Antigen-specific tolerization in human autoimmunity: Inhibition of interferon-beta1a anti-drug antibodies in multiple sclerosis

Background: Antigen-specific tolerance in auto-immune diseases is the goal for effective treatment with minimal side-effects. Whilst this is achievable in animal models, notably via intravenous delivery of the model-specific autoantigen following transient CD4 T cell depletion, specific multiple sclerosis autoantigens remain unproven. However, anti-drug antibodies to human therapeutic proteins represent a model human autoimmune condition, which may be used to examine immune-tolerance induction. Some people with MS (PwMS) on interferon-beta1a (IFN{beta}1a) develop neutralizing antibodies to IFN{beta}1a that do not disappear in repeated tests over years. Methods: One PwMS was recruited, as part of a planned phase IIa trial (n=15), who had developed neutralizing antibodies to subcutaneous IFN{beta}1a. Mitoxantrone (12mg/m2) was administered as a lymphocyte depleting agent followed by four days of (88g/day + three 132g/day) intravenous IFN{beta}1a. Subcutaneous IFN{beta}1a three times a week was maintained during follow-up. IFN{beta}1a neutralizing antibody responses in serum were measured during treatment and three-monthly for 12 months. Findings: One participant was recruited and, within 6 months of tolerization, the neutralizing antibodies were undetectable. The tolerization treatment was well tolerated. However, the study was terminated after the first enrolment, on ethical grounds, as treatment alternatives became available and the potential risks of mitoxantrone use increased. Interpretation: The data suggest that it may be possible to induce antigen-specific tolerance by providing tolerogenic antigen following transient immune depletion. Further studies are warranted. Funding: The study was supported by an unrestricted research grant from Merck-Serono.