The bombesin antagonist JMV4168 is very suitable for application in radionuclide therapy

Objectives Antagonists can show high specific receptor uptake together with rapid clearance, which is of concern when developing radionuclide therapy. DOTA-βAla-βAla-JMV594 (JMV4168) is a bombesin receptor antagonist of Gastrin Releasing Peptide Receptor positive (GRPR+) human tumours. The consequences of faster washout and lower cellular internalization kinetics by antagonists is unknown. The radiation dosimetry of the JMV4168 was compared to the GRPR+ agonist AMBA.

Methods The internalization capacity of [¹¹¹In]JMV4168 and [¹¹¹In]AMBA was determined in GRPR+ PC3 cells. Cell doses were calculated for internalised and cell-surface bound fractions. Biodistribution of [¹⁷⁷Lu]JMV4168 was studied in nude mice with PC-3 tumour xenografts at 4, 24, 48 and 96 h. The doses to the 500mg tumour, the pancreas and the kidneys were calculated by using S-values for a 25 g mouse phantom.

Results As expected the antagonist showed a factor 3 lower internalization rate in PC3 cells: 0.3-4.0 %/mg [¹¹¹In]JMV4168 than for [¹¹¹In]AMBA at 10^-7-10^-10 M. For [¹¹¹In]JMV4168 the internalization fraction was (6-13%), and [¹¹¹In]AMBA (21-68%). The PC-3 cells had a radius of: 12±2μm and its cell density was 2×10⁶ cells/mg. With the antagonist [¹¹¹In]JMV4168 the cell dose was by surface bound activity (73%), whereas for the agonist [¹¹¹In]AMBA 82% was by internalized activity. The total cell dose by the agonist AMBA was just slightly higher. Biodistribution studies with [¹⁷⁷Lu]JMV4168 showed huge differences in both the uptake and wash-out of the pancreas between JMV4168 and published data for [¹⁷⁷Lu]AMBA. All other organ doses were comparable in this mouse model.

Conclusions The antagonist JMV4168 is most promising for use in both clinical imaging and therapy of bombesin receptor-positive tumours. The high tumour doses together with the low radiation doses to pancreas and kidneys by rapid washout makes this antagonist suitable for therapy.

Research Support COST action BM0607Targeted Radionuclide Therap

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Radiation dosimetry ¹⁷⁷Lu-JMV(antagonist) and ¹⁷⁷Lu-AMBA (agonist) in PC3 tumors