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Kevin G Peters, Ji-kui Shen, Yuanyuan liu, Astrid Nottebaum, Dietmar Vestweber, Michael Flynn, Peter A Campochiaro; A VE-PTP Antibody Activates Tie2 and Suppresses VEGF-Induced Retinal Vascular Leakage. Invest. Ophthalmol. Vis. Sci. 2018;59(9):199. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Tie2 pathway activation has emerged as an important axis for vascular stabilization and a prime target for treatment of diabetic retinopathy and exudative age-related macular degeneration (AMD). VE-PTP (vascular endothelial-protein tyrosine phosphatase) is a key negative regulator of Tie2 activation and a compelling target for therapeutic Tie2 activation. The purpose of this study was to test the hypothesis that a VE-PTP extracellular domain (ECD) antibody activates Tie2 and suppresses VEGF-induced leakage in the retina.
Tie2 activation was assessed in vitro by serial anti-phosphotyrosine/Tie2 western blot of Tie2 immunoprecipitated from murine endothelial cells following 15 minute incubations with a rat anti-mouse VE-PTP ECD antibody (Ab109.1; 5-100 nM) or an isotype control (100 nM). In vivo Tie2 activation was assessed by phospho-Tie2 immunohistochemistry of retinas from mice with oxygen-induced ischemic retinopathy 24 hours following a single intravitreal (IVT) injection of Ab109 (2 µg) or equivalent volume of vehicle. To assess efficay, Tet/opsin/VEGF transgenic mice with doxycycline-inducible expression of VEGF in the retina were given an IVT injection of 1.9 µg of rat IgG (isotype control), 1.9 µg of Ab109.1, 10 µg of aflibercept, or both Ab109.1 and aflibercept, and 2 mg/mL of doxycycline was added to drinking water. After 3 days of doxycycline treatment, fundus photographs were graded by a masked investigator for total, partial or no exudative retinal detachment.
Ab109.1 induced robust increases in Tie2 phosphorylation in endothelial cells in vitro and in retinal neovessels and pre-existent vessels in vivo. On day three after initiation of retinal VEGF expression, all Tet/opsin/VEGF mice injected with rat IgG had severe leakage from retinal vessels resulting in total or partial exudative retinal detachment. All treatments reduced retinal detachment compared to control. The Ab109.1/aflibercept combination reduced retinal detachment more than either monotherapy treatment, an effect that reached statistical significance vs control (p < 0.01).
These data provide preclinical PoC for efficacy of a VE-PTP ECD antibody as an adjunct to anti-VEGF therapy. Based on these results, Aerpio is developing a therapeutic anti-VE-PTP ECD monoclonal antibody for use as an adjunct to anti-VEGF therapy in patients with diabetic macular edema and exudative AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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