Persistent neutralizing antibodies abolish the interferon β bioavailability in MS patients

Bertolotto, Antonio; Gilli, Francesca; Sala, Arianna; Capobianco, Marco; Malucchi, Simona; Milano, Eva; Melis, Fabio; Marnetto, Fabiana; Lindberg, Raija L. P.; Bottero, R.; Sapio, Alessia Di; Giordana, Maria Teresa

doi:10.1212/01.wnl.0000046662.03894.c5

Cited by 160 publications

(122 citation statements)

References 38 publications

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“…The presence of interferon-␤ NAbs reduces the bioavailability of interferon-␤ and the biological response to injections, although the clinical consequences of this have remained controversial. 67 NAb titers have been measured in all major clinical trials of interferon-␤ (TABLE 6). Increasing titers have been correlated with reduced efficacy on relapse rate and MRI endpoints in a number of these and other trials.…”

Section: Neutralizing Antibodiesmentioning

confidence: 99%

Interferon-β Treatment for Multiple Sclerosis

Bermel

Rudick

2007

Neurotherapeutics

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Summary:Multiple sclerosis (MS) is the leading nontraumatic cause of neurologic disability in young adults. Interferon-␤, approved for use in 1993, was the first treatment to modify the course and prognosis of the disease and remains a mainstay of MS treatment. Numerous large-scale clinical trials in early, active patient populations have established the clinical efficacy of interferon-␤ in reducing relapses and delaying disability progression. Although its mechanism of action remains incompletely understood, a reduction in active lesions seen on magnetic resonance imaging implies primary anti-inflammatory properties, a mechanism supported by basic immunologic research. Variation in individual patient responsiveness to interferon-␤ may be due to disease variability or differential induction of interferon-stimulated genes. The magnitude of the therapeutic effect appears to be similar among products, but the optimal dose, route, and frequency of administration of the drug remain uncertain.

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Section: Neutralizing Antibodiesmentioning

confidence: 99%

Interferon-β Treatment for Multiple Sclerosis

Bermel

Rudick

2007

Neurotherapeutics

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“…The presence of NAbs is associated with loss of bioavailable IFN-b. 7,8 Anti- IFN-b antibodies are also associated with a loss of clinical efficacy. 9 The neutralizing antibody in multiple sclerosis (MS) patients is enriched for the IgG4 isotype, and neutralizing IgG antibodies as a whole are found at higher titers than in patients with the non-neutralizing antibody.…”

Section: Introductionmentioning

confidence: 99%

The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4+ T-cell epitope in human interferon-β

Stickler¹,

Valdes

Gebel³

et al. 2004

Genes Immun

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Human CD4 þ T-cell epitopes were identified in interferon-beta (IFN-b)-1b. A prominent peptide epitope region was found that induced a proliferative response in 16% of all donors tested. Responses corresponded to the presence of the HLA-DR2 haplotype. Responsive donors expressing the HLA-DQ6 allele showed an increased level of proliferation to the epitope as compared to peptide-responsive HLA-DQ6 negative donors. A similar result was found for HLA-DR15-expressing donors. PBMC from donors expressing HLA-DR15 were more likely to proliferate in response to IFN-b in a whole-protein in vitro assay than donors who did not carry this haplotype. It is striking that the common DQ6 allele HLA-DQB1*0602 is found in linkage disequilibrium with HLA-DRB1*1501, and this combination defines the HLA genotype associated with the development of multiple sclerosis. The HLA association between a response to IFN-b and MS might explain the prevalence of neutralizing antibody development, and may underlie the etiology of the disease.

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“…Many use an arbitrary titer of 20 neutralizing units (NU) per milliliter as the cutoff value for NAb-positivity, although there is evidence that higher titers (e.g., more than 100 or 200 NU/mL) are more likely to have an impact on clinical parameters and biomarkers than lower titers. 29,31,32,41,48,49 Additionally, some patients revert from NAb-positive to NAb-negative status over time. Reversion is more likely with NAb titers of less than 200 NU/mL, although it can happen at titers as high as 3,094 NU/mL.…”

Section: -49mentioning

confidence: 99%

“…In a Danish study of 455 patients, the authors reported that the cumulative probability of reverting to definitely NAb-negative status (i.e., two consecutive NAb-negative titers) in IFN␤-1b (Betaseron) treated patients was 57% after 42 months (CI ϭ 0.43 to 0.71) compared to only 19% (CI ϭ 0.07 to 0.30) in IFN␤-1a (Rebif) treated patients over the same time period. 13 Because most patients who revert to NAb-negative status tend to have titers of 100 NU/mL or less 29,32,38,41,48,49 such a difference might reflect higher NAb-titers to IFN␤-1a compared to IFN␤-1b. 51 …”

Section: Analysis Of the Evidencementioning

confidence: 99%

Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: [RETIRED]

et al. 2007

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Abstract-The clinical and radiologic impact of developing neutralizing antibodies (NAbs) to interferon beta (IFN␤) while on this therapy for multiple sclerosis (MS) is assessed. On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFN␤ (Avonex, Betaseron, or Rebif) is associated with the production of NAbs (Level A). NAbs in the serum are probably associated with a reduction in the radiographic and clinical effectiveness of IFN␤ treatment (Level B). In addition, the rate of NAb production is probably less with IFN␤-1a treatment than with IFN␤-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B). Finally, it is probable that there is a difference in seroprevalence due to variability in the dose of IFN␤ injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFN␤-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFN␤ preparations (either IFN␤-1a or IFN␤-1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFN␤ treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs (Ͼ100 to 200 NU/mL) is associated with a reduction in the therapeutic effects of IFN␤ on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff titer to apply (Level U).

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Persistent neutralizing antibodies abolish the interferon β bioavailability in MS patients

Abstract: During IFNbeta therapy, the presence of NAb reduced or abolished bioavailability in a relevant percentage of patients. These data could be important for the early detection of patients with MS who are not responsive to IFNbeta therapy.

Cited by 160 publications

References 38 publications

Interferon-β Treatment for Multiple Sclerosis

Interferon-β Treatment for Multiple Sclerosis

The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4+ T-cell epitope in human interferon-β

Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: [RETIRED]

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