Miller Todd W, Messer Anne
Wadsworth Center, New York State Department of Health, and Department of Biomedical Sciences, University at Albany, Albany, NY 12201, USA.
Mol Ther. 2005 Sep;12(3):394-401. doi: 10.1016/j.ymthe.2005.04.003.
Single-chain Fv and single-domain antibodies retain the binding specificity of full-length antibodies, but they can be expressed as single genes in phage or yeast surface-display libraries, thus allowing efficient in vitro selection from a naive human repertoire. Selected genes can then be expressed intracellularly in mammalian cells as intrabodies, with the potential for alteration of the folding, interactions, modifications, or subcellular localization of their targets. These reagents have been developed as therapeutics against cancer and HIV. Since misfolded and accumulated intracellular proteins characterize a wide range of neurodegenerative disorders, they are also potentially useful intrabody targets. Here, we review the extension of intrabody technology to the nervous system, in which studies of Huntington's disease have been used to develop the approach, and anti-synuclein and -beta-amyloid strategies are in the early stages of development. Research on several other neurodegenerations, including Parkinson's, Alzheimer's, and prion diseases, provides support for the development of intrabodies directed against specific targets, or possibly against more common downstream targets, as novel therapeutics and as drug discovery tools.
单链Fv抗体和单域抗体保留了全长抗体的结合特异性，但它们可以作为单个基因在噬菌体或酵母表面展示文库中表达，从而能够从天然人类抗体库中进行高效的体外筛选。然后，所选基因可以在哺乳动物细胞内作为细胞内抗体表达，有可能改变其靶标的折叠、相互作用、修饰或亚细胞定位。这些试剂已被开发用于治疗癌症和艾滋病病毒。由于错误折叠并积累的细胞内蛋白质是多种神经退行性疾病的特征，它们也是潜在有用的细胞内抗体靶标。在这里，我们综述了细胞内抗体技术在神经系统中的扩展应用，其中对亨廷顿舞蹈病的研究已用于开发该方法，而抗突触核蛋白和抗β-淀粉样蛋白策略正处于早期开发阶段。对包括帕金森病、阿尔茨海默病和朊病毒病在内的其他几种神经退行性疾病的研究，为开发针对特定靶标或可能针对更常见下游靶标的细胞内抗体作为新型治疗方法和药物发现工具提供了支持。
