 李超 侯田田 王三龙[1] 耿兴超[1] 周晓冰[1] ZHAO Manman;JIANG Lijun;WANG Chao;HUO Guitao;JIANG Hua;BEN Liang;LI Chao;HOU Tiantian;WANG Sanlong;GENG Xingchao;ZHOU Xiaobing(Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs,Institute for Safety Evaluation,National Institutes for Food and Drug Control,Beijing 100176,China;Tuohua Bio-technology Co.,Ltd.,Siping 136001,China)

机构地区：[1]中国食品药品检定研究院安全评价研究所,药物非临床安全评价研究北京市重点实验室,北京100176 [2]吉林省拓华生物科技有限公司,吉林四平136001

出　　处：《中国药学杂志》2024年第20期1881-1888,共8页Chinese Pharmaceutical Journal

基　　金：国家重点研发计划课题资助(2021YFA1101602)。

摘　　要：目的 评价肿瘤患者血液来源的混合活化杀伤(mixed activated killer, MAK)免疫细胞在免疫缺陷小鼠体内的安全性及生物分布特征。方法 使用免疫缺陷NOG小鼠,尾静脉注射给予MAK细胞9次,末次给药后持续观察28 d,考察小鼠临床症状、体质量和摄食量变化、血液学和血清生化指标、细胞因子指标和组织病理学变化特点,同时伴随考察MAK在外周血及各组织脏器分布特征。结果 MAK细胞对小鼠临床症状、注射部位、体质量和摄食量无明显影响,小鼠血清可检测到人源干扰素-γ,MAK细胞体外输注可导致小鼠外周血淋巴细胞百分比、单核细胞百分比、白细胞数升高,嗜碱性粒细胞百分比降低,全身多数组织脏器可见混合细胞聚集。给予MAK细胞28 d后,小鼠全身多数组织出现MAK细胞的大量扩增。结论 MAK细胞在免疫缺陷NOG小鼠体内增殖并引起机体免疫应答反应,未见明显毒性反应风险。本研究数据可为相关产品非临床安全性评价提供借鉴。OBJECTIVE To evaluate the safety and biodistribution characteristics of mixed activated killer(MAK)immune cells derived from the blood of tumor patients in immunodeficient mice.METHODS Immunodeficient NOG mice were injected with MAK cells 9 times via the tail vein.The mice were observed continuously for 28 d after the last administration.The clinical symptoms,body weight,food intake,hematological and serum biochemical indexes,cytokine indexes and histopathological changes in mice were investigated.In the meanwhile,the distribution characteristics of MAK cells in peripheral blood and various tissues and organs were investigated.RESULTS MAK cells had no significant effect on clinical symptoms,the injection site,body weight and food intake in mice,and could increase the level of human interferon gamma in serum of mice.MAK cells could elevate lymphocytes%,monocytes%,white blood cells and decrease basophils%in peripheral blood.Mix cell aggregates were observed in most organs.Massive expansion of MAK cells was observed in most tissues of mice after administration of MAK cells for 28 d.CONCLUSION MAK cells could proliferate and induce immune responses in immunodeficient NOG mice without obvious toxic reactions.Given the above,the data of this study can provide a reference for the non-clinical safety evaluation of related products.

关 键 词：混合活化杀伤免疫细胞 免疫缺陷小鼠 毒性评价 生物分布 

分 类 号：R96[医药卫生—药理学]