Abstract A190: Effect of anti-VEGF acute treatment on tumor uptake of trastuzumab in a xenograft model.

Abstract

Abstract Overexpression of both human epidermal growth factor receptor 2 (HER-2/neu) and vascular endothelial growth factor (VEGF) are associated with aggressive disease and decreased survival among breast cancer patients. Accordingly, the combination of bevacizumab (anti-VEGF) with trastuzumab (anti-HER2) has demonstrated promising results in both preclinical and clinical studies. However, little is known about anti-VEGF antibody's effects on the disposition and pharmacokinetics of other antibodies. This study assessed the biodistribution of trastuzumab in the presence or absence of an anti-VEGF antibody, with a particular emphasis on tumor uptake. Mice bearing HER2 expressing KPL-4 breast cancer xenografts received trastuzumab or a non-HER2 binding antibody radiolabeled with either 125I or 111In to assess the real time kinetics and cumulative tumor uptake with and without pre-administration of an anti-VEGF antibody. Acute anti-VEGF treatment reduced tumor uptake of trastuzumab. This effect was consistently observed by tissue distribution, autoradiography, and SPECT-CT imaging despite comparable blood exposures and similar distributions in most other tissues. A similar trend was also observed for an isotype-matched IgG with no affinity for HER2. Reduced tumor blood flow was observed following anti-VEGF treatment, and immunohistochemistry showed evidence of reduced vascular density. In conclusion, anti-VEGF pre-administration resulted in decreased tumor uptake of trastuzumab, and this phenomenon may be explained, at least in part, by reduced vascular permeability and blood flow. These findings add to the current understanding of combination anti-HER2/anti-VEGF therapy and may ultimately lead to improved clinical outcomes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A190.