²²⁵Ac-RAX104: A novel PSMA-targeted radioligand optimized for actinium-225 demonstrates enhanced tumor retention and superior efficacy
Presenter: Guangzhou Han, PhD Session: Targeted Radiopharmaceuticals and Combination Strategies in Cancer Therapy Time: 4/22/2026 9:00:00 AM → 4/22/2026 12:00:00 PM
Authors
Xupeng Hu , Yang Cao , Min Hong , Shuanglong Liu , Guangzhou Han , Gang Chen RadAlliance Therapeutics Inc, San Diego, CA
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.
Disclosure
X. Hu, None.. Y. Cao, None.. M. Hong, None.. S. Liu, None.. G. Han, None.. G. Chen, None.
Cited in
Control: 1711 · Presentation Id: 3895 · Meeting 21436