title: 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.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL 60612, USA; Department of Neurology and Rehabilitation, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL 60612, USA.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thiruppathi
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL 60612, USA; Department of Neurology and Rehabilitation, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL 60612, USA.
authors.forename: Jian Rong
authors.initials: JR
authors.lastname: Sheng
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL 60612, USA; Department of Neurology and Rehabilitation, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL 60612, USA.
authors.forename: Liangcheng
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL 60612, USA.
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.affiliation: Novartis Institutes for Biomedical Research, 220 Massachusetts Ave, Building 600, 304C, Cambridge, MA 02139, USA. Electronic address: matthew.meriggioli@novartis.com.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Meriggioli
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage* / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage; D007167:Immunotherapy / Q000379:methods*; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy*; D011950:Receptors, Cholinergic / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; D016753:Interleukin-10
keywords: EAMG; Fc; IVIg; IgG; Multimers; Regulatory T cells