{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T22:32:35Z","timestamp":1791757955785,"version":"4.3.4"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012023","name":"Stichting Sanquin Bloedvoorziening","doi-asserted-by":"publisher","award":["PPOC 07-017 , PPOC 09-032"],"award-info":[{"award-number":["PPOC 07-017 , PPOC 09-032"]}],"id":[{"id":"10.13039\/501100012023","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 <jats:italic>in silico<\/jats:italic>. 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\u2019 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.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1549781","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T14:31:11Z","timestamp":1751639471000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The TNF\u03b1-binding domain of the therapeutic antibody adalimumab elicits CD4 T-cell responses in rheumatoid arthritis patients"],"prefix":"10.3389","volume":"16","author":[{"given":"Mateusz","family":"Makuch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josine","family":"van Beek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla A.","family":"Wijbrandts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja","family":"Aalbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Stas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander B.","family":"Meijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja ten","family":"Brinke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Rispens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul Peter","family":"Tak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gertjan","family":"Wolbink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Schuurman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W. 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