Roberts Stanley A, Andrews Paul A, Blanset Diann, Flagella Kelly M, Gorovits Boris, Lynch Carmel M, Martin Pauline L, Kramer-Stickland Kimberly, Thibault Stephane, Warner Garvin
SAR Safety Assessment, 14677 Via Bettona, Suite #100 - 432, San Diego, CA 92127, USA.
Regul Toxicol Pharmacol. 2013 Dec;67(3):382-91. doi: 10.1016/j.yrtph.2013.08.017. Epub 2013 Sep 5.
Antibody drug conjugates (ADCs) include monoclonal antibodies that are linked to cytotoxic small molecules. A number of these agents are currently being developed as anti-cancer agents designed to improve the therapeutic index of the cytotoxin (i.e., cytotoxic small molecule or cytotoxic agent) by specifically delivering it to tumor cells. This paper presents primary considerations for the nonclinical safety evaluation of ADCs and includes strategies for the evaluation of the entire ADC or the various individual components (i.e., antibody, linker or the cytotoxin). Considerations are presented on how to design a nonclinical safety assessment program to identify the on- and off-target toxicities to enable first-in-human (FIH) studies. Specific discussions are also included that provide details as to the need and how to conduct the studies for evaluating ADCs in genetic toxicology, tissue cross-reactivity, safety pharmacology, carcinogenicity, developmental and reproductive toxicology, biotransformation, toxicokinetic monitoring, bioanalytical assays, immunogenicity testing, test article stability and the selection of the FIH dose. Given the complexity of these molecules and our evolving understanding of their properties, there is no single all-encompassing nonclinical strategy. Instead, each ADC should be evaluated on a case-by-case scientifically-based approach that is consistent with ICH and animal research guidelines.
抗体药物偶联物（ADC）包括与细胞毒性小分子相连的单克隆抗体。目前正在研发多种此类药物作为抗癌药物，旨在通过将细胞毒素（即细胞毒性小分子或细胞毒性药物）特异性递送至肿瘤细胞来提高其治疗指数。本文介绍了ADC非临床安全性评价的主要考虑因素，并包括评价整个ADC或各个单独组分（即抗体、连接子或细胞毒素）的策略。阐述了如何设计非临床安全性评估方案以识别靶向和非靶向毒性，从而开展首次人体试验（FIH）研究。还进行了具体讨论，详细说明了在遗传毒理学、组织交叉反应性、安全药理学、致癌性、发育和生殖毒理学、生物转化、毒代动力学监测、生物分析测定、免疫原性检测、受试物稳定性以及FIH剂量选择等方面评估ADC所需开展的研究及如何进行这些研究。鉴于这些分子的复杂性以及我们对其性质的不断深入了解，不存在单一的全面非临床策略。相反，应根据具体情况，采用基于科学的方法对每个ADC进行评估，该方法应符合国际人用药品注册技术协调会（ICH）和动物研究指南。
