The Icarian flight of antibody-drug conjugates: target selection amidst complexity and tackling adverse impacts.

Journal: Protein & cell
Published Date: Jul 19, 2025

Abstract

Antibody-drug conjugates (ADCs) represent a promising class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads. Despite their therapeutic potential, the use of ADCs faces significant challenges, including off/on-target toxicity and resistance development. This review examines the current landscape of ADC development, focusing on the critical aspects of target selection and antibody engineering. We discuss strategies to increase ADC efficacy and safety, including multitarget approaches, pH-dependent antibodies, and masked peptide technologies. The importance of comprehensive antigen expression profiling in both tumor and normal tissues is emphasized, highlighting the role of advanced technologies, such as single-cell sequencing and artificial intelligence, in optimizing target selection. Furthermore, we explore combination therapies and innovations in linker‒payload chemistry, which may provide approaches for expanding the therapeutic window of ADCs. These advances pave the way for the development of more precise and effective cancer treatments, potentially extending ADC applications beyond oncology.

Authors

  • Han Liu
    Shenzhen Key Laboratory of Photonic Devices and Sensing Systems for Internet of Things, Guangdong and Hong Kong Joint Research Centre for Optical Fibre Sensors, State Key Laboratory of Radio Frequency Heterogeneous Integration, Shenzhen University, Shenzhen 518060, China.
  • Hongye Zeng
    State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China.
  • Xiaojing Qin
    State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China.
  • Wenjing Ning
    State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China.
  • Lin Xu
    Key Laboratory of Grain and Oil Processing and Food Safety of Sichuan Province, College of Food and Bioengineering, Xihua University Chengdu 610039 China xingyage1@163.com.
  • Shiting Yang
    State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China.
  • Xue Liu
    Center for Brain-Inspired Computing Research (CBICR), Beijing Innovation Center for Future Chip, Optical Memory National Engineering Research Center, Department of Precision Instrument, Tsinghua University, Beijing 100084, China.
  • Wenxin Luo
    Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.
  • Ningshao Xia

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