Selective inhibition of vascular endothelial growth factor (VEGF) receptor2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice

Vascular endothelial growth factor (VEGF) is a multifunctional angiogenic g rowth factor that is a primary stimulant of the development and maintenance of a vascular network in embryogenesis and the vascularization of solid tu mors. At the present time there are two well-characterized receptors for VE GF that are selectively expressed on endothelium. VEGF receptor 2 [VEGFR2 ( KDR/Flk-1)] mediates endothelial cell mitogenesis and permeability increase s, whereas the role of VEGF receptor 1 [VEGFR1 (Flt-1)] has not been clearl y defined. In the present study, a monoclonal antibody, 2C3, is shown to bl ock the interaction of VEGF with VEGFR2 but not with VEGFR1 through ELISA, receptor binding assays, and receptor activation assays. 2C3 blocks the VEG F-induced vascular permeability increase in guinea pig skin. 2C3 has potent antitumor activity, inhibiting the growth of newly injected and establishe d human tumor xenografts in mice. These findings demonstrate the usefulness of 2C3 in dissecting the pathways that are activated by VEGF in cells that express both VEGFR1 and VEGFR2, as well as highlighting the dominant role of VEGFR2 in mediating VEGF-induced vascular permeability increases and tum or angiogenesis.