Monoclonal Antibodies for Alzheimer's Immunotherapy

用于阿尔茨海默病免疫治疗的单克隆抗体

基本信息

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
项目类别：
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&apos 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

项目摘要

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针对阿尔茨海默病 (AD) 的产品。 AD 是医院、长期疗养院以及家庭环境中发病率和死亡率日益重要的原因。据保守估计，美国 AD 的直接和间接费用为 1490 亿美元。到 2010 年，仅医疗保险支出预计将增加到 1600 亿美元。目前还没有任何治疗方法可以延缓或阻止 AD 脑细胞的恶化。在第一阶段项目中，针对 Aβ 淀粉样肽产生了鼠单克隆抗体 (mAb)。测量了这些mAb与Aβ不同构象聚集体的结合，并鉴定了许多以高亲和力识别可溶性Aβ寡聚体的mAb。这些单克隆抗体是在独特的植物表达系统中作为小鼠-人类杂交体高水平产生的。此外，还构建了人 ScFv 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。在该提案的具体目标 1 中，将对新的人类单克隆抗体进行评估并与现有的杂交抗体进行比较。该群体中最好的 5 种抗体将在 APPswe/PS1dE9 转基因小鼠体内进行体内测试，以评估注射抗体对小鼠认知功能的影响（具体目标 2）。在具体目标 3 中，该小组中最好的单克隆抗体将在 GMP 设施中生产，用于支持 IND 的研究，以支持一期安全试验。在最终目标“具体目标 4”中，cGMP 生产的 mAb 将用于完成研究性新药 (IND) 启用研究（药理学和毒理学，CMC），以实现 IND 提交。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这种疾病。该提案中的实验将为这些潜在疗法的临床评估提供基础，以确保其安全性和有效性。