Abstract 1333: Uncovering the mechanisms of action of 177Lu- and 212Pb- based PSMA radioligand therapies

Abstract Introduction: 177Lu-PSMA-617 is the first FDA-approved targeted radioligand therapy (RLT), and in clinical trials, significantly prolonged survival and improved quality of life in patients with metastatic castration resistant prostate cancer (mCRPC). However, approximately 30% of the patients do not respond to the treatment and most initial responders ultimately relapse. Compared to the beta-emitter 177Lu, the alpha therapy isotope 212Pb may prove to be advantageous due to its short half-life, high linear energy transfer, and efficient induction of immunogenic cell death. Here we used in vitro and in vivo models to elucidate the intrinsic cellular mechanisms of response to 177Lu-PSMA and 212Pb-PSMA treatment. Methods: 177Lu-PSMA-I&T and 212Pb-ADVC001 were used as PSMA-targeted 177Lu- and 212Pb-RLT, respectively. The cytotoxic activity in prostate cancer (PC) cell lines was measured by a cell viability assay. In vivo studies were performed in human PC-bearing mice to compare preclinical efficacy of 177Lu- and 212Pb-PSMA therapy. The kinetic mechanisms associated with 177Lu-PSMA-I&T and 212Pb-ADVC001 mediated cell-death were assessed ex vivo using proteomics, and their impact on the PC cell cycle by flow cytometry. Results: 212Pb-ADVC001 displayed potent cytotoxic activity with an average EC50 of 2.7, 7.2 and 3.3 kBq/mL in PC cell lines PC-3-PIP (PSMAhigh), C4-2 (PSMAint) and LNCaP (PSMAint), respectively, compared to 177Lu-PSMA-I&T (430.7, 434.9 and 814.4 kBq/mL, respectively). In PSMAhigh xenograft models, 212Pb-ADVC001 (0.43 MBq) significantly improved median survival to 84 days compared to 48 days for 177Lu-PSMA I&T (20 MBq). Multidose efficacy studies demonstrated superior tumor response with two cycles of 212Pb-ADVC001 (0.46 MBq) compared to two cycles of 177Lu-PSMA I&T (15 MBq). 212Pb-ADVC001 administration in 177Lu-PSMA I&T-relapsed mice resulted in improved survival. In PSMAint xenograft models, 212Pb-ADVC001 (0.9 MBq) also suppressed tumor progression more effectively than 177Lu-PSMA-I&T (30 MBq), resulting in prolonged survival. Proteomics analysis of RLT-treated tumors revealed a specific impact of 212Pb-ADVC001 on cell cycle checkpoints and DNA replication. In vitro cell cycle experiment further confirmed that 212Pb-ADVC001 caused significant DNA damage, and reduced DNA content in the S-phase of the cell cycle with a concomitant increase in the G1 and G2/M-phase arrest compared to 177Lu-PSMA-I&T (p<0.05). Conclusion: Comparison studies of 177Lu- and 212Pb-PSMA treatment on PC cells showed a higher efficacy of 212Pb-PSMA in vitro and in vivo supporting the clinical application of 212Pb-PSMA for mCRPC. Mechanistic studies furthered the understanding of PC radiobiology and cellular responses to beta- and alpha-RLT with the identification of a cell cycle arrest in PC specifically induced by 212Pb-PSMA. Citation Format: Feifei Liu, Melissa E. Monterosso, Didier Boucher, Stelle Shakti, Kwong Ching Li, Aimee Horsfall, Saawan Kumar, Johannes Koehbach, Kevin Kuan, William Tieu, Stephen Rose, Anna Karmann, Simon Puttick, Gary Li, Thomas Kryza. Uncovering the mechanisms of action of 177Lu- and 212Pb- based PSMA radioligand therapies [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 1333.