Harnessing Fc-directed bioconjugation for the synthesis of site-specifically modified radioimmunoconjugates Journal Article
| Authors: | Grimaldi, C.; Sebastiano, J.; Kao, W. S. M.; Strugala, E.; McGlone, S. A.; Watanabe, T.; Aoki, T.; Fujii, T.; Zeglis, B. M. |
| Article Title: | Harnessing Fc-directed bioconjugation for the synthesis of site-specifically modified radioimmunoconjugates |
| Abstract: | A growing body of preclinical and clinical evidence has shown that site-specifically and site-selectively modified immunoconjugates exhibit improved in vivo 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 [177Lu]Lu3+to produce [177Lu]Lu-DTPA-PODSAJICAP-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 [177Lu]Lu-DTPA-PODSAJICAP-5B1 produced high activity concentrations in tumor tissue as well as high tumor-to-background activity concentration ratios and displayed performance that compared favorably to177Lu-labeled analogues synthesized with traditional stochastic and thiol-selective bioconjugation strategies. © 2025 Elsevier B.V., All rights reserved. |
| Keywords: | mouse; animal; animals; mice; cell line, tumor; chemistry; nude mouse; tissue distribution; mice, nude; tumors; tumor cell line; in-vivo; radioisotope; mammals; radioisotopes; performance; bio-conjugation; antibody conjugate; immunoconjugates; lutetium; clinical translation; lutetium-177; radioimmunoconjugates; humans; human; site-specific; immunoconjugate; lutetium compounds; activity concentration; growing bodies; american chemical society |
| Journal Title: | Bioconjugate Chemistry |
| Volume: | 36 |
| Issue: | 8 |
| ISSN: | 1043-1802 |
| Publisher: | American Chemical Society |
| Date Published: | 2025-08-20 |
| Start Page: | 1588 |
| End Page: | 1594 |
| Language: | English |
| DOI: | 10.1021/acs.bioconjchem.5c00306 |
| PUBMED: | 40782054 |
| PROVIDER: | scopus |
| PMCID: | PMC12371682 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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