Abstract 7185: 225Ac-RAX104: A novel PSMA-targeted radioligand optimized for actinium-225 demonstrates enhanced tumor retention and superior efficacy

Abstract Prostate cancer is the second most common malignancy in men and remains a significant cause of cancer-related mortality worldwide. Although the clinical success of 177Lu-PSMA-617 (Pluvicto) has established PSMA-targeted radioligand therapy (RLT) as an effective treatment for metastatic castration-resistant prostate cancer (mCRPC), emerging clinical evidence indicates that 225Ac-based RLT can deliver even greater therapeutic efficacy owing to the high linear energy transfer of α-particles and the radionuclide’s 9.92-day physical half-life. To fully exploit these properties, 225Ac-RAX104 was rationally designed to enhance PSMA affinity and tumor retention, thereby kinetically matching the physical and radiobiological characteristics of 225Ac to maximize antitumor potency. RAX104 was successfully synthesized and radiolabeled with 225Ac at a molar activity of up to 3 µCi/nmol, achieving radiochemical purity greater than 95% and maintaining stability for more than 110 hours. Surface plasmon resonance analysis revealed that the RAX104 precursor exhibited approximately 22-fold higher affinity for PSMA than PSMA-617, primarily driven by slower dissociation kinetics. In PSMA-overexpressing PC3 cells, 225Ac-RAX104 showed markedly enhanced cellular uptake and internalization compared with 225Ac-PSMA-617. In PSMA-low 22Rv1 xenografts, 225Ac-RAX104 achieved more than 3-fold higher tumor-absorbed activity (AUC0-∞) and a significantly prolonged biological half-life in tumors relative to 225Ac-PSMA-617, while both radioligands showed comparable blood pharmacokinetics. Consistent with these pharmacokinetic advantages, 225Ac-RAX104 demonstrated superior antitumor efficacy: a single 14.8 kBq dose produced greater tumor growth inhibition and longer survival than 74 kBq (fivefold higher activity) of 225Ac-PSMA-617 in the 22Rv1 model. Toxicity evaluation in normal ICR mice revealed only transient and reversible reductions in white blood cell, neutrophil, and reticulocyte counts, without clinical chemistry abnormalities, indicating a favorable safety profile. An investigator-initiated trial (IIT) of 225Ac-RAX104 has been proposed in mCRPC patients to generate human dosimetry data to inform the design of subsequent clinical studies. Collectively, these results demonstrate that 225Ac-RAX104 achieves optimal kinetic alignment with 225Ac’s physical decay and biological action, delivering enhanced tumor exposure and potent therapeutic efficacy at one-fifth the dose of 225Ac-PSMA-617. These findings support 225Ac-RAX104 as a promising next-generation PSMA α-radioligand therapy with the potential to improve outcomes in mCRPC and warrant further clinical development. Citation Format: Xupeng Hu, Yang Cao, Min Hong, Shuanglong Liu, Guangzhou Han, Gang Chen, . 225Ac-RAX104: A novel PSMA-targeted radioligand optimized for actinium-225 demonstrates enhanced tumor retention and superior efficacy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7185.