Inhibition of 5ß1 Integrin Function in Cynomolgus Monkeys with a Potent Function-blocking Fab, Eos200F, Inhibits Angiogenesis in a Laser-induced Model of Choroidal Neovascularization

Abstract

Abstract: : Purpose: The α5ß1 integrin is up-regulated in angiogenesis as measured by a proprietary gene chip, EosHu03. A potent inhibitory Fab, Eos200F, directed against α5ß1, was tested in the laser-induced injury model of choroidal neovascularization in cynomolgus monkeys. Fluorescein angiography (FA) was used to determine if inhibition of α5ß1 integrin has a functional consequence leading to the inhibition of neovascularization. Treatment of animals adhered to all pertinent regulations and guidelines for the humane care and use of laboratory animals Methods: A total of 5 primates were used, and in all animals choroidal neovascularization (CNV) was induced by laser treatment to the maculae in both eyes on D1, resulting in 9 distinct 2 mm lesions. Intravitreal injections (100µg/50µl) were administered on Day 1, Day 8, Day 15, and Day 22 as follows: Fluorescein angiography (FA) was performed on Day 6, Day 13, Day 20 and Day 27, to determine the extent of neovasularisation as determined by the leakage of fluorescein through neovessels, the validated endpoint of CNV in this model. Results: Based on a masked review of the data generated by FA, CNV was clearly detected on day 13 and day 20 and persisted until day 27 in control groups [Group 1 and Group 3 (OD)]. In contrast, the incidence of CNV was significantly reduced in Eos200F-treated eyes [Group 2 and Group 3 (OS)]. Though FA was also done on day 6, evidence of CNV was not clear in the most eyes of any group at this early stage. Opthalmologic examinations further showed that no adverse effects were observed related to the administration of the Eos200F drug. Conclusions: Eos200F, the potent inhibitor of α5ß1 integrin function in vitro, is also a potent inhibitor of angiogenesis in vivo as determined in a model of CNV in primate eyes, and the data supports further evaluation of this Fab for the alleviation of various neovascular retinal diseases, such as macular degeneration.  

Keywords: receptors: pharmacology/physiology • choroid: neovascularization • age-related macular degeneration