Abstract PS4-04-08: 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) overexpression occurs in several cancers including breast cancer. HER2 targeted therapies such as trastuzumab have significantly improved outcomes for HER2-positive breast cancer patients, however resistance and recurrence remain challenging. Radioimmunotherapy (RIT) utilizing trastuzumab could provide an additional treatment option for HER2+ breast cancer patients. We produced the theranostic pair 64/67Cu-SAR-trastuzumab and assessed the PET imaging and therapeutic potential of these agents in a HER2-posive mouse model. Methods: A bifunctional variant of the macrobicyclic cage amine sarcophagine (SAR) was conjugated to the monoclonal antibody trastuzumab. Proof of concept studies were performed using SKOV-3 tumour bearing BALB/c nu/nu mice, intravenously injected with a single dose of 64Cu-SAR-trastuzumab or 67Cu-SAR-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, cold SAR-trastuzumab, or 67Cu-SAR-trastuzumab was intravenously administered and endpoints assessed. Results: PET/CT imaging 48 hours after administration with 64Cu-SAR-trastuzumab demonstrated excellent tumor uptake, with mean SUVmax = 21.0 ± 2.5. 64Cu-SAR-trastuzumab and 67Cu-SAR-trastuzumab showed comparable high tumour-specific uptake in biodistribution studies, with tumour uptake at 48 hours of 61 ± 6 % IA/g for 64Cu-SAR-trastuzumab and 59 ± 7 % IA/g for 67Cu-SAR-trastuzumab. Uptake of ≤10 % IA/g was observed for both agents in all other organs measured. Mice treated with 67Cu-SAR-trastuzumab tolerated the treatment well with limited side effects or AEs. A transient reduction in animal body weight (≤7 % of baseline) was observed in all cohorts but this did not differ significantly from the vehicle control. 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 demonstrate the potential of 64/67Cu-SAR-trastuzumab as a new theranostic approach for the treatment of HER2-positive cancer. This theranostic pair exhibit similar biodistribution in the same model, with the high tumor uptake of 64Cu-SAR-trastuzumab resulting in high quality PET images. 67Cu-SAR-trastuzumab effectively increased the survival of all treated groups. The outstanding therapeutic outcomes demonstrate the potential of 67Cu-SAR-trastuzumab as an RIT candidate for translation to clinical trials. Citation Format: S. E. Rudd, J. Van Zuylekom, B. Blyth, M. Harris, E. Sztangret, P. 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 San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-04-08.