Vascular endothelial-cadherin (
VE-cadherin) is an endothelial cell-specific adhesion molecule that is localized exclusively at cell-cell contacts referred to as adherens junctions.
VE-cadherin-mediated adhesion is crucial for proper assembly of vascular structures during angiogenesis as well as for maintenance of a normal vascular integrity. We have shown previously that a
monoclonal antibody (BV13) to
VE-cadherin not only inhibits the formation of vascular tubes during
tumor angiogenesis but also disrupts adherens junctions of normal vasculature with a concomitant increase in vascular permeability. The goal of the current studies was to block
VE-cadherin function during angiogenesis without disrupting existing junctions on normal endothelium. Using in vitro screening assays to test for functional blocking of adherens junction formation and in vivo assays to detect antibody effects on vascular permeability in normal tissues, we have identified a novel blocking
antibody (E4G10) that inhibits
VE-cadherin function during angiogenesis but does not disrupt existing adherens junctions on normal vasculature. E4G10 inhibited formation of vascular tubes in vivo in the
Matrigel plug and corneal micropocket assays. E4G10 also inhibited
tumor growth in three models of mouse and human
tumors via an antiangiogenic mechanism. Examination of normal mouse and
tumor tissues showed that E4G10 bound to endothelial cells in a subset of
tumor vasculature but not to normal vasculature.
Bromodeoxyuridine labeling experiments showed that E4G10 specifically targeted a subset of
tumor endothelium that is undergoing active cell proliferation, which likely reflects the activated, angiogenic endothelium. These findings indicate that
VE-cadherin can be selectively targeted during states of
pathological angiogenesis, despite its ubiquitous distribution throughout the entire vasculature. Our data also suggest that
antibody E4G10 recognizes
VE-cadherin epitopes that are only accessible on endothelial cells forming new adherens junctions, such as in angiogenic
tumor vasculature.