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目的:通过对食蟹猴静脉重复给药抗HER2人源化单克隆抗体,进行其临床前安全性评价,为临床设计人用剂量及临床毒副反应的监测提供参考依据。方法:将食蟹猴随机分为4组,分别为溶媒对照组、低(15 mg·kg-1)、中(50 mg·kg-1)和高(150 mg·kg-1)剂量组,每组8只动物,雌雄各半。静脉注射给药,每周1次,连续8周,恢复期为4周,分别在检疫期、首次给药后、给药结束以及恢复期的不同时间点进行动物的临床症状、体温、体重、摄食量、血压、心电图、尿液学、血液学、血清生化以及组织病理等各项毒理学指标检测。结果:多次静脉注射给药,各组动物的临床症状、体重、摄食量、体温、心电图、血压、尿液分析和血液学检测均未发现与供试品相关的异常改变。血清生化结果显示中、高剂量组动物在给药期间以及给药结束后出现血清IgG水平上升以及白蛋白与球蛋白比下降的变化。与溶媒对照组相比较,中、高剂量组动物的血清肌酐及尿素氮(BUN)的极轻微升高。但各组动物与其自身检疫期的测定结果相比,无显著差异。组织病理学分析显示在不同剂量给药组动物发现脾脏和腹股沟淋巴结生发中心出现易染体巨噬细胞增多现象。结论:食蟹猴连续静脉注射抗HER2人源化抗体,总体上动物具有良好的剂量耐受性,但BUN轻微升高也提示进入临床试验时应密关注机体肾功能指标的变化,这些研究结果为国产人源化抗HER2单克隆抗体进入临床试验奠定了基础。
OBJECTIVE: To evaluate the preclinical safety of anti-HER2 humanized monoclonal antibody by repeated administration of veins in cynomolgus monkeys to provide a reference for the clinical design of human dosage and clinical toxicity monitoring. Methods: The cynomolgus monkeys were randomly divided into 4 groups: vehicle control group, low (15 mg · kg -1), medium (50 mg · kg -1) and high (150 mg · kg -1) Eight animals in each group, half male and half female. Intravenous injection, once a week for 8 weeks, convalescence for 4 weeks, respectively, in the quarantine period, after the first administration, the end of administration and recovery time points at different time points for animal clinical symptoms, body temperature, Food intake, blood pressure, electrocardiogram, urology, hematology, serum biochemistry and histopathology and other toxicological indicators detection. Results: There were no abnormal changes associated with the test product in the intravenous administration. The clinical symptoms, body weight, food intake, body temperature, electrocardiogram, blood pressure, urinalysis and hematological examination of the animals in each group were not found. Serum biochemical results showed that the serum IgG level increased and the ratio of albumin and globulin decreased after administration and at the end of administration. Compared with the vehicle control group, serum creatinine and urea nitrogen (BUN) in the medium and high dose groups increased slightly. However, there was no significant difference between each group of animals and the results of their own quarantine period. Histopathological analysis showed that in the different doses of animals found in the spleen and inguinal lymph node germinal center prone to edema macrophage phenomenon. Conclusions: Cynomolgus monkeys injected with anti-HER2 humanized antibody continuously have good dose tolerance in general. However, a slight increase in BUN also suggests that the clinical indicators of renal function should be closely followed when entering clinical trials. These findings The domestic humanized anti-HER2 monoclonal antibody entered the clinical trial laid the foundation.