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Are ex vivo neutralising antibodies against IFN-ß always detrimental to therapeutic efficacy in multiple sclerosis?

Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

N. Koch-Henriksen

Department of Neurology, Aalborg Hospital, Aalborg, Denmark and The Danish MS Treatment Register, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

K. Bendtzen

Institute for Inflammation Research, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, pss{at}rh.dk

Neutralising antibodies (NAbs) against interferon (IFN)-ß reduce the treatment effect in multiple sclerosis (MS). However, data from pivotal trials of IFN-ß in MS suggest that NAb-positive patients may have a reduced relapse rate during the first six to 12 months of therapy. We collected clinical data and plasma samples for NAb measurements prospectively, every six months, in 468 patients treated with the same IFN-ß preparation for at least 24 months. NAbs were measured blindly with a cytopathic effect (CPE) assay. During treatment months 0-6, patients who became NAb-positive had significantly fewer relapses compared to patients who maintained the NAb-negative status, whereas the opposite was observed after month 6. This is in accordance with observations in randomised studies of the three different IFN-ß preparations, showing that patients who become NAb-positive have lower relapse rates during the first six or 12 months of therapy. We hypothesise that low affinity NAbs, present early after the start of IFN-ß therapy, though neutralising in vitro in sensitive assays increase the half-life of IFN-ß in vivo and, thereby, enhance the therapeutic effect. With affinity maturation, NAbs effectively prevent IFN-ß binding to its receptors also in vivo and, hence, abolish the treatment effect. Multiple Sclerosis 2007; 13: 616-621. http://msj.sagepub.com

Key Words: binding antibodies • interferon-beta • multiple sclerosis • neutralising antibodies • therapy • treatment effect

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