TY - JOUR T1 - Pretargeted Theranostic Radioimmunotherapy with a Cu-64/Cu-67 Isotopologue Pair JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 132 LP - 132 VL - 61 IS - supplement 1 AU - Outi Keinaenen AU - Kimberly Fung AU - James Brennan AU - Nicholas Zia AU - Matthew Harris AU - Ellen Van Dam AU - Colin Biggin AU - Amos Hedt AU - Jon Stoner AU - Paul Donnelly AU - Jason Lewis AU - Brian Zeglis Y1 - 2020/05/01 UR - http://jnm.snmjournals.org/content/61/supplement_1/132.abstract N2 - 132Objectives: Our aim was to develop a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on the inverse electron demand Diels-Alder (IEDDA) ligation between a trans-cyclooctene (TCO)-modified immunoconjugate and tetrazine (Tz)-based radioligands using a sarcophagine chelator labeled with 64Cu (for PET) and 67Cu (for endoradiotherapy). Methods: Three control cohorts and three PRIT cohorts (n = 10) of athymic nude mice bearing SW1222 colorectal carcinoma xenografts were employed. The first control cohort received only saline, the second received only the TCO-modified variant of the huA33 antibody (huA33-TCO) (100 µg, 0.7 nmol, 5 TCO/mAb), and the third received only [67Cu]Cu-MeCoSar-Tz (55.5 MBq, 0.7 nmol). In each of the three PRIT cohorts, huA33-TCO (100 µg, 0.7 nmol, 5 TCO/mAb) was administered intravenously to the mice 72 h prior to the administration of the radiotracer. In the first PRIT cohort, the mice received 55.5 MBq of [67Cu]Cu-MeCoSar-Tz (0.7 nmol). To explore the efficacy of fractioned dosing, mice in the second PRIT cohort received two 27.8 MBq doses of [67Cu]Cu-MeCoSar-Tz (0.7 nmol) separated by a 48 h interval. In the final PRIT cohort − the ‘theranostic’ group − the mice were administered [64Cu]Cu-MeCoSar-Tz (11 MBq, 0.7 nmol) followed 24 h later by [67Cu]Cu-MeCoSar-Tz (55.5 MBq, 0.7 nmol). PET imaging of these animals was performed 4, 24, and 48 h after the injection of [64Cu]Cu-MeCoSar-Tz. The uptake of [64Cu]Cu-MeCoSar-Tz was determined from PET images acquired 48 h post-injection and subsequently compared to the rate of tumor growth. Tumor volumes and weights of the mice were measured twice a week, and blood samples were collected and analyzed once a week. Results: Each of the PRIT cohorts exhibited a short initial period of tumor growth, after which the tumor volumes decreased dramatically. In contrast, the tumor growth in the control cohorts continued unabated (Fig. 1A). The efficacy of PRIT is clearly visualized in the Kaplan-Meier plot (Fig. 1B) which illustrates the prolonged survival of the PRIT cohorts compared to the control cohorts. When tumor uptake values of [64Cu]Cu-MeCoSar-Tz were compared to the tumor growth curves of individual mice in the theranostic PRIT cohort (Fig. 1C), the data suggest the tumors with the lowest uptake of [64Cu]Cu-MeCoSar-Tz regrew earliest, while those with the highest uptake of [64Cu]Cu-MeCoSar-Tz were the first to shrink. Conclusions: We have successfully employed the sequential injection of two Tz-based radioligands in an IEDDA-based pretargeting schema. This multi-injection approach can be employed both for the administration of fractioned radiotherapy and in a theranostic strategy using sarcophagine based radioligands labeled with 64Cu and 67Cu. Acknowledgements: We are very grateful to the National Institutes of Health (U01CA22104) for their support. We also thank the MSKCC Small Animal Imaging Core Facility and Radiochemistry and Molecular Imaging Probe Core, which receive support from NIH grants P30 CA08748 and S10 RR020892-01. $$graphic_B2D900F5-C864-4D43-9D8A-B46BD286616A$$ ER -