Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove

Biomarkers of Systemic Treatment Outcomes in Psoriasis (BSTOP) Study Group, Teresa Tsakok, Jake Saklatvala, Theo Rispens, Floris C Loeff, Annick de Vries, Michael H Allen, Ines A Barbosa, David Baudry, Tejus Dasandi, Michael Duckworth, Freya Meynell, Alice Russell, Anna Chapman, Sandy McBride, Kevin McKenna, Gayathri Perera, Helen Ramsay, Raakhee Ramesh, Kathleen SandsAlexa Shipman, A David Burden, Christopher Em Griffiths, Nick J Reynolds, Richard B Warren, Satveer Mahil, Jonathan Barker, Nick Dand, Catherine Smith, Michael A. Simpson

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Original languageEnglish
Article numbere156643
JournalJCI Insight
Issue number4
Publication statusPublished - 22 Feb 2023


  • Humans
  • Adalimumab/therapeutic use
  • Genome-Wide Association Study
  • Antibodies
  • Psoriasis
  • HLA-DR Antigens


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