阻断人 FcRn 可降低循环 IgG 水平并抑制 IgG 免疫复合物介导的免疫应答。

Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.

机构信息

Syntimmune Inc., Boston, MA 02116, USA.

Biologics Consulting, Alexandria, VA 22314, USA.

出版信息

Sci Adv. 2019 Dec 18;5(12):eaax9586. doi: 10.1126/sciadv.aax9586. eCollection 2019 Dec.

DOI:10.1126/sciadv.aax9586

PMID:31897428

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6920022/

Abstract

The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.

摘要

新生儿晶型片段受体（FcRn）作为免疫球蛋白 G（IgG）的细胞内保护受体发挥作用。最近，几项临床研究报告通过 FcRn 阻断降低循环单体 IgG 水平，从而有可能治疗自身免疫性疾病。然而，许多自身免疫性疾病都源于 IgG 免疫复合物（ICs）的影响。我们在小鼠、非人灵长类动物（NHPs）和人类中生成、表征和评估了 SYNT001（一种 FcRn 阻断单克隆抗体）的效果。正如我们在首次人体 I 期、单次递增剂量研究中所展示的，SYNT001 降低了人类循环中的所有 IgG 亚型和 IgG IC。此外，IgG IC 诱导的炎症途径依赖于 FcRn 并被 SYNT001 抑制。这些研究通过表明 FcRn 不仅控制 IgG 免受代谢破坏的保护，还控制与涉及多种自身免疫性疾病的 IgG IC 相关的炎症途径，从而扩展了 FcRn 在人类中的作用。