State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Office of Scientific Research, Zhongnan Hospital of Wuhan University, Wuhan, China.
Drug Discov Today. 2021 Aug;26(8):1857-1874. doi: 10.1016/j.drudis.2021.06.012. Epub 2021 Jul 3.
Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody-drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status. Nevertheless, progress in duocarmycin-based ADCs also faces challenges, with setbacks including the termination of BMS-936561/MDX-1203. In this review, we discuss issues associated with the efficacy, pharmacokinetic profile, and toxicological activity of these biotherapeutics. Furthermore, we summarize the latest advances in duocarmycin-based ADCs that have different target specificities and linker chemistries. Evidence from preclinical and clinical studies has indicated that duocarmycin-based ADCs are promising biotherapeutics for oncological application in the future.
道诺霉素是一类 DNA 小沟结合的烷化分子。在过去的十年中，各种道诺霉素类似物已被用作抗体药物偶联物 (ADC) 的有效载荷。目前，已有超过 15 种基于道诺霉素的 ADC 进行了临床前研究，其中一些，如 SYD985，已被授予快速通道指定地位。然而，基于道诺霉素的 ADC 的进展也面临挑战，包括 BMS-936561/MDX-1203 的终止。在这篇综述中，我们讨论了这些生物疗法的疗效、药代动力学特征和毒理学活性相关的问题。此外，我们总结了基于道诺霉素的 ADC 的最新进展，这些 ADC 具有不同的靶向特异性和连接子化学。临床前和临床研究的证据表明，基于道诺霉素的 ADC 是未来肿瘤学应用有前途的生物疗法。
