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: 7984646
• 负责人: Sudhir Paul
• 金额: $ 52.88万
• 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/7984646
• 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; Peptides; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Property; Protein Engineering; Public Health; Reaction; Reagent; Risk; Safety; Serum; Specificity; Testing; Transgenic Mice; Treatment Efficacy; amyloid peptide; 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.

性状（由申请方提供）：淀粉样蛋白蓄积？肽（A？）脑中的聚集体被认为是导致在阿尔茨海默病（AD）中观察到的神经退行性变化的中心事件。有共识，免疫球蛋白（Ig）与特定的A？结合活性是AD治疗的可行候选物。我们建议开发新的催化免疫球蛋白，提高疗效和安全性作为候选免疫制剂的AD。我们的实验方法是基于这些考虑。一个单一的催化IG分子水解数千A？分子的寿命，这应该赋予上级效力的催化免疫球蛋白在去除A？与常规化学计量结合Ig相比，催化剂不与A？形成稳定的免疫复合物，减少炎症反应的可能性。在A？在血管中观察到使用传统的免疫球蛋白是不可能的，因为A？通过催化免疫球蛋白消化。我们已经确定了催化IG可变结构域（IgV）适合进一步开发为AD药物。我们将应用蛋白质工程方法来制备具有改善的稳定性和降低的免疫原性的适合于施用给人的催化IgV衍生物。将对所得Ig的催化速率和特异性进行表征。然后将测试它们的功效（A？清除、行为改善）和使用AD转基因小鼠模型的安全性。如果我们的假设是正确的，这些研究将验证催化免疫球蛋白作为代理适合AD治疗。 公共卫生相关性声明：寻找有效和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。