Antigen-independent suppression of ocular angiogenesis via the Fc receptor

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Abstract Aberrant angiogenesis, a process of new blood vessel formation, is implicated in a variety of diseases that affect nearly 10% of the world’s population. In new and exciting work, we made the surprising observation that human IgG1, as a class, suppresses multiple models of ocular and non-ocular angiogenesis in mice and cells independent of their actual target. This target- independent angiostatic effect is mediated through FcγRI receptor signaling. Given the abundance of IgG1 proteins in the blood, as well as their widespread therapeutic use, our findings assume broad importance in better understanding the full range of the biological effects of antibodies. The extent and precise mechanisms of IgG/Fc receptor modulation of the vasculature remain to be deciphered. Therefore, it is critical to define the immunological molecular signaling pathways responsible for mediating the angioinhibitory effects of human IgG1/FcγRI ligation. It is also important to delineate the influence of therapeutic FcγRI-binding proteins on the cell types and molecular pathways involved in aberrant angiogenesis. In addition to advancing the fundamental biology of IgG/Fc-mediated angiosuppression, our findings may also address a significant ophthalmic need by improving existing IgG1-containing medicines. To that end, we will determine whether a rationally guided re-dosing or reformulation of bevacizumab, a full-length humanized IgG1 antibody, can substantially improve its therapeutic efficacy by exploiting this newly discovered anti-angiogenic activity, which is separate from VEGFA neutralization. In order to accomplish these goals, we propose to perform detailed studies in models that better mimic the human vascular and immune systems. We will utilize mouse (including humanized) models of corneal and choroidal neovascularization to provide novel functional and molecular insights into how IgG1/FcγRI signaling contributes to modulation of angiogenesis. Findings from this project will help illuminate innovative molecular basis of the vasculature that can be targeted in the multitude of ocular pathologies caused by abnormal vessel growth. As such, this proposal is aligned with the dual goals of the Retinal Diseases and Immunology Programs of NEI's Vision Research: Needs, Gaps, and Opportunities Strategic Plan.