Human antibodies recognizing oligomeric tau

可溶性纤维前寡聚体tau(寡聚tau)已被确定为神经退行性变的主要来源。 紧张症。在野生型和转基因小鼠中注射寡聚tau诱导tau病理，并 通过细胞间传播的毒性。针对寡聚-tau的抗体是一种重要的机械性工具 研究，以及用于诊断生物标记物和治疗干预的潜在工具。这项提议旨在 以解决现有的抗寡聚tau抗体的三个主要局限性。首先，所有已知的寡核苷酸抗体都是 小鼠免疫球蛋白。这一限制翻译了现有的人类寡tau抗体结果，在 特别是研究抗体介导的抑制细胞间传播的作用。二是缺乏高亲和力 寡头蛋白抗体。在阿尔茨海默病的小鼠模型中，只有一小部分tau被寡聚，据估计 这一更小的比例将在细胞外找到。这些抗体可以结合这些微量的 寡聚-tau将导致在临床样本中检测到，并可能抑制细胞间的传播。 最后，根据分子特征进一步区分寡头物种是必要的。许多 已知在脑匀浆中存在不同的有毒可溶性tau菌株，它们可以诱导不同的模式 病理学和传播学。特别是，考虑到翻译后修改(PTM)，例如 特定部位的磷酸化和乙酰化也与疾病的进展有关，分类 基于PTM态的寡头-tau将带来新的见解。本提案旨在应对这些挑战 通过开发针对寡头蛋白的高亲和力人类抗体。基于现有的寡头- Tau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中不连续的表位对于寡聚体的特异性至关重要。我们将写一部小说 抗体工程策略，模拟体细胞超突变过程，使识别 不连续的表位，导致高亲和力而不影响抗体特异性。

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.