Human antibodies recognizing oligomeric tau

识别寡聚 tau 蛋白的人类抗体

基本信息

批准号：
9896514
负责人：
Yongku Peter Cho
金额：
$ 44.28万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896514
关键词：
Acetylation Address Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Antibodies Antibody Affinity Antibody Specificity Antigens Binding Brain Cells Clinical Complementarity Determining Regions Detection Discrimination Disease Progression Distant Engineering Epitopes Equilibrium Future Human Immunoglobulin Somatic Hypermutation Immunoglobulins Immunohistochemistry In Vitro Injections Insertion Mutation Lead Length Lysine Major Histocompatibility Complex Mass Spectrum Analysis Measures Mediating Molecular Conformation Molecular Profiling Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Oligonucleotides Outcome Study Pathology Patients Pattern Peptides Phosphorylation Post-Translational Modification Site Post-Translational Protein Processing Process Recombinants Sampling Scheme Serine Site Source Specificity Stretching Structure T-Cell Receptor Tauopathies Techniques Testing Therapeutic Intervention Threonine Tissues Toxic effect Transgenic Mice Translating Variant Western Blotting Wild Type Mouse Work antibody engineering antibody libraries base diagnostic biomarker experimental study extracellular immunocytochemistry improved in vivo insight mouse model mutant novel receptor binding screening tau Proteins tau aggregation therapeutic development tool transmission process

项目摘要

Soluble, pre-fibrillar oligomeric tau (oligo-tau) has been identified as a major source of neurodegeneration in tauopathies. Injection of oligo-tau in wild-type and transgenic mice induces tau pathology, and propagates toxicity through cell-to-cell transmission. Antibodies specific to oligo-tau are an essential tool for mechanistic studies, and potential tools for diagnostic biomarkers as well as therapeutic intervention. This proposal aims to address three major limitations in existing anti-oligo-tau antibodies. First, all known oligo-tau antibodies are mouse immunoglobulins. This limit translating existing results from oligo-tau antibodies in humans, in particular to study antibody-mediated inhibition of cell-to-cell transmission. Second is the lack of high affinity oligo-tau antibodies. In mouse models of AD, only a small fraction of tau is oligomerized, and it is estimated that even smaller fraction would be found extracellularly. Antibodies that can engage these trace amounts of oligo-tau would lead to detection in clinical samples and potentially inhibition of cell-to-cell transmission. Finally, further distinction of oligo-tau species based on molecular signature would be necessary. Many distinct toxic soluble tau strains are known to exist in brain homogenates, and they induce distinct patterns of pathology and propagation. In particular, considering that post-translational modifications (PTMs) such as site-specific phosphorylation and acetylation have been also associated with disease progression, classifying oligo-tau based on PTM state would lead to novel insights. This proposal aims to address these challenges by developing high affinity human antibodies targeting oligo-tau. Based on the evidence that existing oligo- tau specific or conformation-specific antibodies recognize discontinuous epitopes, we hypothesize that recognizing discontinuous epitopes within tau would be critical for oligomer specificity. We will develop a novel antibody engineering strategy that mimics the somatic hypermutation process to enable the recognition of discontinuous epitopes, leading to high affinity without compromising antibody specificity.

可溶性，原纤维寡聚tau（寡核-tau）已被确定为神经变性的主要来源 tauopathies。在野生型和转基因小鼠中注射寡-TAU会诱导tau病理，并传播通过细胞到细胞传播的毒性。寡核-tau的抗体是机械的必不可少的工具研究以及诊断生物标志物以及治疗干预的潜在工具。该提议的目的解决现有抗oligo-TAU抗体的三个主要局限性。首先，所有已知的寡核-tau抗体均为小鼠免疫球蛋白。这种限制转化了人类中的寡-tau抗体的现有结果，特定研究抗体介导的细胞对细胞传播的抑制作用。第二是缺乏高亲和力寡-TAU抗体。在AD的鼠标模型中，仅将一小部分tau降低，并且估计将在细胞外发现甚至较小的部分。可以参与这些痕量的抗体 Oligo-Tau将导致在临床样品中检测并可能抑制细胞向细胞传播。最后，需要基于分子特征的寡-TAU物种进一步区分。许多已知在脑匀浆中存在明显的有毒可溶性tau菌株，它们诱导了不同的模式病理和传播。特别是考虑到翻译后修改（PTM），例如位点特异性的磷酸化和乙酰化也与疾病进展有关，分类基于PTM状态的Oligo-Tau将导致新颖的见解。该建议旨在应对这些挑战通过开发针对寡核-tau的高亲和力人类抗体。基于证据表明现有的寡聚特异性或构象特异性抗体识别不连续的表位，我们假设识别tau内的不连续表位对于低聚物特异性至关重要。我们将发展一本小说抗体工程策略，模仿躯体超突变过程，以使人们能够识别不连续的表位，导致高亲和力而不会损害抗体特异性。