Duocarmycin-based antibody-drug conjugates as an emerging biotherapeutic entity for targeted cancer therapy: Pharmaceutical strategy and clinical progress

  • Drug Discov Today. 2021 Aug;26(8):1857-1874. doi: 10.1016/j.drudis.2021.06.012.
Hang-Ping Yao  1 ,  Hui Zhao  2 ,  Rachel Hudson  3 ,  Xiang-Min Tong  4 ,  Ming-Hai Wang  5
Affiliations
  • 1. 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. Electronic address: [email protected].
  • 2. Office of Scientific Research, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address: [email protected].
  • 3. Cancer Biology Research Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA; Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
  • 4. Department of Hematology, Zhejiang Provincial People's Hospital and People's Hospital of Hangzhou Medical College, Hangzhou, China. Electronic address: [email protected].
  • 5. 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; Cancer Biology Research Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA; Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA. Electronic address: [email protected].
PMID: 34224904 DOI: 10.1016/j.drudis.2021.06.012
Abstract

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.

Keywords
Antibody–drug conjugate; Clinical trials; Cytotoxic payload; Drug targets; Duocarmycins; Linker chemistry; Monoclonal antibody; Pharmacokinetics; Preclinical development; Therapeutic efficacy; Toxicological activity.
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