Theranostic Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist NeoBOMB1: Preclinical and First Clinical Results.

Abstract

We recently introduced the potent gastrin-releasing peptide receptor (GRPR) antagonist 68Ga-SB3 (68Ga-DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), showing excellent tumor localizing efficacy in animal models and in patients. By replacement of the C-terminal Leu13-Met14-NH2 dipeptide of SB3 by Sta13-Leu14-NH2, the novel GRPR antagonist NeoBOMB1 was generated and labeled with different radiometals for theranostic use. We herein report on the biologic profile of resulting 67/68Ga-, 111In-, and 177Lu-NeoBOMB1 radioligands in GRPR-expressing cells and mouse models. The first evidence of prostate cancer lesion visualization in men using 68Ga-NeoBOMB1 and PET/CT is also presented.

METHODS:

NeoBOMB1 was radiolabeled with 67/68Ga, 111In, and 177Lu according to published protocols. The respective metalated species natGa-, natIn-, and natLu-NeoBOMB1 were also synthesized and used in competition binding experiments against [125I-Tyr4]BBN in GRPR-positive PC-3 cell membranes. Internalization of 67Ga-, 111In-, and 177Lu-NeoBOMB1 radioligands was studied in PC-3 cells at 37°C, and their metabolic stability in peripheral mouse blood was determined by high-performance liquid chromatography analysis of blood samples. Biodistribution was performed by injecting a 67Ga-, 111In-, or 177Lu-NeoBOMB1 bolus (74, 74, or 370 kBq, respectively, 100 μL, 10 pmol total peptide ± 40 nmol Tyr4-BBN: for in vivo GRPR blockade) in severe combined immunodeficiency mice bearing PC-3 xenografts. PET/CT images with 68Ga-NeoBOMB1 were acquired in prostate cancer patients.

RESULTS:

NeoBOMB1 and natGa-, natIn-, and natLu-NeoBOMB1 bound to GRPR with high affinity (half maximal inhibitory concentration, 1-2 nM). 67Ga-, 111In-, and 177Lu-NeoBOMB1 specifically and strongly bound on the cell membrane of PC-3 cells displaying low internalization, as expected for receptor antagonists. They showed excellent metabolic stability in peripheral mouse blood (>95% intact at 5 min after injection). After injection in mice, all 3 (67Ga-, 111In-, and 177Lu-NeoBOMB1) showed comparably high and GRPR-specific uptake in the PC-3 xenografts (e.g., 30.6 ± 3.9, 28.6 ± 6.0, and >35 percentage injected dose per gram at 4 h after injection, respectively), clearing from background predominantly via the kidneys. During a translational study in prostate cancer patients, 68Ga-NeoBOMB1 rapidly localized in pathologic lesions, achieving high-contrast imaging.

CONCLUSION:

The GRPR antagonist radioligands 67Ga-, 111In-, and 177Lu-NeoBOMB1, independent of the radiometal applied, have shown comparable behavior in prostate cancer models, in favor of future theranostic use in GRPR-positive cancer patients. Such translational prospects were further supported by the successful visualization of prostate cancer lesions in men using 68Ga-NeoBOMB1 and PET/CT.

• Authors: Berthold A Nock, Aikaterini Kaloudi, Emmanouil Lymperis, Athina Giarika, Harshad R Kulkarni, Ingo Klette, Aviral Singh, Eric P Krenning, Marion de Jong, Theodosia Maina, Richard P Baum
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 58 Issue 1 Pg. 75-80 (Jan 2017) ISSN: 1535-5667 [Electronic] United States
• PMID: 27493272 (Publication Type: Journal Article)
• Copyright: © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Radioisotopes
• Radiopharmaceuticals
• Receptors, Bombesin
• Bombesin

Topics

• Animals
• Bombesin (pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Cell Survival (radiation effects)
• Humans
• Male
• Metabolic Clearance Rate
• Mice
• Pilot Projects
• Prostatic Neoplasms (diagnosis, metabolism, radiotherapy)
• Radioisotopes (pharmacokinetics, therapeutic use)
• Radiopharmaceuticals (pharmacokinetics, therapeutic use)
• Receptors, Bombesin (antagonists & inhibitors, metabolism)
• Theranostic Nanomedicine (methods)
• Tissue Distribution
• Treatment Outcome