Antineonatal Fc Receptor Antibody Treatment Ameliorates MOG-IgG–Associated Experimental Autoimmune Encephalomyelitis

Abstract

Background and ObjectivesMyelin oligodendrocyte glycoprotein antibody–associated disorder (MOGAD) is a rare, autoimmune demyelinating CNS disorder, distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Characterized by pathogenic immunoglobulin G (IgG) antibodies against MOG, a potential treatment strategy for MOGAD is to reduce circulating IgG levels, e.g., by interference with the IgG recycling pathway mediated by the neonatal Fc receptor (FcRn). Although the optic nerve is often detrimentally involved in MOGAD, the effect of FcRn blockade on the visual pathway has not been assessed. Our objective was to investigate effects of a monoclonal anti-FcRn antibody in murine MOG-IgG–associated experimental autoimmune encephalomyelitis (EAE).MethodsWe induced active MOG35-55 EAE in C57Bl/6 mice followed by the application of a monoclonal MOG-IgG (8-18C5) 10 days postimmunization (dpi). Animals were treated with either a specific monoclonal antibody against FcRn (α-FcRn, 4470) or an isotype-matched control IgG on 7, 10, and 13 dpi. Neurologic disability was scored daily on a 10-point scale. Visual acuity was assessed by optomotor reflex. Histopathologic hallmarks of disease were assessed in the spinal cord, optic nerve, and retina. Immune cell infiltration was visualized by immunohistochemistry, demyelination by Luxol fast blue staining and complement deposition and number of retinal ganglion cells by immunofluorescence.ResultsIn MOG-IgG–augmented MOG35-55 EAE, anti-FcRn treatment significantly attenuated neurologic disability over the course of disease (mean area under the curve and 95% confidence intervals (CIs): α-FcRn [n = 27], 46.02 [37.89–54.15]; isotype IgG [n = 24], 66.75 [59.54–73.96], 3 independent experiments), correlating with reduced amounts of demyelination and macrophage infiltration into the spinal cord. T- and B-cell infiltration and complement deposition remained unchanged. Compared with isotype, anti-FcRn treatment prevented reduction of visual acuity over the course of disease (median cycles/degree and interquartile range: α-FcRn [n = 16], 0.50 [0.48–0.55] to 0.50 [0.48–0.58]; isotype IgG [n = 17], 0.50 [0.49–0.54] to 0.45 [0.39–0.51]).DiscussionWe show preserved optomotor response and ameliorated course of disease after anti-FcRn treatment in an experimental model using a monoclonal MOG-IgG to mimic MOGAD. Selectively targeting FcRn might represent a promising therapeutic approach in MOGAD.

The therapeutic age of the neonatal Fc receptor

“…In addition, using the previously mentioned Seldeg approach, which consisted of an Abdeg Fc mutant fused with myelin oligodendrocyte glycoprotein (MOG), also reduced disease activity by exclusive degradation of pathogenic autoantibodies 157 , 158 . FcRn blockade also limited optomotor defects in a similar IgG-mediated EAE model of MS, reduced spinal demyelination and specifically altered macrophage infiltration into the spinal cord, with no differences in B cells, T cells or complement deposition 159 . In a passive transfer model of anti-muscle-specific kinase IgG4 from patients with MG, IgG1 MST-HN effectively ameliorated muscle weakness, weight loss and improved calf compound muscle action potentials, which correlated with lowering of serum pathogenic antibodies 160 .…”

Treatment with MDL 72527 Ameliorated Clinical Symptoms, Retinal Ganglion Cell Loss, Optic Nerve Inflammation, and Improved Visual Acuity in an Experimental Model of Multiple Sclerosis

“…Several studies have indicated reduced visual acuity in the rodent EAE model [ 71 , 73 , 74 , 75 ]. Visual acuity changes and RGC dysfunction have also been reported in MS patients [ 17 , 76 ].…”

Repurposing MS immunotherapies for CIDP and other autoimmune neuropathies: unfulfilled promise or efficient strategy?

“…211 In MOG-associated EAE, treatment with an FcRn-antibody ameliorated disease severity. 212 Data in experimental neuritis: We could not identify any specific studies evaluating FcRn inhibitors in autoimmune neuritis models.…”