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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\u201336 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.<\/jats:p>","DOI":"10.1172\/jci.insight.156643","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T14:01:08Z","timestamp":1676988068000},"source":"Crossref","is-referenced-by-count":5,"title":["Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1895-6070","authenticated-orcid":true,"given":"Teresa","family":"Tsakok","sequence":"first","affiliation":[{"name":"Department of Medical and Molecular Genetics and"},{"name":"St John\u2019s Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King\u2019s College London, London, United Kingdom."},{"name":"St John\u2019s Institute of 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