Fusion antibody for Alzheimer's disease with bidirectional transport across the blood-brain barrier and Aβ fibril disaggregation
Fusion antibody for Alzheimer's disease with bidirectional transport across the blood-brain barrier and Aβ fibril disaggregation
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DOI：
10.1021/bc060349x
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发表时间：
2007-03-01
影响因子：
4.7
通讯作者：
Pardridge, William M.
中科院分区：
文献类型：
--
作者：
Boado, Ruben J.;Zhang, Yufeng;Pardridge, William M.
单克隆抗体治疗药物的跨血脑屏障递送是抗体药物诊断或治疗中枢神经系统疾病的障碍。阿尔茨海默病的免疫治疗试图用抗a β单克隆抗体分解阿尔茨海默病的淀粉样斑块。目前的工作是基于阿尔茨海默病免疫治疗的三步模型：(1)抗- a β单克隆抗体在血液中穿过血脑屏障流入脑方向，(2)脑内a β原纤维的结合和分解，(3)抗- a β单克隆抗体在脑内穿过血脑屏障流入血液方向。这是通过一种三功能融合抗体的基因工程来完成的，该抗体结合(1)人类胰岛素受体，它介导血液穿过血脑屏障流入大脑，(2)a β纤维分解淀粉样斑块，(3)Fc受体，它介导从大脑穿过血脑屏障流入血液。这种融合蛋白是一种新的基于抗体的治疗阿尔茨海默病的药物，它是专门设计的，可以在两个方向上穿过人类血脑屏障。
Delivery of monoclonal antibody therapeutics across the blood-brain barrier is an obstacle to the diagnosis or therapy of CNS disease with antibody drugs. The immune therapy of Alzheimer's disease attempts to disaggregate the amyloid plaque of Alzheimer's disease with an anti-A beta monoclonal antibody. The present work is based on a three-step model of immune therapy of Alzheimer's disease: (1) influx of the anti-A beta monoclonal antibody across the blood-brain barrier in the blood to brain direction, (2) binding and disaggregation of A beta fibrils in brain, and (3) efflux of the anti-A beta monoclonal antibody across the blood-brain barrier in the brain to blood direction. This is accomplished with the genetic engineering of a trifunctional fusion antibody that binds (1) the human insulin receptor, which mediates the influx from blood to brain across the blood-brain barrier, (2) the A beta fibril to disaggregate amyloid plaque, and (3) the Fc receptor, which mediates the efflux from brain to blood across the blood-brain barrier. This fusion protein is a new antibody-based therapeutic for Alzheimer's disease that is specifically engineered to cross the human blood-brain barrier in both directions.