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