Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization.
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.
Institute for Molecular Medicine Finland, Department of Pathology, Haartman Institute, Helsinki University Central Hospital, University of Helsinki, Finland.
Denis
D
Tvorogov
Andrey
A
Anisimov
Wei
W
Zheng
Veli-Matti
VM
Leppänen
Tuomas
T
Tammela
Simonas
S
Laurinavicius
Wolfgang
W
Holnthoner
Hanna
H
Heloterä
Tanja
T
Holopainen
Michael
M
Jeltsch
Nisse
N
Kalkkinen
Hilkka
H
Lankinen
Päivi M
PM
Ojala
Kari
K
Alitalo
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D009024:Morphogenesis; D055503:Protein Multimerization; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D018719:Erb-b2 Receptor Tyrosine Kinases; D042582:Vascular Endothelial Growth Factor C; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C508053:ERBB2 protein, human