Monoclonal antibodies with excellent selectivity and a broad collection of targets have important applications in both research and therapy, but require modification by fluorophores, drugs and other biological reagents before use. Current antibody conjugation methods include non-specific reactions with nucleophilic residues, such as lysine and tyrosine, which result in heterogeneous products. Other methods require additional antibody engineering to introduce a reactive tag for site-specific modifications, but often suffer from high expense and low yield. To carry out site-specific antibody labeling without antibody engineering or UV/chemical treatment, we developed a novel proximity-induced site-specific antibody modification method (pClick). A noncanonical amino acid was introduced into an antibody affinity peptide to react with a proximal lysine residue on the antibody Fc domain and form a covalent linkage upon binding.To explore the applications of our method, a fluorophore-conjugated antibody complex was constructed to visualize Her2 receptors on breast cancer cells. The successful labeling of Her2 positive cells indicated pClick’s potential for diagnostic applications. Additionally, we crosslinked the bone-targeting drug alendronate to an affinity peptide to make antibody-drug conjugates. The cytotoxicity experiments revealed a significant decrease of tumor size upon injection which demonstrated pClick’s broad prospects for bone cancer and bone metastasis treatment. Our studies establish the proximity-based approach as a powerful technique in the toolbox for native antibody modifications.

Proximity induced site-specific antibody conjugation and modification for breast cancer imaging and bone cancer therapy

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.