Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics.
Male
Humans
Radiopharmaceuticals
/ therapeutic use
Dipeptides
/ therapeutic use
Prostate-Specific Antigen
Prostatic Neoplasms, Castration-Resistant
/ metabolism
Glutamate Carboxypeptidase II
/ metabolism
Antigens, Surface
/ metabolism
Radioisotopes
/ therapeutic use
Salivary Glands
/ diagnostic imaging
Kidney
/ metabolism
Lutetium
/ therapeutic use
Glutamate carboxypeptidase III
Metastatic castration-resistant prostate cancer
Off-target toxicity
PSMA
PSMA-617
Radioligand therapy
Journal
European journal of nuclear medicine and molecular imaging
ISSN: 1619-7089
Titre abrégé: Eur J Nucl Med Mol Imaging
Pays: Germany
ID NLM: 101140988
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
31
05
2022
accepted:
19
09
2022
pubmed:
3
10
2022
medline:
24
1
2023
entrez:
2
10
2022
Statut:
ppublish
Résumé
Recently, Pluvicto™ ([ 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. 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. 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.
Identifiants
pubmed: 36184692
doi: 10.1007/s00259-022-05982-8
pii: 10.1007/s00259-022-05982-8
doi:
Substances chimiques
glutamate carboxypeptidase
EC 3.4.17.11
Radiopharmaceuticals
0
Dipeptides
0
Prostate-Specific Antigen
EC 3.4.21.77
Glutamate Carboxypeptidase II
EC 3.4.17.21
Antigens, Surface
0
Radioisotopes
0
Lutetium
5H0DOZ21UJ
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
957-961Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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