title: Structural basis of the broadly neutralizing anti-interferon-α antibody rontalizumab.
abstract: Interferons-alpha (IFN-α) are the expressed gene products comprising thirteen type I interferons with protein pairwise sequence similarities in the 77-96% range. Three other widely expressed human type I interferons, IFN-β, IFN-κ and IFN-ω have sequences 29-33%, 29-32% and 56-60% similar to the IFN-αs, respectively. Type I interferons act on immune cells by producing subtly different immune-modulatory effects upon binding to the extracellular domains of a heterodimeric cell-surface receptor composed of IFNAR1 and IFNAR2, most notably anti-viral effects. IFN-α has been used to treat infection by hepatitis-virus type C (HCV) and a correlation between hyperactivity of IFN-α-induced signaling and systemic lupus erythematosis (SLE), or lupus, has been noted. Anti-IFN-α antibodies including rontalizumab have been under clinical study for the treatment of lupus. To better understand the rontalizumab mechanism of action and specificity, we determined the X-ray crystal structure of the Fab fragment of rontalizumab bound to human IFN-α2 at 3Å resolution and find substantial overlap of the antibody and IFNA2 epitopes on IFN-α2.
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Maurer
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bosanac
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.
authors.forename: Steven
authors.initials: S
authors.lastname: Shia
authors.affiliation: Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.
authors.forename: Mandy
authors.initials: M
authors.lastname: Kwong
authors.affiliation: Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.
authors.forename: Racquel
authors.initials: R
authors.lastname: Corpuz
authors.affiliation: Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.affiliation: Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.|Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D053633:Receptor, Interferon alpha-beta / Q000737:chemistry / Q000276:immunology; D013329:Structure-Activity Relationship
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D007140:Immunoglobulin Fab Fragments; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta; C577244:rontalizumab
keywords: X-ray crystallography; antibody; interferon-alpha receptor; systemic lupus erythematosis; type I interferons