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

Han LIU; Hongye ZENG; Xiaojing QIN; Wenjing NING; Lin XU; Shiting YANG; Xue LIU; Wenxin LUO; Ningshao XIA

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

Author: Han LIU ¹ ; Hongye ZENG ¹ ; Xiaojing QIN ¹ ; Wenjing NING ¹ ; Lin XU ¹ ; Shiting YANG ¹ ; Xue LIU ¹ ; Wenxin LUO ¹ ; Ningshao XIA ¹
Author Information

1. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China.
Publication Type:Review
Keywords: antibody-drug conjugates; normal and tumor tissue; off-target toxicity; response strategies; target selection
MeSH: Humans; Immunoconjugates/adverse effects*; Neoplasms/immunology*; Animals; Antibodies, Monoclonal/therapeutic use*; Antineoplastic Agents/therapeutic use*
From: Protein & Cell 2025;16(7):532-556
CountryChina
Language:English
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.