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Andreas Stahl, Michael T. Stumpp, Anja Schlegel, Savira Ekawardhani, Gottfried Martin, Maya Gulotti-Georgieva, Denis Villemagne, Patrik Forrer, Hansjürgen T. Agostini, Kaspar H. Binz; Inhibition Of Vascular Leakage And Choroidal Neovascularization Using Vegf-inhibiting Darpins In Rodents. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3009.
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Vascular endothelial growth factor (VEGF) is a key controller of pathological angiogenesis and leakage in various retinal diseases. Clinically, anti-VEGF agents have revolutionized treatment of exudative age related macular degeneration (AMD), diabetic retinopathy and retinal vein occlusion. However, one of the main limitations of current VEGF inhibitors remains the need for repeated intravitreal injections. Second-generation VEGF inhibitors should thus aim at providing more efficient VEGF-inhibition to reduce injection frequency.
In the current study, we use highly potent anti-VEGF DARPins (designed ankyrin repeat proteins) to inhibit VEGF receptor phosphorylation and endothelial cell sprouting in vitro, retinal vascular leakage in rabbits and choroidal angiogenesis in the Laser CNV model in rats.
Our results demonstrate the successful isolation and purification of several DARPins with picomolar affinity to VEGF. In vitro, VEGF receptor phosphorylation was strongly inhibited compared to controls. Functional experiments using endothelial spheroid sprouting demonstrated potent inhibition of VEGF-induced angiogenic tube formation. Upon intravitreal injection, DARPins were found to penetrate into the retina and inhibit VEGF-induced retinal vascular leakage (p=0.025 vs. controls). In addition, topical DARPin application was found to suppress Laser-induced choroidal neovascularization in rats (p=0.025 vs. controls). No ocular or systemic side effects were observed in both in vivo models.
DARPins are a new class of antibody mimetic molecules with increased anti-VEGF potency and prolonged intraocular activity that are derived from the abundant protein family of naturally occurring ankyrin repeat proteins. Anti-VEGF DARPins are promising candidates for the treatment of neovascular eye diseases in humans and currently under investigation in phase I/II clinical trials.
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