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Eunice Cheung, Ivan B. Lobov, George D. Yancopoulos, Stanley J. Wiegand; Effects of VEGF Trap and Bevacizumab on Neovascularization and Retinal Revascularization in Murine Model of Oxygen Induced Retinopathy (OIR). Invest. Ophthalmol. Vis. Sci. 2012;53(14):2943.
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Vascular Endothelial Growth Factor (VEGF) plays an essential role in normal and pathological angiogenesis. VEGF Trap (aflibercept), is a potent VEGF inhibitor that binds all isoforms of VEGF-A as well as the VEGF R1 ligands, placental growth factor (PlGF) and VEGF-B. When administered systemically, VEGF Trap effectively blocks pathological neovascularization in OIR, while promoting normative revascularization of the retina (IOVS 2006; 47:E-Abstract 1750; IOVS 2011:E-Abstract 3210). In this preclinical study, we evaluated the effects of VEGF Trap and bevacizumab, a selective blocker of VEGF-A, in the murine model of OIR.
Because bevacizumab effectively binds and blocks only human, and not murine VEGF-A, these experiments employed transgenic mice in which the gene for murine VEGF-A was replaced by the gene encoding human VEGF-A, exons 2-7. (huVEGF mice). huVEGF mice were place in a hyperoxic environment (75% O2) at postnatal day 6 (P6) and returned to room air at P11. VEGF Trap, bevacizumab or a control protein (Fc region of human IgG1) were administered i.p. on P12 at the same dose (6.25mg/kg), one day following return to room air. Hypoxyprobe (Hypoxyprobe, Inc.) was injected at P16, eyes were harvested one hour later, and retinal flatmounts were stained with anti-hypoxyprobe FITC-labeled antibody (Hypoxyprobe, Inc.) and with biotinylated Isolectin (Sigma) and streptavidin Alexa Fluor 594 (Invitrogen) to visualize blood vessels.
Compared to controls, both VEGF Trap and bevacizumab treatments tended to accelerate the regrowth of retinal blood vessels in huVEGF mice. However, VEGF Trap treated eyes had both the smallest residual avascular areas as well as the greatest reduction in neovascularization compared to both bevacizumab treated mice and controls. Similarly, although both treatments produced a marked, concomitant reduction in retinal hypoxia, as determined by hypoxyprobe staining, VEGF Trap treated eyes had smaller areas of retinal hypoxia compared to bevacizumab treated eyes.
In this preclinical study, systemic administration of anti-VEGF agents shortly after return to room air not only prevented pathological neovascularization, but also promoted normal vascular regrowth. VEGF Trap markedly reduced hypoxic areas and reduced vascular abnormalities, to a greater extent than seen with bevacizumab. Whether this difference is attributable to the higher binding affinity of VEGF Trap, or its ability to neutralize PlGF and VEGF-B, as well as VEGF-A, remains to be determined.
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