Treatment with a recombinant human IgM that recognizes PSA-NCAM preserves brain pathology in MOG-induced experimental autoimmune encephalomyelitis.

Abstract

A single peripheral dose of CNS-binding IgMs promote remyelination and preserve axons in a number of animal models of neurologic disease. A myelin-binding recombinant human IgM (rHIgM22) is presently in a safety trial in MS patients following an acute MS exacerbation. rHIgM22 (directed against oligodendrocytes) or rHIgM12 (directed against neurons) were administered to mice with MOG-induced experimental autoimmune encephalomyelitis (EAE) with study endpoints: clinical deficits and brain and spinal cord pathology. IgMs were administered at a therapeutic dose of 100 μ g intra peritoneal at the time of immunization (day -1, 0, +$1), disease onset (15 days) or peak of the disease (28 days). Disease course was not worsened by either human IgM regardless of the time of treatment. Of note, the human IgM that recognizes a carbohydrate epitope on gangliosides and NCAM, rHIgM12, reduced brain pathology when given at time of immunization or at onset of disease, but did not reduce clinical deficits or spinal cord disease burden. Hence, treatment with rHIgM12 resulted in marked reduction in meningeal inflammation. Data consistent with the hypothesis that in the EAE model this molecule has an immune-modulatory effect. Treatment with an anti-CD4 blocking IgG prevented both clinical course and CNS pathology. This pre-clinical study further supports the safety of therapeutic CNS-binding human IgMs in the presence of autoimmunity and clearly differentiates them from IgGs directed against MOG or aquaporin-4 that worsen neurologic disease.

• Authors: Hernan Nicolas Lemus, Arthur E Warrington, Aleksandar Denic, Bharath Wootla, Moses Rodriguez
• Journal: Human antibodies (Hum Antibodies) Vol. 25 Issue 3-4 Pg. 121-129 ( 2017) ISSN: 1875-869X [Electronic] Netherlands
• PMID: 28269761 (Publication Type: Journal Article)

Chemical References

• Immunoglobulin M
• Immunologic Factors
• Myelin-Oligodendrocyte Glycoprotein
• Neural Cell Adhesion Molecule L1
• Neuroprotective Agents
• Peptide Fragments
• Recombinant Proteins
• Sialic Acids
• myelin oligodendrocyte glycoprotein (35-55)
• polysialyl neural cell adhesion molecule
• Freund's Adjuvant

Topics

• Animals
• Brain (drug effects, immunology, pathology)
• Cognitive Dysfunction (chemically induced, drug therapy, immunology, pathology)
• Demyelinating Diseases (chemically induced, drug therapy, immunology, pathology)
• Drug Administration Schedule
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, drug therapy, immunology, pathology)
• Female
• Freund's Adjuvant (administration & dosage)
• Humans
• Immunoglobulin M (pharmacology)
• Immunologic Factors (pharmacology)
• Injections, Intraperitoneal
• Mice
• Mice, Inbred C57BL
• Myelin Sheath (drug effects, immunology, pathology)
• Myelin-Oligodendrocyte Glycoprotein (administration & dosage)
• Neural Cell Adhesion Molecule L1 (immunology, metabolism)
• Neurons (drug effects, immunology, pathology)
• Neuroprotective Agents (pharmacology)
• Oligodendroglia (drug effects, immunology, pathology)
• Peptide Fragments (administration & dosage)
• Protein Binding
• Recombinant Proteins (pharmacology)
• Sialic Acids (immunology, metabolism)
• Spinal Cord (drug effects, immunology, pathology)