Vascular endothelial growth factor (
VEGF) is critical for physiological and
pathological angiogenesis. Within the tumor microenvironment,
VEGF functions as an endothelial cell survival factor, permeability factor,
mitogen, and chemotactic agent. The majority of these functions are mediated by
VEGF-induced activation of
VEGF receptor 2 (VEGFR2), a high affinity
receptor tyrosine kinase expressed by endothelial cells and other cell types in the tumor microenvironment.
VEGF can also ligate other
cell surface receptors including VEGFR1 and
neuropilin-1 and -2. However, the importance of
VEGF-induced activation of these receptors in
tumorigenesis is still unclear. We report the development and characterization of r84, a fully human
monoclonal antibody that binds human and mouse
VEGF and selectively blocks
VEGF from interacting with VEGFR2 but does not interfere with
VEGF:VEGFR1 interaction. Selective blockade of
VEGF binding to VEGFR2 by r84 is shown through ELISA, receptor binding assays, receptor activation assays, and cell-based functional assays. Furthermore, we show that r84 has potent anti-
tumor activity and does not alter tissue histology or blood and urine chemistry after chronic high dose
therapy in mice. In addition, chronic r84
therapy does not induce elevated blood pressure levels in some models. The ability of r84 to specifically block
VEGF:VEGFR2 binding provides a valuable tool for the characterization of
VEGF receptor pathway activation during
tumor progression and highlights the utility and safety of selective blockade of
VEGF-induced VEGFR2 signaling in
tumors.