title: Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation.
abstract: OBJECTIVE
  Millions of patients worldwide are treated with therapeutic monoclonal antibodies. These biological therapeutics can be immunogenic, resulting in anti-drug antibody formation which leads to loss of response. Fully human biological agents, such as the anti-tumour necrosis factor α (anti-TNFα) antibody adalimumab, are considered to be weakly immunogenic, but anti-adalimumab antibodies (AAA) were recently detected in more than half of treated patients with rheumatoid arthritis (RA) within 28 weeks of treatment. A study was undertaken to determine the mechanism by which AAA lead to loss of response.
  
  
  METHODS
  The specificity of the repertoire of AAA was investigated in a cohort of 50 AAA-positive RA patients. Inhibition experiments using TNFα and patient-derived anti-adalimumab monoclonal antibodies were performed.
  
  
  RESULTS
  The antibody response against adalimumab is highly restricted: Fab fragments of a single monoclonal antibody specific for the idiotype of adalimumab inhibited 98.65% (25th-75th percentiles: 98.25-99.90) of the total anti-adalimumab reactivity in serum from 50 AAA-positive patients. The anti-adalimumab response was confined to the TNFα binding region of adalimumab, thereby neutralising its therapeutic efficacy. In line with this restricted specificity, small immune complexes were found in the circulation of AAA-forming patients.
  
  
  CONCLUSIONS
  The humoral immune response against adalimumab is highly restricted and limited to the idiotype of the therapeutic antibody. All antibodies result in functional neutralisation of the drug, thereby providing a mechanism by which AAA formation leads to clinical non-response.
authors: Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, Amsterdam, The Netherlands. p.schouwenburgvan@sanquin.nl
authors: Pauline A
authors: PA
authors: van Schouwenburg
authors: Lotte A
authors: LA
authors: van de Stadt
authors: Rob N
authors: RN
authors: de Jong
authors: Esther E L
authors: EE
authors: van Buren
authors: Simone
authors: S
authors: Kruithof
authors: Els
authors: E
authors: de Groot
authors: Margreet
authors: M
authors: Hart
authors: S Marieke
authors: SM
authors: van Ham
authors: Theo
authors: T
authors: Rispens
authors: Lucien
authors: L
authors: Aarden
authors: Gerrit Jan
authors: GJ
authors: Wolbink
authors: Diana
authors: D
authors: Wouters
mesh_terms: D000068879:Adalimumab; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D000918:Antibody Specificity; D000936:Antigen-Antibody Complex / Q000276:immunology; D018501:Antirheumatic Agents / Q000276:immunology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D018501:Antirheumatic Agents; D000068879:Adalimumab