Abstract
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Objectives: AMG 655 is a fully human IgG1 monoclonal agonist antibody that binds human DR5, activates caspases, and induces apoptosis in sensitive tumor cells. Preliminary microPET studies showed intense and saturable uptake of 64Cu-AMG 655 in DR5 positive Colo205 tumor. The purpose of this study was to evaluate 64Cu-AMG 655 as a PET tracer for measuring DR5 occupancy by AMG 655.
Methods: 64Cu-AMG 655 was prepared from DOTA-AMG 655 and 64CuCl2. In vivo stability was examined in normal SCID mice. Biodistribution was performed in SCID mice bearing Colo205 tumor xenografts. Nine groups (n=4/group) of mice were used: 3 controls (6, 24 and 48 h), 4 AMG 655-treated (doses: 2.5, 25, 250, 1000 μg) at 24 h, and 2 2.4G2-treated (anti-FcR antibody, 0.5 mg) at 6 and 24 h. Tracer (8 μCi, 0.1 μg DOTA-AMG 655) was injected through the tail-vein. Blocking drug was co-injected with the tracer. Tissues were removed, weighed, and counted in a gamma counter. Uptake was expressed in percent injected dose per gram of tissue. Tissue-to-blood ratios (T/B) were used to determine receptor occupancy (RO), assuming 0% RO for tracer alone and 100% for 1000 μg AMG 655.
Results: 64Cu-AMG 655 was readily prepared. Tracer was stable in plasma for 24 h post injection. For controls, median T/B at 6, 24 and 48 h were 0.37, 1.07, and 1.20, respectively. For AMG 655 treated, median T/B at 24 h for 0 (tracer alone), 2.5, 25, 250 and 1000 μg were 1.07, 0.99, 0.63, 0.50, and 0.47, respectively. DR5 RO calculated from median T/B at 24 h was 32%, 80% and 82% for 2.5, 25 and 250 μg AMG 655, respectively. Co-injection of 2.4G2 blocked spleen uptake, suggesting an FcR mediated process.
Conclusions: Preliminary results suggested that 64Cu-AMG 655 is a potential PET tracer for measuring RO in DR5 positive tumors.
- Society of Nuclear Medicine, Inc.