Prostate-specific membrane antigen (PSMA) is an attractive target for detection and treatment of prostate cancer because of its high, selective expression in tumors. However, PSMA-targeted antibody-drug conjugates (ADCs) have seen limited clinical efficacy compared with small-molecule radiopharmaceuticals. We used 18FDCFPyL PET imaging to investigate PSMA dynamics after treatment with a naked anti-PSMA antibody (5D3), aiming to generate insights that could inform dosing strategies for ADCs and other PSMA-targeted antibody therapies. Methods: We evaluated the effect of 5D3 on 18FDCFPyL PSMA binding in vitro at 4 and 37 °C in 22Rv1 prostate cancer cells. In vivo, we assessed the dose-dependent effects of 5D3 (0.3-30 mg/kg) on accessible PSMA levels using PET imaging and ex vivo biodistribution studies in both prostatic and nonprostatic (SKMEL3) tumor models. Immunohistochemistry was performed to validate PET and ex vivo findings. Spatial distribution of 18FDCFPyL within tumors was analyzed. Finally, we examined how time (1-5 d) and tumor burden (TB; 1 vs. 3 tumors) influenced accessible PSMA levels at low (1 mg/kg) and high (10 mg/kg) 5D3 doses. Results: 5D3 treatment led to a dose-dependent reduction in 18FDCFPyL uptake at 37 °C (>98% at 50 nM 5D3) but only a marginal reduction at 4 °C (Conclusion: We demonstrated the value of PSMA PET to quantify PSMA pharmacodynamics after antibody therapy. These findings provide a framework for dosing PSMA-targeted antibodies and may inform strategies to improve the performance of ADCs and other antibody-based therapeutics, particularly in patients with high TB.
Mishra et al. (Wed,) studied this question.