Immunoglobulin G1 and immunoglobulin G4 antibodies in multiple sclerosis patients treated with IFNβ interact with the endogenous cytokine and activate complement

A subset of patients with relapsing-remitting multiple sclerosis (RRMS) on therapy with interferon beta (IFN beta) develop neutralising anti-drug antibodies (ADA) resulting in reduced, or loss of, therapeutic efficacy. The aims were to characterise the relative contributions of anti-IFN beta antibody isotypes to drug neutralising activity, ability of these antibodies to cross-react with endogenous IFN beta, to form immune complexes and activate complement. IFN beta-specific ADA were measured in plasma from RRMS patients treated with IFN beta (Rebif (R)). Neutralisation of endogenous and therapeutic IFN beta by ADA was determined by IFN beta bioassay. IFN beta-ADA profile was predominantly comprised of IgG1 and IgG4 antibody isotypes. The contribution of IgG4-ADA towards neutralising activity was found to be minimal. Neutralising IFN beta-ADA blocks endogenous IFN beta activity. ADA interaction with therapeutic IFN beta results in immune complex formation and complement activation. In summary, IgG1 and IgG4 IFN beta-ADA have the ability to neutralise therapeutic and endogenous protein and to activate complement. (C) 2013 Authors. Published by Elsevier Inc. All rights reserved.