Monitoring response to anti-angiogenic mTOR inhibitor therapy in vivo using (111)In-bevacizumab

BACKGROUND: The ability to image vascular endothelial growth factor (VEGF) could enable prospective, non-invasive monitoring of patients receiving anti-angiogenic therapy. This study investigates the specificity and pharmacokinetics of (111)In-bevacizumab binding to VEGF and its use for assessing response to anti-angiogenic therapy with rapamycin. Specificity of (111)In-bevacizumab binding to VEGF was tested in vitro with unmodified radiolabelled bevacizumab in competitive inhibition assays. Uptake of (111)In-bevacizumab in BALB/c nude mice bearing tumours with different amounts of VEGF expression was compared to that of isotype-matched control antibody ((111)In-IgG1κ) with an excess of unlabelled bevacizumab. Intratumoural VEGF was evaluated using ELISA and Western blot analysis. The effect of anti-angiogenesis therapy was tested by measuring tumour uptake of (111)In-bevacizumab in comparison to (111)In-IgG1κ following administration of rapamycin to mice bearing FaDu xenografts. Uptake was measured using gamma counting of ex vivo tumours and effect on vasculature by using anti-CD31 microscopy. RESULTS: Specific uptake of (111)In-bevacizumab in VEGF-expressing tumours was observed. Rapamycin led to tumour growth delay associated with increased relative vessel size (8.5 to 10.3, P = 0.045) and decreased mean relative vessel density (0.27 to 0.22, P = 0.0015). Rapamycin treatment increased tumour uptake of (111)In-bevacizumab (68%) but not (111)In-IgGκ and corresponded with increased intratumoural VEGF(165). CONCLUSIONS: (111)In-bevacizumab accumulates specifically in VEGF-expressing tumours, and changes after rapamycin therapy reflect changes in VEGF expression. Antagonism of mTOR may increase VEGF in vivo, and this new finding provides the basis to consider combination studies blocking both pathways and a way to monitor effects. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-017-0297-9) contains supplementary material, which is available to authorized users.