Boado Ruben J, Zhang Yufeng, Zhang Yun, Xia Chun-Fang, Pardridge William M
ArmaGen Technologies, Incorporated, Santa Monica, California, USA.
Bioconjug Chem. 2007 Mar-Apr;18(2):447-55. doi: 10.1021/bc060349x. Epub 2007 Feb 22.
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-Abeta monoclonal antibody. The present work is based on a three-step model of immune therapy of Alzheimer's disease: (1) influx of the anti-Abeta monoclonal antibody across the blood-brain barrier in the blood to brain direction, (2) binding and disaggregation of Abeta fibrils in brain, and (3) efflux of the anti-Abeta 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 Abeta 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.
单克隆抗体疗法跨越血脑屏障是利用抗体药物诊断或治疗中枢神经系统疾病的一个障碍。阿尔茨海默病的免疫疗法试图用抗β淀粉样蛋白单克隆抗体分解阿尔茨海默病的淀粉样斑块。目前的工作基于阿尔茨海默病免疫疗法的三步模型：（1）抗β淀粉样蛋白单克隆抗体在血脑屏障处从血液向脑方向流入，（2）在脑中β淀粉样蛋白原纤维的结合和解聚，以及（3）抗β淀粉样蛋白单克隆抗体在血脑屏障处从脑向血液方向流出。这是通过一种三功能融合抗体的基因工程来实现的，该抗体结合（1）人胰岛素受体，其介导从血液通过血脑屏障流入脑内，（2）β淀粉样蛋白原纤维以分解淀粉样斑块，以及（3）Fc受体，其介导从脑通过血脑屏障流出到血液中。这种融合蛋白是一种新型的基于抗体的阿尔茨海默病治疗药物，经过专门设计可双向穿越人血脑屏障。
