Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development

2013 ◽  
Vol 20 (5) ◽  
pp. 577-587 ◽  
Author(s):  
H Hegen ◽  
A Millonig ◽  
A Bertolotto ◽  
M Comabella ◽  
G Giovanonni ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
De Novo ◽  
Neutralizing Antibody ◽  
Before And After ◽  
European Multicenter Study ◽  
Binding Antibody ◽  
Multiple Sclerosis Patients

Background: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6–18 months on therapy. Objectives: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. Methods: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment in this prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2. Results: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b treatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers ≥ 1:2400 predicted NAb evolution with a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the BAb/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAb-negative samples, respectively, were also diminished compared to BAb/NAb-negative samples. Conclusions: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its abrogation by anti-IFN-b antibodies.

Interferon beta preparations for the treatment of multiple sclerosis patients differ in neutralizing antibody seroprevalence and immunogenicity

2007 ◽  
Vol 13 (2) ◽  
pp. 208-214 ◽  
Author(s):  
A Sominanda ◽  
U Rot ◽  
M Suoniemi ◽  
F Deisenhammer ◽  
J Hillert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Efficacy ◽  
Clinical Setting ◽  
Neutralizing Antibodies ◽  
Treatment Duration ◽  
Interferon Beta ◽  
High Titer ◽  
Neutralizing Antibody ◽  
Multiple Sclerosis Patients

Development of neutralizing antibodies (NAbs) reduces the clinical efficacy of interferon beta (IFNβ) treatment in multiple sclerosis (MS) patients. The aim of this study was to evaluate NAb seroprevalence (frequency of patients with NAbs) and immunogenicity (titer levels) of IFNβ preparations in a clinical setting. We analysed 1115 consecutive MS patients, treated with one of the three available IFNβ preparations, for an average of 40 months (1 – 120 months), for the presence of NAbs with the MxA protein induction assay. Overall, 32% of patients were positive for NAbs with neutralizing titers above 10. The frequency of NAbs, ie, the seroprevalence, was 13% in Avonex-treated patients, 43% for Betaferon, 39% for Rebif22 and 30% for Rebif44. In addition, the potential to induce high titer levels, ie, the immunogenicity, was observed to differ between preparations. Avonex, showing the lowest seroprevalence, also showed low immunogenicity and typically induced low titers. Betaferon, showing the highest seroprevalence when inducing NAbs, induced lower titers compared to Rebif22 and Rebif44. Treatment duration over five years only marginally correlated with decreased seroprevalence and titer levels. In conclusion, NAbs to IFNβ are common in a clinical setting and the IFNβ preparations differ not only in NAb seroprevalence, but also in immunogenicity. Multiple Sclerosis 2007; 13: 208–214. http://msj.sagepub.com

Differing immunogenic potentials of interferon beta preparations in multiple sclerosis patients

2006 ◽  
Vol 12 (6) ◽  
pp. 731-737 ◽  
Author(s):  
C Gneiss ◽  
P Tripp ◽  
F Reichartseder ◽  
R Egg ◽  
R Ehling ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
First Line ◽  
Positive Group ◽  
Treatment Groups ◽  
First Line Therapy ◽  
Multiple Sclerosis Patients ◽  
Patients Experience ◽  
Insight Into

Interferon beta (IFNβ) is a first-line therapy for multiple sclerosis (MS). However, some patients experience a decline in efficacy with continued therapy due to the development of anti-IFNβ neutralizing antibodies (NAb). We investigated the frequency of NAb cross-sectionally in 846 MS patients who were receiving IFNβ-1b, IFNβ-1a im, or IFNβ-1a sc. The frequency of NAb in patients receiving IFNβ-1a im was lower (5%) than in patients treated with any other form of IFNβ (22-35%) (P < 0.0001). Binding antibodies (BAb) were measured in 808 patients. The frequency differed significantly between treatment groups, ranging from 45% (IFNβ-1a im) to 88% (IFNβ-1b). The proportion of NAb-positive patients within the BAb-positive group differed significantly among treatment groups, ranging between 12% (IFNβ-1a im) and 51% (IFNβ-1a sc). The median NAb titer from all IFNβ-1a-treated patients was higher than from IFNβ-1b-treated patients (446 versus 171 NU/mL, P = 0.04). Among NAb-positive patients, the frequency of NAb titers > 100 NU/mL was 71% for IFNβ-1a compared with 58% for IFNβ-1b (P = 0.04). Except for conflicting data regarding IFNβ-1a sc, the results are generally consistent with the literature and together with the differing proportion of NAb-positive patients within the BAb-positive group, provide further insight into the immunogeni-city of the IFNβ preparations.

