Herrendorff Ruben, Hänggi Pascal, Pfister Hélène, Yang Fan, Demeestere Delphine, Hunziker Fabienne, Frey Samuel, Schaeren-Wiemers Nicole, Steck Andreas J, Ernst Beat
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, 4056 Basel, Switzerland.
Department of Biomedicine, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.
Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3689-E3698. doi: 10.1073/pnas.1619386114. Epub 2017 Apr 17.
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 PL(mimHNK-1) 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 PL(mimHNK-1) represents an important step toward an antigen-specific therapy for anti-MAG neuropathy.
抗髓鞘相关糖蛋白（MAG）神经病是一种由识别碳水化合物表位HNK-1（人类自然杀伤细胞-1）的单克隆IgM自身抗体引起的致残性自身免疫性周围神经病。这种糖表位在有髓神经纤维中存在的黏附分子（如MAG）上高度表达。由于抗MAG自身抗体的致病性和脱髓鞘特性已得到充分证实，目前的治疗旨在降低自身抗体水平。然而，目前的疗法主要是免疫抑制性的，缺乏选择性和疗效。因此，我们推测通过用模拟天然HNK-1糖表位的基于碳水化合物的配体选择性中和致病性抗MAG抗体，可以显著改善病情。在抑制试验中，天然HNK-1表位的模拟物（2，mimHNK-1）阻断了MAG与患者血清中致病性IgM抗体的相互作用，但亲和力仅为微摩尔级别。因此，考虑到MAG-IgM相互作用的多价性质，用模拟物2取代了不同大小的聚赖氨酸聚合物。使用最有前景的聚赖氨酸糖聚合物PL(mimHNK-1)，对患者血清的抑制作用可提高至每个表位高达230,000倍，从而产生低纳摩尔级别的抑制效力。由于临床研究表明抗MAG IgM水平的降低与临床改善之间存在相关性，因此开发了一种产生高水平抗MAG IgM的抗MAG神经病的免疫替代小鼠模型。观察到用糖聚合物PL(mimHNK-1)有效清除这些抗体是抗MAG神经病抗原特异性治疗的重要一步。
