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

Abstract

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.