Both human epidermal growth factor receptor 2 (HER-2/neu) and vascular endothelial growth factor (VEGF) overexpression correlate with aggressive phenotypes and decreased survival among breast cancer patients. Concordantly, the combination of trastuzumab (anti-HER2) with bevacizumab (anti-VEGF) has shown promising results in preclinical xenograft studies and in clinical trials. However, despite the known anti-angiogenic mechanism of anti-VEGF antibodies, relatively little is known about their effects on the pharmacokinetics and tissue distribution of other antibodies. This study aimed to measure the disposition properties, with a particular emphasis on tumor uptake, of trastuzumab in the presence or absence of anti-VEGF. Radiolabeled trastuzumab was administered alone or in combination with an anti-VEGF antibody to mice bearing HER2 expressing KPL-4 breast cancer xenografts. Biodistribution, autoradiography, and SPECT-CT imaging all demonstrated that anti-VEGF administration reduced accumulation of trastuzumab in tumors 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, demonstrating reduced vascular permeability to macromolecules. Reduced tumor blood flow (p < 0.05) was observed following anti-VEGF treatment, with no significant differences in the other physiological parameters measured despite immunohistochemical evidence of reduced vascular density. In conclusion, anti-VEGF pre-administration decreased tumor uptake of trastuzumab, and this phenomenon was mechanistically attributed to reduced vascular permeability and blood perfusion. These findings may ultimately help inform dosing strategies to achieve improved clinical outcomes.
- Received September 19, 2011.
- Revision received December 1, 2011.
- Accepted December 21, 2011.
- Copyright © 2012, American Association for Cancer Research.