Abstract 4303: AZD2284: A novel, alpha-particle emitting radioconjugate targeting STEAP2 in metastatic castration-resistant prostate cancer

Abstract Background: AZD2284 is a novel, targeted alpha therapeutic directed against six-transmembrane epithelial antigen of prostate-2 (STEAP2), a receptor highly overexpressed in prostate cancer. AZD2284 is comprised of a humanized, STEAP2-targeting rodent cross-reactive IgG1 monoclonal antibody conjugated with a DOTA chelate and radiolabeled with the alpha-particle emitting radionuclide, actinium-225 [225Ac]. Leveraging high STEAP2 expression in prostate cancer and the high linear energy transfer of the alpha emitter, AZD2284 is presumed to deliver the radioisotope to targeted tumor cells, generating clustered DNA double strand breaks and other cellular damage that ultimately leads to cell death. Methods: Preclinical pharmacological assessments were conducted with the lutetium-177 [177Lu] labeled analog of AZD2284, FPI-2281. In vitro binding and internalization assays with FPI-2281 were performed in STEAP2-positive prostate cancer cell lines with varying levels of target expression. In vivo biodistribution and uptake were evaluated ex vivo across multiple timepoints following FPI-2281 administration to tumor-bearing cell-line derived xenograft (CDX) models. To assess the radiotherapeutic efficacy of AZD2284, a single dose was administered intravenously to prostate cancer CDX and patient-derived xenograft (PDX) models. Results: Binding and internalization studies demonstrated FPI-2281 effectively binds to the STEAP2-positive prostate cancer cell line models (LNCaP, C4-2, and 22Rv1) with over 30% cellular retention at 24 hours. Corresponding in vivo biodistribution profiles showed sustained tumor uptake in xenograft models, with peak tumor uptakes of 60% ID/g in the 22Rv1 model and 83% ID/g in the C4-2 model at 14 days, respectively, with limited normal organ uptake observed at all timepoints. AZD2284 elicited target- and dose-dependent anti-tumor efficacy and sustained tumor regressions in CDX and PDX models with varying levels of STEAP2 expression. Conclusions: In preclinical models, AZD2284 effectively binds to and internalizes in prostate cancer cells, thereby delivering the radioisotope, [225Ac]. Biodistribution studies confirm sustained tumor uptake of AZD2284 with low normal organ uptake. Single-dose administration of AZD2284 leads to durable anti-tumor efficacy in xenograft models. These data suggest AZD2284 is a promising therapeutic candidate in prostate cancer and support the initiation of clinical trials. Citation Format: Darlene Monlish, Brigitte Thériault, Mel Ehudin, Vanessa Muniz-Medina, Dewald van Dyk, Lisa Godfrey, Dipal Patel, William Turnbull, Liang Zhang, Moditha Nawinne, Teresa Collins, Kenneth Thress, Douglas Ferguson, Rajiv Bhalla, Nicolas Giraldo, Melody Handali, Jeong Min Han, Crystal Cheung, Asurayya Worrede, Clare Hoover, Sujiet Puthenveetil, Edward Rosfjord, Frank Comer, Elaine Hurt, Darshan Dalal, Christopher Leamon, John Valliant, Puja Sapra. AZD2284: A novel, alpha-particle emitting radioconjugate targeting STEAP2 in metastatic castration-resistant prostate cancer [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 4303.