Yong Joon Kim Jeffrey, Sang Zhe, Xiang Yufei, Shen Zhuolun, Shi Yi
Center of Protein Engineering and Therapeutics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1, Gustave L. Levy Pl, New York, NY 10029, USA; Medical Scientist Training Program, University of Pittsburgh School of Medicine and Carnegie Mellon University, Pittsburgh, PA, USA.
Center of Protein Engineering and Therapeutics, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1, Gustave L. Levy Pl, New York, NY 10029, USA.
Adv Drug Deliv Rev. 2023 Apr;195:114726. doi: 10.1016/j.addr.2023.114726. Epub 2023 Feb 7.
Variable domains of heavy chain-only antibodies (VH), also known as nanobodies (Nbs), are monomeric antigen-binding domains derived from the camelid heavy chain-only antibodies. Nbs are characterized by small size, high target selectivity, and marked solubility and stability, which collectively facilitate high-quality drug development. In addition, Nbs are readily expressed from various expression systems, including E. coli and yeast cells. For these reasons, Nbs have emerged as preferred antibody fragments for protein engineering, disease diagnosis, and treatment. To date, two Nb-based therapies have been approved by the U.S. Food and Drug Administration (FDA). Numerous candidates spanning a wide spectrum of diseases such as cancer, immune disorders, infectious diseases, and neurodegenerative disorders are under preclinical and clinical investigation. Here, we discuss the structural features of Nbs that allow for specific, versatile, and strong target binding. We also summarize emerging technologies for identification, structural analysis, and humanization of Nbs. Our main focus is to review recent advances in using Nbs as a modular scaffold to facilitate the engineering of multivalent polymers for cutting-edge applications. Finally, we discuss remaining challenges for Nb development and envision new opportunities in Nb-based research.
仅重链抗体的可变区（VH），也称为纳米抗体（Nb），是源自骆驼科仅重链抗体的单体抗原结合结构域。纳米抗体的特点是尺寸小、靶标选择性高、具有显著的溶解性和稳定性，这些共同促进了高质量药物的开发。此外，纳米抗体很容易在包括大肠杆菌和酵母细胞在内的各种表达系统中表达。由于这些原因，纳米抗体已成为蛋白质工程、疾病诊断和治疗中首选的抗体片段。迄今为止，已有两种基于纳米抗体的疗法获得了美国食品药品监督管理局（FDA）的批准。众多针对癌症、免疫紊乱、传染病和神经退行性疾病等广泛疾病的候选药物正处于临床前和临床研究阶段。在此，我们讨论了纳米抗体的结构特征，这些特征使其能够实现特异性、多功能和强靶向结合。我们还总结了纳米抗体鉴定、结构分析和人源化的新兴技术。我们主要关注的是回顾利用纳米抗体作为模块化支架促进用于前沿应用的多价聚合物工程的最新进展。最后，我们讨论了纳米抗体开发中仍然存在的挑战，并展望了基于纳米抗体研究的新机遇。
