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

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

  • Sci Adv. 2019 Dec 18;5(12):eaax9586. doi: 10.1126/sciadv.aax9586.
L J Blumberg 1,  J E Humphries 2,  S D Jones 3,  L B Pearce 2,  R Holgate 4,  A Hearn 4,  J Cheung 5,  A Mahmood 5,  B Del Tito 2,  J S Graydon 1,  L E Stolz 1,  A Bitonti 1,  S Purohit 3,  D de Graaf 1,  K Kacena 6,  J T Andersen 7 8,  G J Christianson 9,  D C Roopenian 9,  J J Hubbard 10 11,  A K Gandhi 10,  K Lasseter 12,  M Pyzik 10,  R S Blumberg 10
Affiliations

Affiliations

  • 1 Syntimmune Inc., Boston, MA 02116, USA.
  • 2 Biologics Consulting, Alexandria, VA 22314, USA.
  • 3 BioProcess Technology Consultants, Woburn, MA 01801, USA.
  • 4 Abzena, Babraham, Cambridge, CB22 3AT, UK.
  • 5 New York Structural Biology Center, New York, NY 10027, USA.
  • 6 BioBridges, Wellesley, MA 02481, USA.
  • 7 Department of Immunology and Centre for Immune Regulation, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo 0424, Norway.
  • 8 Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo 0424, Norway.
  • 9 The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • 10 Department of Medicine, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 11 Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
  • 12 Clinical Pharmacology of Miami, Miami, FL 33014, USA.
PMID: 31897428 DOI: 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.

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