Harnessing Cu-64/Cu-67 for a theranostic approach to pretargeted radioimmunotherapy

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Keinanen, O; Fung, K; Brennan, JM; Zia, N; Harris, M; van Dam, E; Biggin, C; Hedt, A; Stoner, J; Donnelly, PS; ...Date
2020-11-10Source Title
Proceedings of the National Academy of Sciences of USAPublisher
National Academy of SciencesUniversity of Melbourne Author/s
Donnelly, PaulAffiliation
School of ChemistryMetadata
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Keinanen, 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 Status
Open AccessOpen Access at PMC
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668034Abstract
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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