CD40 免疫检查点人源化小鼠的制备及在抗体药物研究中的应用

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。

Establishment of CD40 Immune Checkpoint Humanized Mice and Their Application in Antibody Drug Research #br# #br#

Abstract: 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 preclinicalpharmacodynamics study and safety evaluation of CD40 antibody. Method B-hCD40 mice was constructed byCRISPER / 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 activatedmonoclonal antibodies were evaluated. Result Human CD40 was only expressed in B-hCD40, and the ratio ofdifferent 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 andkidney toxicity of the antibody. Conclusion In our study, B-hCD40 were successfully prepared, which is aneffective animal model for evaluating the efficacy and safety of CD40 antibody drugs.