Harnessing Cu-64/Cu-67 for a theranostic approach to pretargeted radioimmunotherapy
AuthorKeinanen, O; Fung, K; Brennan, JM; Zia, N; Harris, M; van Dam, E; Biggin, C; Hedt, A; Stoner, J; Donnelly, PS; ...
Source TitleProceedings of the National Academy of Sciences of USA
PublisherNational Academy of Sciences
University of Melbourne Author/sDonnelly, Paul
AffiliationSchool of Chemistry
Document TypeJournal Article
CitationsKeinanen, O., Fung, K., Brennan, J. M., Zia, N., Harris, M., van Dam, E., Biggin, C., Hedt, A., Stoner, J., Donnelly, P. S., Lewis, J. S. & Zeglis, B. M. (2020). Harnessing Cu-64/Cu-67 for a theranostic approach to pretargeted radioimmunotherapy. Proceedings of the National Academy of Sciences of the United States of America, 117 (45), pp.28316-28327. https://doi.org/10.1073/pnas.2009960117.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668034
Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels–Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.
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