Research ArticleAutoimmunity

Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors

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Science Translational Medicine  16 Nov 2016:
Vol. 8, Issue 365, pp. 365ra158
DOI: 10.1126/scitranslmed.aaf9418

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Third Fc’s the charm

The activation of Fcγ receptors by autoantibody immune complexes plays a pathogenic role in multiple autoimmune diseases. In an attempt to systematically evaluate potential therapeutic approaches, Ortiz et al. tested different shapes and sizes of Fc-containing molecules. One particular design, a trimer with a Y-shaped configuration, was particularly effective at binding to Fcγ receptors and blocking them without causing inappropriate activation. To demonstrate therapeutic potential, the authors tested this Fc trimer construct in mouse models of three different autoimmune diseases: immune thrombocytopenic purpura, collagen-induced arthritis, and epidermolysis bullosa acquisita, all with promising results.

Abstract

Autoantibody immune complex (IC) activation of Fcγ receptors (FcγRs) is a common pathogenic hallmark of multiple autoimmune diseases. Given that the IC structural features that elicit FcγR activation are poorly understood and the FcγR system is highly complex, few therapeutics can directly block these processes without inadvertently activating the FcγR system. To address these issues, the structure activity relationships of an engineered panel of multivalent Fc constructs were evaluated using sensitive FcγR binding and signaling cellular assays. These studies identified an Fc valency with avid binding to FcγRs but without activation of immune cell effector functions. These observations directed the design of a potent trivalent immunoglobulin G–Fc molecule that broadly inhibited IC-driven processes in a variety of immune cells expressing FcγRs. The Fc trimer, Fc3Y, was highly efficacious in three different animal models of autoimmune diseases. This recombinant molecule may represent an effective therapeutic candidate for FcγR-mediated autoimmune diseases.

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