INCIDENCE AND SIGNIFICANCE OF NEUTRALIZING ANTIBODIES TO INTERFERON BETA-1A IN MULTIPLE-SCLEROSIS

Background: Interferon beta is an effective treatment for relapsing mu ltiple sclerosis (MS), As with other protein drugs, neutralizing antib odies (NAB) can develop that reduce the effectiveness of treatment. Ob jectives: To determine the incidence and biological significance of NA B to interferon beta-1a (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) i n MS patients. Methods: A two-step assay for NAB to IFN-beta-1a was de veloped and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing op en-label study of IFN-beta-1a, The biological significance of NAB to I FN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglo bulin, and the clinical significance was determined by comparing clini cal 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 c ompared in MS patients who had used only IFN-beta-1a with the incidenc e in MS patients who had used only IFN-beta-1b. Results: In patients i n the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon in jections. In patients in the phase III study, develop ment 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 NA B 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 h igher using the same assay for patients exposed only to IFN-beta-1b fo r a similar duration, There were no clinical, MRI, or CSF characterist ics that were predictive of which patients would develop NAB. Conclusi ons: NAB directed against IFN-beta have in vivo biological consequence s in patients with MS. The frequency with which MS patients develop NA B against IFN-beta is significantly greater with IFN-beta-1b therapy c ompared with IFN-beta-1a therapy. Treatment decisions in MS patients t reated with IFN-beta should take into account development of NAB.