Background:As a consequence of the discovery of an extracellular component responsible for the progression of tau pathology, tau immunotherapy is being extensively explored in both preclinical and clinical studies as a disease modifying strategy for the treatment of Alzheimer’s disease. Objective:Describe the characteristics of the anti-phospho (T212/T217) tau selective antibody PT3 and its humanized variant hPT3. Methods:By performing different immunization campaigns, a large collection of antibodies has been generated and prioritized. In depth, in vitro characterization using surface plasmon resonance, phospho-epitope mapping, and X-ray crystallography experiments were performed. Further characterization involved immunohistochemical staining on mouse- and human postmortem tissue and neutralization of tau seeding by immunodepletion assays. Results and Conclusion:Various in vitro experiments demonstrated a high intrinsic affinity for PT3 and hPT3 for AD brain-derived paired helical filaments but also to non-aggregated phospho (T212/T217) tau. Further functional analyses in cellular and in vivo models of tau seeding demonstrated almost complete depletion of tau seeds in an AD brain homogenate. Ongoing trials will provide the clinical evaluation of the tau spreading hypothesis in Alzheimer’s disease.

中文翻译：

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人源化抗磷酸 Tau 选择性单克隆抗体 hPT3 的发现和功能表征。

背景：由于发现了导致 tau 病理学进展的细胞外成分，因此在临床前和临床研究中都广泛探索了 tau 免疫疗法作为治疗阿尔茨海默病的疾病改善策略。目的：描述抗磷酸化（T212/T217）tau选择性抗体PT3及其人源化变体hPT3的特性。方法：通过执行不同的免疫活动，产生了大量抗体并确定了优先顺序。深入地，进行了使用表面等离子体共振、磷酸表位映射和 X 射线晶体学实验的体外表征。进一步的表征包括对小鼠和人类死后组织进行免疫组织化学染色，以及通过免疫耗竭试验中和 tau 种子。结果和结论：各种体外实验证明了对 PT3 和 hPT3 对 AD 脑源性成对螺旋丝以及非聚集磷酸 (T212/T217) tau 的高内在亲和力。在 tau 接种的细胞和体内模型中的进一步功能分析表明，AD 脑匀浆中的 tau 种子几乎完全耗尽。正在进行的试验将为阿尔茨海默病中的 tau 传播假说提供临床评估。