Abstract 696: Anti-NRP1 tumor uptake is impacted by normal tissue sinks in a tumor bearing mouse model

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Neuropilin-1 (NRP1) is a VEGF165 and semaphorin receptor widely expressed by vascular endothelial cells in normal tissues and on some tumor cells. Blocking NRP1 with a human IgG1 against the b domain of NRP1 has been shown to inhibit tumor growth in several preclinical models. However, due to the wide expression of NRP1 in normal tissues, the uptake of anti-NRP1 by tumor cells may be impacted by the uptake in normal tissues. The objective of this study was to determine the normal tissue uptake of anti-NRP1 and assess its impact on tumor tissue uptake in a tumor bearing mouse model. Nude mice bearing tumors with either low, HM7, or high, SKMES, NRP1 expression were dosed with [111In]-DOTA labeled anti-NRP1 with or without excess amounts of unlabeled anti-NRP1 via single IV injection. Following dosing, blood, tumor, and several normal tissues were collected at pre-selected time points for the determination of radioactivity levels using a gamma counter. In the absence of unlabeled anti-NRP1, 3% Injected Dose (ID)/ml of radioactivity was observed in the blood at 15 minutes post-dose and decreased quickly. There was minimal radioactivity seen in tumor tissue. In contrast, the majority of radioactivity was detected in the lungs and liver. With increasing amount of unlabeled anti-NRP1, the radioactivity in the lungs/liver dropped, while increasing in blood and tumor tissue. At ∼10 mg/kg unlabeled anti-NRP1, there was no additional decrease of radioactivity in these normal tissues whereas the tumor radioactivity appeared to reach its peak. Taken together, these data suggest that the lungs/liver are tissue sinks that sequester a majority of the anti-NRP1 when given at lower doses, thus hampering tumor uptake. It is important to optimize the dose and dose regimen in order to overcome this tissue sink binding and allow for a sufficient amount of antibody to be available for tumor uptake. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 696.