Anti-EGFL7

New vessels and their surrounding cells lay down layers of extracellular matrix with important growth-promoting and survival factors including EGFL7.^1-5 Anti-EGFL7 is a monoclonal antibody designed to block endothelial cell adhesion to the EGFL7 protein.⁶ This antibody may disrupt vascular tube formation⁴ and increase endothelial cell stress,^5,6 thereby inhibiting angiogenesis.

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In multiple preclinical tumor models, anti-EGFL7 was shown to augment VEGF inhibition and enhance inhibition of tumor vascularization.⁶

1. VEGF inhibition results in 2 essential antitumor effects: regression of existing tumor vasculature and inhibition of new vessel growth.^7-9

   

2. Vessel regrowth may occur along the extracellular matrix tracks left behind by the regressed vessels.^10-13 Extracellular matrix proteins, including EGFL7, may be present in the tracks.^1,4,6

   

3. Upon binding to EGFL7, anti-EGFL7 may inhibit vascular sprouting.⁶ Preclinical studies also suggest that anti-EGFL7 may increase apoptosis of tumor-related endothelial cells that are already under biological stress due to VEGF inhibition.^5,6

   

References:

1.

Schmidt M, Paes K, De Mazière A, et al. EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development. 2007;134:2913-2923.

2.

Campagnolo L, Leahy A, Chitnis S, et al. EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury. Am J Pathol. 2005;167:275-284.

3.

Fitch MJ, Campagnolo L, Kuhnert F, Stuhlmann H. Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells. Dev Dyn. 2004;230:316-324.

4.

Parker LH, Schmidt M, Jin S-W, et al. The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature. 2004;428:754-758.

5.

Xu D, Perez RE, Ekekezie II, Navarro A, Truog WE. Epidermal growth factor-like domain 7 protects endothelial cells from hyperoxia-induced cell death. Am J Physiol Lung Cell Mol Physiol. 2008;294:L17-L23.

6.

Yeung S, Smyczek T, Cheng J, et al. Inhibiting vascular morphogenesis in tumors: EGFL7 as a novel therapeutic target. Presented at: 11th International Symposium on Anti-Angiogenic Agents; February 5-7, 2009; San Diego, CA.

7.

Borgström P, Hillan KJ, Sriramarao P, Ferrara N. Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res. 1996;56:4032-4039.

8.

Borgström P, Bourdon MA, Hillan KJ, Sriramarao P, Ferrara N. Neutralizing anti-vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo. Prostate. 1998;35:1-10.

9.

Yuan F, Chen Y, Dellian M, Safabakihsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci U S A. 1996;93:14765-14770.

10.

Inai T, Mancuso M, Hashizume H, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35-52.

11.

Mancuso MR, Davis R, Norberg SM, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 2006;116:2610-2621.

12.

Vosseler S, Mirancea N, Bohlen P, Mueller MM, Fusenig NE. Angiogenesis inhibition by vascular endothelial growth factor receptor-2 blockade reduces stromal matrix metalloproteinase expression, normalizes stromal tissue, and reverts epithelial tumor phenotype in surface heterotransplants. Cancer Res. 2005;65:1294-1305.

13.

Baluk P, Hashizume H, McDonald DM. Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev. 2005;15:102-111.