摘要
目的实验动物模型是生物药物开发领域包括肿瘤学研究、抗体药物开发、临床前药效及安全评价等的一种重要工具。制备CD40人源化小鼠能够为CD40抗体的临床前药效、药理研究和安全性评价提供更多的可能。方法利用CRISPER/Cas9系统制备获得CD40人源化小鼠后,通过RT-PCR以及流式细胞术检测CD40人源化小鼠表达人CD40情况。基于CD40人源化小鼠建立肿瘤模型并评价CD40激动剂单克隆抗体的药效作用和安全性。结果CD40人源化小鼠只表达人CD40,并且各淋巴细胞比例与野生型小鼠对比没有明显改变。CD40单克隆抗体作用后能够显著抑制肿瘤生长,发挥药效同时引起的小鼠体质量下降可能与药物作用后引起的小鼠肝脏和肾脏毒副作用有关。结论本研究成功制备了CD40人源化小鼠,是CD40抗体药物作用效果和安全性评价的一种有效动物模型。
Objective Laboratory animal model is an important tool in the field of biological drug development,including oncology research,antibody drug development and preclinical efficacy and safety evaluation.The aim of this study is to prepare CD40 humanized mice(B-hCD40)and provide more possibilities for preclinical pharmacodynamics study and safety evaluation of CD40 antibody.Method B-hCD40 mice was constructed by CRISPER/Cas9 system.Then the expression of human CD40 was detected by RT-PCR and flow cytometry.A tumor model was well established basing on B-hCD40.Meanwhile,anti-tumor efficacy and safety of CD40 activated monoclonal antibodies were evaluated.Result Human CD40 was only expressed in B-hCD40,and the ratio of different lymphocytes had no significant differences compared to wild-type mice.CD40 monoclonal antibody could significantly inhibit tumor growth.The weight loss of mice of the treatment group may be caused by the liver and kidney toxicity of the antibody.Conclusion In our study,B-hCD40 were successfully prepared,which is an effective animal model for evaluating the efficacy and safety of CD40 antibody drugs.
作者
张静
张赞
赵磊
郭雅南
黄蕤
许立达
ZHANG Jing;ZHANG Zan;ZHAO Lei;GUO Yanan;HUANG Rui;XU Lida(Beijing University of Chemical Technology,Beijing 100029,China;Beijing Biocytogen Co.,Ltd.,Beijing 101111,China)
出处
《实验动物科学》
2021年第3期10-16,28,共8页
Laboratory Animal Science
基金
国家“十三五重大新药创制”科技重大专项(2019ZX09721001-007-002)。
