Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom; Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands.
Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands.
Int Rev Cell Mol Biol. 2022;369:45-70. doi: 10.1016/bs.ircmb.2022.05.001. Epub 2022 May 30.
The recent clinical approval of different Bi-specific antibodies (BsAbs) has revealed the great therapeutic potential of this novel class of biologicals. For example, the bispecific T-cell engager (BiTE), Blinatumomab, demonstrated the unique capacity of BsAbs to link T-cells with tumor cells, inducing targeted tumor cell removal. Additionally, Amivantamab, recognizing the EGFR and cMet in cis, revealed a substantial improvement of therapeutic efficacy by concomitantly targeting two tumor antigens. Cis-targeting BsAbs furthermore allow discerning cell populations which concurrently express two antigens, for which each antigen expression pattern in itself might not be selective. In this way, BsAbs harbor the great prospect of being more specific and showing fewer side effects than monoclonal antibodies. Nevertheless, BsAbs have also faced major obstacles, for instance, in ensuring reliable assembly and clinical-grade purification. In this review, we summarize the different available antibody platforms currently used for the generation of IgG-like and non-IgG-like BsAbs and explain which approaches have been used to assemble those BsAbs which are currently approved for clinical application. By focusing on the example of regulatory T-cells (Tregs) and the different, ongoing approaches to develop BsAbs specifically targeting Tregs within the tumor microenvironment, our review highlights the huge potential as well as the pitfalls BsAb face in order to emerge as one of the most effective therapeutic biologicals targeting desired cell populations in a highly selective way. Such BsAb may improve treatment efficacy and reduce side effects, thereby opening novel treatment opportunities for a range of different diseases, such as cancer or autoimmune diseases.
最近不同双特异性抗体（BsAbs）的临床批准揭示了这类新型生物制剂的巨大治疗潜力。例如，双特异性 T 细胞衔接器（BiTE）blinatumomab 显示了 BsAbs 将 T 细胞与肿瘤细胞连接的独特能力，诱导靶向肿瘤细胞清除。此外，同时识别 EGFR 和 cMet 的 amivantamab 通过同时靶向两个肿瘤抗原，显示出治疗效果的显著改善。顺式靶向 BsAbs 还允许区分同时表达两种抗原的细胞群体，对于这些细胞群体，每个抗原表达模式本身可能不具有选择性。通过这种方式，BsAbs 具有比单克隆抗体更具特异性和更少副作用的巨大前景。然而，BsAbs 也面临着重大障碍，例如，确保可靠的组装和临床级别的纯化。在这篇综述中，我们总结了目前用于生成 IgG 样和非 IgG 样 BsAbs 的不同可用抗体平台，并解释了用于组装目前批准用于临床应用的 BsAbs 的方法。通过聚焦于调节性 T 细胞（Tregs）的例子以及开发专门针对肿瘤微环境中 Tregs 的 BsAbs 的不同方法，我们的综述强调了 BsAbs 面临的巨大潜力和陷阱，以便作为最有效的治疗性生物制剂之一，以高度选择性的方式针对所需的细胞群体。这种 BsAb 可能会提高治疗效果并减少副作用，从而为一系列不同疾病（如癌症或自身免疫性疾病）开辟新的治疗机会。
