Abstract 578: ATNM-400 is a novel Actinium-225 antibody radioconjugate with strong efficacy in preclinical models of prostate cancer

Abstract Introduction: In 2024, an estimated 299, 010 new prostate cancer (PCa) cases will be diagnosed in the US, with 35, 250 deaths. While PCa initially responds to androgen deprivation therapy (ADT), it often progresses to metastatic castration-resistant prostate cancer (mCRPC), a challenging condition with limited treatment options. Targeted radiotherapies like Pluvicto, a beta-emitting treatment targeting prostate-specific membrane antigen (PSMA), have shown promise but face limitations due to radiation properties and variability in PSMA expression. mCRPC is driven by persistent androgen receptor signaling and other pathways, often mediated by overexpressed cell surface receptors. We designed ATNM-400 against a target highly expressed in mCRPC that has been previously targeted with naked antibodies or antibody drug conjugates but have been ineffective clinically. Here, we tested ATNM-400, a first-in-class actinium-225 (Ac-225) antibody radioconjugate (ARC) in preclinical models of PCa with the hypothesis that targeted delivery of an alpha-emitter would offer stronger therapeutic potential than existing therapies to address a critical unmet need in mCRPC patients. Methods: ATNM-400 was synthesized by conjugating ATNM400 antibody with p-SCN-Bn-DOTA, followed by radiolabeling with Ac-225. Binding affinity and internalization in PCa cell lines were evaluated using flow cytometry and radioactivity measurement. The biodistribution (BioD), pharmacokinetics (PK), and efficacy of ATNM-400 were tested in preclinical mouse models using 22Rv1 and DU145 PCa cell lines. The potential to overcome Pluvicto resistance in mCRPC was also studied both in vitro and in vivo. Results: ATNM-400 demonstrated over 98% radiochemical purity and rapid internalization into PCa cells. Treatment of PCa cells with ATNM-400 demonstrated potent cytotoxic effects in a dose-dependent manner. In vivo BioD and PK studies in PCa models showed that ATNM-400 accumulated in tumors for up to 144 hours, with minimal accumulation in normal organs. Small animal SPECT/CT images in mouse xenograft models of PCa showed that Indium-111 radiolabeled ATNM400 selectively accumulated in tumors and cleared from healthy tissues. The radiation dose to organs, extrapolated from mouse dosimetry, suggested an acceptable safety profile. In vivo studies in multiple PCa models (22RV1 and DU145) using a single-dose of ATNM-400, showed a potent tumor growth inhibition of 68.5% at 20 µCi/kg and 99.8% at 40 µCi/kg, with all doses well tolerated. Also, ATNM-400 is being tested in Pluvicto-resistant PCa preclinical models, with results forthcoming. Conclusions: ATNM-400 showed strong anti-tumor efficacy and a favorable safety profile in preclinical PCa models. These results highlight ATNM-400's potential as a transformative therapeutic option for PCa patients with unmet clinical needs. Citation Format: Denis Beckford, Sumit Mukherjee, Debbie Lewis, Jason Li, Dina Yang, Karina Peregrina, Amanda Chin, Le-Cun Xu, Monideepa Roy, Adeela Kamal. ATNM-400 is a novel Actinium-225 antibody radioconjugate with strong efficacy in preclinical models of 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 578.