Recombinant IgG2a Fc (M045) multimers effectively suppress experimental autoimmune myasthenia gravis

Abstract

Myasthenia gravis (MG) is an autoimmune disorder caused by target-specific pathogenic antibodies directed toward postsynaptic neuromuscular junction (NMJ) proteins, most commonly the skeletal muscle nicotinic acetylcholine receptor (AChR). In MG, high-affinity anti-AChR Abs binding to the NMJ lead to loss of functional AChRs, culminating in neuromuscular transmission failure and myasthenic symptoms. Intravenous immune globulin (IVIg) has broad therapeutic application in the treatment of a range of autoimmune diseases, including MG, although its mechanism of action is not clear. Recently, the anti-inflammatory and anti-autoimmune activities of IVIg have been attributed to the IgG Fc domains. Soluble immune aggregates bearing intact Fc fragments have been shown to be effective treatment for a number of autoimmune disorders in mice, and fully recombinant multimeric Fc molecules have been shown to be effective in treating collagen-induced arthritis, murine immune thrombocytopenic purpura, and experimental inflammatory neuritis. In this study, a murine model of MG (EAMG) was used to study the effectiveness of this novel recombinant polyvalent IgG2a Fc (M045) in treating established myasthenia, with a direct comparison to treatment with IVIg. M045 treatment had profound effects on the clinical course of EAMG, accompanied by down-modulation of pathogenic antibody responses. These effects were associated with reduced B cell activation and T cell proliferative responses to AChR, an expansion in the population of FoxP3+ regulatory T cells, and enhanced production of suppressive cytokines, such as IL-10. Treatment was at least as effective as IVIg in suppressing EAMG, even at doses 25–30 fold lower. Multimeric Fc molecules offer the advantages of being recombinant, homogenous, available in unlimited quantity, free of risk from infection and effective at significantly reduced protein loads, and may represent a viable therapeutic alternative to polyclonal IVIg.

Multimerized IgG1 Fc molecule as an anti-inflammatory agent

“…The observation that human IgG2 in the serum can form hinge region-dependent dimers led to the design of fully recombinant IgG2a Fc multimers called stradomers; these stradomers demonstrated therapeutic efficacy in several models of autoimmune diseases, including collagen-induced arthritis (CIA), ITP and myasthenia gravis 5,6 . Multivalent Fc structures (containing two or three Fc domains) that exhibit avid FcγR binding without activating FcγR signalling have also been engineered; a trivalent Fc structure, Fc3Y, protected against animal models of autoimmune diseases in which immune complexes or FcγRs are implicated 7 .…”

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…The effect of IVIg in MG and other autoimmune conditions has been attributed to the IgG Fc domains, likely through interaction with Fcγ receptors [120]. Along these lines, recombinant multimeric Fc molecules have been shown to have modulatory effects on the clinical course of experimental MG [121]. The beneficial clinical effects were accompanied by downmodulation of autoantibody responses, reduced B-cell activation, an expansion in FoxP3+ Tregs, and a significant increase in surface expression of the inhibitory FcγRIIB protein [121].…”

“…Along these lines, recombinant multimeric Fc molecules have been shown to have modulatory effects on the clinical course of experimental MG [121]. The beneficial clinical effects were accompanied by downmodulation of autoantibody responses, reduced B-cell activation, an expansion in FoxP3+ Tregs, and a significant increase in surface expression of the inhibitory FcγRIIB protein [121]. The advantages of this approach over IVIg would be a reduced volume load, enhanced availability, and potentially reduced infection risk.…”

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

“…Fusion of the human IgG2 hinge region to human IgG1 Fc or mouse IgG2a Fc led to expression of multimerized Fc fragments that bound FcgR with high avidity (17). These molecules demonstrated therapeutic efficacy in animal models of arthritis and ITP (17), as well as in a model of inflammatory neuropathy (18) and in experimental autoimmune myasthenia gravis (19). 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.…”