A Supramolecular Self-assembly Approach to Site-Specific Antibody Conjugates

Antibody conjugates play a central role across multiple healthcare sectors with a prime example being antibody-drug conjugates (ADCs). Although widely used lysine and hinge cysteine conjugation methods yield products, the lack of site-specificity and spatial control along with the highly heterogeneous composition are significant limitations. We describe a facile supramolecular assembly method based on heterodimer coiled-coil formation for site-specific antibody conjugation. The method affords uniform loading of diverse payloads including anti-cancer agents, polymers, enzymes, fluorophores, etc. under mild aqueous conditions. Further, the facile convergent approach capitalizes on the independent strengths and flexibility of protein expression and peptide chemistry culminating in a final self-assembly step. Coiled-coil conjugation perseveres both antibody antigen binding sites for target engagement and heavy chains constant domains for Fc binding and recycling. An ADC loaded with monomethyl auristatin E targeting HER2+ tumors significantly reduces tumor volume in a human ovarian cancer xenograft model outperforming the antibody alone with validated performance against a best-in-class therapeutic. Supramolecular assembly-driven bioconjugation expands the bioorthogonal chemistry toolbox for antibody modification and opens new avenues for advanced antibody conjugates with multiple payloads.