JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

Nedelcovych, M. T.; Dash, R. P.; Wu, Y.; Choi, E. Y.; Lapidus, R. S.; Majer, P.; Abou, D.; Penet, M.-F.; Nikolopoulou, A.; Amor-Coarasa, A.; Babich, J.; Thorek, D. L.; Rais, R.; Kratochwil, C.; Slusher, B. S.

doi:10.1101/457085

bioRxiv · 10.1101/457085

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

Nedelcovych, M. T.·Dash, R. P.·Wu, Y.·Choi, E. Y.·Lapidus, R. S.·Majer, P.·Abou, D.·Penet, M.-F.·Nikolopoulou, A.·Amor-Coarasa, A.·Babich, J.·Thorek, D. L.·Rais, R.·Kratochwil, C.·Slusher, B. S.

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Abstract

PURPOSEProstate-specific membrane antigen (PSMA) radiotherapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC) with several beta or alpha particle-emitting radionuclide-conjugated small molecules showing efficacy in late stage patients. However, PSMA is also expressed in kidneys and salivary glands where specific uptake causes dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2- (phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Selective delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radiotherapy. EXPERIMENTAL DESIGNA tri-alkoxycarbonyloxy alkyl (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Preclinical pharmacokinetic and imaging experiments were conducted prior to assessment in 3 mCRPC patients receiving PSMA PET and radiotherapy. RESULTSJHU-2545 resulted in 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 {+/-} 0.97 h*nmol/g) and kidneys (359 {+/-} 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 {+/-} 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers 68Ga-PSMA-11 and 18F-DCFPyL by up to 85% without effect on tumor. In a mCRPC patient, JHU-2545 treatment prior to 68Ga-PSMA-617 administration reduced kidney SUVmax by 76% without effect on metastatic lesions. When administered prior to injection of the beta emitter 177Lu-PSMA-617, JHU-2545 shielded both the salivary glands (72% Gy reduction) and kidneys (45% Gy reduction) without effect on metastases dose. CONCLUSIONSJHU-2545 pre-treatment raises the cumulative dose limit and improves the safety and efficacy profile of PSMA radiotherapy. STATEMENT OF TRANSLATIONAL RELEVANCEProstate Specific Membrane Antigen (PSMA) molecular radiotherapy has emerged as a promising treatment for metastatic castration-resistant prostate cancer (mCRPC), but endogenous expression of PSMA in kidneys and salivary glands causes uptake into these organs resulting in dose-limiting toxicities. We describe the discovery of JHU-2545, a PSMA inhibitor prodrug that selectively blocks kidney and salivary gland uptake of PSMA theranostics without altering tumor uptake in both preclinical models and in mCRPC patients. Pretreatment of JHU-2545 thereby improves the safety and efficacy profile of the multiple PSMA radiotherapies in development.

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Nedelcovych, M. T., Dash, R. P., Wu, Y., Choi, E. Y., Lapidus, R. S., Majer, P., Abou, D., Penet, M.-F., Nikolopoulou, A., Amor-Coarasa, A., Babich, J., Thorek, D. L., Rais, R., Kratochwil, C., Slusher, B. S.. 2018-10-30. JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy. https://doi.org/10.1101/457085

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