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Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation
  1. Pauline A van Schouwenburg1,
  2. Lotte A van de Stadt1,2,
  3. Rob N de Jong3,
  4. Esther E L van Buren3,
  5. Simone Kruithof1,
  6. Els de Groot1,
  7. Margreet Hart1,
  8. S Marieke van Ham1,
  9. Theo Rispens1,
  10. Lucien Aarden1,
  11. Gerrit Jan Wolbink1,2,
  12. Diana Wouters1
  1. 1Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Amsterdam, The Netherlands
  2. 2Department of Rheumatology, Jan van Breemen Research Institute | Reade, Amsterdam, Cell & Molecular Science Department, The Netherlands
  3. 3Genmab BV, Utrecht, The Netherlands
  1. Correspondence to Pauline A van Schouwenburg, Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Plesmanlaan 125, Amsterdam 1066 CX, The Netherlands; p.schouwenburgvan{at}sanquin.nl

Abstract

Objectives 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.

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