@article{c3356b3b666d495796c128488b359207,
title = "Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove",
abstract = "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.",
keywords = "Humans, Adalimumab/therapeutic use, Genome-Wide Association Study, Antibodies, Psoriasis, HLA-DR Antigens",
author = "{Biomarkers of Systemic Treatment Outcomes in Psoriasis (BSTOP) Study Group} and Teresa Tsakok and Jake Saklatvala and Theo Rispens and Loeff, {Floris C} and {de Vries}, Annick and Allen, {Michael H} and Barbosa, {Ines A} and David Baudry and Tejus Dasandi and Michael Duckworth and Freya Meynell and Alice Russell and Anna Chapman and Sandy McBride and Kevin McKenna and Gayathri Perera and Helen Ramsay and Raakhee Ramesh and Kathleen Sands and Alexa Shipman and Burden, {A David} and Griffiths, {Christopher Em} and Reynolds, {Nick J} and Warren, {Richard B} and Satveer Mahil and Jonathan Barker and Nick Dand and Catherine Smith and Simpson, {Michael A.}",
note = "Funding Information: This work was funded by the Medical Research Council (MRC) Stratified Medicine award (MR/ L011808/1), the Psoriasis Association (RG2/10), the National Institute for Health Research Biomedical Research Centre at King{\textquoteright}s College London/Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust, the National Institute for Health Research Manchester Biomedical Research Centre, and the National Institute for Health Research Newcastle Biomedical Research Centre. TT is supported by an MRC Clinical Research Training Fellowship (MR/R001839/1). ND is supported by Health Data Research UK (MR/S003126/1). NJR is supported by the Newcastle MRC/EPSRC Molecular Pathology Node and the Newcastle National Institute for Health Research Medtech and In Vitro Diagnostics Co-operative. We acknowledge Gertjan Wolbink, Carmen Bugarin Diz, Konstantinos Douroudis, Kayleigh Mason, and Zenas Yiu for advice on study design and technical implementations and the Psoriasis Stratification to Optimise Relevant Therapy Consortium and BADBIR study group for assistance with study conduct. We are grateful for the contribution of all patient participants and the dermatologists and specialist nurses in the United Kingdom and Ireland who recruited for this study. See Supplemental Acknowledgments for consortia details. Publisher Copyright: Copyright: {\textcopyright} 2023, Tsakok et al.",
year = "2023",
month = feb,
day = "22",
doi = "10.1172/jci.insight.156643",
language = "English",
volume = "8",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "4",
}
