Are neutralising antibodies against IFN-beta always harmful in MS?

P.S. Sorensen, N. Koch-Henriksen, K. Bendtzen on behalf of the Danish Multiple Sclerosis Group

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Background: Neutralizing antibodies (NAbs) against interferon (IFN)-beta is generally believed to reduce the treatment effect in multiple sclerosis (MS). However, data from pivotal trials of IFN-beta in MS have suggested that patients, who were tested NAb-positive with an in vitro assay, had an even reduced relapse rate during the first 6 to 12 months of therapy.

Patients and methods: We collected clinical data and plasma samples for in vitro NAb measurements prospectively every 6 months in 453 patients who after start of IFN-beta therapy were treated with IFN-beta for at least 24 months. NAbs were measured blindly with a cytopathic effect assay (CPE).

Results: During treatment months 0-6, patients who during the first 24 months of therapy became NAb-positive (neutralizing capacity of 20% or more) in a cytopathic effect assay (CPE) of medium sensitivity had significantly fewer relapses (annualized relapse rate 0.60) compared to patients who maintained the NAb-negative status (annualized relapse rate 0.93; p=0.006), whereas the opposite was observed in every 6 month period after month 6.

The annualized relapse rate for months 6-48 was 0.57 in the NAb-positive patients versus 0.46 in NAb-negative patients (p=0.009). Interestingly, measurements of NAbs with a more sensitive CPE assay disclosed that the majority of the patients who became NAb-positive already had measurable neutralizing activity in the blood at month 6.

Conclusion: There is concordant evidence from the present Danish study and the pivotal studies of the three different IFN-beta preparations that patients who become NAb-positive have lower relapse rates during the first 6-12 months of therapy. We hypothesize that low affinity NAbs are present early after start of IFN-beta therapy.

These low-affinity antibodies are neutralizing in vitro, but may increase the half-life of IFN-beta in vivo and, thereby, enhance the therapeutic effect. With affinity maturation, NAbs prevent IFN-beta to bind to its receptor and abolish the treatment effect reflected by increased relapse rate.