单克隆抗体及基于抗体类药物组织交叉反应研究现状及关注点

单克隆抗体及基于抗体类药物组织交叉反应是药物临床前安全性评价的重要组成部分,是国内外药品监管机构如美国FDA、EMEA、ICH及CFDA的要求,其主要目的是发现供试品和靶抗原以外表位结合,即交叉反应,并发现既往未发现的靶位结合,为临床试验毒副作用的监控提供参考。目前,主要使用体外免疫组织化学的方法,在正常人及实验动物组织评估有无交叉反应,要求在新药临床申请Ⅰ期临床试验前完成。组织交叉反应使用供试品作为一抗,存在技术挑战,有时技术上不可行。本文主要对国内外组织交叉反应研究现状及关注点,包括相关指导原则、技术挑战、试验设计、结果判断、报告书写及存在问题进行综述,以期为我国药物临床前安全性评价单克隆抗体及基于抗体类药物组织交叉反应研究提供一定的参考。

Tissue cross reactivity (TCR)studies of monoclonal antibodies and antibody-based therapeutics are not only an important part of the preclinical safety evaluation of drugs but also the requirement of the regulatory agencies of China and other countries or organizations,such as US FDA,EMEA,ICH as well as CFDA.The purpose of TCR studies is to identify off-target binding(i.e.cross reactivity)and sites of on-target binding that has not been previously reported of the test article,and to provide references for the monitoring of the adverse effects of clinical trial.So far,TCR studies were mainly carried out prior to dosing patients using the in vitro immunohistochemistry (IHC)staining method in normal human and experimental animal tissues,and the results were filed with the initial investigational new drug/clinical trial application (IND/CTA)to support first-in-human clinical trials.Since the test article is adopted as primary antibody in TCR studies,there are many technical challenges and sometimes might not be technically feasible.We comprehensively reviewed the current status,such as guidelines,technical challenges,experimental design,interpretation and reporting,and the existing problems of TCR studies and they may provide some references for the TCR studies of monoclonal antibodies and antibody-based therapeutics during preclinical safety evaluation of drugs in China.