{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["36(8)"],"submitter":["Grimaldi C"],"pubmed_abstract":["A growing body of preclinical and clinical evidence has shown that site-specifically and site-selectively modified immunoconjugates exhibit improved <i>in vivo</i> performance compared to their stochastically modified cousins. However, extant approaches to site-specific bioconjugation suffer from a variety of issues that make clinical translation challenging, including instability, complexity, and expense. Herein, we describe a novel chemical approach to the synthesis of site-specifically modified radioimmunoconjugates that is simple and straightforward. To this end, we leveraged an Fc-directed peptide to append free sulfhydryl moieties to unique sites within the Fc domain of the CA19-9-targeting antibody 5B1. These thiols were then modified with phenyloxadiazolyl methylsulfone-bearing variants of the chelator CHX-A″-DTPA, and the immunoconjugate was radiolabeled with [<sup>177</sup>Lu]Lu<sup>3+</sup> to produce [<sup>177</sup>Lu]Lu-DTPA-<sup>PODS</sup>AJICAP-5B1 in high yield, purity, and specific activity. Subsequent analyses confirmed the site-specificity of the modification and demonstrated the high stability and immunoreactivity of the radioimmunoconjugate. Biodistribution studies in athymic nude mice bearing subcutaneous BxPC3 pancreatic cancer xenografts revealed that [<sup>177</sup>Lu]Lu-DTPA-<sup>PODS</sup>AJICAP-5B1 produced high activity concentrations in tumor tissue as well as high tumor-to-background activity concentration ratios and displayed performance that compared favorably to <sup>177</sup>Lu-labeled analogues synthesized with traditional stochastic and thiol-selective bioconjugation strategies."],"journal":["Bioconjugate chemistry"],"pagination":["1588-1594"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12371682"],"repository":["biostudies-literature"],"pubmed_title":["Harnessing Fc-Directed Bioconjugation for the Synthesis of Site-Specifically Modified Radioimmunoconjugates."],"pmcid":["PMC12371682"],"pubmed_authors":["Grimaldi C","Watanabe T","Strugala E","Kao WM","Aoki T","Sebastiano J","McGlone SA","Fujii T","Zeglis BM"],"additional_accession":[]},"is_claimable":false,"name":"Harnessing Fc-Directed Bioconjugation for the Synthesis of Site-Specifically Modified Radioimmunoconjugates.","description":"A growing body of preclinical and clinical evidence has shown that site-specifically and site-selectively modified immunoconjugates exhibit improved <i>in vivo</i> performance compared to their stochastically modified cousins. However, extant approaches to site-specific bioconjugation suffer from a variety of issues that make clinical translation challenging, including instability, complexity, and expense. Herein, we describe a novel chemical approach to the synthesis of site-specifically modified radioimmunoconjugates that is simple and straightforward. To this end, we leveraged an Fc-directed peptide to append free sulfhydryl moieties to unique sites within the Fc domain of the CA19-9-targeting antibody 5B1. These thiols were then modified with phenyloxadiazolyl methylsulfone-bearing variants of the chelator CHX-A″-DTPA, and the immunoconjugate was radiolabeled with [<sup>177</sup>Lu]Lu<sup>3+</sup> to produce [<sup>177</sup>Lu]Lu-DTPA-<sup>PODS</sup>AJICAP-5B1 in high yield, purity, and specific activity. Subsequent analyses confirmed the site-specificity of the modification and demonstrated the high stability and immunoreactivity of the radioimmunoconjugate. Biodistribution studies in athymic nude mice bearing subcutaneous BxPC3 pancreatic cancer xenografts revealed that [<sup>177</sup>Lu]Lu-DTPA-<sup>PODS</sup>AJICAP-5B1 produced high activity concentrations in tumor tissue as well as high tumor-to-background activity concentration ratios and displayed performance that compared favorably to <sup>177</sup>Lu-labeled analogues synthesized with traditional stochastic and thiol-selective bioconjugation strategies.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-05-08T10:45:37.945Z","creation":"2026-04-07T23:47:13.752Z"},"accession":"S-EPMC12371682","cross_references":{"pubmed":["40782054"],"doi":["10.1021/acs.bioconjchem.5c00306"]}}