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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.

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Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
Clinic of Neurology, Department of Medicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland;


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.


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

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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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