文章摘要
王欣,张琳,杨莹,齐卫红,姜华,林志,王海彬,耿兴超.重组抗CD52单克隆抗体的食蟹猴单次静脉注射毒性研究[J].中国药事,2022,36(10):1147-1165
重组抗CD52单克隆抗体的食蟹猴单次静脉注射毒性研究
A Study on Single Dose Toxicity of Recombinant Anti-CD52 Humanized Monoclonal Antibody Injection in Cynomolgus Monkeys
  
DOI：10.16153/j.1002-7777.2022.10.007
中文关键词: CD52抗原  单克隆抗体  食蟹猴  单次给药毒性  安全性评价
英文关键词: CD52 antigen  monoclonal antibody  cynomolgus monkey  single dose toxicity  safety assessment
基金项目:国家“重大新药创制”科技重大专项(编号 2018ZX09201-017)
作者单位
王欣 中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京 100176 
张琳 中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京 100176 
杨莹 中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京 100176 
齐卫红 中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京 100176 
姜华 中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京 100176 
林志 中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京 100176 
王海彬 浙江海正药业股份有限公司,台州 318000 
耿兴超 中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京 100176 
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中文摘要:
      目的：开展食蟹猴静脉注射重组抗CD52人源化单克隆抗体注射液单次给药毒性研究，考察动物体内耐受性、给药后出现的毒性反应及严重程度和药物毒性作用靶器官，评价其安全性。方法：首先应用流式细胞术检测方法，筛选出8只红细胞表面CD52抗原阴性食蟹猴，用于单次给药毒性研究。将动物随机分成4组，包括溶媒对照组和3、10、30 mg·kg-1剂量组，每组2只，雌雄各半。采用静脉推注给药，给药1次。试验期间，每天观察动物的临床症状和摄食量，每周称量1次体质量。分别在给药第2、 8、15 d采集动物外周血液进行临床病理检查，包括血液学(含凝血)、血清生化(含电解质)。分别在给药第2、6、8、15、21 d采集动物外周血液进行T淋巴细胞及亚群和B淋巴细胞的分类计数。于给药第 22 d解剖动物并进行大体病理学检查。结果：动物给药后，在10 mg·kg-1和30 mg·kg-1剂量下，会引起白细胞总数、淋巴细胞、单核细胞数量和比例、T淋巴细胞数量及其亚群细胞数量下降，这些变化与药物的免疫抑制作用相关。受试物还会引起血红蛋白浓度下降，网织红细胞数量和比例和总胆红素升高。 结论：给予食蟹猴单次静脉注射3、10、30 mg·kg-1重组抗CD52人源化单克隆抗体注射液后，动物耐受良好，最大耐受量是30 mg·kg-1。本研究的给药剂量以及与药物相关的毒性发现，为后续开展长期毒性研究提供了参考。
英文摘要:
      Objective: To conduct a study on single dose toxicity of recombinant anti-CD52 humanized monoclonal antibody injection in cynomolgus monkeys in order to investigate the tolerance of the animals, toxicity and severity of the injection and target organs of drug toxicity, and then the safety was evaluated. Methods: Eight cynomolgus monkeys with CD52 antigen negative on erythrocyte surface were selected by fl ow cytometry screening for the single dose toxicity study. All monkeys were randomly divided into four groups, including the vehicle control group and 3, 10, 30 mg·kg-1 dose groups with 2 monkeys in each group, one male and the other female. The drug was administered intravenously for once. During the trial period, clinical symptoms and food intake by animals were observed every day. Body weight was measured once a week. On the 2nd, 8th, and the 15th day, the peripheral blood of animals were collected for clinical pathological examination, including hematology (coagulation included) and serum biochemistry (electrolyte included). On the 2nd, 6th, 8th, 15th and the 21st day, peripheral blood were sampled for counting the T lymphocyte, subsets and B lymphocytes. On the 22nd day after administering drugs, animals were necropsied, and gross pathological examination was performed. Results: Decrease in leukocyte, lymphocyte, monocytequantity and proportion, T lymphocyte and its subsets were found in 10 mg·kg-1 and 30 mg·kg-1 test groups after administering drugs. These changes were considered as related to the immunosuppression of the drug. The test article also caused increases in reticulocyte quantity and proportion and total bilirubin and decrease in hemoglobin concentration. Conclusion: After the cynomolgus monkeys were administrated with 3, 10, 30 mg·kg-1 recombinant anti-CD52 humanized monoclonal antibody injections, the test article was well tolerated in animals. The maximum tolerance dose was 30 mg·kg-1. The doses and the related toxicological fi ndings of this study provide references for a future long-term toxicity study.
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