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Amer Mirza, Jingsong Zhao, Nerissa Mendoza, Ken Der, Susan Babuka, Bob Shimizu, Liching Cao, Paul Rubin; XOMA 089, a Novel Anti-TGF-beta Monoclonal Antibody, Inhibits Experimental Proliferative Vitreoretinopathy in Rabbits. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1121.
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Proliferative vitreoretinopathy (PVR) is the most common complication following rhegmatogenous retinal detachment with no curative treatment presently. Transforming growth factor beta (TGF-beta) plays a central role during its pathogenesis including inflammation, cell proliferation, matrix deposition, and formation of fibrotic membrane. XOMA 089 is a novel, fully human monoclonal antibody that specifically binds and neutralizes TGF-beta 1 and 2 ligands. The purpose of the study is to test this drug in an experimental model of PVR.
PVR was induced in pigmented rabbits by intravitreal injection of cultured rabbit conjunctival fibroblasts followed by intravitreal administration of XOMA 089 once weekly for 28 days or as a single injection. Rabbit eyes were monitored ophthalmoscopically for four weeks. PVR grade was determined by establised classification criteria. At sacrifice, all animals’ eyes were enucleated, fixed, embedded and sectioned for histopathological evaluation.
Intravitreal injection of XOMA 089 reduced the clinical stage and severity of PVR including the severity of retinal detachment and formation of intraocular membrane in both dose and time-dependent manner. Administration of XOMA 089 at 5 mg/vitreous significantly reduced PVR grading by 64.3% on Day 28. The disease severity in the affected eye was reduced from a mean score of 4.5 to 2.0 in one experiment and from 3.25 to 1.25 in another experiment. In addition, we found single injection of XOMA 089 is as efficacious in inhibiting PVR as weekly injection of XOMA 089 at the same dose level. Histopathological examinations confirmed the XOMA 089-mediated changes within retinal compartments characterized by decreased fibrosis, degeneration and detachment. Terminal concentrations of XOMA 089 in rabbit vitreous humor showed sustained levels of exposure and the peak concentrations of XOMA 089 in peripheral blood were delayed and significantly lower than those of eyes.
Taken together, our results demonstrate that XOMA 089 is effective in treating PVR in this animal model and represents a promising new strategy with the potential to ameliorate PVR in humans.
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