食蟹猴静脉注射重组人鼠嵌合抗EGFR单克隆抗体AV02重复给药毒性研究

发布时间：2018-05-14 11:56

本文选题：重组人鼠嵌合抗EGFR单克隆抗体 + 食蟹猴　；参考：《中国新药杂志》2017年13期

【摘要】：目的:评价食蟹猴静脉重复注射重组人鼠嵌合抗EGFR单克隆抗体AV02的安全性,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、AV02低、中和高(12/7.5,38/24,120/75 mg·kg~(-1))剂量组,每组8只,雌雄各半。静脉注射给药,每周1次,连续26周,恢复12周,进行各项毒理学指标检测。结果:AV02多次静脉给药,临床观察可见各剂量组动物皮肤均出现皮疹、干燥粗糙、红斑、脱屑、龟裂、脱毛等反应,病理组织学检查也出现相应的皮肤损伤。中、高剂量组在给药期13,26周可引起ALB,A/G降低,ALT,γ-GT,GLDH升高,恢复期可恢复;并可引起肾脏脏器重量和脏器系数高于对照组。免疫原性检查中,低剂量组有1例动物检出抗药性抗体。除上述反应外,摄食量、体重、体温、血液学、免疫球蛋白、心电图、血压、尿液分析、骨髓、眼科检查均未见与受试物相关的改变。结论:食蟹猴连续静脉注射AV02 26周,主要毒性反应为与药理作用相关的皮肤毒性、可逆性的肝脏功能性损伤、代偿性肾脏增大及发生率极低的免疫原性反应,提示临床试验时应密切关注上述指标的变化。这些研究结果为国产重组人鼠嵌合抗EGFR单克隆抗体进入临床试验奠定了基础。
[Abstract]:Objective: to evaluate the safety of recombinant human mouse chimeric monoclonal antibody (AV02) against EGFR by repeated intravenous injection of crab monkey, and to provide a reference for the monitoring of human dose and clinical toxicity. Methods: Carnivorous monkeys were randomly divided into 4 groups: medium control group (n = 8), control group (n = 8, male and female, n = 8), low AV02 (n = 8, n = 8), control group (n = 8, n = 8), medium control group (n = 8, n = 8). Every toxicology index was detected by intravenous injection once a week for 26 weeks and 12 weeks after recovery. Results the skin rash, dryness and roughness, erythema, detritus, cleavage, depilation and histopathological examination were observed in every dose group. In high dose group, ALB A / G decreased ALT, 纬 -GT G LDH increased, and kidney organ weight and organ coefficient were higher in high dose group than in control group at 1326 weeks after administration. In the immunogenicity test, one animal in the low dose group detected drug-resistant antibodies. In addition to the above reactions, no changes were found in food intake, body weight, body temperature, hematology, immunoglobulin, electrocardiogram, blood pressure, urine analysis, bone marrow, and ophthalmology. Conclusion: after continuous intravenous injection of AV02 for 26 weeks, the main toxic reactions were skin toxicity associated with pharmacological action, reversible liver functional damage, compensatory renal enlargement and very low incidence of immunogenicity. It is suggested that the changes of the above indexes should be paid close attention to in clinical trials. These results laid a foundation for the clinical trial of recombinant human mouse chimeric monoclonal antibody against EGFR.
【作者单位】：广东省生物资源应用研究所广东省动物保护与资源利用重点实验室广东省野生动物保护与利用公共实验室;广东莱恩医药研究院有限公司;佛山安普泽生物医药有限公司;
【基金】：广东省科学院创新药物安全性评价研究团队(2016GDASRC-0104);广东省科学院领军人才(2016GDASRC-0206);广东省科学院科技发展专项(2017GDASCX-0107)
【分类号】：R392-33

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