Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability.
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.
Liao
Fang
F
ImClone Systems Incorporated, New York, NY 10014, USA. fangl@imclone.com
Doody
Jacqueline F
JF
Overholser
Jay
J
Finnerty
Bridget
B
Bassi
Rajiv
R
Wu
Yan
Y
Dejana
Elisabetta
E
Kussie
Paul
P
Bohlen
Peter
P
Hicklin
Daniel J
DJ
D022005:Adherens Junctions / Q000187:drug effects / Q000276:immunology; D020533:Angiogenesis Inhibitors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015703:Antigens, CD; D015820:Cadherins / Q000276:immunology*; D002199:Capillary Permeability / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D003315:Cornea / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006131:Growth Inhibitors / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012878:Skin Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays; D000099152:Cadherin 5
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015820:Cadherins; D006131:Growth Inhibitors; D000099152:Cadherin 5