Molecular basis for passive immunotherapy of Alzheimer's disease
Molecular basis for passive immunotherapy of Alzheimer's disease
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DOI：
10.1073/pnas.0705888104
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发表时间：
2007-10-02
影响因子：
11.1
通讯作者：
Dealwis, Chris
中科院分区：
文献类型：
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作者：
Gardberg, Anna S.;Dice, Lezlee T.;Dealwis, Chris
淀粉样蛋白-β（A β）肽的淀粉样蛋白聚集体与阿尔茨海默病的病理学有关。抗A β单克隆抗体（mAb）已显示在体外和动物研究中减少淀粉样蛋白斑块。因此，被动免疫被认为是治疗阿尔茨海默氏症，抗A β单克隆抗体目前正在进行II期试验。我们报告了两种单克隆抗体（PFA 1和PFA 2）的分离，识别A β单体，原纤维和原纤维及其与A β（1-8）肽DAEFRHDS复合的抗原结合片段（Fab）的结构。免疫显性EFRHD序列形成盐桥、氢键和疏水接触，包括与抗原结合片段的显著WWDDD基序的相互作用。我们还表明，一个类似的序列（AKFRHD）来自人类蛋白质GRIN是能够交叉反应与PFA 1和PFA 2，当与PFA 1共结晶，结合在一个相同的构象A β（1-8）。由于这种交叉反应性对免疫治疗的潜在副作用有影响，我们的结构提供了一个模板，用于设计靶向A β的具有改进特异性和更高亲和力的衍生mAb。
Amyloid aggregates of the amyloid-beta (A beta) peptide are implicated in the pathology of Alzheimer's disease. Anti-A beta monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-A beta mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize A beta monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the A beta(1-8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIN is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to A beta(1-8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target A beta with improved specificity and higher affinity.