Monoclonal Antibodies for Alzheimer's Immunotherapy

用于阿尔茨海默病免疫治疗的单克隆抗体

• 批准号: 7617622
• 负责人: Andrew C Hiatt
• 金额: $ 99.58万
• 依托单位: MAPP BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617622
• 关键词: Active Immunization; Address; Affinity; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Antibodies; Autoantibodies; Autoimmunity; B-Lymphocytes; Binding; Biological Products; Biotechnology; Brain; Capital; Cell Culture Techniques; Characteristics; Clinical; Clinical Trials; Data; Deposition; Deterioration; Development; Disadvantaged; Discrimination; Disease; Dose; Ensure; Environment; Epitopes; Expenditure; Facilities and Administrative Costs; Family; Foundations; Frequencies; Generations; Goals; Hospitals; Human; Hybrids; Immune response; Immunization; Immunoglobulin Constant Region; Immunoglobulin Variable Region; Immunotherapy; In Vitro; Individual; Industry; Inflammatory Response; Intravenous Immunoglobulins; Investigational Drugs; Kentucky; Lead; Learning; Length; Libraries; Life; Macaca fascicularis; Mammalian Cell; Measures; Medicare; Memory; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nicotiana; Nursing Homes; Passive Immunotherapy; Patients; Peptide antibodies; Peptides; Performance; Phage Display; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Plants; Population; Positioning Attribute; Preparation; Prevention; Prevention therapy; Production; Proteins; Radial; Reagent; Reporting; Safety; Scientist; Serum; Severities; Source; Specificity; Staging; System; Techniques; Technology; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Visual; Water; amyloid peptide; base; bioprocess; brain cell; cognitive function; cost; design; drug production; experience; human monoclonal antibodies; improved; in vivo; mortality; mouse model; next generation; nonhuman primate; novel therapeutics; prevent; product development; protein aminoacid sequence; research and development; research clinical testing; research study; success

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.

描述（由申请人提供）：该II期提案的主要重点是开发一种抗阿尔茨海默病（AD）的产品。AD是医院和长期疗养院以及家庭环境中发病和死亡的日益重要的原因。保守估计，美国AD的直接和间接成本为1，490亿美元，仅医疗保险支出预计到2010年将增加到1，600亿美元。目前还没有任何治疗方法可以延缓或阻止AD脑细胞的恶化。在第一阶段的项目中，鼠单克隆抗体（mAb）产生的A？？淀粉样肽这些单克隆抗体的不同构象的A？？测量和一些单克隆抗体，识别可溶性寡聚体的A？？鉴定出具有高亲和力的。这些mAb在独特的植物表达系统中作为小鼠-人杂交体以高水平产生。此外，构建人ScFv的噬菌体展示文库以鉴定由人自身免疫产生的另外的独特抗体。在本提案的具体目标1中，将对新的人源mAb进行评价，并与现有杂交种进行比较。将在APPswe/PS1 dE 9转基因小鼠中对来自该群体的最佳五种抗体进行体内测试，以评估注射的抗体对鼠认知功能的影响（具体目标2）。在特定目标3中，该组中最好的mAb将在GMP设施中生产，用于IND使能研究，以支持I期安全性试验。在最终目标（具体目标4）中，cGMP生产的mAb将用于完成试验性新药（IND）使能研究（药理学和毒理学，CMC），以提交IND。目前，美国有超过500万人患有阿尔茨海默病（AD）。目前，还没有任何治疗方法可以延缓或阻止AD脑细胞的恶化。该提案的目的是开发新的基于抗体的AD疗法，希望最终能够预防和治疗该疾病。提案中的实验将为这些潜在疗法的临床评价提供基础，以确保其安全性和有效性。