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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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？人们认为大脑中的肽（A？）聚集体被认为是导致阿尔茨海默氏病（AD）观察到神经退行性变化的中心事件。有共识认为具有特定A的免疫球蛋白（IG）？结合活性是广告疗法的可行候选者。我们建议开发具有提高功效和安全性作为AD的候选免疫治疗剂的新型催化IG。我们的实验方法是基于这些考虑因素。单个催化Ig分子水解了数千个A？分子在其一生中，它应该赋予催化Ig在去除A的催化Ig中的效果？与常规的石化结合Ig相比，低聚物的寡聚物。催化剂不会与A形成稳定的免疫复合物，从而降低了炎症反应的可能性。沉积？在使用常规IG观察到的血管中，不太可能因为A？催化IG消化。我们已经确定了适合作为AD药物进一步开发的催化Ig变量域（IGV）。我们将采用蛋白质工程方法来制备具有提高稳定性和降低免疫原性的催化IGV衍生物，适合于人类。所得的IG将在催化速率和特异性方面进行表征。然后，将使用AD的转基因小鼠模型对它们进行疗效（清除率，行为改善）和安全性测试。如果我们的假设是正确的，这些研究将验证催化Ig作为适合AD治疗的药物。公共卫生相关性声明：为阿尔茨海默氏病寻找有效且安全的治疗是重要的公共卫生需求。我们计划测试和开发催化抗体，以清除淀粉样β肽对阿尔茨海默氏病免疫疗法。