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Vascular Targeting of Ocular Neovascularization with a Vascular Endothelial Growth Factor₁₂₁/Gelonin Chimeric Protein

Departments of Ophthalmology (H.L.) and Neuroscience (H.A., R.L.S., S.K., J.S., C.H., N.U., S.F.H., S.A., M.K., P.A.C.), The Johns Hopkins University School of Medicine, Baltimore, Maryland; and Immunopharmacology and Targeted Therapy Section, Department of Experimental Therapeutics, M. D. Anderson Cancer Center, Houston, Texas (K.A.M., M.G.R.)

Tumors provide an extremely abnormal microenvironment that stimulates neovascularization from surrounding vessels and causes altered gene expression within vascular cells. Up-regulation of vascular endothelial growth factor (VEGF) receptors has allowed selective destruction of tumor vessels by administration of a chimeric protein consisting of VEGF₁₂₁ coupled to the toxin gelonin (VEGF/rGel). We sought to determine whether there is sufficient up-regulation of VEGF receptors in endothelial cells participating in ocular neovascularization to permit a similar strategy. After intravenous injection of 45 mg/kg VEGF/rGel, but not uncoupled recombinant gelonin (rGel), there was immunofluorescent staining for rGel within choroidal neovascularization in mice and regression of the neovascularization occurred, demonstrating successful vascular targeting via the systemic circulation. Intraocular injection of 5 ng of VEGF/rGel also caused significant regression of choroidal neovascularization and regression of retinal neovascularization in two models, transgenic mice with expression of VEGF in photoreceptors and mice with ischemic retinopathy, whereas injection of 5 ng of rGel had no effect. These data suggest that the strategy of vascular targeting can be applied to nonmalignant neovascular diseases and could serve as the basis of a new treatment to reduce established ocular neovascularization.

Address correspondence to: Dr. Peter A. Campochiaro, Maumenee 719, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287-9277. E-mail: pcampo{at}jhmi.edu

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