Abstract 2779: Non-invasive quantification of pharmacodynamic effects of an antibody targeting PSMA by PET imaging (2020)

Abstract Introduction: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancers (PCa) and a target for the development of a variety of therapeutics. Knowledge of how those therapeutics engage tumor PSMA could improve dose finding and optimization. Here we studied the pharmacodynamic effects of a PSMA monoclonal antibody (5D3, mAb) on target engagement and accessible levels of PSMA in the tumors in PCa and melanoma xenograft models known to express PSMA. We also sought to evaluate effect of tumor burden on the pharmacodynamic effects of the mAb and accessible tumor PSMA levels. To quantify accessible PSMA levels, we used [18F]DCFPyL, an established PSMA binding positron emission tomography (PET) imaging agent. Methods: Prostate (22RV1) and skin (SKMEL3) cancer cells were tested for PSMA expression by flow cytometry. Corresponding tumors were generated in the upper flanks of male NSG mice and used for PET imaging and biodistribution studies. [18F]DCFPyL was synthesized using established procedures. To assess the effect of 5D3 dose on accessible PSMA levels, mice with 22RV1 tumors were treated with a single dose of 0.3, 1, 3, 10 and 30 mg/kg of mAb or saline as a control. Mice with one and three 22RV1 tumors were used to establish low and high tumor burden models, respectively and treated with a single 1 and 10 mg/kg dose of 5D3. All the treatments were performed for 24h. After 5D3 treatment, [18F]DCFPyL was injected and imaging and biodistribution studies were performed at 1 hour after radiotracer injection. All the data were normalized and presented as % of injected dose per gram (%ID/g). Results: We observed a negative correlation between [18F]DCFPyL uptake in tumors and antibody dose, indicating a decrease in accessible tumor PSMA levels with increased mAb dose. Ex vivo biodistribution studies showed high [18F]DCFPyL uptake (13.2±1.4 %ID/g) in saline treated controls and a 25, 46 and 76% reduction in mice treated with 0.3, 1 and 10 mg/kg dose of mAb, respectively. Those findings were validated in SKMEL3 tumors with 4-fold lower PSMA expression. Collectively, these data establish that accessible PSMA levels in the tumors are reduced for [18F]DCFPyL binding with increased 5D3 dose. Next, we studied the effect of tumor burden on antibody dose and accessible PSMA levels at the tumor. In mice bearing one 22RV1 tumor (low tumor burden), [18F]DCFPyL uptake in tumors was reduced by 52% and 77% in mice treated with 1 and 10 mg/kg dose of 5D3, respectively. In mice with three tumors (high tumor burden), [18F]DCFPyL uptake in tumors was reduced by 29% and 56% at 1 and 10 mg/kg dose of 5D3, respectively. No differences were observed in saline treated controls between mice with one or three tumors. These data suggest higher accessible PSMA levels in mice with three tumors compared to mice with one tumor when treated with the same dose of an mAb. These observations indicate that high tumor burden leads to increased antibody processing and accessible PSMA levels in tumors, which could have implication for dosing of PSMA targeted therapeutics. Conclusion: Quantification of accessible PSMA levels, measured using [18F]DCFPyL uptake, can be used as a tool for dose-finding and optimization of PSMA targeted therapeutics. Citation Format: Akhilesh Mishra, Zora Nováková, Ala Lisok, Dhiraj Kumar, Ronnie C. Mease, Cyril Bařinka, Sridhar Nimmagadda. Non-invasive quantification of pharmacodynamic effects of an antibody targeting PSMA by PET imaging [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2779.