Abstract 2438: Bevacizumab treatment hampers tumor uptake of antibodies in human tumor bearing mice

Abstract

Abstract Background: Extensive angiogenesis, defective vascular architecture, impaired lymphatic drainage and increased vascular permeability are characteristics unique for solid tumors. These characteristics result in enhanced tumor permeability and retention (EPR) effect. The EPR effect has been recognized as an important factor for intratumoral delivery of macromolecular drugs, like antibodies. Rapid changes in tumor vasculature and permeability due to antiangiogenic treatment could possibly restrain the EPR effect and thereby lead to a decreased uptake of antibodies. This would have implications for combining antiangiogenic therapy with monoclonal antibodies. We therefore investigated the effect of bevacizumab treatment on the tumor uptake of antibodies by means of immunoPET imaging. Methods: The effect of bevacizumab treatment on the antibody tumor uptake was studied with in vivo PET imaging of 89Zr-trastuzumab, 89Zr-bevacizumab and 89Zr-IgG in a SKOV-3 human xenograft tumor model. PET images were made before and during bevacizumab (5mg/kg; 2qw) or placebo (normal saline) treatment. All animals also received trastuzumab, bevacizumab or IgG labeled with the near-infrared fluorescence dye IRDye 800CW as a co-injection. Immunohistochemistry was performed to determine the mean vascular density (MVD). Immunofluorescence was used to visualize trastuzumab-800CW, bevacizumab-800CW and IgG-800CW and to determine vessel normalization by vessel pericyte coverage. Results: Bevacizumab treatment decreased 89Zr-trastuzumab, 89Zr-bevacizumab and 89Zr-IgG tumor uptake with 41 ± 5% (P<0.0001), 43 ± 4% (P<0.0001) and 28 ± 6% (P=0.0004) respectively. Placebo treatment did not affect tumor uptake of 89Zr-IgG. Immunofluorescence showed less accumulation of IgG-800CW in bevacizumab treated tumor sections compared to placebo treated tumor sections. In all groups, bevacizumab treatment decreased the MVD (P<0.0003). Remaining vessels in bevacizumab treated tumor sections showed an increase in the amount and degree of vessel pericyte coverage compared to placebo. Conclusion: Bevacizumab treatment reduces tumor uptake of trastuzumab, bevacizumab and IgG possibly by restraining the EPR effect through vessel normalization. This deserves attention in the design of clinical trials, when combining antiangiogenic treatment with antibodies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2438. doi:1538-7445.AM2012-2438