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Effect of neutralizing antibodies on biomarker responses to interferon beta

The INSIGHT study

From the University of Medicine and Dentistry of New Jersey (A.R.P.), New Jersey Medical School, Newark, NJ; and Biogen Idec, Inc. (J.D.W., A.P., S.G.), Cambridge, MA.

Address correspondence and reprint requests to Dr. Andrew R. Pachner, UMDNJ–New Jersey Medical School, 185 South Orange Ave., MSBH506, Newark, NJ 07103 pachner{at}umdnj.edu

Background: Interferon beta (IFNβ) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNβ therapies. Biomarkers of the IFNβ response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNβ bioactivity.

Methods: In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNβ-1a, subcutaneous (SC) IFNβ-1a, or IFNβ-1b.

Results: Treatment with IM IFNβ-1a was associated with a lower rate of NAb formation among 718 patients screened (p < 0.0001 vs SC IFNβ-1a 22 µg, 44 µg, and IFNβ-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb–)/NAb-negative (NAb–) patients (all p < 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers 100 TRU compared with BAb–/NAb– patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6.

Conclusions: These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.

Abbreviations: BAb = binding antibody; cELISA = capture ELISA; IFIT-1 = interferon-induced protein with tetratricopeptide repeats 1; IFNAR = interferon /β receptor; IFNβ = interferon beta; INSIGHT = Impact of Neutralizing Antibodies on Interferon Responsive Genes Highlights Biomarker Response; MS = multiple sclerosis; MxA = myxovirus resistance protein A; NAb = neutralizing antibody; NR = normalization ratio; OR = odds ratio; SC = subcutaneous; TRU = tenfold reduction unit.

Supplemental data at www.neurology.org

See also page 1485

*A list of investigators appears in the appendix at the end of this article.

Supported by Biogen Idec.

Disclosure: Author disclosures are provided at the end of the article.

Received March 26, 2009. Accepted in final form August 20, 2009.

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Neurology 2009 73: 1485-1492. [Abstract] [Full Text] [PDF]