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Structural basis of the broadly neutralizing anti-interferon-? antibody rontalizumab.

ABSTRACT: Interferons-alpha (IFN-?) 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-?, IFN-? and IFN-? have sequences 29-33%, 29-32% and 56-60% similar to the IFN-?s, 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-? has been used to treat infection by hepatitis-virus type C (HCV) and a correlation between hyperactivity of IFN-?-induced signaling and systemic lupus erythematosis (SLE), or lupus, has been noted. Anti-IFN-? 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-?2 at 3Å resolution and find substantial overlap of the antibody and IFNA2 epitopes on IFN-?2.

SUBMITTER: Maurer B

PROVIDER: S-EPMC4570538 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Structural basis of the broadly neutralizing anti-interferon-α antibody rontalizumab.

Maurer Brigitte B Bosanac Ivan I Shia Steven S Kwong Mandy M Corpuz Racquel R Vandlen Richard R Schmidt Kerstin K Eigenbrot Charles C

Protein science : a publication of the Protein Society 20150818 9

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 comp ...[more]

PMID: 26099203

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Project description:Influenza viruses take a yearly toll on human life despite efforts to contain them with seasonal vaccines. These viruses evade human immunity through the evolution of variants that resist neutralization. The identification of antibodies that recognize invariant structures on the influenza haemagglutinin (HA) protein have invigorated efforts to develop universal influenza vaccines. Specifically, antibodies to the highly conserved stem region of HA neutralize diverse viral subtypes. These antibodies largely derive from a specific antibody gene, heavy-chain variable region IGHV1-69, after limited affinity maturation from their germline ancestors, but how HA stimulates naive B cells to mature and induce protective immunity is unknown. To address this question, we analysed the structural and genetic basis for their engagement and maturation into broadly neutralizing antibodies. Here we show that the germline-encoded precursors of these antibodies act as functional B-cell antigen receptors (BCRs) that initiate subsequent affinity maturation. Neither the germline precursor of a prototypic antibody, CR6261 (ref. 3), nor those of two other natural human IGHV1-69 antibodies, bound HA as soluble immunoglobulin-G (IgG). However, all three IGHV1-69 precursors engaged HA when the antibody was expressed as cell surface IgM. HA triggered BCR-associated tyrosine kinase signalling by germline transmembrane IgM. Recognition and virus neutralization was dependent solely on the heavy chain, and affinity maturation of CR6261 required only seven amino acids in the complementarity-determining region (CDR) H1 and framework region 3 (FR3) to restore full activity. These findings provide insight into the initial events that lead to the generation of broadly neutralizing antibodies to influenza, informing the rational design of vaccines to elicit such antibodies and providing a model relevant to other infectious diseases, including human immunodeficiency virus/AIDS. The data further suggest that selected immunoglobulin genes recognize specific protein structural 'patterns' that provide a substrate for further affinity maturation.

Dataset Information

Structural basis of the broadly neutralizing anti-interferon-? antibody rontalizumab.

Publications

Structural basis of the broadly neutralizing anti-interferon-α antibody rontalizumab.

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