Study of binding and neutralising antibodies to interferon-? in two groups of relapsing-remitting multiple sclerosis patients

Fernández, Óscar; Mayorga, Cristobalina; Luque, Gloria M.; Guerrero, Miguel; Guerrero, R.; Leyva, Laura; Blanca, Miguel

doi:10.1007/s004150170178

Cited by 27 publications

(15 citation statements)

References 22 publications

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“…As previously discussed, data from clinical trials suggest that the development of NAbs may reduce the therapeutic efficacy of IFNβ therapy [4,6,8]. However, there is no consensus on the immunomodulatory role of anti-IFNβ antibodies, and some authors have published findings that refute their reported antitherapeutic effect [19][20][21]. The discrepancies among the published data may be explained by differences in both methodology and numbers of patients analysed.…”

Section: Discussionmentioning

confidence: 80%

The clinical impact of interferon beta antibodies in relapsing-remitting MS

Perini

Calabrese

Biasi

et al. 2004

Journal of Neurology

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We analysed the kinetics and clinical impact of binding antibodies (BAbs) and neutralizing antibodies (NAbs) to three interferon beta (IFNbeta) products in patients with relapsing-remitting MS (RRMS). Patients with RRMS received IFNbeta-1b 8 MIU subcutaneously (SC) every other day, intramuscular (IM) IFNbeta-1a 30 mcg once weekly, or SC IFNbeta-1a 22 mcg three times weekly for up to 4 years. The changes of BAbs and IFNbeta were measured using enzyme-linked immunosorbent assay (ELISA), and positive BAb samples were then analysed for neutralizing activity using an antiviral cytopathic effect assay. Patients were considered BAb+ if they had a positive sample with an optical density (OD)>mean + 3SD of the OD of the control sample; high BAb titers were defined as >1:500. Patients were considered NAb+ if they had titers > or =20 LU/mL, with high NAb titers defined as >1:100. The impact of BAbs and NAbs on relapses and Expanded Disability Status Scale (EDSS) score also was evaluated. Thirty patients were enrolled in each treatment group. Over the course of the study, 83% of patients developed BAbs to IFNbeta-1b, 13% to IM IFNbeta-1a, and 47 % to SC IFNbeta-1a. Forty percent of patients developed NAbs to IFNbeta-1b, 6.7% to IM IFNbeta-1a, and 26.7% to SC IFNbeta-1a. Of 22 NAb+ patients, 10 patients (45.5%) demonstrated high titers of both NAbs and BAbs (20% IFNbeta-1b, 3.3% IM IFNbeta-1a, 10% SC IFNbeta-1a). The relapse rate significantly increased after the appearance of high NAb titers (p=0.03); however, an even higher significance level (p<0.001) was observed in patients with high titers of both NAbs and BAbs. In 10 patients with high titers of both NAbs and BAbs, an increase in mean EDSS score from 2.2 +/- 0.8 at baseline to 3.6 +/- 1.2 at year 2 (p<0.01) was observed. NAb-negative patients showed no significant change in EDSS score at year 2. These findings demonstrate that high titers of both BAbs and NAbs reduce the clinical efficacy of IFNbeta in patients with RRMS, which is important for the long-term efficacy of these drugs.

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Section: Discussionmentioning

confidence: 80%

The clinical impact of interferon beta antibodies in relapsing-remitting MS

Perini

Calabrese

Biasi

et al. 2004

Journal of Neurology

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“…Therefore, a review of the comparative trials, which used a single assay method, is necessary to critically evaluate differences in immunogenicity among IFNβs. Several studies have compared the incidence of NAbs among IFNβ products [3,6,15,23,32,37]. However, herein we review only studies that did the following: contained a reasonable number of patients, followed patients for ≥ 12 months, and controlled for the potential interference of residual IFNβ in peripheral blood after injection (blood collection occurred ≥ 36 hours after IFNβ injection).…”

Section: Comparative Studiesmentioning

confidence: 98%

Immunogenicity of interferon beta: differences among products

et al. 2004

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Protein-based therapies are useful in a variety of diseases; however, their potential for immunogenicity is a disadvantage. Neutralizing antibodies (NAbs) that develop to interferon beta (IFNbeta) products (IFNbeta-1b, IFNbeta-1a-Avonex((R)), or IFNbeta-1a-Rebif((R))), which are first-line therapies for the treatment of multiple sclerosis, are reported to reduce the clinical efficacy of these agents. In individual clinical studies of each commercially available IFNbeta product, 28% to 47% of patients develop NAbs to IFNbeta-1b, 12% to 28 % to IFNbeta-1a-Rebif, and 2% to 6% to IFNbeta-1a-Avonex. Problems exist in comparing the incidence of NAbs among IFNbeta products across studies because of differences in study methodology, including assay methods, treatment duration, and the definition of NAb positive. Results from studies that have directly compared these products are consistent with results from the respective clinical trials of IFNbetas. Both the clinical trials and the independent studies have shown that NAbs develop more frequently with IFNbeta-1b treatment than with IFNbeta-1a treatment and that, among IFNbeta-1a products, NAbs develop more frequently with IFNbeta-1a-Rebif treatment than with IFNbeta-1a-Avonex treatment. Factors that may affect the immunogenicity of IFNbetas, including the dosing regimens and the biochemical properties of the products, are discussed.

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“…IFN-␤ was selected as a model protein because neutralizing Ab responses develop in multiple sclerosis patients undergoing IFN-␤ therapy (15)(16)(17). The effect of neutralizing Abs on IFN-␤ efficacy is controversial (16, 18 -20).…”

Section: T He Number Of Epitope Regions Recognized Within Protein Immmentioning

confidence: 99%

Elimination of an Immunodominant CD4+ T Cell Epitope in Human IFN-β Does Not Result in an In Vivo Response Directed at the Subdominant Epitope

Yeung¹,

Chang²,

Miller³

et al. 2004

The Journal of Immunology

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The BALB/cByJ mouse strain displays an immunodominant T cell response directed at the same CD4+ T cell epitope peptide region in human IFN-β, as detected in a human population-based assay. BALB/cByJ mice also recognize a second region of the protein with a lesser magnitude proliferative response. Critical residue testing of the immunodominant peptide showed that both BALB/cByJ mice and the human population response were dependent on an isoleucine residue at position 129. A variant IFN-β molecule was constructed containing the single amino acid modification, I129V, in the immunodominant epitope. The variant displayed 100% of control antiproliferation activity. Mice immunized with unmodified IFN-β responded weakly in vitro to the I129V variant. However, BALB/cByJ mice immunized with the I129V variant were unable to respond to either the I129V variant or the unmodified IFN-β molecule by either T cell proliferation or Ag-specific IgG1 Ab production. This demonstrates that a single amino acid change in an immunodominant epitope can eliminate an immune response to an otherwise intact therapeutic protein. The elimination of the immunodominant epitope response also eliminated the response to the subdominant epitope in the protein. Modifying functionally immunodominant T cell epitopes within proteins may obviate the need for additional subdominant epitope modifications.

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Study of binding and neutralising antibodies to interferon-? in two groups of relapsing-remitting multiple sclerosis patients

Cited by 27 publications

References 22 publications

The clinical impact of interferon beta antibodies in relapsing-remitting MS

The clinical impact of interferon beta antibodies in relapsing-remitting MS

Immunogenicity of interferon beta: differences among products

Elimination of an Immunodominant CD4+ T Cell Epitope in Human IFN-β Does Not Result in an In Vivo Response Directed at the Subdominant Epitope

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