New linker structures applied in glycosite-specific antibody drug conjugates†
Glycosite-specific antibody drug conjugates (ADCs) allow selective conjugation of a small-molecule payload onto the conserved N-glycan of Asn297 of antibody Fc domains, and lead to a highly homogeneous structure in specific conjugation site and fixed drug-to-antibody ratio (DAR), which are crucial for pharmacokinetics, pharmacodynamics and efficacy of the ADCs. The limited structural diversity of linkers in glycosite-specific ADCs is due to the scarcity of efficient chemistry for IgG glycan conjugation. Herein we describe two new linkers, 2-aminobenzamidoxime and mercaptoethylpyrazolone, which rapidly, efficiently and selectively react with aldehyde-tagged N-glycan after IgG glycoengineering. The constructed novel glycosite-specific ADCs demonstrated excellent anti-tumor cytotoxicity and fluorescence properties or enhanced stability.