食蟹猴静脉注射抗CD20功能人源化单克隆抗体SM09重复给药毒性研究  

Toxicity of functionally humanized anti-CD20 monoclonal antibody SM09 for cynomolgus monkey following repeated intravenous administration

作　　者：周晓冰[1] 李正东 孙立[1] 齐卫红[1] 杨艳伟[1] 王秀文[1] 梁瑞安 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]香港中国抗体制药有限公司,香港999077

出　　处：《中国新药杂志》2012年第6期616-622,共7页Chinese Journal of New Drugs

基　　金：国家"重大新药创制"科技重大专项(2008ZX09305-002)

摘　　要：目的:评价食蟹猴静脉重复给药抗CD20功能人源化单克隆抗体SM09的安全性。方法:将食蟹猴随机分为溶媒对照组,SM09低、高剂量组(25,50 mg.kg-1),每组6只,静脉注射给药,每周1次,连续8周,恢复期12周,进行各项毒理学指标检测。结果:除个别动物偶见呕吐外,体重、进食量、体温、尿、心电图、骨髓细胞计数等均未显示与供试品相关的改变。SM09给药后能够诱导动物产生快速深度的外周血B细胞清除,至恢复期结束,多数动物外周血中B细胞水平恢复正常。给药4周,动物血液白细胞及淋巴细胞下降,之后逐渐回升。给药结束时动物补体C4水平略有降低。组织病理学检查结果除药理学作用相关的改变外,未见其他与供试品相关的改变。结论:食蟹猴连续静脉注射SM09,总体上具有良好的剂量耐受性,除观察到与药理作用相关的效应外,未见其他毒性反应。Objective： To evaluate the preclinical toxicity of a functionally humanized anti-CD20 monoclonal antibody SM09 for cynomolgus monkeys following repeated intravenous administration. Methods： Cynomol- gus monkeys were randomly divided into vehicle control, SM09 low dose and high dose groups （25, 50 mg.kg^- 1 ）. All animals were intravenously given vehicle or SM09 once a week for 8 weeks followed by 12-week recovery. Toxicological parameters were determined. Results： There were no obvious abnormalities in body weight, food consumption, body temperature, electrocardiogram, bone marrow cell counts and urine that could be attributed to the administration of SM09, despite the observation of incidental vomitting in one of the animals tested. SM09 induced a rapid and in-depth peripheral B cell depletion in cynomolgus monkeys. Upon the cessation of SM09 administration, B cell counts in the peripheral blood in the majority of the treated animals returned to normal level, except for a few whose B cell counts remained partially depleted. Although transient decreases in white blood cell and lymphocyte counts were noted on week 4 after treatments, their levels returned to normal at the end of the study. Furthermore, the level of complement C4 in the SM09 group was found to be slightly lower than that of the control group Other than the d could be attribut ep ed letion of B cells and induction of lymphoid follicular atrophy, no histopathological findings that to SM09 were found. Conclusion： Repeated intravenous dosing of anti-CD20 monoclonal anti- body was well tolerated by cynomolgus monkeys. Except for pharmacologically-related reactions, as manifested in the form of peripheral CD20 positive B cell depletion and ses were found.

关 键 词：抗CD20单克隆抗体 食蟹猴 临床前安全性 毒性 

分 类 号：R965.3[医药卫生—药理学]