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Konrad Kauper, Paul Stabila, Vincent Ling, Sue Elliot, Cahil McGovern, Sandy Sherman, Mike Rivera, Alline Lelis, Pam Heatherton, Weng Tao; Pharmacokinetics and Bioactivity of a Potent VEGF Inhibitor Following Sustained Intraocular Delivery to the Rabbit Eye Using Neurotech’s Encapsulated Cell Technology. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3223.
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Vascular endothelial growth factor (VEGF) is implicated in neovascular diseases of the eye, including choroidal neovascularization associated with age-related macular degeneration (wet-AMD). Although treatment with VEGF inhibitors such as Lucentis, Avastin and VEGF-Trap have proven to be clinically efficacious, the relatively short half-lives of these biologics require monthly administration of high doses, creating potential clinical safety risks as well as patient compliance issues. To address these treatment deficiencies, Neurotech has developed a cell-based, intraocular implant engineered to continuously deliver a VEGF inhibitor to the eye, potentially eliminating the need for repeated intraocular injections.
Polymer membrane encapsulated NTC-200 cell lines were engineered to secrete several classes of VEGF inhibitors. Following safety, stability, potency and bioactivity evaluations, a specific ECT-produced VEGF inhibitor, designated 834, was identified for further characterization, including pharmacokinetic behavior in rabbits. Multiple cell lines secreting varying levels of 834 were encapsulated and characterized in vitro and in vivo over a 3-month period in rabbits. Secretion of 834 from explanted devices, corresponding vitreous levels of 834 and encapsulated cell viability were evaluated over the course of the implant period. The VEGF inhibitors were further characterized by VEGF binding affinity, ability to block VEGF-induced endothelial cell proliferation, and Western blot analysis.
The encapsulated 834 cell lines produced VEGF inhibitor protein ranging from 50 to greater than 1000 ng/day over a prolonged study period. Vitreous levels of 834 were maintained at a steady state concentration in the rabbit eye. The VEGF inhibitors were shown to effectively block VEGF-induced proliferation of endothelial cells and completely bind free VEGF at equimolar concentration. No safety or tolerability issues in the rabbit eye were observed following prolonged ECT implantation.
Long-term intraocular implants in rabbits, via encapsulated cell technology, suggest that steady-state concentrations of a potent VEGF inhibitor can be maintained. Furthermore, sustained ECT delivery of a VEGF inhibitor to the eye may potentially preclude the need for repeated intraocular injections currently required to manage neovascular eye diseases.
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