Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc.
It is well established that high doses of monomeric immunoglobulin G (IgG) purified from pooled human plasma [intravenous immunoglobulin (IVIG)] confer anti-inflammatory activity in a variety of autoimmune settings. However, exactly how those effects are mediated is not clear because of the heterogeneity of IVIG. Recent studies have demonstrated that the anti-inflammatory activity of IgG is completely dependent on sialylation of the N-linked glycan of the IgG Fc fragment. Here we determine the precise glycan requirements for this anti-inflammatory activity, allowing us to engineer an appropriate IgG1 Fc fragment, and thus generate a fully recombinant, sialylated IgG1 Fc with greatly enhanced potency. This therapeutic molecule precisely defines the biologically active component of IVIG and helps guide development of an IVIG replacement with improved activity and availability.
Anthony
Robert M
RM
Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10021, USA.
Nimmerjahn
Falk
F
Ashline
David J
DJ
Reinhold
Vernon N
VN
Paulson
James C
JC
Ravetch
Jeffrey V
JV
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000188:drug therapy*; D002236:Carbohydrate Conformation; D005690:Galactose / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy; D011961:Receptors, Fc / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D011134:Polysaccharides; D011961:Receptors, Fc; D011994:Recombinant Proteins; D019158:N-Acetylneuraminic Acid; D005690:Galactose