Human Proteolytic Beta-Amyloid Specific Antibodies for Treatment of Alzheimers Di

描述(由申请人提供)： 蛋白水解性抗体是一种新的治疗方式，可能会影响目前的基于抗体的治疗。该项目的最终目标是开发有效的蛋白水解性人类抗β淀粉样蛋白的单抗(MAb)，用于治疗阿尔茨海默病。为了实现这一目标，开发了一种新的方法来制备酵母细胞内人单抗文库(IHuMab)，该文库可以产生1016种可能的独特抗体。将利用iHuMAbeta文库和高度特异且调控严格的多报告系统筛选具有蛋白酶活性的A(β淀粉样蛋白)特异性单抗。在第一阶段结束时，我们预计将表达、纯化和鉴定多达10种独特的A特异性蛋白水解性抗体。它们的A40特异性水解性、结合亲和力和中和能力将得到验证。在第二阶段A阶段，将大规模生产具有最高亲和力和蛋白酶活性的特定抗体，以进一步测试A40在阿尔茨海默病小鼠模型中的中和效果。同样在第二阶段，根据IND临床试验申请的提交，最有希望的分子将在动物模型中进行临床前评估。 公共卫生相关性： 治疗性单抗是发展最快的生物技术部门之一，在治疗各种疾病方面取得了显着的成功。蛋白水解性抗体是一种潜在的新型治疗方法，可以提供类似或更好的益处，但需要更少的剂量，从而在降低成本的同时提高疗效。在这个项目中，iHuMAbeta技术平台被开发来鉴定人类抗β-淀粉样肽的蛋白水解性抗体，β-淀粉样肽是治疗阿尔茨海默病的一个有前景的靶点。

DESCRIPTION (provided by applicant): Proteolytic antibodies are a novel therapeutic modality potentially impacting current antibody- based therapy. The ultimate goal of this project is to develop potent proteolytic human monoclonal antibodies (mAb) against beta Amyloids (Ab) for treatment of Alzheimer's disease. To achieve the objective, a novel approach was developed to produce a yeast intracellular human monoclonal antibody library (iHuMab) that can create 1016 possible unique antibodies. A (beta amyloid) specific monoclonal antibodies with protease activity will be screened using iHuMAbeta library and highly specific and tightly regulated multi-reporter system. At the end of phase I, we expect up to 10 unique A specific proteolytic antibodies will be expressed, purified and characterized. Their A40 specific hydrolysis, binding affinity and neutralization capacity will be validated. In phase II A specific antibodies having the highest affinity and protease activity will be produced in large scale quantities for further testing of A40 neutralization effects in mouse models of Alzhemer's disease. Also in Phase II, the most promising molecules would be subjected to pre-clinical evaluation in animal models, pursuant to submission of an IND application for clinical trials. PUBLIC HEALTH RELEVANCE: Therapeutic monoclonal antibodies are one of the fastest growing biotechnology sectors showing marked success for the treatment of various diseases. Proteolytic antibodies are a potential novel therapeutic that could provide a comparable or better benefit but requiring reduced dosages, therefore reducing the cost while increase efficacy. In this project, iHuMAbeta technology platform is developed to identify human proteolytic antibodies against beta-amyloid peptide, a promising target for the treatment of Alzheimer's Disease.