Epitope Specificity of Neutralizing Antibodies Against IFN-β

Abstract

Neutralizing antibodies (NAb), a subset of antibodies against interferon-beta (IFN-beta) that inhibit activation of the IFN-beta receptor, are presumed to bind to the receptor-binding site of IFN-beta. The aim of this study was to identify specific epitopes for human NAb and nonneutralizing antibodies (NNAb) on the IFN-beta molecule. Thirty-one 12-mer peptides and one 11-mer peptide representing the amino acid sequence of the human IFN-beta molecule were used as antigens in an ELISA antibody assay. Significant antibody binding was observed at residues 1-12, 121-132, and 151-162. NNAb and NAb recognized residues 121-132 with equal frequency, but NAb had higher titers. NAb bound significantly more frequently to residues 1-12 and 151-162. There was a significant positive correlation between NAb titers and titers against residues 1-12. Binding to residues 1-12 was more pronounced in patients treated with IFN-beta1a than in patients treated with IFN-beta1b. Our results indicate a qualitative and quantitative difference between NAb and NNAb, with special emphasis on the recognition of different epitopes.

Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies

“…At present, we may only speculate that following IFN-beta injection, NABs do not neutralize all IFN molecules and those left can still bind to the receptor, thus allowing some effector expression. Third, binding between IFN and NAB is reversible and anti-IFN-beta NABs with different affinity and specificity have been demonstrated in vivo [42][43][44][45].…”

Review: Neutralizing antibodies against interferon-beta

“…There was a positive correlation between NAb titers and titers against residues 1-12 [Gneiss et al 2004a].…”

Important sources of variability in clinical studies of neutralizing antibodies against interferon beta

“…Although both NAbs and nonneutralizing or binding Abs (BAbs) bound equally well to the epitope on residues 121-132, NAbs bound significantly more strongly to residues 1-12 and 151-162 than BAbs (p = 0.006 for both sequences), suggesting that these two epitopes were important for NAb binding [25]. NAb binding to residues 1-12, the N-terminus end of the IFN beta molecule, was more pronounced in patients treated with IFN beta-1a (Avonex®, Rebif®) than in those treated with IFN beta-1b (Betaseron®) [25]. The NAb titers were significantly higher against residues 1-12 in IFN beta-1a-treated patients than IFN beta-1b-treated patients [25].…”

“…A study investigated the epitope (antibody-binding site) specificity of NAbs from RRMS patients treated with the human IFN beta molecule and identified three epitopes located on amino acid residues 1-12, 121-132 and 151-162 of the IFN beta molecule [25]. Although both NAbs and nonneutralizing or binding Abs (BAbs) bound equally well to the epitope on residues 121-132, NAbs bound significantly more strongly to residues 1-12 and 151-162 than BAbs (p = 0.006 for both sequences), suggesting that these two epitopes were important for NAb binding [25].…”