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Positive and Negative Regulation of Angiogenesis by Soluble Vascular Endothelial Growth Factor Receptor-1
Open AccessArticle

ScFvs as Allosteric Inhibitors of VEGFR-2: Novel Tools to Harness VEGF Signaling

Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen, Switzerland
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(5), 1334;
Received: 30 March 2018 / Revised: 23 April 2018 / Accepted: 23 April 2018 / Published: 1 May 2018
(This article belongs to the Special Issue Vascular Endothelial Growth Factor)
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Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is the main mediator of angiogenic signaling in endothelial cells and a primary responder to VEGF. VEGF dependent VEGFR-2 activation regulates endothelial cell migration and proliferation, as well as vessel permeability. VEGF is presented as an antiparallel homodimer, and its binding to VEGFR-2 brings two receptors in close proximity. Downstream signaling is triggered by receptor dimerization, kinase activation, and receptor internalization. Our aim was to further investigate allosteric inhibition using binders targeting extracellular subdomains 4–7 of VEGFR-2 as an alternative to existing anti-angiogenic therapies, which rely on neutralizing VEGF or blocking of the ligand-binding site on the receptor. We applied phage display technology to produce single chain antibody fragments (scFvs) targeting VEGFR-2. Selected antibody fragments were characterized using biophysical and biological assays. We characterized several antibody fragments, which exert their inhibitory effect of VEGFR-2 independent of ligand binding. These reagents led to rapid clearance of VEGFR-2 from the cell surface without kinase activation, followed by an increase in intracellular receptor-positive vesicles, suggesting receptor internalization. Our highly specific VEGFR-2 binders thus represent novel tools for anti-angiogenic therapy and diagnostic applications. View Full-Text
Keywords: angiogenesis; VEGFR-2; VEGF; scFv; inhibition; receptor downregulation angiogenesis; VEGFR-2; VEGF; scFv; inhibition; receptor downregulation

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Ballmer-Hofer, K.; A.C. Hyde, C.; Schleier, T.; Avramovic, D. ScFvs as Allosteric Inhibitors of VEGFR-2: Novel Tools to Harness VEGF Signaling. Int. J. Mol. Sci. 2018, 19, 1334.

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