Advances in Antibody–Drug Conjugate Conjugation: Methods, Challenges, and Improvements

Antibody-drug conjugates (ADCs) are targeted biopharmaceuticals that constitutes monoclonal antibody selectivity with the cytotoxic strength of small-molecule drugs. Over the past decades, a growing number of reagents and studies have been proposed, and substantial progress has been achieved in improving conjugate homogeneity, linker chemistry, and payload design. One of the typical conjugation methods, maleimide-thiol conjugation, has been proposed in the first-generation ADCs, and the problems related to retro-Michael conjugation have been tackled by the study of succinimide ring hydrolysis. Apart from that, a wide range of reagents and new linkers for disulfide bond re-bridging have been studied as well. This mini-review summarises these core strategies, critically examining their mechanistic principles, limitations, and recent innovations that collectively shape the evolution of next-generation ADC design.