Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
J Biol Chem. 2021 Jan-Jun;296:100057. doi: 10.1074/jbc.REV120.013168. Epub 2020 Nov 22.
The antibody-binding crystallizable fragment (Fc) γ receptors (FcγRs) are expressed by leukocytes and activate or suppress a cellular response once engaged with an antibody-coated target. Therapeutic mAbs that require FcγR binding for therapeutic efficacy are now frontline treatments for multiple diseases. However, substantially fewer development efforts are focused on the FcγRs, despite accounting for half of the antibody-receptor complex. The recent success of engineered cell-based immunotherapies now provides a mechanism to introduce modified FcγRs into the clinic. FcγRs are highly heterogeneous because of multiple functionally distinct alleles for many genes, the presence of membrane-tethered and soluble forms, and a high degree of post-translational modification, notably asparagine-linked glycans. One significant factor limiting FcγR improvement is the fundamental lack of knowledge regarding endogenous receptor forms present in the human body. This review describes the composition of FcγRs isolated from primary human leukocytes, summarizes recent efforts to engineer FcγRs, and concludes with a description of potential FcγR features to enrich for enhanced function. Further understanding FcγR biology could accelerate the development of new clinical therapies targeting immune-related disease.
抗体结合的可结晶片段 (Fc) γ 受体 (FcγRs) 由白细胞表达，一旦与抗体包被的靶标结合，就会激活或抑制细胞反应。需要 FcγR 结合才能发挥治疗效果的治疗性 mAbs 现已成为多种疾病的一线治疗方法。然而，尽管 FcγRs 占抗体-受体复合物的一半，但实际上开发工作的重点要少得多。最近基于细胞的工程免疫疗法的成功为将修饰的 FcγRs 引入临床提供了一种机制。由于许多基因的功能不同的等位基因、膜结合和可溶性形式的存在以及高度的翻译后修饰，特别是天冬酰胺连接的糖基化，FcγRs 高度异质。限制 FcγR 改进的一个重要因素是对人体内存在的内源性受体形式缺乏基本了解。这篇综述描述了从原代人白细胞中分离的 FcγRs 的组成，总结了最近工程 FcγRs 的努力，并以描述潜在的 FcγR 特征来富集增强功能结束。进一步了解 FcγR 生物学可以加速开发针对免疫相关疾病的新型临床治疗方法。
