Formation and clearance of TNF-TNF inhibitor complexes during TNF inhibitor treatment

Millions of patients with inflammatory diseases are treated with tumour necrosis factor (TNF) inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF-TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic...

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Bibliographic Details
Published in:	British journal of pharmacology Vol. 181; no. 8; pp. 1165 - 1181
Main Authors:	Berkhout, Lea Catharina, I'Ami, Merel Jeanne, Kruithof, Simone, Vogelzang, Erik Hans, Hooijberg, Femke, Hart, Margaretha Hendrika Louise, Bentlage, Arthur Ebel Herman, Thomas, Debby, Vermeire, Severine, Vidarsson, Gestur, Ten Brinke, Anja, Nurmohamed, Michael Twahier, Wolbink, Gerrit Jan, Rispens, Theo
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-04-2024
Subjects:	Adalimumab - pharmacology Adalimumab - therapeutic use Antigen-antibody complexes Antirheumatic Agents Arthritis, Rheumatoid - drug therapy Etanercept Etanercept - pharmacology Etanercept - therapeutic use Humans Immune clearance Inflammatory bowel diseases Infliximab Infliximab - pharmacology Infliximab - therapeutic use Internalization Macrophages Monoclonal antibodies TNF inhibitors Tumor Necrosis Factor Inhibitors - therapeutic use Tumor Necrosis Factor-alpha Tumor necrosis factor-TNF Tumor necrosis factor-α Ulcerative colitis Valency anti-drug antibodies TNF inhibitor clearance tumour necrosis factor pharmacokinetic immune complexes target-mediated drug disposition
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Summary:	Millions of patients with inflammatory diseases are treated with tumour necrosis factor (TNF) inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF-TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic insight into the structural aspects and biological significance of TNF-TNFi complexes is lacking. We hypothesized a role for Fc-mediated clearance of TNF-TNFi immune complexes. Therefore, we investigated circulating TNF-TNFi complexes upon treatment with certolizumab-lacking Fc tails-in comparison with adalimumab, golimumab, infliximab and etanercept. Drug-tolerant ELISAs were developed and used to quantify TNF during adalimumab, golimumab, etanercept, certolizumab and infliximab treatment in patients with inflammatory arthritis or ulcerative colitis for a maximum follow-up of 1 year. Effects on in vitro TNF production and Fc-mediated uptake of TNF-TNFi complexes were investigated for all five TNFi. Circulating TNF concentrations were >20-fold higher during certolizumab treatment compared with adalimumab, reaching up to 23.1 ng·ml . Internalization of TNF-TNFi complexes by macrophages depended on Fc valency, with efficient uptake for the full antibody TNFi (three Fc tails), but little or no uptake for etanercept and certolizumab (one and zero Fc tail, respectively). TNF production was not affected by TNFi. Total TNF load did not affect clearance rate of total TNFi. Differences in TNFi structure profoundly affect clearance of TNF, while it is unlikely that TNF itself significantly contributes to target-mediated drug disposition of TNFi.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0007-1188 1476-5381
DOI:	10.1111/bph.16269