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首页> 外文期刊>Journal of Neuroimmunology: Official Bulletin of the Research Committee on Neuroimmunology of the World Federation of Neurology >Conjugation of acetylcholine receptor-protecting Fab fragments with polyethylene glycol results in a prolonged half-life in the circulation and reduced immunogenicity.
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Conjugation of acetylcholine receptor-protecting Fab fragments with polyethylene glycol results in a prolonged half-life in the circulation and reduced immunogenicity.

机译：乙酰胆碱受体保护性Fab片段与聚乙二醇的缀合导致循环中半衰期延长和免疫原性降低。

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Antibodies to the acetylcholine receptor (AChR) cause AChR loss, resulting in the disease, myasthenia gravis (MG). The majority of the pathogenic antibodies seem to be directed against the main immunogenic region (MIR) of the AChR. In contrast to the intact antibodies, Fab fragments of anti-AChR antibodies are not themselves pathogenic and such fragments of anti-MIR monoclonal antibodies (mAbs) protect the AChR in vitro and in vivo against the pathogenic antibodies. However, Fab fragments have a very short in vivo half-life and are immunogenic, obstacles which must be overcome before their clinical use can be envisaged. We investigated the effect of conjugating Fab fragments to polyethylene glycol (PEG), a method known to increase the in vivo half-life and reduce the immunogenicity of proteins. When the Fab' fragments of two rat anti-MIR mAbs (nos. 35 and 195) were conjugated to methoxy-PEG-maleimide, the conjugates retained about 10% of their AChR binding activity and efficiently protected the AChR against the binding and modulating activity of myasthenic antibodies. Their in vivo half-life in rats was approximately 15 times longer than that of the unconjugated Fab' fragment and they were much less immunogenic in mice. This work represents an important step towards the clinical use of AChR-protective anti-MIR Fabs, but further improvements are needed before their clinical use is attempted.
机译：乙酰胆碱受体（AChR）的抗体会导致AChR丢失，从而导致重症肌无力（MG）。大多数病原性抗体似乎针对AChR的主要免疫原性区域（MIR）。与完整抗体相反，抗AChR抗体的Fab片段本身不是致病性的，抗MIR单克隆抗体（mAb）的此类片段可在体外和体内保护AChR免受致病性抗体的侵害。然而，Fab片段具有非常短的体内半衰期并且是免疫原性的，在可以设想其临床用途之前必须克服这些障碍。我们研究了将Fab片段与聚乙二醇（PEG）结合的作用，聚乙二醇是一种已知的增加体内半衰期并降低蛋白质免疫原性的方法。当将两个大鼠抗MIR mAb（第35和195号）的Fab'片段与甲氧基PEG-马来酰亚胺偶联时，偶联物保留了约10％的AChR结合活性并有效保护了AChR免受结合和调节活性肌无力抗体。它们在大鼠体内的半衰期比未结合的Fab'片段长约15倍，并且在小鼠中的免疫原性低得多。这项工作代表了AChR保护性抗MIR Fabs临床应用的重要一步，但是在尝试将其临床应用之前，还需要进一步的改进。

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