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Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3689-E3698. doi: 10.1073/pnas.1619386114. Epub 2017 Apr 17.

Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy.

Author information

1
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
2
Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
3
Clinic of Neurology, Department of Medicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
4
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland; beat.ernst@unibas.ch.

Abstract

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.

KEYWORDS:

HNK-1 glycoepitope; IgM autoantibodies; demyelinating peripheral neuropathy; glycosylated polylysine; myelin-associated glycoprotein

PMID:
28416698
PMCID:
PMC5422814
DOI:
10.1073/pnas.1619386114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement. R.H., P.H., A.J.S., and B.E. are co-founders of a University of Basel spin-off, Polyneuron Pharmaceuticals AG, whose activity is related to the subject matter of this article. A.J.S. and B.E. are members of the advisory board, and B.E. is also a member of the board of directors. R.H., H.P., F.Y., A.J.S., and B.E. are named as co-inventors on relevant patent applications.

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