Abstract 588: Preclinical evaluation of a novel 212Pb-based, PSMA-targeted radioligand, 212Pb-ADVC001, for prostate cancer treatment

Abstract Introduction: PSMA-targeted radioligand therapy (RLT) with lutetium-177 (177Lu), a beta-emitter, has been clinically proven to be efficacious for the treatment of prostate cancer (PC). Although emerging clinical data indicate that better efficacy can be achieved by alpha-emitters, the toxicities associated with actinium-225 (225Ac) may limit its broad application especially in early lines of treatment. Lead-212 (212Pb), is a promising isotope for alpha therapy with a high linear energy transfer, a half-life of 10.6 hours, and a simple decay scheme. These properties promote efficient targeting of PSMA+ PC cells while limiting off-target toxicities. Pb-ADVC001 is a novel Pb-based PSMA-targeted RLT currently in Phase Ib/IIa clinical trial (NCT05720130) for patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: The affinity of ADVC001 and Pb-ADVC001 to PSMA was determined by SPR and radioligand-binding assays in PSMA+ PC cell lines. Cytotoxic activity was measured by cell viability and clonogenic assays. In vivo biodistribution and anti-tumor efficacy studies were performed in human-derived PC-bearing mice. The intrinsic molecular and cellular mechanisms associated with Pb-ADVC001 mediated cell-death were assessed using transcriptomics and proteomics. Results: ADVC001 binds human, mouse and rat PSMA with comparable nanomolar activities, and efficiently internalizes upon binding to PSMA+ PC cells. In vitro, Pb-ADVC001 showed specific and potent cytotoxic activity against multiple PSMA+ human PC cell lines, while sparing PSMA- cells. In vivo biodistribution of Pb-ADVC001 showed tumor uptake at 19.6, 20.9, 9.4 and 5.4 %ID/g at 1, 3, 24 and 48 h, respectively, with retention out to 72 h. High tumor uptake and fast renal clearance resulted in favorable tumor/kidney ratios. Minimal uptake was observed in other normal tissues. Single administration of Pb-ADVC001 in PSMA+ PC xenografts led to dose-dependent anti-tumor response and significant survival benefit. Transcriptomic analysis of in vitro treated PC cells and proteomic analysis of tumors harvested longitudinally revealed multiple mechanisms of action involving DNA damage, cell cycle arrest and cell death, and immune response modulation. Conclusion: Preclinical data demonstrated the potential of Pb-ADVC001 for the treatment of patients with PSMA+ prostate cancer. Transcriptomic and proteomic analyses indicate multiple mechanisms of action collectively resulting in effective cancer therapy. Citation Format: Melissa E. Monterosso, Feifei Liu, Didier Boucher, Stelle Shakti, Kwong Ching Li, Aimee Horsfall, Saawan Kumar, Johannes Koehbach, Kevin Kuan, William Tieu, Stephen Rose, Anna Karmann, Gary Li, Simon Puttick, Thomas Kryza. Preclinical evaluation of a novel Pb-based, PSMA-targeted radioligand, Pb-ADVC001, for prostate cancer treatment [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 588.