CD46 is a cell-surface protein highly expressed in prostate cancer, positioning it as a promising therapeutic target. CD46-targeted agents have advanced to clinical translation, with ongoing trials assessing PET imaging (NCT05245006, NCT05892393) and antibody-drug conjugate therapies (NCT03575819, NCT05011188). In this study, CD46-targeted PET imaging agent [89Zr]DFO-YS5 and alpha particle emitting therapeutic agent [225Ac]Macropa-PEG4-YS5 were evaluated in disseminated prostate cancer models. In preclinical studies, [89Zr]DFO-YS5 effectively visualized disseminated prostate tumors, and [225Ac]Macropa-PEG4-YS5 selectively delivered high radiation doses to tumor cells, achieving effective tumor ablation. Therapeutic efficacy significantly depended on microtumor size and homogeneity of radiation dose distribution (Figure 1). Smaller disseminated tumors exhibited uniform radiation dosing, resulting in enhanced tumor eradication and prolonged survival. In contrast, larger lesions (>1 mm) displayed heterogeneous radiation distribution, potentially enabling tumor persistence and regrowth, thus limiting therapeutic effectiveness. Early therapeutic intervention with CD46-targeted alpha therapy markedly improved outcomes, highlighting the importance of early treatment before tumors surpass critical size thresholds.
By demonstrating efficacy in a disseminated prostate cancer model, these results strengthen the rationale for theranostic approaches beyond PSMA in prostate cancer. Furthermore, the results highlight the importance of tumoral microdosimetry in guiding drug development and predicting response to radiopharmaceutical therapies in preclinical models.
These findings position CD46-targeted alpha therapy as a promising approach for patients with PSMA-negative or PSMA-low prostate cancer, particularly those with liver metastases frequently associated with poor prognosis and reduced PSMA expression. This study provides robust preclinical rationale supporting clinical translation of [225Ac]Macropa-PEG4-YS5, complementing ongoing clinical trials evaluating CD46-targeted therapies (NCT05245006, NCT03575819, NCT05011188). Clinical validation through ongoing and future trials will be critical to confirm and further develop CD46-targeted therapies, ultimately expanding treatment options for advanced and heterogeneous prostate cancer.
Figure 1. Radiation dose and DNA damage following CD46 targeting alpha particle therapy ([225Ac]Macropa-PEG4-YS5). (A) Bioluminescence (BLI) and CD46 PET/CT imaging showing liver tumor dissemination. (B) Autoradiography-based dose map of liver tumors. (C) Tumor region with homogeneous radiation dose and corresponding uniform γ-H2AX foci formation (lower panel). (D) Tumor region with heterogeneous radiation dose and variable γ-H2AX foci formation.
Written by: Anil P. Bidkar,1 Robin Peter,2 Anju Wadhwa,1 Kondapa Naidu Bobba,1 Scott Bidlingmaier,3 Niranjan Meher,4 Jonathan Chou,1 Nancy Greenland,5 Chandrashekhar Dasari,1 Shubhankar Naik,6 Athira Raveendran,5 Megha Basak,1 Juan Antonio Camara Serrano,1 Veronica Steri,1 Scott Kogan,1 Adam Oskowitz,1 Jiang He,7 David M. Wilson,1 Rahul Aggarwal,1 Renuka Sriram,1 Henry F. VanBrocklin,1 Youngho Seo,1 Bin Liu,1 Robert R. Flavell1
- University of California, San Francisco, San Francisco, CA, United States.
- University of California, Berkeley, United States.
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States.
- National Institute of Pharmaceutical Education and Research, Lucknow, UP, India.
- University of California, San Francisco, United States.
- University of California, Berkeley, Berkeley, United States.
- University of Virginia, Charlottesville, VA, United States.