Effective Suppression of Vascular Network Formation by Combination of Antibodies Blocking VEGFR Ligand Binding and Receptor Dimerization

SummaryAntibodies that block vascular endothelial growth factor (VEGF) have become an integral part of antiangiogenic tumor therapy, and antibodies targeting other VEGFs and receptors (VEGFRs) are in clinical trials. Typically receptor-blocking antibodies are targeted to the VEGFR ligand-binding site. Here we describe a monoclonal antibody that inhibits VEGFR-3 homodimer and VEGFR-3/VEGFR-2 heterodimer formation, signal transduction, as well as ligand-induced migration and sprouting of microvascular endothelial cells. Importantly, we show that combined use of antibodies blocking ligand binding and receptor dimerization improves VEGFR inhibition and results in stronger inhibition of endothelial sprouting and vascular network formation in vivo. These results suggest that receptor dimerization inhibitors could be used to enhance antiangiogenic activity of antibodies blocking ligand binding in tumor therapy.

Graphical AbstractFigure optionsDownload high-quality image (404 K)Download as PowerPoint slideHighlights
► We report a monoclonal antibody that blocks VEGF receptor dimerization
► This antibody shows enhanced VEGF receptor inhibition at high ligand concentrations
► Blocking both ligand binding and receptor dimerization improves VEGFR inhibition
► This antibody combination should outperform current inhibitors of tumor angiogenesis