Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2

Miao, Hua‐Quan; Hu, Ke; Jimenez, Xenia; Navarro, Elizabeth; Zhang, Haifan; Lü, Dan; Ludwig, Dale L.; Balderes, Paul; Zhu, Zhenping

doi:10.1016/j.bbrc.2006.04.119

Cited by 83 publications

(51 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recombinant VEGF-A 165 was purchased from RELIATech GmbH (Brauschweig, Germany); DLL4 (rDLL4) extracellular domain was from R&D Systems (Abingdon, Oxfordshire, UK); L685,458 (␥-secretase inhibitor) from Calbiochem (Nottingham, UK); and IMC1121b (human VEGFR-2 inhibitor) and IMC-18F1 (human VEGFR-1 inhibitor) (18,19) were both kindly provided by ImClone Systems Corp. (New York, NY). ADAM inhibitors GI250423X (ADAM-10 inhibitors) and GW28026X (ADAM-10/17 inhibitor) (20) were both kindly provided by GlaxoSmithKline.…”

Section: Methodsmentioning

confidence: 99%

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Caolo

Akker

Verbruggen

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The DELTA like-4 ligand (DLL4) belongs to the highly conserved NOTCH family and is specifically expressed in the endothelium. DLL4 regulates crucial processes in vascular growth, including endothelial cell (EC) sprouting and arterial specification. Its expression is increased by VEGF-A. In the present study, we show that VEGF-induced DLL4 expression depends on NOTCH activation. VEGF-induced DLL4 expression was prevented by the blockage of NOTCH signaling with ␥-secretase or ADAM inhibitors in human cardiac microvascular ECs. Similar to VEGF-A, recombinant DLL4 itself stimulated NOTCH signaling and resulted in up-regulation of DLL4, suggesting a positive feed-forward mechanism. These effects were abrogated by NOTCH inhibitors but not by inhibition of VEGF signaling. NOTCH activation alone suffices to induce DLL4 expression as illustrated by the positive effect of NOTCH intracellular domain (NICD)-1 or -4 overexpression. To discriminate between NICD/RBP-J and FOXC2-regulated DLL4 expression, DLL4 promoter activity was assessed in promoter deletion experiments. NICD induced promoter activity was dependent on RBP-J site but independent of the FOXC2 binding site. Accordingly, constitutively active FOXC2 did not affect DLL4 expression. The notion that the positive feed-forward mechanism might propagate NOTCH activation to neighboring ECs was supported by our observation that DLL4-eGFP-transfected ECs induced DLL4 expression in nontransfected cells in their vicinity. In summary, our data provide evidence for a mechanism by which VEGF or ligand-induced NOTCH signaling up-regulates DLL4 through a positive feedforward mechanism. By this mechanism, DLL4 could propagate its own expression and enable synchronization of NOTCH expression and signaling between ECs.The NOTCH family encompasses a fundamental signaling pathway involving four receptors (NOTCH-1, -2, -3, and -4) and, in vertebrates, five cognate ligands (DLL-1, -3, and -4, and JAGGED-1 and -2). Cell-cell contact is a prerequisite for NOTCH signaling as all members are membrane bound. The first activation step upon receptor-ligand interaction involves cleavage of the extracellular domain of the NOTCH receptor by ADAM (a disintegrin and metalloprotease). Subsequently, the ␥-secretase complex instigates a second proteolytic cleavage resulting in the release of the NOTCH intracellular domain (NICD) 2 into the cytoplasm. Next, the NICD translocates to the nucleus, where it associates with the Recombinant signal binding protein for immunoglobulin kappa J region (RBP-J) CBF1/RBP-J, Su(H), Lag1 (CSL) transcription factor to initiate the transcription of its downstream targets basic helix-loop-helix proteins HES (hairy/enhancer of split) and hairy related transcription factors (HRT, HEY, and

show abstract

Section: Methodsmentioning

confidence: 99%

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Caolo

Akker

Verbruggen

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…VEGFR-1 may be involved in angiogenic processes as well when it heterodimerizes with VEGFR-2, but it is also believed to sequester VEGF, preventing it from interacting with VEGFR-2 (Hiratsuka et al, 1998). Inhibitors of the kinase component of VEGFR-2 (i.e., SU5416), sometimes in combination with inhibitors of other receptors including platelet-derived growth factor (PDGF) or stem cell factor, have been tested and found effective in animal models of CNV (Miao et al, 2006;Kinose et al, 2005;Takahashi et al, 2006).…”

Section: 113mentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

View full text Add to dashboard Cite

Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

show abstract

“…40), and DC101 and 1121b, antimurine and human VEGFR-2 monoclonal antibodies, respectively (both supplied by ImClone Systems Incorporated; refs. 41,42), were incubated with murine or human endothelial cells 2 h before and throughout the stimulation with tumor-conditioned medium. SU5416 was dissolved in DMSO (stock solution, 4 Â 10 À2 mol/L) and diluted with medium before use.…”

Section: Cellsmentioning

confidence: 99%

Vascular Endothelial Growth Factor Stimulates Organ-Specific Host Matrix Metalloproteinase-9 Expression and Ovarian Cancer Invasion

Belotti

Calcagno

Garofalo

et al. 2008

Molecular Cancer Research

View full text Add to dashboard Cite

Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP) regulate each other, contributing to tumor progression. We have previously reported that MMP9 induces the release of tumor VEGF, promoting ascites formation in human ovarian carcinoma xenografts. The aim of this study was to investigate whether tumor-derived VEGF regulated the expression of gelatinase by the stroma, influencing the invasive properties of ovarian tumors. Tumor variants derived from 1A9 human ovarian carcinoma, stably expressing VEGF 121 in the sense (1A9-VS-1) and antisense orientations (1A9-VAS-3), were used. In vivo, zymographic analysis of tumors from 1A9-VS-1 implanted in the peritoneal cavity of nude mice showed higher levels of gelatinases, particularly murine MMP9, indicating that VEGF stimulates host expression of the matrix-degrading enzyme. Murine MMP9 expression was also high in the ovaries of mice bearing 1A9-VS-1 tumors. The effect on host MMP9 activity was organ-specific. The levels of host pro-MMP9 in ovaries correlated with the plasma levels of tumor VEGF and with the selective invasion of the ovaries. Induction of host MMP9 expression in tumors and ovaries was independent of the site of tumor growth as it was seen in mice carrying both intraperitoneal and subcutaneous tumors. The anti-VEGF antibody bevacizumab (Avastin) inhibited MMP9 expression and tumor invasion in the ovaries of mice bearing 1A9-VS-1 tumors. These findings point to a complex cross-talk between VEGF and MMPs in the progression of ovarian tumor and suggest the possibility of using VEGF inhibitors to affect MMP-dependent tumor invasion.

show abstract

Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2

Cited by 83 publications

References 39 publications

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Vascular endothelial growth factor in eye disease

Vascular Endothelial Growth Factor Stimulates Organ-Specific Host Matrix Metalloproteinase-9 Expression and Ovarian Cancer Invasion

Contact Info

Product

Resources

About