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

Tsakok, T. et al. (2023) Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove. JCI Insight, 8(4), e156643. (doi: 10.1172/jci.insight.156643) (PMID:36810251) (PMCID:PMC9977494)

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.

• Item Type: Articles
• Keywords: Drug therapy, molecular genetics, adaptive immunity, therapeutics, adalimumab - therapeutic use, genome-wide association study, humans, HLA-DR antigens, genetics, antibodies, psoriasis.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Burden, Professor David
• Authors: Tsakok, T., Saklatvala, J., Rispens, T., Loeff, F. C., de Vries, A., Allen, M. H., Barbosa, I. A., Baudry, D., Dasandi, T., Duckworth, M., Meynell, F., Russell, A., Chapman, A., McBride, S., McKenna, K., Perera, G., Ramsay, H., Ramesh, R., Sands, K., Shipman, A., Burden, A. D., Griffiths, C. E.M., Reynolds, N. J., Warren, R. B., Mahil, S., Barker, J., Dand, N., Smith, C., and Simpson, M. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: JCI Insight
• Publisher: American Society for Clinical Investigation
• ISSN: 2379-3708
• ISSN (Online): 2379-3708
• Copyright Holders: Copyright © 2022 Tsakok et al.
• First Published: First published in JCI Insight 8(4): e156643
• Publisher Policy: Reproduced under a Creative Commons License