最低预期生物效应剂量法在免疫调节类药物临床起始剂量设计中应用的研究现状

Current status of research on the application of the minimal anticipated biological effect level method in the design of clinical starting doses of immunomodulatory drugs

首次临床试验起始剂量的拟定是药物从临床前推进到临床阶段的关键节点。免疫调节类药物因其对机体免疫系统的调控,可引发包括细胞因子风暴、过敏等严重免疫相关毒性。在TGN1412事件发生后,传统的以毒理学终点为基础的临床起始剂量计算在免疫调节类药物中的应用面临很大挑战。本文结合欧洲药品管理局、美国食品药品监督管理局对高风险药物首次临床试验的指南,以及国家药品监督管理局药品审评中心发表的相关电子刊物,总结了最低预期生物效应剂量(minimum expected biological effect dose,MABEL)法出现的背景、发展趋势以及基于MABEL法的临床起始剂量计算考量要素等。最后,以免疫激活药白细胞介素-2和CD3:hEGFRvⅢ双特异性抗体、免疫抑制药CD28单克隆抗体等临床在研药物为案例,介绍了其基于MABEL法的首次人体试验剂量的设计过程,旨在为免疫调节类药物提供重要参考。

The formulation of the starting dose for the first-in-human trial is a critical point in the advancement of a drug from preclinical to clinical phase.Immunomodulatory drugs can trigger serious immune-related toxicities including cytokine storm and allergy due to their modulation of the body’s immune system.In the wake of TGN1412,the application of traditional clinical starting dose calculations based on toxicological endpoints in immunomodulatory drugs has faced great challenges.In this study,we summarize the background of the emergence of the minimum expected biological effect dose(MABEL) method,the development trend,and the consideration elements of the clinical starting dose calculation based on the MABEL method,taking into account the guidelines of the European Medicines Agency and the US Food and Drug Administration for the first clinical trials of high-risk drugs,as well as the relevant electronic publications published by the National Medical Products Administration.Finally,the design process of first-in-human trial doses based on the MABEL method is introduced with the case studies of the immune activator interleukin-2 and CD3:hEGFRvⅢ bispecific antibodies,and the immunosuppressant CD28 monoclonal antibody,aiming to provide a pivotal reference for immunomodulatory drugs.