Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.
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Herrendorff R
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
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Hänggi P
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
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Pfister H
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
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Yang F
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
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Demeestere D
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
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Hunziker F
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
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Frey S
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
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Schaeren-Wiemers N
Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
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Steck AJ
Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
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Ernst B
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland; beat.ernst@unibas.ch.
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Published in:
- Proceedings of the National Academy of Sciences of the United States of America. - 2017
English
Anti-MAG (myelin-associated glycoprotein) neuropathy is a disabling autoimmune peripheral neuropathy caused by monoclonal IgM autoantibodies that recognize the carbohydrate epitope HNK-1 (human natural killer-1). This glycoepitope is highly expressed on adhesion molecules, such as MAG, present in myelinated nerve fibers. Because the pathogenicity and demyelinating properties of anti-MAG autoantibodies are well established, current treatments are aimed at reducing autoantibody levels. However, current therapies are primarily immunosuppressive and lack selectivity and efficacy. We therefore hypothesized that a significant improvement in the disease condition could be achieved by selectively neutralizing the pathogenic anti-MAG antibodies with carbohydrate-based ligands mimicking the natural HNK-1 glycoepitope 1. In an inhibition assay, a mimetic (2, mimHNK-1) of the natural HNK-1 epitope blocked the interaction of MAG with pathogenic IgM antibodies from patient sera but with only micromolar affinity. Therefore, considering the multivalent nature of the MAG-IgM interaction, polylysine polymers of different sizes were substituted with mimetic 2. With the most promising polylysine glycopolymer PL84(mimHNK-1)45 the inhibitory effect on patient sera could be improved by a factor of up to 230,000 per epitope, consequently leading to a low-nanomolar inhibitory potency. Because clinical studies indicate a correlation between the reduction of anti-MAG IgM levels and clinical improvement, an immunological surrogate mouse model for anti-MAG neuropathy producing high levels of anti-MAG IgM was developed. The observed efficient removal of these antibodies with the glycopolymer PL84(mimHNK-1)45 represents an important step toward an antigen-specific therapy for anti-MAG neuropathy.
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bronze
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https://sonar.ch/global/documents/150107
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