Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.
Document Type
Article
Publication Date
12-18-2019
Keywords
JMG
JAX Source
Sci Adv 2019 Dec 18; 5(12):eaax9586
Volume
5
Issue
12
First Page
9586
Last Page
9586
ISSN
2375-2548
PMID
31897428
DOI
https://doi.org/10.1126/sciadv.aax9586
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.
Recommended Citation
Blumberg L,
Humphries J,
Jones S,
Pearce L,
Holgate R,
Hearn A,
Cheung J,
Mahmood A,
Del Tito B,
Graydon J,
Stolz L,
Bitonti A,
Purohit S,
de Graaf D,
Kacena K,
Andersen J,
Christianson GJ,
Roopenian DC,
Hubbard J,
Gandhi A,
Lasseter K,
Pyzik M,
Blumberg R.
Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses. Sci Adv 2019 Dec 18; 5(12):eaax9586