title: Immunoglobulin G1 and immunoglobulin G4 antibodies in multiple sclerosis patients treated with IFNβ interact with the endogenous cytokine and activate complement.
abstract: A subset of patients with relapsing-remitting multiple sclerosis (RRMS) on therapy with interferon beta (IFNβ) develop neutralising anti-drug antibodies (ADA) resulting in reduced, or loss of, therapeutic efficacy. The aims were to characterise the relative contributions of anti-IFNβ antibody isotypes to drug neutralising activity, ability of these antibodies to cross-react with endogenous IFNβ, to form immune complexes and activate complement. IFNβ-specific ADA were measured in plasma from RRMS patients treated with IFNβ1a (Rebif(®)). Neutralisation of endogenous and therapeutic IFNβ by ADA was determined by IFNβ bioassay. IFNβ-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 IFNβ-ADA blocks endogenous IFNβ activity. ADA interaction with therapeutic IFNβ results in immune complex formation and complement activation. In summary, IgG1 and IgG4 IFNβ-ADA have the ability to neutralise therapeutic and endogenous protein and to activate complement.
authors.affiliation: MRC Centre for Drug Safety Science and Institute of Translational Medicine, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Buildings, Liverpool L69 3GE, UK.
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Sethu
authors.forename: Karthik
authors.initials: K
authors.lastname: Govindappa
authors.forename: Paul
authors.initials: P
authors.lastname: Quinn
authors.forename: Meenu
authors.initials: M
authors.lastname: Wadhwa
authors.forename: Richard
authors.initials: R
authors.lastname: Stebbings
authors.forename: Mike
authors.initials: M
authors.lastname: Boggild
authors.forename: Dean
authors.initials: D
authors.lastname: Naisbitt
authors.forename: Ian
authors.initials: I
authors.lastname: Kimber
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Kevin
authors.initials: K
authors.lastname: Park
authors.forename: Jean
authors.initials: J
authors.lastname: Sathish
mesh_terms: D000328:Adult; D003167:Complement Activation / Q000502:physiology*; D003429:Cross Reactions; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood* / Q000145:classification / Q000276:immunology; D007155:Immunologic Factors / Q000276:immunology / Q000627:therapeutic use*; D016899:Interferon-beta / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D012008:Recurrence; D055815:Young Adult
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D007155:Immunologic Factors; D016899:Interferon-beta
keywords: Anti-drug antibody;; Complement; Immunogenicity;; Interferon beta;; Neutralising antibody;; Relapsing-remitting multiple sclerosis;