6NHA

Crystal structure of SYNT001, a human FcRn blocking monoclonal antibody

Summary for 6NHA

• Entry DOI: 10.2210/pdb6nha/pdb
• Descriptor: IgG receptor FcRn large subunit p51, Beta-2-microglobulin, SYNT001-Fab light chain, ... (6 entities in total)
• Functional Keywords: fcrn, b2m, circulating igg and igg immune complex, synt001, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 90404.19

Authors

Blumberg, R.S.,Cheung, J.,Mahmood, A.,Gandhi, A.K. (deposition date: 2018-12-21, release date: 2019-12-25, Last modification date: 2024-11-06)

Primary citation

Blumberg, L.J.,Humphries, J.E.,Jones, S.D.,Pearce, L.B.,Holgate, R.,Hearn, A.,Cheung, J.,Mahmood, A.,Del Tito, B.,Graydon, J.S.,Stolz, L.E.,Bitonti, A.,Purohit, S.,de Graaf, D.,Kacena, K.,Andersen, J.T.,Christianson, G.J.,Roopenian, D.C.,Hubbard, J.J.,Gandhi, A.K.,Lasseter, K.,Pyzik, M.,Blumberg, R.S.
Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.
Sci Adv, 5:eaax9586-eaax9586, 2019

PubMed 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.

PubMed: 31897428
DOI: 10.1126/sciadv.aax9586

Experimental method

X-RAY DIFFRACTION (2.381 Å)