Therapeutic evaluation of [212Pb]Pb-AB001 and [177Lu]Lu-PSMA-617 in a mouse model of disseminated prostate cancer

Anna Julie Kjøl Høyvik; Monika Kvassheim; Li-Wei Ma; Elisabeth Wiig; Tiril Hillestad; Mona-Elisabeth Revheim; Rugile Liukaityte; Øyvind Bruland; Asta Juzeniene

doi:10.1007/s00259-025-07330-y

Therapeutic evaluation of [²¹²Pb]Pb-AB001 and [¹⁷⁷Lu]Lu-PSMA-617 in a mouse model of disseminated prostate cancer

Eur J Nucl Med Mol Imaging. 2025 May 21. doi: 10.1007/s00259-025-07330-y. Online ahead of print.

Authors

Anna Julie Kjøl Høyvik^{1

2

3}, Monika Kvassheim^{3

4}, Li-Wei Ma¹, Elisabeth Wiig¹, Tiril Hillestad⁵, Mona-Elisabeth Revheim^{3

6}, Rugile Liukaityte^{1

2}, Øyvind Bruland^{3

7}, Asta Juzeniene^{8

9}

Affiliations

¹ Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.
² ARTBIO AS, Oslo, 0379, Norway.
³ Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, 0318, Norway.
⁴ Department of Physics and Computational Radiology, Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, 0379, Norway.
⁵ Department of Core Facilities, Institute for Cancer Research and Molecular Imaging, Oslo University Hospital, Oslo, 0379, Norway.
⁶ The Intervention Centre, Oslo University Hospital, Oslo, 0372, Norway.
⁷ Department of Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway.
⁸ Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, 0379, Norway. astaj@ous-hf.no.
⁹ Faculty of Physics, University of Oslo, Oslo, 0318, Norway. astaj@ous-hf.no.

PMID: 40397137
DOI: 10.1007/s00259-025-07330-y

Abstract

Background: Metastatic castration-resistant prostate cancer (mCRPC) frequently leads to bone and soft tissue metastases, leading to poor prognosis. The beta-emitting radioligand [¹⁷⁷Lu]Lu-PSMA-617 targets the prostate-specific membrane antigen (PSMA) and may be less efficient against micrometastatic disease. The alpha-emitting radioligand [²¹²Pb]Pb-AB001 could offer enhanced treatment by delivering high energy over a short range. This study compared the efficacy of [²¹²Pb]Pb-AB001 and [¹⁷⁷Lu]Lu-PSMA-617 in a mouse model of disseminated prostate cancer.

Methods: Binding and internalisation of radioligands were evaluated in PC-3 PIP-luc cells. A mouse model was established by intracardiac injection of these cells. Treatments with 0.24‒1.0 MBq [²¹²Pb]Pb-AB001 or 22‒66 MBq [¹⁷⁷Lu]Lu-PSMA-617 were initiated 7 d post-cell inoculation. Metastatic burden was measured using bioluminescence imaging, and PSMA-targeted uptake was determined with [¹⁸F]F-PSMA-1007 µPET/µCT. Gamma-autoradiography evaluated [²¹²Pb]Pb-AB001 distribution, and bone metastases were identified by radiography.

Results: Both radioligands displayed comparable in vitro binding. In vivo studies revealed metastatic formation in clinically relevant organs. µPET/µCT demonstrated increased [¹⁸F]F-PSMA-1007 uptake in metastases, matching the bioluminescence imaging results. Focal [²¹²Pb]Pb-AB001 distribution in the metastatic xenograft indicated heterogeneously distributed micrometastases in the organs. A median survival up to 47 d was achieved with [²¹²Pb]Pb-AB001, compared to 25 d for controls and 27 d for [¹⁷⁷Lu]Lu-PSMA-617. An activity-dependent reduction in bone metastases was observed for [¹⁷⁷Lu]Lu-PSMA-617, while no bone lesions were detected in [²¹²Pb]Pb-AB001-treated mice.

Conclusion: [²¹²Pb]Pb-AB001 showed significant efficacy against micrometastases and advantages over [¹⁷⁷Lu]Lu-PSMA-617 in preventing or treating early bone metastases for the investigated injected activities. This implies clinical potential for treating mCRPC, including patients at risk of early metastatic disease, but further studies including dosimetry and toxicity analyses are required with regards to activity levels.

Keywords: 177Lu; 212Pb; Disseminated prostate cancer model; PSMA; Targeted alpha therapy.