A monoclonal antibody to vascular endothelial-cadherin inhibits tumor angiogenesis without side effects on endothelial permeability.
Vascular endothelial cadherin (VE-cadherin) is an endothelial-specific, trans-membrane protein that promotes homophilic cell adhesion. Inhibition of VE-cadherin by the blocking monoclonal antibody (mAb) BV13 inhibited angiogenesis and tumor growth in vivo. However, this effect was accompanied by a marked increase in lung and heart permeability. In the present paper, we characterize a different VE-cadherin mAb (BV14) that is able to inhibit angiogenesis without affecting vascular permeability. In vitro studies show that BV14, in contrast to BV13, did not increase paracellular permeability of endothelial monolayers and did not disrupt VE-cadherin clusters at junctions. However, both antibodies could inhibit formation of vascularlike structures in collagen gels and increase migration of endothelial cells into wounded areas. In vivo, BV14 and BV13 were equally active in inhibiting angiogenesis in the mouse cornea and in reducing the growth of hemangioma and C6 glioma. In contrast to BV13, BV14 did not change vascular permeability in all the organs tested and at any dose used. BV14 and BV13 bind to VE-cadherin extracellular repeats EC4 and EC1, respectively. We propose that, in resting vessels, where junctions are stable and well-structured, antibody binding to EC1 but not EC4 disrupts their organization and increases permeability. In contrast, in growing vessels, where endothelial cells are migrating and junctions are weaker, antibody binding to EC4 may be sufficient to disrupt cell-to-cell adhesion and inhibit assembly of new vascular structures.
Corada
Monica
M
FIRC Institute of Molecular Oncology, Milan, Italy.
Zanetta
Lucia
L
Orsenigo
Fabrizio
F
Breviario
Ferruccio
F
Lampugnani
Maria Grazia
MG
Bernasconi
Sergio
S
Liao
Fang
F
Hicklin
Daniel J
DJ
Bohlen
Peter
P
Dejana
Elisabetta
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology; D015820:Cadherins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D018604:Epitope Mapping; D007365:Intercellular Junctions / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control*; D014407:Tumor Cells, Cultured / Q000637:transplantation; D000099152:Cadherin 5
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D015820:Cadherins; D000099152:Cadherin 5