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Kameran Lashkari, Jie Ma, Yu Sun, Gianna C Teague, Megan E Baldwin; VGX-300, a ‘Trap’ for VEGF-C and VEGF-D, Inhibits Choroidal Neovascularization and Vascular Leakage in a Mouse Model of Wet AMD. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4802.
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Choroidal neovascularization (CNV) is the major cause of severe visual loss in subjects with wet AMD. At least 45% of subjects with wet AMD exhibit some degree of resistance to anti-VEGF-A monotherapy. This may be mediated by the activity of other proangiogenic factors such as VEGF-C and VEGF-D that can signal through both VEGFR-2 and VEGFR-3. VGX-300 (OPT-302) is a soluble form of VEGFR-3 that traps VEGF-C and D and inhibits their biological activity. We investigated the efficacy of VGX-300 as monotherapy and in combination with Eylea® (aflibercept) to inhibit laser-induced CNV.
Laser lesions were created (day 0) in C57BL/6 mice under direct visualization using a Micron III fundus camera (532 nm; 4 - 6 spots; 50 uM size, 50 ms, 600 Mw). Mice were treated with either a single intravitreal (IVT) injection of a negative isotype control antibody (IgG), Eylea®, VGX-300 or the combination of VGX-300 and Eylea®. CNV leakage and lesion areas were measured by fluorescein angiography and intracardiac perfusion of FITC-dextran/gelatin and graded using an established system.
When administered after laser-induced injury (day 0), VGX-300 significantly reduced CNV leakage and lesion formation to a comparable extent as Eylea® in a dose-responsive manner. In a regression model in which treatments 7 days after CNV lesions were established, VGX-300 and combination of VGX-300 and Eylea® inhibited lesion development and vascular leakage more effectively than Eylea® alone. In these cases, 90% of lesions graded as 2B on experimental day 7 had reduced in size to Grade 0 on day 14. Overall, all treatments were more effective at inhibiting CNV when administered on day 0 compared to day 7.
Inhibition of VEGF-C and D by VGX-300 inhibited laser-induced CNV and vascular leakage to a comparable extent as Eylea®. Combination of VGX-300 and Eylea® demonstrated superior inhibition of CNV lesion development and vascular leakage compared to either agent alone. A more complete blockade of VEGF pathways can be more effective in reducing wet AMD lesion development and leakage and may be an effective way to target resistance to anti-VEGF-A monotherapy. Treatment with VGX-300 alone or in combination with other anti-VEGF-A agents may be an effective approach for clinically resistant cases of wet AMD.
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