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

Denis Tvorogov, Andrey Anisimov, Wei Zheng, Veli Matti Leppänen, Tuomas Tammela, Simonas Laurinavicius, Wolfgang Holnthoner, Hanna Heloterä, Tanja Holopainen, Michael Jeltsch, Nisse Kalkkinen, Hilkka Lankinen, Päivi M. Ojala, Kari Alitalo

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

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.

Original languageEnglish
Pages (from-to)630-640
Number of pages11
JournalCancer Cell
Volume18
Issue number6
DOIs
StatePublished - 14 Dec 2010
Externally publishedYes

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