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

项目总结/文摘

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.