摘要
抗体偶联药物(ADC)是由抗体、有效载荷(细胞毒性小分子化合物)和连接子组成的新型特异性抗肿瘤药物。ADC具有高特异性和不良反应少等特点,但其安全性受到抗体特异性、连接子稳定性和有效载荷性质等因素的影响。ADC的剂量限制性毒性主要与有效载荷有关,且在临床和非临床研究中具有很好的相关性。ADC的毒性机制包括靶向毒性和脱靶毒性,靶向毒性主要由靶点的表达决定,脱靶毒性则由偶联不稳定和非特异性摄取等因素引起。简要概述ADC的毒性机制,重点介绍ADC非临床安全性评价中的毒性病理学检查关注点,以期为我国ADC非临床安全性评价提供一定参考。
Antibody-drug conjugate drug(ADC)are novel specific anti-tumor drugs composed of antibodies,payloads(cytotoxic small molecule compounds)and linkers.ADC is characterized by high specificity and few side effects,but their safety is affected by factors such as antibody specificity,stability of linker,and nature of payload.The dose-limiting toxicity of ADC is mainly related to the payload and has been well correlated in clinical and nonclinical studies.The toxicity mechanism of ADC includes on-target toxicity and off-target toxicity.On-target toxicity is mainly determined by the expression of the target,whereas off-target toxicity is caused by factors such as coupling instability and non-specific uptake.The toxicity mechanism of ADC is briefly reviewed,and the toxicologic pathology examination during nonclinical safety evaluation of ADC is emphasized,so as to provide some references for the nonclinical safety evaluation of ADC in China.
作者
田爱军
李佳霖
汪春娅
张浩琳
李玲
雷亚萍
项玉
李一昊
李言川
吕建军
TIAN Aijun;LI Jialin;WANG Chunya;ZHANG Haolin;LI Ling;LEI Yaping;XIANG Yu;LI Yihao;LI Yanchuan;LYU Jianjun(Hubei Topgene Xinsheng Biotechnology Co.,Ltd.,Wuhan 430207,China)
出处
《药物评价研究》
CAS
北大核心
2024年第8期1678-1686,共9页
Drug Evaluation Research
基金
基于AI的创新药物研发服务平台项目。
关键词
抗体偶联药物
非临床安全性评价
靶向毒性
脱靶毒性
毒性病理学
antibody-drug conjugate
nonclinical safety evaluation
on-target toxicity
off-target toxicity
toxicologic pathology
