title: The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region.
abstract: BACKGROUND
  In a subset of patients, anti tumour necrosis factor (TNF) therapeutic antibodies are immunogenic, resulting in the formation of antidrug antibodies (ADAs). Neutralising ADAs compete with TNF for its binding site and reduces the effective serum concentration, causing clinical non-response. It is however unknown to which extent ADAs are neutralising.
  
  
  OBJECTIVE
  To study which proportion of antibodies to human(ised) anti-TNF (adalimumab, golimumab, certolizumab) as well as chimeric anti-TNF (infliximab) is neutralising.
  
  
  METHODS
  Neutralising capacity of ADAs was assessed using a TNF competition assay in ADA-positive sera of patients treated with adalimumab (n=21), golimumab (n=4), certolizumab (n=9) or infliximab (n=34) sent in to our diagnostic department.
  
  
  RESULTS
  In 34 sera with ADAs to adalimumab, golimumab or certolizumab, >97% of the antibodies were neutralising. In 34 sera with ADAs to infliximab >90% of the antibodies were neutralising. Further characterisation of the broader antibody response to infliximab revealed that non-neutralising antibodies to infliximab do not target murine domains, but may bind infliximab-unique domains not involved in TNF binding (located outside the paratope).
  
  
  CONCLUSIONS
  Our study shows that ADAs to human(ised) as well as chimeric anti-TNF therapeutic antibodies are largely neutralising. This highly restricted ADA response suggests an immunodominant role for the paratope of anti-TNF therapeutics.
authors.affiliation: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: K A
authors.initials: KA
authors.lastname: van Schie
authors.affiliation: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: Hart
authors.affiliation: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: E R
authors.initials: ER
authors.lastname: de Groot
authors.affiliation: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Kruithof
authors.affiliation: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Aarden
authors.affiliation: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Wolbink
authors.affiliation: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Rispens
mesh_terms: D000068879:Adalimumab; D000906:Antibodies / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology*; D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing / Q000276:immunology*; D018501:Antirheumatic Agents / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000276:immunology*; D000068582:Certolizumab Pegol; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D000069285:Infliximab; D011092:Polyethylene Glycols; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D018501:Antirheumatic Agents; D007140:Immunoglobulin Fab Fragments; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab; D000068582:Certolizumab Pegol
keywords: Anti-TNF; Rheumatoid Arthritis; TNF-alpha