Service de Médecine Interne Immunologie Clinique, CHU de Tours, F-37032 Tours, France.
EA7501, GICC, Faculté de Médecine, Université de Tours, F-37032 Tours, France.
Int J Mol Sci. 2022 Aug 24;23(17):9604. doi: 10.3390/ijms23179604.
Understanding the biological mechanisms underlying the pH-dependent nature of FcRn binding, as well as the various factors influencing the affinity to FcRn, was concurrent with the arrival of the first recombinant IgG monoclonal antibodies (mAbs) and IgG Fc-fusion proteins in clinical practice. IgG Fc-FcRn became a central subject of interest for the development of these drugs for the comfort of patients and good clinical responses. In this review, we describe (i) mAb mutations close to and outside the FcRn binding site, increasing the affinity for FcRn at acidic pH and leading to enhanced mAb half-life and biodistribution, and (ii) mAb mutations increasing the affinity for FcRn at acidic and neutral pH, blocking FcRn binding and resulting, in vivo, in endogenous IgG degradation. Mutations modifying FcRn binding are discussed in association with pH-dependent modulation of antigen binding and (iii) anti-FcRn mAbs, two of the latest innovations in anti-FcRn mAbs leading to endogenous IgG depletion. We discuss the pharmacological effects, the biological consequences, and advantages of targeting IgG-FcRn interactions and their application in human therapeutics.
理解 FcRn 结合的 pH 依赖性的生物学机制，以及影响与 FcRn 亲和力的各种因素，与第一批重组 IgG 单克隆抗体（mAbs）和 IgG Fc 融合蛋白进入临床实践是同时发生的。IgG Fc-FcRn 成为开发这些药物的一个核心关注点，以提高患者的舒适度和获得良好的临床反应。在这篇综述中，我们描述了（i）接近和远离 FcRn 结合位点的 mAb 突变，增加了酸性 pH 下对 FcRn 的亲和力，导致 mAb 半衰期和生物分布的增强，以及（ii）增加了 mAb 在酸性和中性 pH 下对 FcRn 的亲和力，阻断 FcRn 结合，导致体内内源性 IgG 降解的突变。我们讨论了与 pH 依赖性抗原结合调节相关的 FcRn 结合修饰突变，以及（iii）抗 FcRn mAbs，这是抗 FcRn mAbs 的最新创新中的两种，导致内源性 IgG 耗竭。我们讨论了靶向 IgG-FcRn 相互作用的药理学作用、生物学后果和优势，及其在人类治疗学中的应用。
