Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET

Abstract

Purpose: We recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [89Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models. Experimental Design: [89Zr]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+, prostate-specific membrane antigen–negative (PSMA−)] or 22Rv1 (AR+, CD46+, PSMA+) tumors, and in NOD/SCID gamma mice bearing patient-derived adenocarcinoma xenograft, LTL-331, and neuroendocrine prostate cancers, LTL-331R and LTL-545. Results: [89Zr]DFO-YS5 binds specifically to the CD46-positive human prostate cancer DU145 and 22Rv1 xenografts. In biodistribution studies, the tumor uptake of [89Zr]DFO-YS5 was 13.3 ± 3.9 and 11.2 ± 2.5 %ID/g, respectively, in DU145 and 22Rv1 xenografts, 4 days postinjection. Notably, [89Zr]DFO-YS5 demonstrated specific uptake in the PSMA- and AR-negative DU145 model. [89Zr]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 ± 5.3 %ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days postinjection). Conclusions: [89Zr]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.

Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen

“…The radiolabeling of 89 Zr oxalate to NPs was accomplished in a single-step chelation with the deferoxamine B ligand (DFB) present on the surface of the NPs (Figure a). ,, To optimize the appropriate DFB ligand concentration, NPs with different wt % of PLGA- b -PEG-DFB conjugates were subjected to 89 Zr radiolabeling using previously described conditions. ,, The reaction yield was determined at 1 h by iTLC and also by measuring the isolated radioactivity following purification using centrifugation. These yields are summarized in Figure b.…”

“…Representative iTLC spectra of DFB(25) NP reaction mixture before and after purification are presented in Figures 3c,d The relative binding affinities of the formulated NPs were estimated, similar to our prior report, by 68 Ga-PSMA-11-based competitive radioligand binding assay (Figure 4c). 27,44 Although the IC 50 values of these NPs were observed in the μg/mL range, a relatively lower IC 50 value was obtained for DFB( 25)ACUPA(75) NPs (0.11 μg/mL) than that of DFB( 25)ACUPA( 25) NPs (0.59 μg/mL). This demonstrated the superior binding affinity of DFB( 25)ACUPA(75) NPs, owing to the higher number of ACUPA ligands on the surface of the NPs.…”

“…41,44,45 To optimize the appropriate DFB ligand concentration, NPs with different wt % of PLGA-b-PEG-DFB conjugates were subjected to 89 Zr radiolabeling using previously described conditions. 41,44,45 The reaction yield was determined at 1 h by iTLC and also by measuring the isolated radioactivity following purification using centrifugation. These yields are summarized in Figure 3b.…”

CD46 targeted212Pb alpha particle radioimmunotherapy for prostate cancer treatment

“…The ADC is in a multi-center phase I trial (NCT03575819) and a phase I/II combination trial (NCT05011188) for mCRPC. Our recent work also demonstrated that the 89 Zr radiolabeled YS5 ( 89 Zr-DFO-YS5) can detect prostate cancer in vivo in both PSMA positive and PSMA negative mCRPC cell line xenograft (CDX) models and patient derived xenograft (PDX) models of both the adenocarcinoma and neuroendocrine subtypes (17), and a first-in-human study of this novel PET agent is ongoing in mCRPC patients (NCT05245006). In this study, we report the synthesis and evaluation of tolerability and therapeutic efficacy of the 212 Pb-radiolabeled human antibody YS5 ( 212 Pb-TCMC-YS5) in multiple prostate cancer small animal models, including subcutaneous CDX, intraprostate orthotopic CDX, and prostate cancer PDX models.…”

PSMA-specific degradable dextran for multiplexed immunotargeted siRNA therapeutics against prostate cancer

“…CD46 is a membrane protein that protects cells from complement attack. 27 A high expression of CD46 has been observed in several cancers including prostate cancer, 28 with clinical and experimental data supporting an association between increased CD46 expression and malignant transformation, and metastasizing potential. [29][30][31] CD46 is also being investigated as a target in early-phase clinical trials for a variety of cancers including advanced prostate cancer (e.g.…”