Mechanistic insights into the anti-tumor activity of ²¹²Pb-PSMA radioligand therapy
Presenter: Peter Skingley Session: Effects of Ionizing Radiation on Normal Tissues and FLASH Radiation Research Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Feifei Liu , Melissa Monterosso , Didier Boucher , Anna Amiss , Stelle Shakti , Kwong Ching Li , Chanwoo Kim , Aimee Horsfall , Kevin Kuan , William Tieu , Stephen Rose , Simon Puttick , Joana Brilhante , Gary Li , Anna Karmann , Thomas Kryza AdvanCell Pty Ltd, Sydney, Australia
Abstract
Introduction: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (¹⁷⁷Lu) has demonstrated clinical benefit in prostate cancer (PC). Although alpha-emitters offer superior cytotoxic efficacy, the complex toxicity profile of actinium-225 (²²⁵Ac)-PSMA limits its therapeutic application. Lead-212 (²¹²Pb) possesses favorable physical properties, including high linear energy transfer, a 10.6-hour half-life, and a simple decay scheme with a single alpha-emitting daughter nuclide, enabling precise, potent radiation delivery at the cellular level. In this study, we combine in vitro and in vivo models with multiomics and functional assays to elucidate the mechanisms underlying the anti-tumor efficacy of PSMA-targeted RLT. Materials and Methods: 212 Pb-ADVC001, a novel 212 Pb-based PSMA-targeting RLT in Phase I/II clinical development (NCT05720130) for the treatment of metastatic PC, was used as the 212 Pb-PSMA-RLT agent. 177 Lu-PSMA-I&T was used as the 177 Lu-PSMA-RLT agent. The kinetic mechanisms associated with 212 Pb-ADVC001 mediated cell-death were investigated in vitro and ex vivo using transcriptomics and proteomics analyses. To validate the omics findings, functional assays were conducted to assess the effects of 212 Pb-PSMA on PC’s cell cycle progression, reactive oxygen species (ROS) generation, and lipid peroxidation in PC cells. Results: 212 Pb-ADVC001 displayed potent cytotoxic activity with a mean EC 50 of 2.7, 7.2 and 3.3 kBq/mL in PC cell lines PC-3-PIP (PSMA high ), C4-2 (PSMA int ) and LNCaP (PSMA int ), respectively. Transcriptomic and proteomic analysis of in vitro treated PC cells and in vivo tumors harvested longitudinally revealed multiple mechanisms of action involving DNA damage, cell cycle arrest and cell death, and immune response modulation. In vitro functional assays confirmed the involvement of ROS production, lipid peroxidation, and cell cycle arrest upon treatment with 212 Pb-ADVC001. Particularly, 212 Pb-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 177 Lu-PSMA-I&T (p Conclusion: Multiomics analyses highlighted the involvement of multiple mechanisms of action in the efficacy of 212 Pb-ADVC001 which collectively resulted in effective cancer cell death. Mechanistic studies furthered the understanding of PC radiobiology and cellular responses to beta- and alpha-based RLT with the identification of a cell cycle arrest in PC specifically induced by 212 Pb-PSMA.
Disclosure
F. Liu, AdvanCell Pty Ltd Employment. M. Monterosso, AdvanCell Pty Ltd Employment. D. Boucher, AdvanCell Pty Ltd Employment. A. Amiss, AdvanCell Pty Ltd Employment. S. Shakti, AdvanCell Pty Ltd Employment. K. Li, AdvanCell Pty Ltd Employment. C. Kim, AdvanCell Pty Ltd Employment. A. Horsfall, AdvanCell Pty Ltd Employment. K. Kuan, AdvanCell Pty Ltd Employment, Patent. Clarity Pharmaceuticals Stock. W. Tieu, AdvanCell Pty Ltd Employment. S. Rose, AdvanCell Pty Ltd Employment, Stock. S. Puttick, AdvanCell Pty Ltd Employment, Stock. J. Brilhante, AdvanCell Pty Ltd Employment, Stock. Mariana Oncology Stock. Bayer Patent. G. Li, AdvanCell Pty Ltd Employment. A. Karmann, AdvanCell Pty Ltd Employment, Stock. T. Kryza, AdvanCell Pty Ltd Employment, Stock.
Cited in
Control: 2714 · Presentation Id: 9353 · Meeting 21436