CD46 ImmunoPET in mCRPC: A New Theranostic Axis Beyond PSMA

CD46 is a cell‑surface protein that stays highly expressed in aggressive, late‑stage prostate cancer, including PSMA‑low, AR‑negative and neuroendocrine variants. That means CD46 immunoPET can still “see” and quantify disease that PSMA PET misses, and can guide CD46‑targeted therapies in exactly those PSMA‑low/negative patients who respond poorly to PSMA‑directed radioligand therapy.

Using the human antibody YS5, researchers created the immunoPET tracer 89Zr‑DFO‑YS5, which binds a tumor‑selective CD46 epitope with minimal binding to most normal tissues. In mouse models it showed high, specific uptake in both PSMA‑positive and PSMA‑negative prostate cancer, including neuroendocrine xenografts, confirming that CD46 imaging can cover biologic territory beyond the PSMA axis.

The first‑in‑human phase I study of 89Zr‑DFO‑YS5 in mCRPC demonstrated that the tracer is well tolerated, with manageable infusion reactions after premedication and an effective radiation dose in line with other 89Zr‑labeled antibodies. Imaging at five to seven days post‑injection gave the best tumor‑to‑background contrast, with strong uptake in bone and soft‑tissue metastases and tumor‑to‑blood ratios around 10. In 30 men with mCRPC, 89Zr‑DFO‑YS5 detected 144 bone metastases versus 99 on bone scan, and 33 soft‑tissue lesions (lymph nodes, liver, lung) versus 14 on CT(about 45% more bone lesions than bone scintigraphy and roughly 136% more soft‑tissue lesions than CT). In other words, CD46 immunoPET substantially outperforms conventional imaging for mapping metastatic burden in this setting.

CD46 is also being exploited therapeutically using the same YS5 backbone. The antibody–drug conjugate FOR46 (FG‑3246) has shown encouraging activity and acceptable safety in early‑phase mCRPC trials, and CD46‑targeted alpha‑emitter constructs such as 225Ac‑YS5 have produced strong anti‑tumor effects in preclinical models. Because 89Zr‑DFO‑YS5 and these therapies use the same target and antibody, CD46 immunoPET can function as a true theranostic tool, identifying CD46‑avid disease and potentially selecting patients most likely to benefit from CD46‑directed ADC or radioligand therapy.

Source.