Linker Strategies in Antibody-Drug Conjugates: Insights from HER2-Targeted ADCs

In tumors with alterations of human epidermal growth factor receptor 2 (HER2), conventional monoclonal antibodies and tyrosine kinase inhibitors (TKIs) are limited by intratumoral heterogeneity and acquired resistance. Antibody-drug conjugates (ADCs) take advantage of the selectivity of monoclonal antibodies to deliver highly efficient cytotoxins and rely on linkers to achieve spatiotemporal controlled release. Representative HER2-targeted ADCs can be roughly divided into three examples. The first is trastuzumab emtansine (T-DM1), which uses a non-cleavable linker to attach the maytansinoid DM1. The second example is trastuzumab drutecan (T-DXd), which uses the Gly-Gly-Phe-Gly cleavable linker for conjugation with topoisomerase I inhibitors (DXd). Recently, SHR-A1811 introduced a payload carrying a chiral cyclopropyl group, which provided different stability. These improvements enable the drug to be released more controllably within tumor cells and expand the indications from patients with high HER2 expression to those with low HER2 expression or even HER2 mutations. Among these drugs, the linker is no longer merely a simple "bridge"; it also determines the degree of exposure to the load, the way the drug is released in the body, and even affects the toxicity that patients may face. This review summarizes the development of HER2-targeted ADCs, with a focus on the evolution of linker strategies and their impact on efficacy and safety, with the aim of providing ideas for the future design of HER2-targeted ADCs.