{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:16:09Z","timestamp":1793643369486,"version":"4.5.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T00:00:00Z","timestamp":1740614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Unwanted immune responses (UIRs) to biologics can negatively impact treatment efficacy and pharmacokinetics and\/or induce adverse events (AEs). We characterized the UIR profile of adalimumab (ADL) using data from a phase 3, randomized, interchangeability study of reference ADL (ADL-REF; Humira<jats:sup>\u00ae<\/jats:sup>) and ADL biosimilar PF-06410293 in patients with rheumatoid arthritis (RA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eligible patients (18\u221270 years, moderate-to-severe active RA) received ADL-REF from weeks 0\u221210 (lead-in period) then were randomized 1:1 to: 3 switches between PF-06410293 and ADL-REF or continuous ADL-REF treatment until week 32. As interchangeability of PF-06410293 with ADL-REF was previously demonstrated, data were combined across groups to describe the development of antidrug antibodies (ADAs) and their impact on pharmacokinetics and immunologically related AEs. Pharmacokinetic endpoints included maximum observed serum concentration (C<jats:sub>max<\/jats:sub>), area under serum concentration\u2013time curve over dosing interval (AUC<jats:sub>tau<\/jats:sub>), time of maximum observed serum concentration (T<jats:sub>max<\/jats:sub>), average serum concentration (C<jats:sub>av<\/jats:sub>), and apparent clearance (CL\/F), determined from robust pharmacokinetic sampling during weeks 30\u201332; and predose concentrations (C<jats:sub>trough<\/jats:sub>) at prespecified sampling time points. Other endpoints: patients (%) with ADA-positive and neutralizing ADA (NAb)-positive samples, time of first ADA\/NAb detected, ADA titers over time, persistence of ADA\/NAb, and immunologically related AEs by ADA\/NAb status.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 427 randomized patients, 59% were ADA-positive, 52% had persistent ADA, 14% were NAb-positive, and 10% had persistent NAb. In most patients, ADA\/NAb first developed within 16 weeks of ADL treatment regardless of pre-existing (baseline day 1) ADA. ADA\/NAb titers stabilized by week 16 without boosters. C<jats:sub>trough<\/jats:sub> was lower in patients with ADA-positive than ADA-negative samples throughout the study. From weeks 30\u201332, AUC<jats:sub>tau<\/jats:sub>, C<jats:sub>max<\/jats:sub>, and C<jats:sub>av<\/jats:sub> were lower in ADA-positive than ADA-negative samples at week 30, especially in patients with ADA-positive\/NAb-positive samples. Only 3% of patients had immunologically related AEs. Most were injection site and hypersensitivity reactions, and none were considered severe or serious or associated with the presence of ADA\/NAb. Presence of pre-existing ADA did not increase the potential for immunologically related responses to ADL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Presence of ADA (with or without NAb) was associated with lower drug concentrations and faster clearance but not with the development of immunologically related AEs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p>ClinicalTrials.gov, identifier NCT0423021.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1457993","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T09:16:38Z","timestamp":1740647798000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Antidrug antibodies to adalimumab do not associate with immunologically related adverse events"],"prefix":"10.3389","volume":"15","author":[{"given":"Sophie","family":"Tourdot","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Dolores","family":"Vazquez-Abad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna S.","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Hua","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuyan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Lepsy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-015-0134-5","article-title":"Comparative immunogenicity of tnf inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. A systematic review and meta-analysis","volume":"29","author":"Thomas","year":"2015","journal-title":"BioDrugs"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2013.7430","article-title":"Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated inflammatory conditions: systematic review and meta-analysis","volume":"173","author":"Maneiro","year":"2013","journal-title":"JAMA Intern Med"},{"key":"B3","unstructured":"Guidance for industry. Immunogenicity assessment for therapeutic protein products\n          \n          \n          \n          2014"},{"key":"B4","unstructured":"Guideline on similar biological medicinal products containing monoclonal antibodies \u2013 non-clinical and clinical issues\n          \n          \n          \n          2012"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-012-9705-0","article-title":"Igg4 production against adalimumab during long term treatment of ra patients","volume":"32","author":"van Schouwenburg","year":"2012","journal-title":"J Clin Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1111\/all.14984","article-title":"Hypersensitivity reactions to biologicals: an eaaci position paper","volume":"77","author":"Bavbek","year":"2022","journal-title":"Allergy"},{"key":"B7","unstructured":"Clinical trial results: A multi-centre open-label continuation study in moderate to severe chronic plaque psoriasis subjects who completed a preceding psoriasis clinical study with adalimumab. Eudract number 2005-000095-41\n          \n          \n          \n          2009"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s40257-022-00708-w","article-title":"Switching between adalimumab reference product and bi 695501 in patients with chronic plaque psoriasis (Voltaire-X): A randomized controlled trial","volume":"23","author":"Menter","year":"2022","journal-title":"Am J Clin Dermatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e135","DOI":"10.1038\/ctg.2015.63","article-title":"Loss of response to anti-tnfs: definition, epidemiology, and