The TNFα-binding domain of the therapeutic antibody adalimumab elicits CD4 T-cell responses in rheumatoid arthritis patients
Makuch, Mateusz van Beek, Josine Wijbrandts, Carla A Aalbers, Marja Stas, Philippe Meijer, Alexander B ten Brinke, Anja Rispens, Theo Tak, Paul Peter Wolbink, Gertjan
Makuch, Mateusz
van Beek, Josine
Wijbrandts, Carla A
Aalbers, Marja
Stas, Philippe
Meijer, Alexander B
ten Brinke, Anja
Rispens, Theo
Tak, Paul Peter
Wolbink, Gertjan
Series / Report no.
Open Access
Type
Journal Article
Article
Article
Language
en
Date
2025-07-04
Research Projects
Organizational Units
Journal Issue
Title
The TNFα-binding domain of the therapeutic antibody adalimumab elicits CD4 T-cell responses in rheumatoid arthritis patients
Translated Title
Published in
Front Immunol 2025; 16:1549781
Abstract
Treatment efficacy of patients receiving anti-TNF antibodies is limited by the formation of anti-drug antibodies. These are observed in most adalimumab-treated rheumatoid arthritis patients, despite the adjuvant-free and human sequence-derived nature of the antibody. The class switched phenotype and high affinity of these antibodies suggest CD4 T-cell involvement in their formation. In this study, we investigated the potential epitopes in the functional domain of adalimumab and assessed their actual HLA II presentation and induction of CD4 T-cell responses in exposed patients. The binding strength of overlapping adalimumab-derived peptides to 27 DR and 14 DQ HLA alleles was predicted . 10 strong and 44 medium-binding 10-mer peptides were identified within the variable regions of the heavy and light chain of adalimumab. HLA-DR-mediated antigen presentation of selected peptides by monocyte-derived dendritic cells was determined by mass spectrometry of the peptide pool eluted from isolated HLA-DR complexes. Binding of the variable region peptides of heavy (H41-62) and light chains (L18-39) was demonstrated. The presence of adalimumab-specific CD4 T-cells in adalimumab-experienced patients was investigated via peptide stimulation of peripheral blood mononuclear cells and assessment of T-cell proliferation. Anti-adalimumab CD4 T-cell responses were observed against four variable region peptides in a group of adalimumab-experienced RA patients. Some of these responses were also present in healthy control donors. This study identifies immunologically relevant CD4 T-cell epitopes in the variable region of the human therapeutic antibody adalimumab based on RA patients' reactivity. Modification of these epitopes or concomitant therapy that targets or prevents adalimumab-specific T cell responses could be beneficial for patients with significant anti-drug responses.