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

Cancer Cell. 2010 Dec 14;18(6):630-40. doi: 10.1016/j.ccr.2010.11.001. Epub 2010 Dec 2.

Abstract

Antibodies 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Antibodies, Monoclonal / pharmacology*
  • Cells, Cultured
  • Humans
  • Morphogenesis
  • Protein Multimerization*
  • Receptor, ErbB-2 / chemistry
  • Vascular Endothelial Growth Factor C / antagonists & inhibitors
  • Vascular Endothelial Growth Factor C / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-3 / chemistry
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Vascular Endothelial Growth Factor C
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-3