Purpose

Metastatic castration-resistant prostate cancer (mCRPC) has limited treatment options and a poor prognosis. Recently, PSMA-targeted alpha particle therapy agents using Actinium-225 (225Ac) have shown promising results for prostate cancer treatment, but a significant fraction of patients with advanced mCRPC demonstrate loss of PSMA expression. We have previously reported that PSMA-null and PSMA-positive tumors can be detected and treated effectively with CD46-targeted radiopharmaceuticals. This study evaluates the CD46-targeting PET imaging agent [89Zr]DFO-YS5 and the radioimmunotherapy agent [225Ac]Macropa-PEG4-YS5 in disseminated prostate cancer tumors.

Experimental design

Microtumor lesions, primarily observed in the liver, kidneys, and lungs, were successfully detected with [89Zr]DFO-YS5 PET imaging. We used disseminated 22Rv1 tumors for biodistribution studies, dosimetry assessments, and therapeutic efficacy evaluations of [225Ac]Macropa-PEG4-YS5.

Results

Quantitative digital alpha-particle autoradiography revealed high radiation dose deposition from [225Ac]Macropa-PEG4-YS5 in microtumors compared to surrounding liver tissues, although in larger lesions (>1 mm diameter) the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with uniform radiation dose was more effective in ablating tumors and promoting survival. In late-stage lesions of large size, heterogeneous dose deposition limited therapeutic efficacy, requiring higher administered activity to achieve a complete response.

Conclusions

Our findings highlight that [225Ac]Macropa-PEG4-YS5 holds the potential for clinical translation for metastatic prostate cancer and reinforces the value of microdosimetry in understanding the efficacy of and resistance to targeted alpha therapy.