Fluoro arylsulfates: Kinetic analysis reveals new possibilities with sulfatase-cleavable linkers in ADCs

Abstract

Antibody-drug conjugates (ADCs) consisting of monoclonal antibodies covalently conjugated to cytotoxic agents via engineered chemical linkers enable targeted delivery of cytotoxic payloads directly to tumor cells, minimizing off-target effects. It is generally accepted that further advancement in the ADC field is increasingly constrained by the linker technology. Arylsulfate linkers were found to be promising candidates for solving current limitations with linkers strategies. Aiming to further advance sulfatase-cleavable linkers, we designed sulfatase-responsive linker-fluorophore probes and determined enzyme affinity and turnover number for each probe. Having identified a sulfatase-cleavable probe with improved cleavage kinetics, we incorporated it in an ADC and demonstrated efficient killing of cancer cells in vitro.