Chemical evolution of antibody-drug conjugates focused on linker design and conjugation strategies in hematology.

Antibody-drug conjugates (ADCs) have transformed the treatment of hematologic malignancies by coupling antibody selectivity with potent cytotoxic payloads. Their clinical performance depends largely on chemical design, particularly linker stability and conjugation strategy. Advances in site-specific and site-selective platforms, such as ThioMab, GlycoConnect, AJICAP, and AbClick, enable homogeneous ADCs with controlled drug-to-antibody ratio (DAR) and improved safety. Cleavable linkers-protease-sensitive, acid-labile, and redox-responsive-facilitate intracellular drug release, while non-cleavable and solubility-enhancing designs improve stability and pharmacokinetics (PK). Case studies of FDA-approved ADCs, including brentuximab vedotin, polatuzumab vedotin, inotuzumab ozogamicin, and loncastuximab tesirine, demonstrate how these innovations translate into therapeutic benefit. Nonetheless, challenges such as antigen heterogeneity, resistance mechanisms, and off-target toxicities persist. By integrating advances in conjugation chemistry, linker engineering, and payload selection, next-generation ADCs are poised to expand efficacy and safety in hematologic oncology and further refine targeted therapy in blood cancers.