Molecular imaging of prostate cancer targeting CD46 using immunoPET

Purpose:We recently identified CD46 as a novel therapeutic target in prostate cancer (PCa).In the present study, we developed a novel CD46-targeted positron emission tomography (PET) radiopharmaceutical, [ 89 Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine PCa models.Experimental design: [ 89 Zr]DFO-YS5 was prepared and its in vitro binding affinity for CD46 was measured.ImmunoPET imaging was conducted in male athymic nu/nu mice bearing DU145 (AR-, CD46+, PSMA-) or 22Rv1 (AR+, CD46+, PSMA+) tumors, and NSG mice bearing patient derived adenocarcinoma xenograft LTL-331, and neuroendocrine prostate cancers LTL-331R and LTL-545.Result: [ 89 Zr]DFO-YS5 binds specifically to the CD46 positive human PCa DU145 and 22Rv1 xenografts.In biodistribution studies, the tumor uptake of [ 89 Zr]DFO-YS5 was 13.3 ± 3.9 % ID/ gram and 11.2 ± 2.5 % ID/gram respectively in DU145 and 22Rv1 xenografts 4 days post injection.Notably, [ 89 Zr]DFO-YS5 demonstrated specific uptake in the PSMA and AR-negative DU145 model.[ 89 Zr]DFO-YS5 also showed uptake in the patient-derived LTL-331 and 331R models, with particularly high uptake in the LTL-545 neuroendocrine prostate cancer tumors (18.8 ± 5.3, 12.5 ± 1.8, and 32.0 ± 5.3 % ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days post injection).Conclusions: [ 89 Zr]DFO-YS5 is an excellent PET imaging agent across a panel of prostate cancer models, including in both adenocarcinoma and neuroendocrine prostate cancer, both cell line-and patient-derived xenografts, and both PSMA positive and negative tumors.It demonstrates potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in prostate cancer.