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Published on: April 24, 2020
JHU-2545 preferentially shields salivary glands and kidneys during PSMA-targeted imaging
Michael T Nedelcovych1,2,3, Ranjeet P Dash4,5, Ying Wu4
1Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. mtnede@gmail.com.
Purpose:
Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause 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. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy.
Methods:
A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment.
Results:
JHU-2545 resulted in approximately 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]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor.
Conclusions:
JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.
Insights
A new prodrug, JHU-2545, enhances delivery of a prostate-specific membrane antigen (PSMA) inhibitor to non-cancerous tissues. This approach may improve the safety and effectiveness of PSMA radioligand therapy for metastatic castration-resistant prostate cancer.
Area of Science:
- Oncology
- Radiochemistry
- Pharmacology
Background:
- Prostate-specific membrane antigen (PSMA) radioligand therapy shows promise for metastatic castration-resistant prostate cancer (mCRPC).
- PSMA is also present in kidneys and salivary glands, leading to potential dose-limiting toxicities like xerostomia and nephrotoxicity.
- The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can block uptake in kidneys but also in tumors, limiting its clinical use.
Purpose of the Study:
- To develop a prodrug of 2-PMPA (JHU-2545) for preferential delivery to non-malignant tissues.
- To evaluate the pharmacokinetic profile and tissue distribution of JHU-2545 in preclinical models.
- To assess the impact of JHU-2545 pre-treatment on PSMA PET tracer uptake in kidneys, salivary glands, and tumors.
Main Methods:
- Synthesis of a tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, named JHU-2545.
- Pharmacokinetic studies in rodents to compare JHU-2545 delivery of 2-PMPA to plasma, kidney, salivary glands, and prostate tumor xenografts.
- In vivo imaging studies using PSMA PET tracers in rats and mice with and without JHU-2545 pre-treatment.
Main Results:
- JHU-2545 demonstrated significantly higher exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) compared to prostate tumor xenografts (6.79 ± 0.19 h*nmol/g).
- Pre-treatment with JHU-2545 reduced the uptake of PSMA PET tracers ([68Ga]Ga-PSMA-11 and [18F]F-DCFPyL) in rodent kidneys and salivary glands by up to 85%.
- Tumor uptake of PSMA PET tracers was minimally affected by JHU-2545 pre-treatment.
Conclusions:
- JHU-2545 effectively delivers 2-PMPA to non-malignant tissues like kidneys and salivary glands.
- This preferential delivery strategy may mitigate toxicity associated with PSMA radioligand therapy.
- JHU-2545 pre-treatment holds potential for enhancing the safety and efficacy of PSMA radioligand therapy by allowing higher cumulative doses.
