Efficacious and safe antibody catalyzed amyloid beta clearance

有效且安全的抗体催化β淀粉样蛋白清除

• 批准号: 8144329
• 负责人: Sudhir Paul
• 金额: $ 51.11万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144329
• 关键词: Adverse effects; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Antibodies; Antigen Targeting; Antigen-Antibody Complex; Behavioral; Binding; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; C-terminal; Catalytic Antibodies; Cerebrum; Consensus; Deposition; Development; Digestion; Dose-Limiting; Engineering; Ensure; Event; Fc Receptor; Hand; Human; Hydrolysis; Immunization; Immunoglobulin G; Immunoglobulins; Immunotherapeutic agent; Immunotherapy; Inflammatory; Life; Light; Mediating; Methods; Mus; Nerve Degeneration; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Property; Protein Engineering; Public Health; Reaction; Reagent; Risk; Safety; Serum; Specificity; Testing; Transgenic Mice; Treatment Efficacy; base; catalyst; efficacy testing; immunogenic; immunogenicity; improved; in vivo; mouse model; novel; peptide A; polypeptide; public health relevance; response; tissue culture

DESCRIPTION (provided by applicant): Accumulation of amyloid ? peptide (A?) aggregates in the brain is thought to be a central event leading to neurodegenerative changes observed in Alzheimer disease (AD). There is consensus that immunoglobulins (Igs) with specific A? binding activity are viable candidates for AD therapy. We propose to develop novel catalytic Igs with improved efficacy and safety as candidate immunotherapeutic agents for AD. Our experimental approach is based on these considerations. A single catalytic Ig molecule hydrolyzes thousands of A? molecules over its lifetime, which should confer superior efficacy to catalytic Igs in removing A? oligomers compared to conventional stoichiometrically binding Igs. The catalysts do not form stable immune complexes with A?, reducing the likelihood of inflammatory reactions. Deposition of A? in blood vessels observed using conventional Igs is unlikely because of A? digestion by the catalytic Igs. We have identified catalytic Ig variable domains (IgVs) suitable for further development as AD drugs. We will apply protein engineering methods to prepare catalytic IgV derivatives with improved stability and reduced immunogenicity suitable for administration to humans. The resultant Igs will be characterized with respect to catalytic rates and specificity. They will then be tested for efficacy (A? clearance, behavioral improvement) and safety using a transgenic mouse model of AD. If our hypotheses are correct, these studies will validate catalytic Igs as agents suitable for AD therapy. PUBLIC HEALTH RELEVANCE STATEMENT: Finding an effective and safe treatment for Alzheimer disease is an important public health need. We plan to test and develop catalytic antibodies that clear amyloid beta peptide for immunotherapy of Alzheimer disease.

描述（由申请人提供）：淀粉样蛋白的积累？肽（A？）在大脑中的聚集被认为是导致阿尔茨海默病（AD）中观察到的神经退行性变化的核心事件。人们一致认为免疫球蛋白（Igs）具有特异性A？结合活性是 AD 治疗的可行候选者。我们建议开发新型催化 Igs，作为 AD 的候选免疫治疗剂，其功效和安全性得到提高。我们的实验方法是基于这些考虑。单个催化 Ig 分子可水解数千个 A？分子在其整个生命周期内，这应该赋予催化 Igs 在去除 A? 方面的卓越功效。与传统化学计量结合 Igs 相比。这些催化剂不会与 Aβ 形成稳定的免疫复合物，从而降低炎症反应的可能性。 A 的沉积？使用传统 Igs 观察到的血管不太可能，因为 A？被催化 Igs 消化。我们已经确定了适合进一步开发为 AD 药物的催化 Ig 可变域 (IgV)。我们将应用蛋白质工程方法来制备适合人类施用的催化IgV衍生物，其具有更高的稳定性和更低的免疫原性。所得 Igs 将在催化速率和特异性方面进行表征。然后将使用 AD 转基因小鼠模型测试其功效（A？清除、行为改善）和安全性。如果我们的假设正确，这些研究将验证催化 Igs 作为适合 AD 治疗的药物。 公共卫生相关声明：寻找有效且安全的阿尔茨海默病治疗方法是一项重要的公共卫生需求。我们计划测试和开发可清除淀粉样β肽的催化抗体，用于阿尔茨海默病的免疫治疗。