UK Dementia Research Institute at the University of Cambridge, Department of Clinical Neurosciences, Cambridge, UK.
UK Dementia Research Institute at the University of Cambridge, Department of Clinical Neurosciences, Cambridge, UK.
Semin Cell Dev Biol. 2022 Jun;126:138-149. doi: 10.1016/j.semcdb.2021.09.012. Epub 2021 Oct 13.
Antibodies mediate the majority of their effects in the extracellular domain, or in intracellular compartments isolated from the cytosol. Under a growing list of circumstances, however, antibodies are found to gain access to the cytoplasm. Cytosolic immune complexes are bound by the atypical antibody receptor TRIM21, which mediates the rapid degradation of the immune complexes at the proteasome. These discoveries have informed the development of TRIM-Away, a technique to selectively deplete proteins using delivery of antibodies into cells. A range of related approaches that elicit selective protein degradation using intracellular constructs linking antibody fragments to degradative effector functions have also been developed. These methods hold promise for inducing the degradation of proteins as both research tools and as a novel therapeutic approach. Protein aggregates are a pathophysiological feature of neurodegenerative diseases and are considered to have a causal role in pathology. Immunotherapy is emerging as a promising route towards their selective targeting, and a role of antibodies in the cytosol has been demonstrated in cell-based assays. This review will explore the mechanisms by which therapeutic antibodies engage and eliminate intracellularly aggregated proteins. We will discuss how future developments in intracellular antibody technology may enhance the therapeutic potential of such antibody-derived therapies.
抗体在细胞外结构域或与细胞质隔离的细胞内隔室中发挥其大部分作用。然而，在越来越多的情况下，抗体被发现能够进入细胞质。细胞质免疫复合物被非典型抗体受体 TRIM21 结合，TRIM21 介导免疫复合物在蛋白酶体中的快速降解。这些发现为 TRIM-Away 的发展提供了信息，TRIM-Away 是一种使用将抗体递送到细胞内来选择性消耗蛋白质的技术。还开发了一系列使用将抗体片段与降解效应子功能连接的细胞内构建体来引发选择性蛋白降解的相关方法。这些方法有望作为研究工具和新型治疗方法诱导蛋白质的降解。蛋白质聚集体是神经退行性疾病的病理生理学特征，被认为在病理学中具有因果作用。免疫疗法作为一种有前途的靶向治疗方法正在出现，并且在基于细胞的测定中已经证明了抗体在细胞质中的作用。这篇综述将探讨治疗性抗体与细胞内聚集蛋白结合并消除它们的机制。我们将讨论细胞内抗体技术的未来发展如何增强此类抗体衍生疗法的治疗潜力。
