The Evolving Landscape of Enzymatic Technologies for Precision Synthesis of Antibody-Drug Conjugates

Precise control over how and where small-molecule drugs are covalently attached to monoclonal antibodies is increasingly vital for creating consistently efficacious and safe antibody-drug conjugates (ADCs) as powerful targeted therapies. Enzymatic conjugation methods have gained considerable attention for their abilities to efficiently install payloads at defined locations under mild and predictable conditions. This work provides a comprehensive review of current enzymatic technologies for site-specific ADC construction, organized by the biological origin of enzymes. Among various enzyme-based conjugating approaches, a special focus is given to the emerging ADP-ribosyl cyclase-enabled ADC (ARC-ADC) platform. By utilizing genetically fused CD38, a member of the ARC family, together with its dinucleotide-derived inhibitor, site-specific ADCs with defined drug-to-antibody ratios in varied formats could be facilely produced with demonstrated efficacy and specificity in preclinical models of different types of cancer. Unlike most enzymatic methods requiring recognition tags or external catalytic steps, ARC-ADC provides a fully integrated, modular strategy for streamlined ADC discovery and development.