Development and characterization of [47Sc]Sc-NOTA-trastuzumab for targeted radiotherapy in primary and metastatic HER2 + breast cancer

PURPOSE: This study investigates the potential of [⁴⁷Sc]Sc-NOTA-trastuzumab as a novel targeted radionuclide agent in HER2 + breast cancer. Targeted radionuclide therapy offers a promising approach for enhanced delivery and internalization of radiation, minimizing off-target effects and treating advanced metastatic HER2 + breast cancers. By examining the synergistic relationship between [⁴⁷Sc]Sc with trastuzumab, assessing [⁴⁷Sc]Sc-NOTA-trastuzumab's impact on immune function, and monitoring its passage of a compromised blood-brain barrier for targeting HER2 + breast-to-brain metastases, this study provides a path towards synergistic and precision radiotherapy in breast cancer metastasis. EXPERIMENTAL DESIGN: The stability, specificity and reactivity of [⁴⁷Sc]Sc-NOTA-trastuzumab was characterized with high performance liquid chromatography, Lindmo, and cell binding assays. In vivo localization and therapeutic efficacy were assessed with SPECT imaging, biodistribution, and tumor monitoring in models of HER2 + breast cancer. Immunostaining against M1 macrophages was assessed to determine mechanisms of enhanced anti-tumoral immune activity. RESULTS: [⁴⁷Sc]Sc-NOTA-trastuzumab demonstrates high specificity and serum stability in HER2 + cells. SPECT shows [⁴⁷Sc]Sc-NOTA-trastuzumab has high specificity for HER2 + breast cancer cells in vivo in both the primary and metastatic setting. Longitudinally, tumors treated with [⁴⁷Sc]Sc-NOTA-trastuzumab show therapeutic benefit and are comparable to those treated with 16x dose of trastuzumab alone, with no significant toxicity. Exploratory results show radiopharmaceutical uptake in a model of HER2 + brain metastasis. Increased M1-like macrophages were seen in HER2 + tumors relative to HER2- tumors following treatment with [⁴⁷Sc]Sc-NOTA-trastuzumab. CONCLUSION: [⁴⁷Sc]Sc-NOTA-trastuzumab is serum stable and highly specific to HER2 + breast cancer. Developing and characterizing novel targeted radionuclide therapeutics has the potential to significantly improve radionuclide delivery in HER2 + metastatic disease.