• R A Rudick, N A Simonian, J A Alam, M Campion, J O Scaramucci, W Jones, M E Coats, D E Goodkin, B Weinstock-Guttman, R M Herndon, M K Mass, J R Richert, A M Salazar, F E Munschauer, D L Cookfair, J H Simon, and L D Jacobs.
• Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, OH 44106, USA.
• Neurology. 1998 May 1; 50 (5): 1266-72.

BackgroundInterferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment.ObjectivesTo determine the incidence and biological significance of NAB to interferon beta-la (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) in MS patients.MethodsA two-step assay for NAB to IFN-beta-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing open-label study of IFN-beta-1a. The biological significance of NAB to IFN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-beta-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-beta-1a with the incidence in MS patients who had used only IFN-beta-1b.ResultsIn patients in the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in beta-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-beta-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-beta-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-beta-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-beta-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB.ConclusionsNAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.

12 keywords...

hide…