Neutralizing antibodies hamper IFNβ bioactivity and treatment effect on MRI in patients with MS

Sørensen, Per Soelberg; Tscherning, Thomas; Mathiesen, Henrik Kahr; Langkilde, Annika Reynberg; Roß, Christian; Ravnborg, Mads; Bendtzen, Klaus

doi:10.1212/01.wnl.0000242884.76598.bb

Cited by 61 publications

(44 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All our patients had, however, an active MRI scan despite treatment, being all suboptimal responders. The negative impact of NAb on the IFNβ-1b treatment effect confirms the findings of a recent report [21] also showing that NAb-positive patients had more MRI activity.…”

Section: Discussionsupporting

confidence: 88%

The OPTimization of Interferon for MS Study: 375 μg interferon beta-1b in suboptimal responders

et al. 2008

View full text Add to dashboard Cite

We aimed to evaluate the safety and MRI efficacy of interferon beta-1b (IFNbeta-1b) 375 microg (subcutaneously [sc] every other day [eod]) in relapsing-remitting multiple sclerosis (RRMS) patients with a suboptimal response to IFNbeta-1b 250 microg, i.e., with MRI activity or relapses. The OPTimization of Interferon for MS (OPTIMS) study was a prospective multicenter randomized phase 2 trial comprising a 6-month run-in phase (to identify suboptimal responders) and a 6-month randomized phase of open-label clinical and blinded MRI follow-up. During run-in all patients were treated with IFNbeta-1b 250 microg sc eod; during the study phase suboptimal treatment responders were randomized either to IFNbeta-1b 250 or 375 microg sc eod. Primary outcome was the proportion of patients without MRI activity during study Months 9-12 according to the intention-to-treat principle. 216 RRMS patients entered the study: 83 suboptimal responders were identified and randomized, 7 refused to continue treatment, 76 were included in the analysis. More patients treated with 375 microg had no MRI activity at Months 9-12 (30/36 vs.16/40; relative risk, 0.28; 95 % confidence interval, 0.08-0.47; p = 0.0001). Sensitivity analysis ("worst case scenario") confirmed the results. No new or unexpected adverse events were observed, but there was a trend towards more withdrawals in the 375 microg group. Increasing the dose of IFNbeta-1b from 250 microg to 375 microg is a successful strategy for reducing subclinical signs of disease activity in RRMS patients. Further studies are needed to show whether this dose may also improve clinical efficacy.

show abstract

Section: Discussionsupporting

confidence: 88%

The OPTimization of Interferon for MS Study: 375 μg interferon beta-1b in suboptimal responders

et al. 2008

View full text Add to dashboard Cite

show abstract

“…When therapy with IFN-β or GA is not successful, the patient should be evaluated to identify possible reasons (e.g. non-adherence, neutralizing antibodies to IFN-β, infections or even the wrong diagnosis) [8,9]. According to the approval in Europe [4] and to expert guidelines [10], natalizumab is one option in these cases.…”

Section: Discussionmentioning

confidence: 99%

Natalizumab Reduces Clinical and MRI Activity in Multiple Sclerosis Patients with High Disease Activity: Results from a Multicenter Study in Switzerland

et al. 2010

View full text Add to dashboard Cite

Background: Natalizumab has been recommended for the treatment of relapsing-remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-β or glatiramer acetate (disease-modifying treatments – DMT) or in aggressive MS. The pivotal trials were not designed to investigate natalizumab monotherapy in these patient populations. Aim: To investigate the efficacy of natalizumab after treatment failure of previous DMT and in highly active MS. Methods: A retrospective, multicenter study in Switzerland. Three major MS centers reported all RRMS patients who initiated natalizumab ≧12 months prior to study conduction. Results: 85 RRMS patients were included (72% female, mean age 37.3 years, mean Expanded Disability Status Scale 3.1; 88.2% were pretreated with DMT), and mean treatment duration with natalizumab was 18.4 ± 2.6 months. 79% of the patients were relapse-free during the observational period. The annualized relapse rate decreased from 2.0 ± 0.6 to 0.27 ± 0.2, and 92.9% were progression-free after 12 months (p < 0.001). The mean number of gadolinium-enhancing lesions decreased from 1.2 ± 1.2 to 0.1 ± 0.1 at 12 months’ follow-up (91.7% reduction).Discontinuation rate was 11.8% (7.1% for antibody positivity). Conclusions: Patients who initiate natalizumab after previous high disease activity experience a marked reduction of clinical and MRI disease activity.

show abstract

“…10 Natalizumab was originally generated in mice, but humanized by grafting the antibody complementarity determining regions into a human IgG4 antibody frame, but is still immunogenic like other biopharmaceuticals. 11 In the clinical trials about 9% of natalizumab-treated MS patients generated antinatalizumab antibodies, and the presence of these resulted in reduced serum levels of natalizumab, decreased bio-efficacy, and abrogation of the therapeutic efficacy. 3,4,12 In the clinical trials, binding anti-natalizumab antibodies were measured using a sandwich/bridging ELISA method 12 and a flow-cytometric assay to detect blocking anti-natalizumab antibodies.…”

Section: Introductionmentioning

confidence: 99%

Occurrence of antibodies against natalizumab in relapsing multiple sclerosis patients treated with natalizumab

et al. 2011

View full text Add to dashboard Cite

Background: In the clinical trials about 9% of natalizumab treated multiple sclerosis (MS) patients generated antinatalizumab antibodies, of which 6% were persistent and 3% transient. The occurrence of antibodies reduced serum levels of natalizumab, decreased bio-efficacy, and abrogated the therapeutic efficacy. Objective: The objective was to assess the frequency of anti-natalizumab antibodies in an unselected cohort of patients from four different countries. Methods: We measured anti-natalizumab antibodies in a large cohort of 4881 unselected patients from four MS centres that systematically measured antibodies in patients treated with natalizumab. We applied the same ELISA assay developed by Biogen Idec and used in the pivotal trials of natalizumab. Results: Antibodies occurred in 4.5% (95% confidence interval, CI: 4.0-5.1%) of the patients, and were persistent in 3.5% (95% CI: 3.0-4.0%) and transient in 1.0% (95% CI: 0.7-1.3%) of the patients. The frequencies of permanently antibody positive patients did not show statistically significant differences between the four centres, whereas the frequencies of transiently antibody positive patients showed some variations. Conclusion: The frequencies of antibodies appeared to be of the same magnitude in the four centres, but might be less than in the pivotal studies of natalizumab.

show abstract

Neutralizing antibodies hamper IFNβ bioactivity and treatment effect on MRI in patients with MS

Cited by 61 publications

References 11 publications

The OPTimization of Interferon for MS Study: 375 μg interferon beta-1b in suboptimal responders

The OPTimization of Interferon for MS Study: 375 μg interferon beta-1b in suboptimal responders

Natalizumab Reduces Clinical and MRI Activity in Multiple Sclerosis Patients with High Disease Activity: Results from a Multicenter Study in Switzerland

Occurrence of antibodies against natalizumab in relapsing multiple sclerosis patients treated with natalizumab

Contact Info

Product

Resources

About