Monoclonal Antibodies for Alzheimer's Immunotherapy

描述(由申请人提供)：这一第二阶段提案的主要重点是开发一种治疗阿尔茨海默病(AD)的产品。在医院和长期疗养院以及家庭环境中，AD是发病率和死亡率的一个日益重要的原因。在美国，AD的直接和间接成本保守估计为1490亿美元。预计到2010年，仅医疗保险支出就将增加到1600亿美元。目前还没有任何治疗方法可以延缓或阻止阿尔茨海默病患者脑细胞的退化。在第一阶段的项目中，产生了针对A？淀粉样多肽的鼠源性单抗。测定了这些单抗与Aβ不同构象聚集体的结合力，并鉴定了一些能高亲和力识别Aβ可溶低聚物的单抗。这些单抗在一种独特的植物表达系统中以人鼠杂交体的形式大量生产。此外，还构建了人源单链抗体的噬菌体展示文库，以鉴定由人自身免疫产生的其他独特抗体。在本提案的具体目标1中，将对新的人类单抗进行评估，并与现有的杂交种进行比较。来自这一群体的五种最佳抗体将在APPswe/PS1dE9转基因小鼠身上进行体内测试，以评估注射抗体对小鼠认知功能的影响(特定目标2)。在具体目标3中，该组中最好的单抗将在GMP设施中生产，用于IND-Enabling研究，以支持第一阶段安全试验。在最终目标，具体目标4中，cGMP产生的单抗将用于完成新药研究性研究(药理学和毒理学，CMC)，以提交新药。目前，美国有500多万人患有阿尔茨海默病(AD)。目前，还没有一种治疗方法可以延缓或阻止AD脑细胞的恶化。这项提议的目的是为AD开发基于抗体的新疗法，希望这种疗法最终将起到预防和治疗疾病的作用。提案中的实验将为这些潜在疗法的临床评估提供基础，以确保它们的安全性和有效性。

DESCRIPTION (provided by applicant): The primary focus of this Phase II proposal is development of a product against Alzheimer's disease (AD). AD is an increasingly important cause of morbidity and mortality in both hospital and long term nursing homes as well as in family environments. The direct and indirect cost of AD has been conservatively estimated at $149 billion in the U.S. Medicare expenditures alone are expected to increase to $160 billion by 2010. There is not yet any treatment that can delay or stop the deterioration of brain cells in AD. In the Phase I project, murine monoclonal antibodies (mAbs) were generated against the A??amyloid peptide. The binding of these mAbs to different conformational aggregates of A??was measured and a number of mAbs that recognize soluble oligomers of A??with high affinity were identified. These mAbs were produced at high levels as mouse-human hybrids in a unique plant expression system. In addition, a phage display library of human ScFvs was constructed in order to identify additional unique antibodies resulting from a human autoimmunity. In Specific Aim 1 of this proposal, new human mAbs will be evaluated and compared to the existing hybrids. The best five antibodies from this population will be tested in vivo in APPswe/PS1dE9 transgenic mice to assess the impact of injected antibody on murine cognitive function (Specific Aim 2). In Specific Aim 3, the best mAb of the group will be produced in a GMP facility for use in IND-enabling studies to support a Phase 1 safety trial. In the final aim, Specific Aim 4, the cGMP produced mAb will be used to complete Investigational New Drug (IND) enabling studies (pharmacology and toxicology, CMC) to enable an IND submission. More than 5 million people in the U.S. currently have Alzheimer's disease (AD). At this time, there is no treatment that can delay or stop the deterioration of brain cells in AD. The aim of this proposal is to develop new antibody-based therapies for AD that, it is hoped, will ultimately act to both prevent and treat the disease. The experiments in the proposal will provide the foundation for clinical evaluation of these potential therapies to ensure their safety and efficacy.