Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: Binding antibodies predict neutralizing antibody development

Background: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis(MS) patients. NAbs evolve in up to 44% of treated patients, usually between 618 months on therapy. Objectives: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. Methods: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment inthis prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2.Results: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b reatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers>400 predicted NAb evolutionwith a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the Ab/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAbnegative amples, respectively, were also diminished compared to BAb/NAb-negative samples. onclusions: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its brogation by anti-IFN-b antibodies.