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Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics

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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.

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Fig. 1
Fig. 2

Data availability

Data are available free of charge as PDF file in the supplementary information section.

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Acknowledgements

We kindly thank Abdullah Elsayed for the PSMA plasmid design.

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Authors and Affiliations

  1. Philochem AG, Libernstrasse 3, 8112, Otelfingen, (ZH), Switzerland

    Laura Lucaroni, Tony Georgiev, Eleonora Prodi, Sara Puglioli, Nicholas Favalli, Luca Prati, Samuele Cazzamalli, Dario Neri, Sebastian Oehler & Gabriele Bassi

  2. Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland

    Christian Pellegrino & Markus G. Manz

Authors
  1. Laura Lucaroni
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  2. Tony Georgiev
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  3. Eleonora Prodi
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Contributions

All the authors have contributed to manuscript preparation. Gabriele Bassi (GB), Sebastian Oehler (SO), Dario Neri (DN), and Samuele Cazzamalli (SC) conceived the experiments. Luca Prati (LP) and Tony Georgiev (TG) performed compound 1 synthesis. SO, Laura Lucaroni (LL), and Eleonora Prodi (EP) designed, expressed, purified, and characterized GCPIII and PSMA. LL, GB, and SO performed fluorescence polarization studies. Christian Pellegrino (CP), SO, and GB performed immunofluorescence microscopy experiments. Sara Puglioli (SP) performed molecular docking studies.

Corresponding authors

Correspondence to Sebastian Oehler or Gabriele Bassi.

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Conflict of interest

D. N. is CEO and CSO of the Philogen AG. SC, GB, SO, LP, LL, NF, TG, EP, and SP are employed at Philochem AG, the research and development unit of the Philogen group. All other authors declare no competing interests.

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This article is part of the Topical Collection on Oncology-Genitourinary.

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Lucaroni, L., Georgiev, T., Prodi, E. et al. Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics. Eur J Nucl Med Mol Imaging 50, 957–961 (2023). https://doi.org/10.1007/s00259-022-05982-8

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  • DOI: https://doi.org/10.1007/s00259-022-05982-8

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