摘要
目的:对食蟹猴单次静脉注射重组人-鼠嵌合抗CD20单克隆抗体IBI301,观察其产生的急性毒性反应,为评价药物的安全性及重复给药毒性研究剂量设计和主要观察指标提供参考。方法:实验设溶媒对照组和IBI301给药组,每组2只动物,雌雄各半。给药组动物先给予100 mg·kg^(-1)剂量的IBI301,动物能耐受该剂量,2周后对该组动物单次给予160 mg·kg^(-1)的剂量,溶媒对照组动物也在同一时间再次给予溶媒。实验期间观察动物的临床症状、注射部位刺激性,测定体重、摄食量、体温、心电,进行血液学、血液凝固和血清生化检查、CD20^+/CD40^+细胞测定,二次给药结束后2周对所有实验动物进行解剖和大体病理学检查,对发现的异常病变采集组织样本进行组织病理学检查。结果:食蟹猴分别单次静脉注射100和160 mg·kg-1的IBI301,未引起异常临床症状,未影响食蟹猴摄食量和体重增长,引起外周血B淋巴细胞显著减少或消失、脾脏中度白髓淋巴细胞减少。IBI301对其他检测指标均未见明显影响。结论:食蟹猴能耐受静脉注射160mg·kg^(-1)剂量的IBI301,除观察到与药效作用相关的改变外,未见其他明显的毒性作用。本研究同时为重复给药毒性研究设计提供了重要参考。
Objective： To investigate the acute toxicity of IBI301, the engineered chimeric murine/human anti-CD20 monoclonal antibody, through single intravenous injection of the test article in cynomolgus monkeys, and provide references for the safety evaluation of the drug and the design of the dose level and endpoint of repeated dose toxicity composed of IBI301 by in 2 weeks late study. Methods： Two groups were set： vehicle control and IBI301 treatment group. Each group was 1 male monkey and 1 female monkey. The animals in the treatment group were given 100 mg·kg-1 travenous infusion first, and it was tolerated. Then single dose of 160 mg·kg-1 IBI301 was administered r. The control animals were given vehicle control again at the same time. During the study, eachanimal was observed for clinical signs and injection site irritations. Body weights, food consumption, body temperature, and electrocardiogram were measured. Hematology, coagulation, and serum chemistry examinations were conducted. CD20 ~/CDd0 ~ cells were determined by flow cytometry. A full necropsy was conducted 2 weeks post the last dose on all the animals, macroscopic examination was performed, and the abnormal tissues were collected and processed for microscopic examination. Results： IBI301 did not cause abnormal clinical signs, and had no effect Single dose of 100 mg·kg-1 and 160 mg·kg-1 on body weight gain and food consumption. IBI301 induced significant decrease or depletion of B lymphocytes in peripheral blood and decrease in lymphocytes in white pulps of spleen. No obvious abnormality was found in other end points. Conclusion： Cynomolgus monkeys can tolerate 160 mg·kg-1 IBI301 given by intravenous infusion. No obvious abnormality was found except for the changes related to therapeutic effects. This study also supplied reference for the design of repeated dose toxicity study of the test article
出处
《中国新药杂志》
CAS
CSCD
北大核心
2016年第17期1953-1959,共7页
Chinese Journal of New Drugs
基金
国家“重大新药创制”科技重大专项资助项目(2015ZX09501007-004)
关键词
重组人-鼠嵌合抗CD20单克隆抗体
急性毒性研究
食蟹猴
engineered chimeric murine/human anti-CD20 monoclonal antibody
acute toxicity study
cynomolgus monkeys
