Effective Treatment of Disseminated Prostate Cancer Using CD46-Targeted 225Ac Therapy

Area of Science:

• Oncology
• Nuclear Medicine
• Radiopharmaceutical Therapy

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) presents limited therapeutic options.
• Prostate-specific membrane antigen (PSMA)-targeted alpha therapy shows promise but faces challenges with PSMA-negative tumors.
• CD46-targeted radiopharmaceuticals offer an alternative for PSMA-null and PSMA-positive mCRPC.

Purpose of the Study:

• To evaluate the CD46-targeting PET imaging agent [89Zr]DFO-YS5.
• To assess the radioimmunotherapy agent [225Ac]Macropa-PEG4-YS5 for treating disseminated prostate cancer.
• To investigate the efficacy of CD46-targeted alpha therapy in PSMA-expressing and PSMA-null prostate cancer models.

Main Methods:

• Detection of microtumor lesions in liver, kidneys, and lungs using [89Zr]DFO-YS5 PET imaging.
• Biodistribution, dosimetry, and therapeutic efficacy studies of [225Ac]Macropa-PEG4-YS5 in disseminated 22Rv1 tumors.
• Quantitative digital alpha-particle autoradiography for radiation dose assessment in microtumors and surrounding tissues.

Main Results:

• [89Zr]DFO-YS5 successfully detected microtumor lesions.
• [225Ac]Macropa-PEG4-YS5 demonstrated high radiation dose deposition in microtumors.
• Early treatment of smaller tumors with uniform dose was more effective than late-stage treatment of larger, heterogeneous lesions.
• Heterogeneous dose distribution in large lesions limited therapeutic efficacy, necessitating higher activity for complete response.

Conclusions:

• [225Ac]Macropa-PEG4-YS5 shows potential for clinical translation in metastatic prostate cancer.
• Microdosimetry is valuable for understanding efficacy and resistance mechanisms in targeted alpha therapy.
• CD46-targeted therapy provides a viable treatment avenue for mCRPC, including PSMA-negative cases.