Site-Specific Glycan Conjugation Improves Stability and Efficacy of an Antibody–Drug Conjugates Bearing DXd as a Cytotoxic Payload

This study developed a homogeneous ADC via site-specific conjugation of a potent antitumor agent, a camptothecin derivative, to the N-glycan in the Fc domain of an antibody, achieving a drug-to-antibody ratio (DAR) of 4. The resulting glycan-conjugated ADC exhibited improved thermal stability, reduced aggregation, and reduced premature payload release in human plasma. Despite utilizing the same antibody and payload, this glycan-linked ADC outperformed a clinically approved cysteine-conjugated homogeneous ADC (DAR 8) in vivo.