management","volume":"7","author":"Roda","year":"2016","journal-title":"Clin Transl Gastroenterol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00312","article-title":"Immunogenicity of tnf-inhibitors","volume":"11","author":"Atiqi","year":"2020","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s40259-019-00394-x","article-title":"Immunogenicity of biosimilars for rheumatic diseases, plaque psoriasis, and inflammatory bowel disease: A review from clinical trials and regulatory documents","volume":"34","author":"Strand","year":"2020","journal-title":"BioDrugs"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202545","article-title":"Antidrug antibodies (Adab) to tumour necrosis factor (Tnf)-specific neutralising agents in chronic inflammatory diseases: A real issue, a clinical perspective","volume":"72","author":"Vincent","year":"2013","journal-title":"Ann Rheum Dis"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-012-0833-2","article-title":"A survey of applications of biological products for drug interference of immunogenicity assays","volume":"29","author":"Wang","year":"2012","journal-title":"Pharm Res"},{"key":"B14","unstructured":"Guideline on immunogenicity assessment of therapeutic proteins\n          \n          \n          \n          2017"},{"key":"B15","unstructured":"Guidance for industry. Immunogenicity assessment for therapeutic protein products\n          \n          \n          \n          2014"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.092833","article-title":"Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis","volume":"68","author":"Radstake","year":"2009","journal-title":"Ann Rheum Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.406","article-title":"Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up","volume":"305","author":"Bartelds","year":"2011","journal-title":"JAMA"},{"key":"B18","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.cgh.2017.11.050","article-title":"Association of vedolizumab level, anti-drug antibodies, and alpha4beta7 occupancy with response in patients with inflammatory bowel diseases","volume":"16","author":"Ungar","year":"2018","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00161-3","article-title":"Multiple switching between the biosimilar adalimumab pf-06410293 and reference adalimumab in patients with active rheumatoid arthritis: A phase 3, open-label, randomised, parallel-group study","volume":"5","author":"Fleischmann","year":"2023","journal-title":"Lancet Rheumatol"},{"key":"B20","unstructured":"Immunogenicity testing of therapeutic protein products\u2014Developing and validating assays for anti-drug antibody detection\n          \n          \n          \n          2019"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14330","article-title":"Population pharmacokinetics of adalimumab biosimilar adalimumab-adbm and reference product in healthy subjects and patients with rheumatoid arthritis to assess pharmacokinetic similarity","volume":"86","author":"Kang","year":"2020","journal-title":"Br J Clin Pharmacol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2018.1490119","article-title":"Extending human igg half-life using structure-guided design","volume":"10","author":"Booth","year":"2018","journal-title":"MAbs"},{"key":"B23","unstructured":"Common terminology criteria for adverse events (Ctcae) version 5.0\n          \n          \n          \n          2017"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.758","article-title":"Astct consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells","volume":"25","author":"Lee","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.932252","article-title":"Hlaii peptide presentation of infliximab increases when complexed with tnf","volume":"13","author":"Casasola-LaMacchia","year":"2022","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.annemergmed.2006.01.018","article-title":"Second symposium on the definition and management of anaphylaxis: summary report-second national institute of allergy and infectious disease\/food allergy and anaphylaxis network symposium","volume":"47","author":"Sampson","year":"2006","journal-title":"Ann Emerg Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-004225","article-title":"Immunogenicity assessment of bispecific antibody-based immunotherapy in oncology","volume":"10","author":"Zhou","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175207","article-title":"The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: results from a multinational, real-world clinical practice, non-interventional study","volume":"12","author":"Moots","year":"2017","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2022-eular.4701","article-title":"Pos0659 long-term dynamics of antibody response to adalimumab detected with a drug tolerant assay","volume":"81","author":"Atiqi","year":"2022","journal-title":"Ann Rheumatic Dis"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02921","article-title":"Molecular landscape of anti-drug antibodies reveals the mechanism of the immune response following treatment with tnfalpha antagonists","volume":"10","author":"Vaisman-Mentesh","year":"2019","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.638444","article-title":"Efficacy and safety of adalimumab biosimilars: current critical clinical data in rheumatoid arthritis","volume":"12","author":"Lu","year":"2021","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1208\/s12248-015-9857-y","article-title":"Evaluating and reporting the immunogenicity impacts for biological products-a clinical pharmacology perspective","volume":"18","author":"Wang","year":"2016","journal-title":"AAPS J"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1457993\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T09:16:44Z","timestamp":1740647804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1457993\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,27]]},"references-count":32,"alternative-id":["10.3389\/fimmu.2024.1457993"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1457993","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,27]]},"article-number":"1457993"}}