Recent advances in Camptothecin-derived antibody-drug conjugates.

Antibody-drug conjugates (ADCs) represent a major advance in precision cancer therapy by combining the high target specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads through chemical linkers. Among the payload classes topoisomerase I (Topo I) inhibitors, camptothecin and its derivatives have emerged as highly promising warheads owing to their distinct mechanism of action and strong antitumor activity. The clinical success of Enhertu and Trodelvy, which employ the camptothecin-derived payloads DXd and SN-38, respectively, has validated the therapeutic potential of camptothecin-based ADCs and accelerated the development of next-generation candidates. This review summarizes recent progress in camptothecin-based ADCs since 2021, with a focus on strategies for payload modification of camptothecin derivatives, and linker optimization. In addition, current limitations of camptothecin-based ADCs, including resistance and insufficient efficacy, are discussed together with emerging solutions such as combination strategies and dual-payload ADCs. This review is expected to provide a useful framework for the rational design and further development of camptothecin-based ADCs.