Identification of a transiently exposed VE-cadherin epitope that allows for specific targeting of an antibody to the tumor neovasculature

Chad May, Jacqueline R. Doody, Rashed Abdullah, Paul Balderes, Xiaohong Xu, Peter Chen Chien, Zhenping Zhu, Lawrence Shapiro, Paul Kussie, Daniel J. Hicklin, Francesca-Fang Liao, Peter Bohlen

Research output: Contribution to journalArticle

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Abstract

VE-cadherin is an adhesion molecule localized at the adherens junctions of endothelial cells. It is crucial for the proper assembly of vascular structures during angiogenesis and maintaining vascular integrity. We have studied 3 monoclonal antibodies (mAbs) against murine VE-cadherin that inhibit angiogenesis and tumor growth. Two of these, BV13 and 10G4, also disrupted normal vessels, resulting in severe vascular leakage, whereas the third, E4G10, did not. The goal of the current report was to identify the epitope of E4G10 and distinguish it from those of the disruptive mAbs. We mapped the epitope of E4G10 to within the first 10 amino acids of mature VE-cadherin and demonstrated that conserved tryptophan residues in this sequence are required for VE-cadherin-mediated trans-adhesion. The disruptive mAbs target a different epitope within amino acids 45 to 56, which structural homology modeling suggests is not involved in trans-adhesion. From our studies, we hypothesize that E4G10 can only bind the neovasculature, where VE-cadherin has not yet engaged in trans-adhesion and its epitope is fully exposed. Thus, E4G10 can inhibit junction formation and angiogenesis but is unable to target normal vasculature because its epitope is masked. In contrast, BV13 and 10G4 bind an epitope that is accessible regardless of VE-cadherin interactions, leading to the disruption of adherens junctions. Our findings establish the immediate N-terminal region of VE-cadherin as a novel target for inhibiting angiogenesis.

Original languageEnglish (US)
Pages (from-to)4337-4344
Number of pages8
JournalBlood
Volume105
Issue number11
DOIs
StatePublished - Jun 1 2005

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Neoplasm Antibodies
Tumors
Epitopes
Antibodies
Adhesion
Blood Vessels
Adherens Junctions
Monoclonal Antibodies
Amino Acids
Endothelial cells
cadherin 5
Tryptophan
Endothelial Cells
Molecules
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Identification of a transiently exposed VE-cadherin epitope that allows for specific targeting of an antibody to the tumor neovasculature. / May, Chad; Doody, Jacqueline R.; Abdullah, Rashed; Balderes, Paul; Xu, Xiaohong; Chien, Peter Chen; Zhu, Zhenping; Shapiro, Lawrence; Kussie, Paul; Hicklin, Daniel J.; Liao, Francesca-Fang; Bohlen, Peter.

In: Blood, Vol. 105, No. 11, 01.06.2005, p. 4337-4344.

Research output: Contribution to journalArticle

May, C, Doody, JR, Abdullah, R, Balderes, P, Xu, X, Chien, PC, Zhu, Z, Shapiro, L, Kussie, P, Hicklin, DJ, Liao, F-F & Bohlen, P 2005, 'Identification of a transiently exposed VE-cadherin epitope that allows for specific targeting of an antibody to the tumor neovasculature', Blood, vol. 105, no. 11, pp. 4337-4344. https://doi.org/10.1182/blood-2005-01-0010
May, Chad ; Doody, Jacqueline R. ; Abdullah, Rashed ; Balderes, Paul ; Xu, Xiaohong ; Chien, Peter Chen ; Zhu, Zhenping ; Shapiro, Lawrence ; Kussie, Paul ; Hicklin, Daniel J. ; Liao, Francesca-Fang ; Bohlen, Peter. / Identification of a transiently exposed VE-cadherin epitope that allows for specific targeting of an antibody to the tumor neovasculature. In: Blood. 2005 ; Vol. 105, No. 11. pp. 4337-4344.
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