抗CD20人源化单克隆抗体的急性毒性评价  

Evaluation of acute toxicity of humanized anti-CD20 monoclonal antibody

作　　者：周晓冰[1] 林志[1] 李正东 孙立[1] 齐卫红[1] 沈连忠[1] 王超[1] 苗玉发[1] 刘芳[1] 王越[1] 杨艳伟[1] 李保文[1] 王雪[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：《中国生物制品学杂志》2012年第8期995-998,共4页Chinese Journal of Biologicals

基　　金：十一五"重大新药创制"科技重大专项(2008ZX09305-002)

摘　　要：目的评价抗CD20人源化单克隆抗体SM09的急性毒性。方法将食蟹猴随机分为阴性对照组、SM09 10、30和100 mg/kg剂量组,采用注射泵前臂静脉缓慢注射单次给药,阴性对照组给予等体积的生理盐水,于给药前和给药后不同时间进行各项毒理学指标检测。结果食蟹猴注射SM09,在给药速度达600 mg/h时,动物未见明显异常反应;给药后各剂量组动物临床症状、体重、进食量、体温、心电图、血压、血清生化指标均未见明显异常;血液学检测结果显示,100 mg/kg剂量组动物白细胞数量出现一过性降低;给药后第2天,各剂量组动物外周血CD20+B淋巴细胞数量即明显降低,B细胞表现出耗竭状态,给药后3～8周,B细胞水平逐渐回复,且呈剂量相关性。给药后8周剖检,100 mg/kg剂量组雌性动物脾脏呈暗红色且体积增大,镜检可见红髓扩张充血和脾小体数量减少。结论食蟹猴单次静脉注射抗CD20单抗,具有良好的耐受性,除与药理作用相关的外周血B细胞清除效应外,未见其他毒性反应,最大耐受剂量可达100 mg/kg。Objective To evaluate the acute toxicity of humanized anti-CD20 monoclonal antibody.Methods Cynomolgus monkeys were randomly divided into one negative control and three test groups.The monkeys in three test groups were injected i.v.slowly with SM09 at dosages of 10,30 and 100 mg / kg using injection pump respectively,while those in negative control group with physiological saline at the same volume.Toxicological indexes of animals before and at various time points after injection were determined.Results No obviously abnormal reactions were observed in animals injected with SM09 at a rate of 600 mg / h.No obvious abnormalities were observed in clinical symptoms,bodyweights,food consumptions,body temperatures,ECGs,blood pressures or biochemical indexes in sera of animals in various test groups.Haematological test showed transient decrease of leukocyte count in animals injected with 100 mg / kg SM09.On day 2 after injection,the CD20＋ B lymphocyte counts in peripheral blood of animals in various groups decreased significantly,and the B lymphocytes were nearly exhausted.However,the B lymphocytes increased gradually 3 ~ 8 weeks after injection,in a dose-dependent mode.Dissection showed that the spleens of female animals 8 weeks after injection were dark red in color and increased in size,while hyperemia in red marrow and decrease in splenic corpuscle numbers were found under microscope.Conclusion A single intravenous injection with anti-CD20 monoclonal antibody was well tolerated in Cynomolgus monkeys,with a maximum tolerated dose of 100 mg / kg.Except the circulating B cell depletion,no other toxic reactions observed.

关 键 词：CD20 人源化单克隆抗体 急性毒性 安全性 

分 类 号：R392.33[医药卫生—免疫学]