Abstract 6034: PSMA targeted alpha radiopharmaceutical 211AtPSAt-3 inhibits tumor growth in a preclinical model of prostate cancer

Abstract Introduction: Prostate cancer continues to be a highly prevalent cancer diagnosis among men and a leading cause of cancer related deaths worldwide. With the introduction177LuLu-PSMA-617, targeted radionuclide therapy has proven successful in increasing survival time for patients with metastasized castration resistant prostate cancer. However, despite encouraging results, such patients tend to develop progressive disease, and thus, enhanced efficacy is warranted. To this end, the use of radiopharmaceuticals harnessing alpha-emitters is a promising venue due to the potent energy deposition and short range of alpha particles in tissue. Here, we employ the PSMA targeting vector, 211AtPSAt-3, for targeted alpha radionuclide therapy in a preclinical prostate cancer model. Methods: 211AtPSAt-3, a structural derivative of PSMA-617, in which the L-2-naphtylalanine was replaced by L-3-211Atastato-phenylalanine, was obtained by electrophilic 211Atastatodesilylation. Evaluation of 211AtPSAt-3 was conducted in male inbred nude mice of Balb/c background xenografted subcutaneously with human prostate cancer cells (LNCaP). Prior biodistribution studies were carried out with approximately 100 kBq intravenous injections, and subsequent biodistribution 2, 6 and 24h post injection (P. I. ). For establishment of therapeutic effect, a single intravenous dose of 211AtPSAt-3 was administered. To asses hematological toxicity, blood cell composition was assessed weekly. Results: Favorable tumor uptake of 15. 2±6 %ID/g was observed 2h after injection of 211AtPSAt-3 in LNCaP xenografted nude mice, with subsequent 9±5. 1% ID/g and 6. 4±2. 4% ID/g 6 and 24h P. I. , respectively. 211AtPSAt-3 cleared mainly by the kidneys, in which uptake was 72, 38 and 6% ID/g at 2, 6 and 24h P. I. , respectively. Thyroid/throat uptake remained low at ~0. 1% ID for all timepoints investigated, indicating a low degree of de-astatination. Initial efficacy studies using a single intravenous dose of 0. 5 MBq (~20 MBq/kg) demonstrated significant growth delay and tumor volume reduction compared with control mice (saline). Blood platelet count was reduced after administration of 211AtPSAt-3 and subsequently recovered. No signs of severe toxicity, and no significant weight loss between control and treated mice was observed, suggesting that the treatment is well tolerated. Conclusion: 0. 5 MBq 211AtPSAt-3 was well tolerated in mice and demonstrated tumor volume reduction and significant delay of tumor growth. These findings suggest 211AtPSAt-3 as a promising candidate for clinical translation. Citation Format: Lars Hvass, Marius Müller, Anne Clausen, Matthias Herth, Andreas Kjaer. PSMA targeted alpha radiopharmaceutical 211AtPSAt-3 inhibits tumor growth in a preclinical model of prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6034.