biostudies-literatureUnknown18(3)Koehler CEuropean Research CouncilVERAXA Biotech GmbHDue 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 imagiACS chemical biology443-448https://www.ebi.ac.uk/biostudies/studies/S-EPMC10029752biostudies-literatureGenetic Code Expansion for Site-Specific Labeling of Antibodies with Radioisotopes.PMC10029752Pektor SWaldmann CBausbacher NKoehler CSauter PFKlasen BLemke EAMiederer MfalseGenetic 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 imagi2023-01-01T00:00:00Z2023 Mar2025-04-18T15:29:04.915Z2025-04-07T02:12:35.555ZS-EPMC100297523688967810.1021/acschembio.2c00634