Abstract：
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.
摘要：
了解FcRn结合的pH依赖性本质的生物学机制，以及影响与FcRn亲和力的各种因素，与第一个重组IgG单克隆抗体（mAb）和IgGFc融合蛋白在临床实践中的到来同时发生。IgGFc-FcRn成为开发用于患者舒适和良好临床反应的这些药物的关注的中心主题。在这次审查中,我们描述了（i）在FcRn结合位点附近和外部的mAb突变，在酸性pH下增加对FcRn的亲和力，并导致mAb半衰期和生物分布增强，和（ii）在酸性和中性pH下增加对FcRn的亲和力的mAb突变，阻断FcRn结合并产生，在体内，内源性IgG降解。讨论了修饰FcRn结合的突变与抗原结合的pH依赖性调节和（iii）抗FcRnmAb，抗FcRnmAb的两项最新创新导致内源性IgG消耗。我们讨论药理作用，生物学后果，靶向IgG-FcRn相互作用的优势及其在人类治疗中的应用。
