Efficacious and safe antibody catalyzed amyloid beta clearance

描述(申请人提供)：淀粉样蛋白积聚？多肽(A？)大脑中的聚集体被认为是导致阿尔茨海默病(AD)神经退行性变化的中心事件。已有共识认为免疫球蛋白(Ig)与特异性A？结合活性是AD治疗的可行候选者。我们建议开发新的催化免疫球蛋白作为AD的候选免疫治疗剂，具有更好的有效性和安全性。我们的实验方法就是基于这些考虑。一个催化的免疫球蛋白分子可以分解数千个A？在其生命周期中，哪种分子应该比催化免疫球蛋白在去除A方面具有更好的效果？低聚物与传统的化学计量结合的免疫球蛋白进行比较。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。A的证词？在使用常规免疫球蛋白观察到的血管中不太可能是因为A？被催化的免疫球蛋白消化。我们已经确定了适合作为AD药物进一步开发的催化Ig可变区(IgV)。我们将应用蛋白质工程方法来制备稳定性更好、免疫原性更低的催化IGV衍生物，适合人体使用。生成的免疫球蛋白将根据催化速率和特异性进行表征。然后，他们将接受疗效测试(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适合AD治疗的试剂。

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.