In vivo bioactivity of interferon-beta in multiple sclerosis patients with neutralising antibodies is titre-dependent

Background: Development of neutralising antibodies (NAbs) against recombinant interferon-beta (IFN beta) is a significant clinical problem in the treatment of multiple sclerosis ( MS). Several methods are available to assess NAbs, but there is a lack of consensus on how the different NAb titre levels interfere with the efficacy of the drug, especially in the individual patient. Methods: NAb titres were measured with an in vitro MxA induction assay and the in vivo IFN beta response was assessed by measuring MxA mRNA expression using real-time PCR. Results: We identified titre levels of NAbs at which the IFN beta biological activity was reduced or abrogated. Patients with NAb titres of up to 150 TRU/ml (ten times reduction units per ml) still had retained IFN beta bioactivity, whereas greatly reduced levels of IFN beta bioactivity were found in patients with NAbs of 150-600 TRU/ml. Titres above 600 TRU/ml were associated with loss of IFN beta bioactivity. Similar results were obtained when TRAIL mRNA was used as a marker of the in vivo response to IFNb. Conclusion: There is a stepwise loss of IFN beta bioactivity with increasing NAb titres and it is possible to identify functionally critical NAb titre levels that are useful to support treatment decisions at the individual patient level.