Recent Advances in Peptide Linkers of Antibody–Drug Conjugates

Antibody-drug conjugates (ADCs) represent a promising class of cancer therapeutics. This innovative molecular design perfectly integrates the targeting and extended half-life of antibodies with the cytotoxicity of small molecules, enabling the selective delivery of payloads to cancer cells. The linker molecule is crucial to the efficacy of an ADC. Although ADC linkers can be cleavable or noncleavable, most approved ADCs utilize cleavable peptide linkers. These linkers, cleaved by enzymes such as cathepsin, plasmin, or legumain, balance the stability of ADCs in the circulatory system with selective release of the cytotoxic payload in tumors. Linker chemistry has thus become a highly important and integral part of the ADC development. In this perspective, we elucidate the role of peptide linkers in the ADC development, highlight advancements in peptide linkers, and provide insights on future directions for ADC linker designs.