Human antibodies recognizing oligomeric tau

可溶性前纤维状寡聚tau蛋白（oligo-tau）已被鉴定为神经变性的主要来源， tau蛋白病在野生型和转基因小鼠中注射寡聚tau蛋白诱导tau蛋白病理学， 通过细胞间传递产生毒性。寡聚tau蛋白特异性抗体是一种重要的机制工具， 研究，以及诊断生物标志物和治疗干预的潜在工具。这项建议旨在 以解决现有抗寡聚tau抗体的三个主要局限性。首先，所有已知的寡聚tau抗体都是 小鼠免疫球蛋白。这限制了在人类中翻译来自寡聚tau抗体的现有结果， 特别是研究抗体介导的细胞间传递抑制。其次是缺乏高亲和力 寡-tau抗体。在AD的小鼠模型中，只有一小部分tau是寡聚化的，并且据估计， 甚至更小的部分会在细胞外被发现。抗体可以与这些微量的 寡-tau将导致在临床样品中的检测和潜在地抑制细胞到细胞的传递。 最后，基于分子特征的寡聚tau种类的进一步区分将是必要的。许多 已知不同的毒性可溶性tau菌株存在于脑匀浆中，并且它们诱导不同的模式， 病理学和传播学。特别是，考虑到翻译后修饰（PTM），如 位点特异性磷酸化和乙酰化也与疾病进展有关， 基于PTM状态的oligo-tau将导致新的见解。本提案旨在应对这些挑战 通过开发靶向寡tau的高亲和力人抗体。根据现有的证据， tau特异性或构象特异性抗体识别不连续表位，我们假设， 识别tau内的不连续表位对于寡聚体特异性是至关重要的。我们要写一部小说 抗体工程策略，其模拟体细胞超突变过程以使得能够识别 不连续的表位，导致高亲和力而不损害抗体特异性。

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.