Nix Matthew A, Wiita Arun P
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA; Cartography Biosciences, South San Francisco, California, USA.
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA; Chan Zuckerberg Biohub San Francisco, San Francisco, California, USA; Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.
Cytotherapy. 2024 Jul;26(7):729-738. doi: 10.1016/j.jcyt.2024.02.024. Epub 2024 Mar 2.
Chimeric antigen receptor T (CAR-T) cells are a remarkably efficacious, highly promising and rapidly evolving strategy in the field of immuno-oncology. The precision of these targeted cellular therapies is driven by the specificity of the antigen recognition element (the "binder") encoded in the CAR. This binder redirects these immune effector cells precisely toward a defined antigen on the surface of cancer cells, leading to T-cell receptor-independent tumor lysis. Currently, for tumor targeting most CAR-T cells are designed using single-chain variable fragments (scFvs) derived from murine or human immunoglobulins. However, there are several emerging alternative binder modalities that are finding increasing utility for improved CAR function beyond scFvs.
Here we review the most recent developments in the use of non-canonical protein binding domains in CAR design, including nanobodies, DARPins, natural ligands, and de novo-designed protein elements.
Overall, we describe how new protein binder formats, with their unique structural properties and mechanisms of action, may possess key advantages over traditional scFv CAR designs.
These alternative binder designs may contribute to enhanced CAR-T therapeutic options and, ultimately, improved outcomes for cancer patients.
嵌合抗原受体T（CAR-T）细胞是免疫肿瘤学领域一种极其有效、前景广阔且发展迅速的策略。这些靶向细胞疗法的精准性由CAR中编码的抗原识别元件（“结合物”）的特异性驱动。这种结合物将这些免疫效应细胞精确地重定向至癌细胞表面的特定抗原，导致不依赖T细胞受体的肿瘤溶解。目前，对于肿瘤靶向，大多数CAR-T细胞是使用源自鼠源或人源免疫球蛋白的单链可变片段（scFv）设计的。然而，有几种新兴的替代结合物模式在改善CAR功能方面的应用越来越多，其作用超出了scFv。
在此，我们综述了在CAR设计中使用非经典蛋白质结合域的最新进展，包括纳米抗体、亲环素结合蛋白、天然配体和从头设计的蛋白质元件。
总体而言，我们描述了新的蛋白质结合物形式如何凭借其独特的结构特性和作用机制，可能比传统的scFv CAR设计具有关键优势。
这些替代结合物设计可能有助于增加CAR-T治疗选择，并最终改善癌症患者的治疗效果。