scholarly journals Deficient Phosphorylation of Stat1 in Leukocytes Identifies Neutralizing Antibodies in Multiple Sclerosis Patients Treated with Interferon-Beta

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e88632 ◽  
Author(s):  
Sonia Gavasso ◽  
Ellen Faergestad Mosleth ◽  
Tove Marøy ◽  
Katarina Jørgensen ◽  
Hanne-Linda Nakkestad ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
Multiple Sclerosis Patients

Polymorphisms of innate pattern recognition receptors, response to interferon-beta and development of neutralizing antibodies in multiple sclerosis patients

2010 ◽  
Vol 16 (8) ◽  
pp. 942-949 ◽  
Author(s):  
Christian Enevold ◽  
Annette B Oturai ◽  
Per Soelberg Sørensen ◽  
Lars P Ryder ◽  
Nils Koch-Henriksen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Pattern Recognition ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
Pattern Recognition Receptors ◽  
Single Nucleotide ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Background: Interferon-beta therapy of patients with relapsing—remitting multiple sclerosis involves repeated ‘immunizations’ with exogenous protein solutions. Innate pattern recognition receptors play an important role in immune responses towards foreign substances and may thus be related to treatment outcome. Objective: To determine the genotypes at 42 single nucleotide polymorphism loci in selected pattern recognition receptors for 567 prospectively followed relapsing—remitting multiple sclerosis patients treated with recombinant interferon-beta, and test for relationships to several outcome parameters, including formation of interferon-beta neutralizing antibodies. Results: The results suggest an association between the rs5743810 polymorphism (Ser249Pro) of TLR6 and development of neutralizing antibodies after 24 months of therapy in males ( p = 0.00002), but not in females ( p = 0.2). This association survived crude Bonferroni correction ( pcorrected = 0.02). Additional associations were observed in carriers of the TLR2-rs5743708 and NOD2-rs3135499 SNPs (time to relapse), the TLR7-rs179008 and NOD1-rs2075820 SNPs (time to disease progression) and the TLR4-rs7873784, TLR9-rs5743836, and NOD2-rs2066842 SNPs (frequency of neutralizing antibodies development). All of these, however, failed to survive correction for multiple testing. There were no significant differences between interferon-beta responders and non-responders for any of the investigated single nucleotide polymorphisms. Conclusions: The rs5743810 polymorphism of TLR6 may be involved in development of anti-interferon-beta antibodies in males, although further studies are required to firmly establish this.

Interferon-beta specific T cells are associated with the development of neutralizing antibodies in interferon-beta treated multiple sclerosis patients

2018 ◽  
Vol 88 ◽  
pp. 83-90 ◽  
Author(s):  
Sudhakar Reddy Kalluri ◽  
Verena Grummel ◽  
Zsuzsanna Hracsko ◽  
Viola Pongratz ◽  
Verena Pernpeintner ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
Multiple Sclerosis Patients

Neutralizing antibody (NAb) assays in multiple sclerosis patients receiving interferon-β therapy

2007 ◽  
Vol 13 (1_suppl) ◽  
pp. 44-48 ◽  
Author(s):  
Florian Deisenhammer
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Diagnostic Value ◽  
Diagnostic Methods ◽  
Type I ◽  
Interferon Β ◽  
First Line Therapy ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Interferon-β (IFN-β), a type I cytokine, is first-line therapy for relapsing-remitting multiple sclerosis (RRMS), a progressive neurological disease that can result in severe disability. As with all protein-based therapies, treatment with IFN-β can result in the development of neutralizing antibodies (NAbs), which has been shown to reduce the efficacy of the regimen. Recently, assays that evaluate patients for the presence of NAbs have received increased attention as a potentially valuable diagnostic tool in assessing the therapeutic effect of a chosen IFN-β regimen. However, despite the clinical desire to consistently monitor NAb levels in these patients, no standardized NAb assay has yet been identified. A lack of method standardization can lead to confusion when comparing NAb results over time and reduces the overall diagnostic value of assessing NAb status. This review will offer a summary of current NAb diagnostic methods and the factors that limit their consistency and practicality in the clinical setting. Alternatives to current methods for assessing NAb status will also be briefly discussed. Multiple Sclerosis 2007; 13: S44—S48. http://msj.sagepub.com

Sign in / Sign up

Export Citation Format

Share Document