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: 6885172
• 负责人: ANDREW C HIATT
• 金额: $ 29.51万
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885172
• 关键词: Alzheimer' s disease; SDS polyacrylamide gel electrophoresis; amyloid proteins; behavior test; clinical research; disease /disorder model; enzyme linked immunosorbent assay; epitope mapping; genetically modified animals; genetically modified plants; immunologic substance development /preparation; immunotherapy; ion exchange chromatography; laboratory mouse; learning; memory; molecular cloning; monoclonal antibody; nonhuman therapy evaluation; polymerase chain reaction; protein metabolism; surface plasmon resonance; transfection /expression vector

DESCRIPTION (PROVIDED BY APPLICANT): Transgenic mice administered anti-amyloid peptide antibodies, acutely or subchronically, show markedly improved learning and memory performance. Recent reports suggest that the toxicity of the amyloid peptide and other amyloidogenic proteins lies not in the insoluble fibrils that accumulate but rather in the soluble oligomeric intermediates. A panel of monclonal antibodies has been developed by Mapp Biopharmaceutical, which recognizes the internal domain of soluble amyloid beta peptide. These antibodies are candidates for use in passive immunotherapy. The potential advantages of a passive approach include: (1) the dose of drug given to any patient can be determined precisely, eliminating potential variability which will occur with active immunization; (2) therapy can be started or stopped at any time. Potential disadvantages include: (1) whether enough reagent can be generated to treat large numbers of individuals and (2) cost. The purpose of this study is to evaluate a set of candidate monoclonal antibodies that are intended to contribute to our overall understanding of the benefits of passive Alzheimer's immunization in humans and produce these antibodies in a system, which ultimately minimizes the capital burden of antibody drug production and hence reduces the overall costs. In Specific Aim 1, the panel will be characterized with respect to affinity, oligomer binding, and epitope specificity. The variable regions of a selection of monoclonals will then be cloned in Specific Aim 2 and the genes introduced the into plant expression vectors as both mouse IgG and mouse-human chimeric IgG. Finally, in Specific Aim 3, the expression vectors will be introduced into plants to generate quantities of monoclonal sufficient for in vitro comparison to the original hybridoma expressed monoclonal.

描述（由申请人提供）：急性或亚慢性施用抗淀粉样肽抗体的转基因小鼠表现出显着改善的学习和记忆性能。最近的报告表明，淀粉样肽和其他淀粉样蛋白的毒性不在于积累的不溶性原纤维，而在于可溶性寡聚中间体。 Mapp Biopharmaceutical 开发了一组单克隆抗体，可识别可溶性淀粉样蛋白 β 肽的内部结构域。这些抗体是用于被动免疫疗法的候选抗体。被动方法的潜在优点包括：（1）可以精确地确定给予任何患者的药物剂量，消除主动免疫中可能出现的潜在变异性； (2)治疗可以随时开始或停止。潜在的缺点包括：（1）是否可以产生足够的试剂来治疗大量个体；（2）成本。本研究的目的是评估一组候选单克隆抗体，旨在帮助我们全面了解被动阿尔茨海默病免疫对人类的益处，并在系统中生产这些抗体，最终最大限度地减少抗体药物生产的资本负担从而降低总体成本。在具体目标 1 中，将针对亲和力、寡聚物结合和表位特异性来表征该组。然后将选择的单克隆抗体的可变区克隆到Specific Aim 2中，并将基因作为小鼠IgG和小鼠-人嵌合IgG引入植物表达载体中。最后，在具体目标 3 中，将表达载体引入植物中以产生足以在体外与原始杂交瘤表达的单克隆进行比较的量的单克隆。