Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica

• Published in: Neuropharmacology Vol. 133; pp. 345 - 353
• Main Authors: Tradtrantip, Lukmanee, Felix, Christian M., Spirig, Rolf, Morelli, Adriana Baz, Verkman, A.S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2018
• Subjects: Administration, Intravenous; Animals; AQP4; Aquaporin 4 - genetics; Aquaporin 4 - immunology; Aquaporin 4 - metabolism; Aquaporin 4 - toxicity; Astrocyte; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Autoantibodies - therapeutic use; CHO Cells; Complement; Complement C1q - metabolism; Cricetulus; Deoxyuracil Nucleotides - immunology; Deoxyuracil Nucleotides - metabolism; Deoxyuracil Nucleotides - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; Fc multimer; Female; Glial Fibrillary Acidic Protein - metabolism; Humans; Immunoglobulin; Immunoglobulin Fc Fragments - genetics; Immunoglobulin Fc Fragments - therapeutic use; Immunoglobulin G - chemistry; Immunoglobulin G - therapeutic use; In Vitro Techniques; Mutation - genetics; Neuroinflammation; Neuromyelitis Optica - immunology; Neuromyelitis Optica - pathology; Neuromyelitis Optica - therapy; NMO; Rats; Rats, Sprague-Dawley; Recombinant Proteins - immunology; Recombinant Proteins - metabolism; Spinal Cord - pathology; Statistics, Nonparametric; Time Factors; Transfection; CDC; ITP; Neuroinflammation; IVIG; AQP4; Complement; Immunoglobulin; PFA; Astrocyte; AQP4-IgG; MAC; GFAP; NMO; BSA; Fc multimer; NK cell; MBP; ADCC
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2018.02.002

Intravenous human immunoglobulin G (IVIG) may have therapeutic benefit in neuromyelitis optica spectrum disorders (herein called NMO), in part because of the anti-inflammatory properties of the IgG Fc region. Here, we evaluated recombinant Fc hexamers consisting of the IgM μ-tailpiece fused with the Fc region of human IgG1. In vitro, the Fc hexamers prevented cytotoxicity in aquaporin-4 (AQP4) expressing cells and in rat spinal cord slice cultures exposed to NMO anti-AQP4 autoantibody (AQP4-IgG) and complement, with >500-fold greater potency than IVIG or monomeric Fc fragments. Fc hexamers at low concentration also prevented antibody-dependent cellular cytotoxicity produced by AQP4-IgG and natural killer cells. Serum from rats administered a single intravenous dose of Fc hexamers at 50 mg/kg taken at 8 h did not produce complement-dependent cytotoxicity when added to AQP4-IgG-treated AQP4-expressing cell cultures. In an experimental rat model of NMO produced by intracerebral injection of AQP4-IgG, Fc hexamers at 50 mg/kg administered before and at 12 h after AQP4-IgG fully prevented astrocyte injury, complement activation, inflammation and demyelination. These results support the potential therapeutic utility of recombinant IgG1 Fc hexamers in AQP4-IgG seropositive NMO. •Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system.•Recombinant Fc hexamers, consisting of the IgM μ-tailpiece fused with the Fc region of human IgG1, were studied for treatment of NMO.•Fc hexamers inhibited complement- and cell-mediated cytotoxicity caused by NMO autoantibody in vitro and prevented NMO pathology in a rat model of NMO.