Vectorized scFv antibodies to treat tau pathology in Alzheimers disease enhancing epitope targeting and delivery strategies

项目总结/摘要 越来越多的证据支持tau蛋白作为细胞外蛋白的存在，以及其跨细胞的概念。 传播作为阿尔茨海默病（AD）的起始和进展的机制。在这种情况下，使用 靶向tau病理学的抗体似乎是清除AD中神经元缠结的适当方法 模型在临床前模型中，常规tau免疫疗法仅实现了tau的不完全清除 并在潜在炎症不良事件，长期可持续性， 合规性和成本。此外，有效的血脑屏障渗透和正确的tau表位的选择是有效的。 仍然是公开辩论的主题。在临床试验中，针对tau蛋白N末端的几种抗体没有发挥作用。 在前驱/早发AD或其他tau蛋白病受试者中的任何获益，提出了是否 所使用的抗体在正确的时间接合正确的tau表位。最近的一些研究 在体外和临床前模型中，证明了靶向中心tau表位在预防 tau播种和繁殖。在此补充申请中，我们将运用我们在 抗tau单克隆抗体及其重组变体的产生和处理 免疫疗法在这里，我们提出产生新的抗tau抗体，测序，并将它们转化为scFv， 拓宽tau免疫治疗管道的意图。

PROJECT SUMMARY/ABSTRACT Increasing evidence supports the existence of tau as an extracellular protein, and the concept of its trans-cellular propagation as a mechanism for the initiation and progression of Alzheimer's disease (AD). In this context, using antibodies to target tau pathology appears as an appropriate approach to clear neurofibrillary tangles in AD models. In preclinical models, conventional tau immunotherapy has achieved only incomplete clearance of tau pathology and presents limitations in terms of potential inflammatory adverse events, long-term sustainability, compliance and costs. Also, effective blood brain barrier penetration and choice of the correct tau epitope are still subject of an open debate. In clinical trials, several antibodies directed against tau’s N-terminus did not exert any benefit in participants with prodromal/early onset AD or other tauopathies, raising the question as to whether the antibodies in use are engaging the right epitope of tau at the right time. Some recent studies have demonstrated, in in vitro and preclinical models, the advantage of targeting central-tau epitopes in preventing tau seeding and propagation. In this supplement application, we will apply our extensive experience in the generation and handling of anti-tau monoclonal antibodies and their recombinant variants in the context of immunotherapy. Here we propose to generate new anti-tau antibodies, sequence, and turn them into scFv with the intent to broaden the tau immunotherapy-pipeline.