Inhibition of Corneal Angiogenesis by Antibody to Integrin b3 Subunit

ABSTRACT

Vascular endothelial cell expression of avb3, and integrin receptor that binds von Willebrand factor, vitronectin, and fibrinogen, increases in response to angiogenic stimuli such as basic fibroblast growth factor(bFGF) and during capillary proliferation in vivo. We investigated the importance of avb3 function during bFGF-induced corneal angiogenesis by examining the effects of 9D491, a monoclnal natibody against b3 that blocks avb3-mediated cell adhesion to vitronectin and fibrinogen in vitro. A hydrogel disk containing 500ng of bFGF was implanted into the superior corneal stroma of each of twelve New Zealand white rabbit eyes. Each eye also received a second hydrogel disk placed adjacent of the firtt, randomized to contain either 3ug of 9D491 mAb(n=6) or 6E10, an irrelevant antibody of the same isotype, (n=6). Both disks were positioned 1.2mm from the superior limbus. Eyes were examined daily under a streomicroscope by two masked observers and counted an angiogenesis score based on number and length of new blood vessels. On days 5 through 7 post-implantation, angiogenesis scores were significantly lower in eyes treated with avb3 mAb(averaged score=3.3) as compared to eyes treated with 6E10(averaged score=8.0)(p<0.002, Wilcoxon rank sum test). In a rabbit corneal pocket model of angiogenesis, neutralizing monoclonal antibody to b3 inhibits corneal angiogenesis induced by bFGF. Substances that target the integrin b3 subunit may have therapeutic potential in disorders characterized by ocular neovascularization.