Boron-Rich Biologics Enabled by Reactive Organic Carboranes

Carboranes are endowed with unique structural and electronic features and are applied across diverse research areas. General methods for their high-content incorporation, however, remain limited. We report the development of organic carborane reagents based on N-hydroxysuccinimide (NHS) esters as a versatile platform for selective conjugation to amine-containing residues of small molecules and polypeptides. Bifunctional carborane reagents obtained by this method enable peptide-driven multimerization into carborane-peptide polymers, an original class of hybrid materials. Therapeutic antibodies functionalized with these reagents yield boron-rich conjugates containing up to 13 carboranes per antibody molecule that retain native antibody activity. Linker length is critical for maximizing loading efficiency. Mass spectrometry mapping revealed up to 30 preferential lysine modification sites per antibody, located outside the complementarity-determining region(s). Prevalence-ranked lysine mapping of IgG antibodies under native-like conditions using NHS esters bearing hydrophobic (carborane) substituents provides a useful framework for the rational design and optimization of antibody-drug conjugates. These constructs, integrating therapeutic antibody targeting features with boron delivery capabilities, hold promise as multimodal agents for boron neutron capture therapy (BNCT).