Efficacious and safe antibody catalyzed amyloid beta clearance

描述（由申请人提供）：淀粉样蛋白积累？大脑中的肽（A?）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中心事件。免疫球蛋白（Igs）与特异性A？结合活性是阿尔茨海默病治疗的可行候选药物。我们建议开发具有更高疗效和安全性的新型催化Igs作为AD的候选免疫治疗剂。我们的实验方法是基于这些考虑。一个具有催化作用的Ig分子可以水解数千个A？分子的寿命，这应该赋予催化性Igs在去除A？低聚物与传统化学计量结合Igs的比较。催化剂不能与A？，减少炎症反应的可能性。A？由于A？催化溶出。我们已经确定了适合作为AD药物进一步开发的催化Ig可变结构域（igv）。我们将应用蛋白质工程方法制备具有更高稳定性和降低免疫原性的催化IgV衍生物，适合于人类给药。所得的Igs将根据催化速率和特异性进行表征。然后测试它们的功效(A？清除，行为改善)和安全性使用转基因AD小鼠模型。如果我们的假设是正确的，这些研究将证实催化性Igs是适用于阿尔茨海默病治疗的药物。

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.