Recombinant IgG Fc Fragments Effectively Suppress Experimental Myasthenia Gravis (S35.002)

Objective: To investigate the therapeutic effects of intravenous administration of fully recombinant forms of polyvalent IgG Fc fragments in murine experimental myasthenia gravis. Background Intravenous immune globulin (IVIg) has been shown to have broad therapeutic application in the treatment of autoimmune diseases, including myasthenia gravis (MG). The anti-inflammatory activities of IVIg are now generally attributed to the immunoglobulin G (IgG) Fc domains. Interestingly, soluble immune aggregates bearing intact Fc fragments have been shown to be effective in the treatment of a variety of autoimmune disorders in mice. To study the mechanisms by which soluble Fc containing immune complexes can suppress autoimmunity, a series of fully recombinant forms of polyvalent IgG2a Fc were created by linking the hinge-CH2-CH3 regions of murine IgG2a Fc to one or more multimerization domains (MD). Design/Methods: Recombinant polyvalent IgG2a fusion proteins (400µg) were administered via tail vein to mice with well-established experimental myasthenia gravis (EAMG) on five consecutive days. Control EAMG mice received a) IVIg (0.4 g/kg) X 5 days or b) PBS. Effectiveness of treatment was assessed by improvement in myasthenic weakness as determined by a standard clinical scoring protocol, circulating serum levels of anti-AChR antibodies, and immunological evaluation of lymph nodes and spleens. Results: Treatment of EAMG mice with recombinant polyvalent IgG2a Fc fusion proteins produced a significant improvement in myasthenic weakness, and an equivalent magnitude of beneficial effect compared to IVIg. Results of anti-AChR antibody levels and immunological studies of splenocytes and lymph node cells will be presented. Conclusions: Recombinant polyvalent IgG2a Fc fusion proteins were equally effective in ameliorating EAMG compared to IVIg, and may represent a feasible alternative, offering the advantages of being completely recombinant, of unlimited supply, free of infectious risks, and effective at doses 1 -2 log orders lower than IVIg. Supported by: The NIH (National Institute of Neurologic Disorders and Stroke, K08NS058800, and the Muscular Dystrophy Association (MDA) MNM and JRS; and National Institute of Allergy and Infectious Diseases, RO1 AI 058190, BSP. Study material (Recombinant IgG2a Fc fusion proteins (stradomersTM) was provided by Gliknik, Inc. Disclosure: Dr. Meriggioli has received personal compensation for activities with Athena Diagnostics, Talecris Biotherapeutics, Gliknik, and Celegene Corporation. Dr. Meriggioli receives patent payments for a patent on bispecific antibody coated dendritic cells. Dr. Meriggioli has received research support from the NIH/NINDS and the Muscular Dystrophy Association. Dr. Sheng has nothing to disclose. Dr. Li has nothing to disclose. Dr. Muthusamy has nothing to disclose. Dr. Prabhakar has received personal compensation for activities with Gliknik Inc. as a consultant.Dr. Prabhakar has received research support from NIH.