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Tetsuhiro Yasuma, Reo Yasuma, Younghee Kim, Takeshi Mizutani, Nagaraj Kerur, Ana Bastos-Carvalho, Bradley D Gelfand, Jayakrishna Ambati; Generic, target-independent suppression of choroidal neovascularization by human IgG1 antibodies via Fc gamma receptor I. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1937.
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One of the recent greatest progresses in treatment of eye diseases is the development of antibodies blocking vascular endothelial growth factor (VEGF). They are used to treat angiogenic conditions like age-related macular degeneration, retinal vein occlusion, and diabetic retinopathy. Bevacizumab is a humanized monoclonal IgG1 that binds human VEGFA. There are many reports of anti-angiogenic effects of bevacizumab in murine angiogenic models despite its inability to bind murine Vegfa. As previous reports used vehicles as negative control, we hypothesized that the anti-angiogenic effect of bevacizumab in mouse models was due to the Fc portion of the IgG, and not due to Vegfa blockade. To test this hypothesis, we tested 9 clinically used therapeutic monoclonal antibodies in laser-induced choroidal neovascularization (CNV) in mice.
To induce CNV, laser photocoagulation was performed on both eyes using a 532-nm laser. Bevacizumab, adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab, tocilizumab (all human IgG1 Abs), ranibizumab (human IgG1 Fab), and denosumab (human IgG2 Ab) were intravitreously administered immediately after laser photocoagulation. At 7 days after treatment, eyes were enucleated and CNV volumes were measured using a confocal microscope. Tnf-/-, CD20-/-, and IgE-deficient mice were used as well as C57BL/6J, Fcgr humanized, and Fcgr1-/- mice.
All full-length human IgG1 antibodies, but not human IgG1 Fab or human IgG2, suppressed CNV in WT and Fcgr humanized mice but not in Fcgr1-/- mice. Adalimumab in Tnf-/-, ofatumumab in CD20-/-, and omalizumab in IgE-deficient mice also suppressed CNV.
These results indicate full-length human IgG1 Abs have anti-angiogenic effects in the mouse CNV model via FcgRI, and these effects were independent of their bona-fide targets. Identical data in WT and Fcgr humanized mice suggest that these antibodies can suppress angiogenesis in the human system as well.
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