Effect of neutralizing antibodies on biomarker responses to interferon beta The INSIGHT study

Background: Interferon beta (IFN beta) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFN beta therapies. Biomarkers of the IFN beta 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 IFN beta 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 IFN beta-1a, subcutaneous (SC) IFN beta-1a, or IFN beta-1b. Results: Treatment with IM IFN beta-1a was associated with a lower rate of NAb formation among 718 patients screened (p < 0.0001 vs SC IFN beta-1a22 mu g, 44 mu g, and IFN beta-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. Neurology (R) 2009; 73: 1493-1500