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

项目摘要/摘要 越来越多的证据支持tau作为一种胞外蛋白的存在，以及它跨细胞的概念。 传播是阿尔茨海默病(AD)发生和发展的一种机制。在这种情况下，使用 靶向tau病理的抗体似乎是清除AD患者神经原纤维缠结的合适方法 模特们。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。 并在潜在的炎症性不良事件、长期可持续性、 合规性和成本。此外，有效的血脑屏障穿透和选择正确的tau表位也是 仍然是一场公开辩论的主题。在临床试验中，针对tau‘s N-末端的几种抗体并不起作用 对患有前驱症状/早发性AD或其他肌萎缩侧索硬化症的参与者有任何益处，这引发了这样一个问题： 正在使用的抗体在正确的时间结合了正确的tau表位。最近的一些研究表明 在体外和临床前模型中，证明了以中央tau表位为靶点在预防 陶粒播种和繁殖。在本补充申请中，我们将把我们的丰富经验应用于 抗tau单抗及其重组变异体的产生和处理 免疫疗法。在这里，我们建议产生新的抗tau抗体，测序，并将它们转化为scFv 扩大tau免疫治疗渠道的意向。

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.