Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics
- 3 October 2022
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Nuclear Medicine and Molecular Imaging
- Vol. 50 (3), 957-961
- https://doi.org/10.1007/s00259-022-05982-8
Abstract
Purpose Recently, Pluvicto™ ([177Lu]Lu-PSMA-617), a small-molecule prostate-specific membrane antigen (PSMA) radioligand therapeutic, has been approved by the FDA in metastatic castration-resistant prostate cancer. Pluvicto™ and other PSMA-targeting radioligand therapeutics (RLTs) have shown side effects due to accumulation in certain healthy tissues, such as salivary glands and kidney. Until now, the molecular mechanism underlying the undesired accumulation of PSMA-targeting RLTs had not been elucidated. Methods We compared the sequence of PSMA with the entire human proteome to identify proteins closely related to the target. We have identified glutamate carboxypeptidase III (GCPIII), N-acetylated alpha-linked acidic dipeptidase like 1 (NAALADL-1), and transferrin receptor 1 (TfR1) as extracellular targets with the highest similarity to PSMA. The affinity of compound 1 for PSMA, GCPIII, NAALADL-1, and TfR1 was measured by fluorescence polarization. The expression of the putative anti-target GCPIII was assessed by immunofluorescence on human salivary glands and kidney, using commercially available antibodies. Results A fluorescent derivative of Pluvicto™ (compound 1) bound tightly to PSMA and to GCPIII in fluorescence polarization experiments, while no interaction was observed with NAALADL-1 and TfR1. Immunofluorescence analysis revealed abundant expression of GCPIII both in healthy human kidney and salivary glands. Conclusion We conclude that the membranous expression of GCPIII in kidney and salivary gland may be the underlying cause for unwanted accumulation of Pluvicto™ and other Glu-ureido PSMA radio pharmaceuticals in patients.Keywords
This publication has 25 references indexed in Scilit:
- 68Ga-PSMA-11 PET/CT in recurrent prostate cancer: efficacy in different clinical stages of PSA failure after radical therapyEuropean Journal of Nuclear Medicine and Molecular Imaging, 2018
- Radionuklidtherapie des Prostatakarzinoms mittels PSMA-LutetiumDer Urologe, 2016
- The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate CancerJournal of Nuclear Medicine, 2016
- Comparison of human glutamate carboxypeptidases II and III reveals their divergent substrate specificitiesThe FEBS Journal, 2016
- Design of Highly Potent Urea-Based, Exosite-Binding Inhibitors Selective for Glutamate Carboxypeptidase IIJournal of Medicinal Chemistry, 2015
- Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and IIIThe FEBS Journal, 2009
- A Portable Albumin Binder from a DNA‐Encoded Chemical LibraryAngewandte Chemie, 2008
- A Portable Albumin Binder from a DNA-Encoded Chemical LibraryAngewandte Chemie, 2008
- Biochemical characterization of human glutamate carboxypeptidase IIIJournal of Neurochemistry, 2006
- Phase I Trial of 177Lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients With Androgen-Independent Prostate CancerJournal of Clinical Oncology, 2005