Methods for the Generation of Single-Payload Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) have emerged as a powerful form of targeted therapy that can deliver drugs with a high level of selectivity towards a specific cell type, reducing off-target effects and increasing the therapeutic window compared to small molecule therapeutics. However, creating ADCs that are stable, homogeneous, and with controlled drug-to-antibody ratio (DAR) remains a significant challenge. Whilst a myriad of methods have been reported to generate ADCs with a DAR of 2, 4, and 8, strategies to generate DAR 1 constructs are seldom reported despite the advantages of low drug loading to tune ADC properties or to allow access to antibody-antibody and antibody-protein constructs. This concept article highlights the diversity of methods that have been employed to access single-payload ADCs and explores the outlook for the field.