Abstract 573: Radioimmunotherapy using 64/67copper labelled trastuzumab in mice bearing HER2-positve xenografts as a model for breast cancer therapy

Abstract Background and Purpose: Human epidermal growth factor receptor 2 (HER2) is overexpressed in several cancers including breast cancer. In the treatment of HER2 positive breast cancer, patients have shown significant improvements with trastuzumab therapy. Radioimmunotherapy (RIT) utilizes an antibody targeted to a receptor overexpressed on tumors to deliver radiation to the target. RIT utilizing trastuzumab could provide an additional treatment option for HER2+ breast cancer patients. We have produced the theranostic pair [64Cu]Cu-MeCOSar-trastuzumab, for PET imaging, and [67Cu]Cu-MeCOSar-trastuzumab, for therapy via beta emission, to evaluate this Targeted Copper Theranostic (TCT) approach as an effective radioimmunotherapy. Methods: The MeCOSar chelator was conjugated to trastuzumab and subsequently radiolabeled with either copper-64 (Cu-64) or copper-67 (Cu-67). Proof of concept studies were performed using SKOV-3 tumor bearing mice, injected with one dose of [64Cu]Cu-MeCOSar-trastuzumab or [67Cu]Cu-MeCOSar-trastuzumab to compare biodistribution of the theranostic pair. Tumor uptake was assessed using PET/CT imaging and/or ex vivo biodistribution studies. In therapy studies, a single dose of saline, MeCOSar-trastuzumab, or [67Cu]Cu-MeCOSar-trastuzumab was administered and endpoints assessed. Results: [64Cu]Cu-MeCOSar-trastuzumab and [67Cu]Cu-MeCOSar-trastuzumab showed comparable high tumor-specific uptake in biodistribution studies, with tumor uptake at 48 hours of 61 ± 6 % IA/g for [64Cu]Cu-MeCOSar-trastuzumab and 59 ± 7 % IA/g for [67Cu]Cu-MeCOSar-trastuzumab. Mice treated with [67Cu]Cu-MeCOSar-trastuzumab tolerated the treatment well with limited side effects or AEs. Treated mice also showed significant tumor growth inhibition and extended survival in a dose dependent manner compared with the control groups. The median survival was 32 days in the control groups and 102 days in the 9 MBq group. Conclusion: These results show high tumor uptake for [64Cu]Cu-MeCOSar-trastuzumab and [67Cu]Cu-MeCOSar-trastuzumab with very similar biodistribution profiles at 48 hours in SKOV-3 xenograft model. [67Cu]Cu-MeCOSar-trastuzumab demonstrated significant tumor growth inhibition compared to the control groups and effectively increased the survival of the treated group. This study demonstrates the potential of [67Cu]Cu-MeCOSar-trastuzumab for clinical translation. Citation Format: Stacey E. Rudd, Jessica Van Zuylekom, Benjamin Blyth, Matthew Harris, Paul S. Donnelly. Radioimmunotherapy using 64/67copper labelled trastuzumab in mice bearing HER2-positve xenografts as a model for breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 573.