The antibody aducanumab reduces Aβ plaques in Alzheimer's disease
The antibody aducanumab reduces Aβ plaques in Alzheimer's disease
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DOI：
10.1038/nature19323
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发表时间：
2016-09-01
期刊：
影响因子：
64.8
通讯作者：
Sandrock, Alfred
中科院分区：
文献类型：
--
作者：
Sevigny, Jeff;Chiao, Ping;Sandrock, Alfred
阿尔茨海默病（Alzheimer's disease，AD）是一种以脑内β淀粉样蛋白（amyloid-beta，A β）斑块和神经元缠结沉积为特征，伴有突触功能障碍和神经退行性变的疾病。针对A β的基于抗体的免疫疗法以触发其清除或减轻其神经毒性迄今为止尚未成功。在这里，我们报告了aducanumab的产生，aducanumab是一种选择性靶向聚集的A β的人单克隆抗体。在AD转基因小鼠模型中，aducanumab显示可进入大脑，结合实质A β，并以剂量依赖性方式减少可溶性和不溶性A β。在前驱期或轻度AD患者中，每月静脉输注aducanumab一年，以剂量和时间依赖性方式降低脑A β。这伴随着通过临床痴呆评定总和和简易精神状态检查评分测量的临床衰退的减缓。主要的安全性和耐受性结果是淀粉样蛋白相关的成像异常。这些结果证明了进一步开发aducanumab治疗AD的合理性。如果正在进行的3期临床试验证实临床衰退的减缓，这将为淀粉样蛋白假说提供令人信服的支持。
Alzheimer's disease (AD) is characterized by deposition of amyloid-beta (A beta) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against A beta to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated A beta. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal A beta, and reduce soluble and insoluble A beta in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain A beta in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.