Genetic Code Expansion for Site-Specific Labeling of Antibodies with Radioisotopes

Due to their target specificity, antibody-drug conjugates─monoclonal antibodies conjugated to a cytotoxic moiety─are efficient therapeutics that can kill malignant cells overexpressing a target gene. Linking an antibody with radioisotopes (radioimmunoconjugates) enables powerful diagnostics and/or closely related therapeutic applications, depending on the isotope. To generate site-specific radioimmunoconjugates, we utilized genetic code expansion and subsequent conjugation by inverse electron-demand Diels-Alder cycloaddition reactions. We show that, using this approach, site-specific labeling of trastuzumab with either zirconium-89 (⁸⁹Zr) for diagnostics or lutetium-177 (¹⁷⁷Lu) for therapeutics yields efficient radioimmunoconjugates. Positron emission tomography imaging revealed a high accumulation of site-specifically ⁸⁹Zr-labeled trastuzumab in tumors after 24 h and low accumulation in other organs. The corresponding ¹⁷⁷Lu-trastuzumab radioimmunoconjugates were comparably distributed in vivo.