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

Autor: Tsakok T; Department of Medical and Molecular Genetics and.; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.; St John's Institute of Dermatology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom., Saklatvala J; Department of Medical and Molecular Genetics and., Rispens T; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands., Loeff FC; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands.; Biologics Lab, Sanquin Diagnostic Services, Amsterdam, Netherlands., de Vries A; Biologics Lab, Sanquin Diagnostic Services, Amsterdam, Netherlands., Allen MH; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Barbosa IA; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Baudry D; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Dasandi T; St John's Institute of Dermatology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom., Duckworth M; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Meynell F; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Russell A; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom., Chapman A; Department of Dermatology, Queen Elizabeth Hospital, London, United Kingdom., McBride S; Department of Dermatology, Royal Free London National Health Service Foundation Trust, London, United Kingdom., McKenna K; Department of Dermatology, Belfast Health and Social Care Trust, Belfast, United Kingdom., Perera G; Department of Dermatology, Chelsea and Westminster Hospital National Health Service Foundation Trust, London, United Kingdom., Ramsay H; Department of Dermatology, Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield, United Kingdom., Ramesh R; Department of Dermatology, Sandwell and West Birmingham National Health Service Trust, Birmingham, United Kingdom., Sands K; Department of Dermatology, East Kent Hospitals University National Health Service Foundation Trust, Kent, United Kingdom., Shipman A; Department of Dermatology, Portsmouth Hospitals National Health Service Trust, Portsmouth, United Kingdom., Burden AD; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Griffiths CE; Dermatology Centre, Salford Royal National Health Service Foundation Trust, Manchester, United Kingdom.; The University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Manchester Biomedical Research Centre, Manchester, United Kingdom., Reynolds NJ; Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NHS Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom.; Institute of Translational and Clinical Medicine, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle upon Tyne, United Kingdom., Warren RB; Dermatology Centre, Salford Royal National Health Service Foundation Trust, Manchester, United Kingdom.; The University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Manchester Biomedical Research Centre, Manchester, United Kingdom., Mahil S; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.; St John's Institute of Dermatology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom., Barker J; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.; St John's Institute of Dermatology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom., Dand N; Department of Medical and Molecular Genetics and.; Health Data Research UK, London, United Kingdom., Smith C; St John's Institute of Dermatology, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.; St John's Institute of Dermatology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom., Simpson MA; Department of Medical and Molecular Genetics and.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2023 Feb 22; Vol. 8 (4). Date of Electronic Publication: 2023 Feb 22.
DOI: 10.1172/jci.insight.156643
Abstrakt: 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.
Databáze: MEDLINE