Sigurdsson Einar M
Departments of Neuroscience and Physiology, and Psychiatry, New York University School of Medicine, New York, N.Y., USA.
Neurodegener Dis. 2016;16(1-2):34-8. doi: 10.1159/000440842. Epub 2015 Nov 10.
In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-β (Aβ) pathology, greater clinical efficacy may be achieved by clearing tau than Aβ aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects.
近年来，tau免疫疗法已从概念验证研究（[西格德松EM，美国国立卫生研究院R01AG020197，2001年；阿苏尼AA等人：《神经科学杂志》2007年；27：9115 - 9129]）发展而来，我们和其他人现已对这些研究进行了证实和拓展。目前正在开展关于主动和被动tau免疫接种的I期临床试验，近期可能还会启动多项针对阿尔茨海默病和其他tau蛋白病的被动tau抗体试验。由于tau蛋白病变比淀粉样β蛋白（Aβ）病变与痴呆程度的相关性更好，在疾病后期认知障碍明显时，清除tau蛋白可能比清除Aβ聚集体能取得更大的临床疗效。目前已在靶向哪些表位、作用机制和潜在毒性方面获得了大量见解，但仍有许多有待阐明。所有这些因素可能都取决于模型/疾病或病理阶段以及免疫原/抗体。有趣的是，tau抗体可在细胞外和细胞内与该蛋白相互作用，但每个位点对tau蛋白清除的重要性尚未明确界定。一些抗体很容易被神经元摄取，而其他抗体则不然。可以说，细胞外清除可能比神经元内清除和/或隔离更安全，但在防止tau蛋白病变的分泌和进一步扩散方面效果较差。治疗性tau抗体的开发已催生了基于抗体的成像探针，其比已在临床试验中的基于染料的化合物更具特异性。这种特异性可能会提供有关病理性tau表位谱的有价值信息，进而指导选择治疗性抗体以实现最大疗效和安全性。有望tau免疫疗法在临床试验中取得成效，并通过实验模型中的机制阐明、生物标志物的见解以及临床受试者的尸检分析得到进一步推进。
