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Ana Bastos-Carvalho, Sasha Bogdanovich, Younghee Kim, Reo Yasuma, Takeshi Mizutani, Nagaraj Kerur, Tetsuhiro Yasuma, Bradley D Gelfand, Jayakrishna Ambati; Human therapeutic monoclonal antibodies inhibit corneal neovascularization via FcγRI in a target-independent manner. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5049.
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Bevacizumab (Avastin™), a humanized IgG1 monoclonal antibody (mAb), is used in numerous systemic and ocular conditions, like age-related macular degeneration (AMD). Although bevacizumab binds human VEGF but not mouse VEGF, it has been reported to suppress angiogenesis in the mouse. We hypothesized that an intrinsic characteristic of the IgG1 mAb, independent of its target, was responsible for its angioinhibitory effect.
We tested the effect of bevacizumab, ranibizumab and 7 other therapeutic human mAbs in the murine model of suture-induced corneal neovascularization (KNV), which is pathophysiologically relevant to human KNV. Corneal sutures and intra-stromal injection of mAbs were performed in wild-type (WT) mice, in mice lacking FcγRI (the high affinity receptor for IgG) and in transgenic mice expressing human FcγRs (huFcγR). KNV (CD31+Lyve1- blood vessels) was measured on day 10. To further elucidate the mechanism of angioinhibition, we assessed macrophages (known to be involved in angiogenic response and to express FcγRI) by immunostaining of NV lesions, quantification of KNV after bone marrow transplant (BMT), and migration assay, after exposure to bevacizumab.
All full-length human IgG1 mAbs suppressed KNV. However, ranibizumab (which does not bind FcγRI, as it lacks the Fc portion), as well as the IgG2 denosumab (an isotype with low binding affinity for FcγRI), did not inhibit KNV. Angiosuppression was also abrogated in FcγRI-/- mice. Importantly, mAbs inhibited angiogenesis in huFcγR mice, suggesting the effect is sustained in the human system. Consistent with angiosuppression being mediated by FcγRI in macrophages, bevacizumab did not inhibit angiogenesis in WT mice receiving BMT from FcγRI-/- mice, but did so in FcγRI-/- mice receiving WT BMT. Further, bevacizumab decreased macrophage migration and infiltration to the injury site.
We describe a novel angioinhibitory pathway mediated by FcγRI activation via IgG1. Multiple therapeutic IgG1 mAbs used in millions of people worldwide can activate this pathway, impairing angiogenesis in a target-independent manner. These findings open a new avenue for utilization of IgG1 mAbs as anti-angiogenic agents in ocular conditions like KNV, AMD or diabetic retinopathy, and in systemic conditions, such as cancer. They also raise concerns of possible undesired anti-angiogenic effects of these therapies.
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