Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis

Richard 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, L. D. Jacobs

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Abstract

Background: Interferon 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. Objectives: To determine the incidence and biological significance of NAB to interferon beta-1a (IFN-β-1a; Avonex; Biogen, Cambridge, MA) in MS patients. Methods: A two-step assay for NAB to IFN-β-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-β-1a, and from patients in an ongoing open-label study of IFN-β-1a. The biological significance of NAB to IFN-β-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and β- 2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-β-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-β-1a with the incidence in MS patients who had used only IFN-β-1b. Results: In patients in the open-label study, development of NAB to IFN-β-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 β-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-β-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-β-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-β-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-β-lb for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. Conclusions: NAB directed against IFN-β have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-β is significantly greater with IFN-β-1b therapy compared with IFN-β- la therapy. Treatment decisions in MS patients treated with IFN-β should take into account development of NAB.

Original languageEnglish (US)
Pages (from-to)1266-1272
Number of pages7
JournalNeurology
Volume50
Issue number5
DOIs
StatePublished - May 1998

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ASJC Scopus subject areas

  • Clinical Neurology

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Rudick, R. A., Simonian, N. A., Alam, J. A., Campion, M., Scaramucci, J. O., Jones, W., Coats, M. E., Goodkin, D. E., Weinstock-Guttman, B., Herndon, R. M., Mass, M. K., Richert, J. R., Salazar, A. M., Munschauer, F. E., Cookfair, D. L., Simon, J. H., & Jacobs, L. D. (1998). Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Neurology, 50(5), 1266-1272. https://doi.org/10.1212/WNL.50.5.1266