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Robert T. Wicks, Junko Yoshida, Andrea Zambrano, Betty Tyler, Kashi Javaherian, Peter Gehlbach, Yassine J. Daoud, Henry Brem, Walter J. Stark; Inhibition Of Angiogenesis By Fc-endostatin. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6694.
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Endostatin is a potent angiogenic inhibitor with a brief, 2 hour half-life. Fc-endostatin (FcE) is a recombinant form of human endostatin bound to the Fc domain of IgG antibody, which increases its half-life to several weeks. We assessed the antiangiogenic effect of subconjunctival injected FcE compared to bevacizumab (Avastin®) (BV), using a rabbit VEGF-induced corneal neovascularization, micropocket assay.
Neovascularization was induced in rabbit corneas through intrastromal implantation of VEGF polymer at 6 and 12 o’clock, 2mm from the limbus. A total of 32 pellets were placed in the 16 eyes of 8 adult rabbits. Rabbits were randomized to 4 treatment groups, each receiving subconjunctival injections in both eyes on Days 0, 5, 8, and 12 of: 1) 0.1mL saline, 2) 0.1mL BV 25mg/mL, 3) 0.125mL FcE 2mg/mL (FcE 2), or 4) 0.125mL of FcE 20mg/mL (FcE 20). Corneas were digitally-imaged on Days 0, 5, 8, 12, and 15. An angiogenesis index (AI) was calculated [vessel length (mm) x vessel number] for each polymer observation.
All treatment groups showed a significant decrease in the AI compared to saline on all observation days (p<0.001). FcE 2 decreased angiogenesis by a factor of 8.1, 7.0, 8.8, and 6.8 on Days 5, 8, 12, and 15, respectively. FcE 20 decreased angiogenesis by a factor of 68, 2.7, 3.6, and 2.4 at 5, 8, 12, and 15 days. BV, the positive control, decreased VEGF-induced angiogenesis compared to saline by a factor of 138 on Day 15, with no vessel growth at 5, 8, and 12 days. BV was a significantly better inhibitor than FcE 20 by Day 8 (p<0.01). By Day 15, FcE 2 inhibited angiogenesis significantly better than FcE 20 (p<0.01).
FcE at both 2mg/mL and 20mg/mL doses significantly inhibited angiogenesis. Lower concentration FcE 2 exhibited better inhibition of vessel growth than FcE 20. These results are consistent with previous FcE studies referencing a biphasic dose-response curve. FcE 20 was found to be a less potent VEGF inhibitor than BV. FcE should be further investigated as a novel therapy for corneal neovascularization.
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