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Yang Liu, Zida Li, Daniel Reef, Ming Yuan, Jingtai Cao, George D Yancopoulos, Stanley J Wiegand; Effects of Anti-PDGFRβ Therapy Alone or in Combination with VEGF Trap on Corneal Neovascularization (NV) and Pericyte Recruitment in Mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3239.
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To evaluate the effects of anti-PDGFRβ antibody alone or in combination with VEGF Trap on pericyte investment of corneal NV following injury.
Corneal NV was induced in adult male mice by corneal suture placement or chemical injury. In prevention studies, anti-PDGFRβ antibody (25 mg/kg) was administered subcutaneously (sc) one day before suture placement and then every other day following corneal injury. Control mice received no treatment or an equimolar amount of human Fc (10 mg/kg) following the same schedule. On day 9 after injury, the vasculature was labeled by intravenous injection of fluorescein-conjugated lectin (lycopersicon esculentum) and pericytes were labeled by NG2 immunostaining. Corneal NV and pericyte coverage were evaluated in corneal flat-mounts. Treatment studies evaluated the effects of anti-PDGFRβ or VEGF Trap monotherapy, as well as the effects of combined treatment of anti-PDGFRβ (25 mg/kg, sc, every other day) and VEGF Trap at either efficacious (6.25 mg/kg, sc, every 6 days) or suboptimal doses (0.5 mg/kg or 1.5 mg/kg, sc, every other day). In these studies, treatment was delayed until corneal NV was established (2-3 weeks after injury). Effects of anti-VEGF and anti-PDGFRβ monotherapy, or combined treatment on regression of corneal NV and pericyte coverage were evaluated approximately 2 weeks following the initiation of dosing in corneal flatmounts using the methods described above.
Anti-PDGFRβ monotherapy (25 mg/kg, sc) significantly inhibited pericyte recruitment to newly developing corneal neovessels and also stripped pericytes from established corneal NV, but did not alter pericyte investment of normal corneal limbal vessels in uninjured eyes. Combined treatment with anti-PDGFRβ augmented the anti-angiogenic effects of VEGF inhibition by VEGF Trap, only when low, suboptimal dose (0.5 mg/kg) of VEGF Trap were administered.
Anti-PDGFRβ monotherapy can significantly inhibit pericyte recruitment to developing corneal neovessels and also deplete pericytes from established corneal NV. Combined administration of anti-PDGFRβ and low, suboptimal dose of VEGF Trap produced a significantly greater anti-angiogenic effect than VEGF Trap alone, administered at the same low dose.
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