抗HER2人源化单克隆抗体的重复给药毒性研究  

Repeated dose toxicity of humanized anti-HER2 monoclonal antibody

作　　者：周晓冰[1] 孙立[1] 盛晓丽 霍桂桃[1] 苗玉发[1] 朱聪[1] 杨艳伟[1] 霍艳[1] 王雪[1] 汪巨峰[1] 李波[1] 

机构地区：[1]中国食品药品检定研究院国家药物安全评价监测中心,北京100176 [2]北京天广实生物技术股份有限公司,北京101111

出　　处：《中国新药杂志》2016年第1期36-41,共6页Chinese Journal of New Drugs

摘　　要：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 humanized anti-HER2 monoclonal antibody in cynomolgus monkeys following repeated-doses of intravenous administration,and provide evidences for determining clinical human dosage and monitoring of clinical adverse drug reactions. Methods： Cynomolgus monkeys were randomly divided into four groups including vehicle control,low-,middle-,and high-dose of humanized anti-HER2 monoclonal antibody groups（ 15,50 and 150 mg·kg-1）. Each group contained eight monkeys with female and male in half. All the animals were intravenously given vehicle or test drug every week continuously for 8 weeks followed by a 4-week recovery phase. Then a series of toxicologic parameters including clinical signs,body temperature,weight,food consumption,blood pressure,electrocardiogram,urinalysis,hematology,serum biochemistry and histopathologic analysis were determined during the quarantine period,after the first dosing,at the end of dosing and during the recovery period,respectively. Results： Following repeated intravenous administration of test articles,there were no obvious abnormalities in clinical signs,weight,food consumption,body temperature,electrocardiogram,blood pressure,urinalysis and hematology analysis in all the groups. Serum biochemical analysis showed Ig G level increase and ratio of albumin and globulin decrease in animals in the medium-and high-dosegroups during dosing period and after administration. Compared with the control group,serum BUN and CRE levels were slightly elevated in animals in the middle-and high-dose groups,but no significant differences were observed in comparison with results from the quarantine period. Histopathological analysis found increased tingible-body macrophage in spleen and inguinal lymph node germinal centers in the test article-treated groups. Conclusion： Repeated intravenous dosing of anti-HER2 monoclonal antibody was well tolerated in cynomolgus monkeys,and no obvious toxicological responses were found. But slight increase of BUN sugg

关 键 词：抗HER2人源化单克隆抗体 食蟹猴 重复给药毒性 免疫毒性 

分 类 号：R965.3[医药卫生—药理学]