Research: Neutralizing antibodies to interferons

Epub: Jungedal R et al. Prevalence of anti-drug antibodies against interferon beta has decreased since routine analysis of neutralizing antibodies became clinical practice. Mult Scler. 2012 May 2.

Background: Neutralizing antibodies (NAbs) against interferon beta (IFNβ) lead to loss of treatment effect in MS. The seroprevalence of NAbs (how common it is) in MSers treated with IFNβ during 2003-2004 was 32% in a cross-sectional analysis of routine data.

Objectives: The aim of this study was to investigate whether the seroprevalence of NAbs, the levels of NAb titres and the IFNβ preparations used for treatment of MSers had changed in 2009-2010.

Methods: This study included 1296 MSers, analysed for NAbs with the myxovirus resistance protein A gene expression assay in 2009-2010

The latter is simply an assay that looks at the ability of blood from someone on IFNβ to inhibit the production of a specific antiviral protein. 
Results: The seroprevalence of NAbs had decreased to 19% in 2009-2010, which is significantly lower compared with the previous study in 2003-2004 (p<0.0001). This decrease was attributed to the introduction of less immunogenic IFNβ-1a preparations only, not to IFNβ-1b. The frequency of patients with high positive titres decreased the most, from 16% to 7% (p<0.0001).

Conclusions: NAb seroprevalence has decreased since NAb monitoring became clinical practice in 2003, especially for patients with high NAb titres. This might be due to the stricter monitoring of NAb titres that prompt NAb positive patients to stop treatment, to preferential use of less immunogenic drugs and to alteration of drug formulations.

NAb+ MSers are more likely to progress on the EDSS than NAb-ve MSers.
“This is a good story; I was actively involved in the programme to make IFNβ less immunogenic, i.e. to improve it so  that it induces less antibodies. In my opinion this is why it appears that IFNβ has become more effective in clinical trials. I still worry however, that MSers who develop NABs are at risk of developing problems with recurrent infections, secondary malignancies and possibly brittle bone disease in the future. NAbs are not found in normal people and they inhibit your own IFNβ, which is a vital part of our own biology and is used to fight infections, in particular viruses, tumour surveillance, which eliminates cancers before they causes problems, and bone remodelling. I have asked several of the companies who manufacture and market IFNβ to start long-term registers of MSers with NABs to assess this but none have stepped up to the plate. Why should they? If any data like this emerges it will impact negatively on their sales. We mustn’t forget that IFNβ is a blockbuster drug with annual sales over $5b per year.”

“We are currently running a clinical trial to try and re-educate the immune system to get rid of NAbs. Despite this being a very important study we are having major problems recruiting subjects to this study.”

“If you have you been on IFNβ for 12 months or more your neurologist should check to see if you have developed NAbs. Please ask him or her if they have not.”

Conflict of interests: multiple, in particular I was the PI or principal investigator on the Rebif New Formulation (RNF) study; RNF was developed to reduce the immunogenicity of IFNβ-1a.

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