Vectorized scFv antibodies to treat tau pathology in Alzheimer's disease: enhancing epitope targeting and delivery strategies

用于治疗阿尔茨海默氏病 tau 病理的矢量化 scFv 抗体：增强表位靶向和递送策略

• 批准号: 10260598
• 负责人: Cristina d'Abramo
• 金额: $ 41.88万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260598
• 关键词: Adopted; Adult; Adverse event; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Antibodies; Antigen-Antibody Complex; Blood - brain barrier anatomy; Brain; Cells; Characteristics; Clinical Trials; Cognitive; Complex; Data; Dependovirus; Development; Disease Progression; Dose; Effectiveness; Engineering; Epitopes; Excision; Extracellular Protein; Fc Immunoglobulins; Functional disorder; Goals; Hippocampus (Brain); Human; Immunoglobulin Variable Region; Immunotherapy; Impaired cognition; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injections; Intramuscular; Intramuscular Injections; Laboratories; Light; Literature; Mediating; Microglia; Modeling; Molecular Conformation; Monoclonal Antibodies; Mus; Muscle; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Parents; Passive Immunization; Passive Immunotherapy; Pathologic; Pathology; Peripheral; Pharmacology; Phosphorylation; Play; Prevention; Process; Protocols documentation; Publishing; Reaction; Recombinants; Role; Route; Source; Specificity; Tauopathies; Testing; Therapeutic; Time; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Translating; Treatment Efficacy; Viral Vector; Work; adeno-associated viral vector; base; behavioral outcome; behavioral phenotyping; blood-brain barrier crossing; blood-brain barrier penetration; cost; cost effective; design; extracellular; hyperphosphorylated tau; mouse model; novel therapeutic intervention; preservation; prevent; response; success; targeted delivery; tau Proteins; tau aggregation; tau conformation; therapeutically effective; tool; translational approach; uptake; vector

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 appeared as an appropriate approach to clear neurofibrillary tangles in AD models. A conspicuous amount of data has been produced by different laboratories showing reduction of tau pathology in transgenic animal models using tau monoclonal antibodies, with a different degree of success according to which epitopes were targeted. Unfortunately, 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 this application, we will employ scFv (single chain variable fragments), to target pathological tau. scFv are composed of the variable regions of the heavy and light chains of antibodies, joined by a short linker, preserving the epitope specificity and affinity of the parent monoclonal antibodies (mAb), but with a much smaller size and reduced chance of triggering unwanted inflammatory responses. scFv expression will be driven by viral vectors (adeno-associated virus, AAV) after intracerebral or intramuscular injection. Our published data show that intracranial administration of vectorized scFv-MC1, the recombinant version of the native anti-tau conformational mAb MC1, significantly reduces brain pathological tau species in adult tau transgenic JNPL3 mice. Here, we will try to further potentiate the therapeutic efficacy of scFv-MC1 preventing tau accumulation (prevention paradigm) and reducing established tau pathology (reversion protocol): we will employ an epitope- based dual therapy, combining scFv-MC1 with scFv directed against other tau epitopes, according to what observed in AD pathophysiology. We will also adopt a dual delivery strategy, intracranial or intramuscular, fulfilling both a proof of concept and a translational approach. Finally, our data show that microglia have a role in up-taking the scFv-tau complex and can degrade it, without an overt inflammatory response. Here, we will deepen our understanding of the role of microglia in this process. The overall objective of this proposal is to develop and characterize a novel therapeutic approach for AD and tauopathies, with the goal to advance peripheral administration of engineered anti-tau antibodies, which will have relevant translational potential.

项目总结/文摘