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

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.

rIgG1 Fc Hexamer Inhibits Antibody-Mediated Autoimmune Disease via Effects on Complement and FcγRs

“…8E). These findings are in line with previous data obtained with similar molecules (17,20). Third, as mentioned earlier, blockade of FcRn may be an additional protective mechanism.…”

“…This finding is in line with recent reports on other multimeric Fc molecules such as the Stradomer (17), hexameric Fc (21,22), and Fc3Y (20). Ortiz et al (20) established that structures with more than three Fc fragments led to Syk and ERK phosphorylation; furthermore, a trimeric lead molecule (Fc3Y) did not activate but, on the contrary, potently inhibited immune complex-mediated effector cell activation. Indeed, the activation of innate cells through FcgR would not be a desirable property of an Fc multimer in the treatment of autoimmune diseases.…”

“…This functional feature is surprising and appears to be unique to Fc-mTP-L309C compared with similar molecules. For example, Ortiz et al (20) reported no significant impact of the trimeric Fc molecule on complement activation. Studies with Hexa-Fc (21) bound to a solid phase indicated full complement activation; therefore, the inhibitory activity of Fc-mTP-L309C in solution was unexpected.…”

“…Interestingly, in most models, efficacy was achieved with low doses of ∼50 mg/kg body weight, compared with the standard dose of 1000-2000 mg/kg for IVIG in inflammatory indications. Using an alternative strategy, Ortiz et al (20) studied Fc multimers of increasing valency and identified molecules that bound FcgRs with high avidity without triggering activating signals. A trivalent molecule termed Fc3Y showed protection in mouse models of ITP, arthritis, and epidermolysis bullosa acquisita (20).…”

“…Using an alternative strategy, Ortiz et al (20) studied Fc multimers of increasing valency and identified molecules that bound FcgRs with high avidity without triggering activating signals. A trivalent molecule termed Fc3Y showed protection in mouse models of ITP, arthritis, and epidermolysis bullosa acquisita (20). Finally, a hexameric Fc molecule showed increased binding to FcgRs and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin, appeared to fully activate complement (C1q binding and C5b-9 deposition) (21), and effectively interfered with FcgR function (22).…”