Screening and Immunization: A Novel Approach to Tau Antibody Therapeutics

筛查和免疫：Tau 抗体治疗的新方法

• 批准号: 8718236
• 负责人: Jennifer Furman
• 金额: $ 5.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718236
• 关键词: Affect; Affinity; Age; Alzheimer' s Disease; American; Americas; Amyloid beta-Protein; Animals; Antibodies; Antibody Affinity; Antibody Formation; Antigens; B-Lymphocytes; Behavioral; Binding; Biological Assay; Blocking Antibodies; Brain; Cells; Clinical Trials; Cognition; Cognitive deficits; Dementia; Deposition; Detection; Development; Diamond; Disease; Effectiveness; Endocytosis; Enzyme-Linked Immunosorbent Assay; Epitopes; Exhibits; Extracellular Space; Fluorescence Resonance Energy Transfer; Future; Goals; Harvest; Human; Hybridomas; I-antigen; Image; Image Analysis; Immunization; Immunohistochemistry; Impaired cognition; In Vitro; Laboratories; Lead; Measurement; Measures; Molecular Conformation; Monitor; Monoclonal Antibodies; Mus; Neurodegenerative Disorders; Optics; Outcome Measure; Passive Immunization; Pathology; Patients; Physiological; Production; Proteins; Protocols documentation; Recombinants; Recovery of Function; Reliance; Seeds; Signal Transduction; Synapses; Synaptophysin; System; Tauopathies; Technology; Testing; Therapeutic; Therapeutic antibodies; Time; Work; antigen binding; base; brain tissue; cognitive function; conditioned fear; drebrins; effective therapy; improved; in vivo; innovation; monoclonal antibody production; novel; novel strategies; novel therapeutics; peptide A; prion-like; public health relevance; research study; screening; tau Proteins; tau aggregation; therapeutic development

DESCRIPTION (provided by applicant): Approximately 5.3 million Americas currently suffer from Alzheimer's disease and, in the absence of effective treatments, this number is expected to balloon to over 14 million by the year 2050. Current immunization studies targeting A? pathology have been largely unsuccessful at stabilizing or restoring cognitive deficits, suggesting that they do not target the proper species: tau. By the time patients are showing signs of dementia, tau pathology is likely to be the principal driver of disease, not A?. A major limitation to current tau antibody therapeutic strategies is the reliance on linear epitope binding for screening, selection, and production of novel antibodies. In this manner, physiologically-relevant tau species may not be targeted. My central hypothesis is that the field of anti-tau antibody development can be improved by two separate means: by employing novel screening technology for selection of monoclonal antibodies and by optimizing immunization antigens for production of monoclonal antibodies. The main goals of this proposal are 1) to determine whether a correlation exists between efficacy of blocking tau seeding in vitro and functional recovery in vivo, as suggested in a recent study by the Diamond and Holtzman Laboratories (Yanamandra et al., in press) and 2) to investigate novel tau aggregates for animal immunization. Aim 1 will test if inhibition of tau seeding in vitro predicts in vivo efficacy. A lage panel of pre-existing antibodies will be screened for their capacity to inhibit tau seeding using two separate aggregation detection assays. Six antibodies will be chosen, over a range of efficacies, for in vivo administration into mid- to late-age P301S mice. After either 6 or 18 weeks of treatment, animals will be assessed pathologically (with immunohistochemistry and ELISA), behaviorally (with fear conditioning), and synaptically (with functional connectivity and optical intrinsic signal imaging) to determine if tau seeding inhibition is predictive of functional recovey. Aim 2 will develop novel anti-tau antibodies from a panel of tau antigens. Recombinant or human-derived tau aggregates of variable sizes (large fibrils, trimer, ~10mer, ~20mer, ~40mer) will be used to immunize mice, and resultant antibodies will be screened for antigen-binding capacity and tau seeding inhibition. Per antigen, six antibodies will be selected for purification and use in future studies outside the scope of this proposal. Cumulatively, it is expected that thi proposal will produce antibodies superior to those currently available because of our innovative approach for targeting tau seeds or seeding activity, rather than linear epitopes. The completion of these Aims will have a significant and direct impact on the development of future novel AD therapeutics.

描述（由申请人提供）：目前约有530万美国人患有阿尔茨海默病，在缺乏有效治疗的情况下，预计到2050年，这一数字将激增至1400万以上。目前针对A？病理学在稳定或恢复认知缺陷方面基本上是不成功的，这表明它们不靶向适当的物种：tau。当患者出现痴呆症状时，tau病理学可能是疾病的主要驱动因素，而不是A？。当前tau抗体治疗策略的主要限制是依赖于线性表位结合 用于筛选、选择和生产新型抗体。以这种方式，生理学相关的tau种类可能不会被靶向。我的中心假设是，抗tau抗体开发领域可以通过两种独立的手段来改善：通过采用新的筛选技术来选择单克隆抗体，以及通过优化免疫抗原来生产单克隆抗体。该提议的主要目标是1）确定在体外阻断tau接种的功效与体内功能恢复之间是否存在相关性，如Diamond和Holtzman实验室的最近研究中所建议的（Yanamandra等人，出版中）和2）研究用于动物免疫的新型tau聚集体。目的1将测试体外tau接种的抑制是否预测体内功效。将使用两种单独的聚集检测测定筛选一组拉格预先存在的抗体抑制tau接种的能力。将在一系列功效中选择六种抗体用于体内施用至中至晚龄P301 S小鼠中。6周或18周后 在治疗后，将对动物进行病理学（用免疫组织化学和ELISA）、行为学（用恐惧条件反射）和突触学（用功能连接和光学固有信号成像）评估，以确定tau接种抑制是否预测功能恢复。目的2将从一组tau抗原开发新的抗tau抗体。可变大小的重组或人源tau聚集体（大原纤维、三聚体、~ 10聚体、~ 20聚体、~ 40聚体）将用于免疫小鼠，并且将筛选所得抗体的抗原结合能力和tau接种抑制。对于每种抗原，将选择6种抗体进行纯化，并用于本提案范围以外的未来研究。累积地，预期该提议将产生上级目前可用的那些抗体的抗体，因为我们的用于靶向tau种子或接种活性而不是线性表位的创新方法。这些目标的完成将对未来新型AD治疗药物的开发产生重大而直接的影响。