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Kameran Lashkari, Jie Ma, Gianna C Teague, Chenying Guo, Megan E Baldwin; VEGF-C and VEGF-D Blockade by VGX-300 Inhibits Choroidal Neovascularization and Leakage in a Mouse Model of wet AMD. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1823.
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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. Resistance may be related to other proangiogenic factors such as VEGF-C & D. VEGF-C & D can participate in CNV by promoting angiogenesis and vascular leakage by binding and activating VEGFR-2 and VEGFR-3. VGX-300 is a soluble form of VEGFR-3 that potently inhibits the activity of VEGF-C & D. We investigated the efficacy of VGX-300 as monotherapy and in combination with an anti-VEGF-A therapeutic (aflibercept, Eylea®) to inhibit CNV lesion formation and vascular leakage in the mouse laser-induced model of CNV.
Laser-induced CNV was created in C57BL/6 mice using a 532 nm laser under direct visualization using Micron® fundus camera (6-9 spots/eye; 50 uM size, 50 ms, 550 Mw). Mice were administered a single intravitreal injection of IgG, Eylea®, VGX-300 (trap for VEGF-C & D), or combination of VGX-300 and Eylea®. CNV areas and extent of leakage were determined by fluorescein angiography followed by intracardiac perfusion of FITC-dextran in gelatin (10%) on day 14 post-laser.
Treatment with VGX-300 or Eylea® significantly reduced the number and size of CNV lesions compared to the IgG treated group. VGX-300 and Eylea® were comparable in reducing lesion leakage and CNV area. Fluorescence intensities of laser-induced CNV lesions treated with either VGX-300 or Eylea® were significantly lower than treatment with the negative control antibody. Combining VGX-300 and Eylea® induced the lowest fluorescence intensity and smallest CNV lesion size. Immunostaining of CNV lesions showed increased expression of VEGF-C and VEGFR-3 around CNV lesions.
VGX-300 (soluble VEGFR-3), a potent inhibitor of VEGF-C & D, exhibits comparable efficacy to Eylea® in the laser-induced mouse model of CNV. Combined VGX-300 and Eylea® demonstrated superior efficacy to either agent alone. Our data indicates more complete blockade of the VEGF pathways may be an effective way of targeting resistance to existing anti-VEGF-A therapies. Treatment with VGX-300 alone or in combination with other anti-VEGF-A agents such as Eylea® may be an effective approach in inhibiting CNV lesions in clinicially resistant cases.
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