This document summarizes a study comparing a new bombesin peptide antagonist (JMV4168) to agonists for targeting gastrin releasing peptide receptors (GRPR) overexpressed on prostate and breast cancers. In vitro assays showed JMV4168 bound to GRPR-expressing cells, with most radiation dose from the cell surface, unlike the agonist which was mostly internalized. In vivo studies in mice found JMV4168 had fast clearance from the pancreas and other tissues, suggesting it could be safely used for clinical imaging and treatment of GRPR-overexpressing tumors. The antagonist showed superior profile compared to agonists.

1. A new tumour targeting bombesin peptide: agonist vs antagonist
Linda M. van der Graaf1, Thea Maina2, Pantelis J. Marsouvanidis2, Marleen Melis1, Eric P.
Krenning1, Jean martinez3, Luc Brunel3, Jean-Alain Fehrentz3, Berthold A. Nock2, Marion de Jong1
1
Erasmus MC, dept. of Nuclear Medicine, Rotterdam, the Netherlands, 2 NCSR “Demokritos”, Athens, Greece, 3 Faculté
de Pharmacie, CNRS-Universités de Montpellier 1 et 2, Montpellier, France
Introduction: Aim:
In the current study the new bombesin antagonist
radionuclide peptide target (receptor) JMV4168 was characterized, which is an attractive
alternative to agonists (e.g. AMBA) because of its
Bombesin peptide analogues specifically bind to biosafety
Gastrin Releasing Peptide receptors (GRPR) that
are overexpressed on prostate and breast cancers. Materials and Methods:
When radiolabelled with radionuclides, diagnostic In vitro assays using GRPR expressing PC3 cells
imaging (e.g. 111In) or therapeutic application (e.g. were performed to determine characteristics of
177
Lu) is feasible. 111In-JMV4168. Cell radiation doses were
Proof of concept has been obtained clinically using calculated for internalized and cell-surface bound
peptide agonists, however severe side effects were fractions. In vivo behaviour was tested in
observed in patients. Recent studies have revealed biodistribution studies and in 1 hour dynamic
the superior profile of GRPR-antagonists as SPECT/CT imaging studies with PC3 and PC295
compared to agonists. xenografted female SCID or male nu/nu mice, 1-72
h post injection (p.i.) of 10 pmol (biodistribution) or
Results: 250 pmol (imaging) of 111In-JMV4168 or 177Lu-
JMV4168. For in vivo blockade, a separate 4 h
group was co-injected with an excess of unlabelled
JMV4168
With 111In-JMV4168 73% of the cell dose came
from the cell surface, whereas 82% of the cell dose
originated from internalized activity with 111In-
AMBA.
Discussion and conclusion:
Because of the fast clearance from the GRPR-rich pancreas and background tissues , we conclude that
JMV4168 is a potent bombesin receptor antagonist for safe future use in clinical imaging and therapy of
patients with GRPR-overexpressing tumours