Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands.
Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Br J Pharmacol. 2024 Apr;181(8):1165-1181. doi: 10.1111/bph.16269. Epub 2023 Dec 5.
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.
数以百万计的炎症性疾病患者接受肿瘤坏死因子（TNF）抑制剂（TNFi）治疗。个体治疗反应存在差异，部分原因与药物清除率的差异有关。TNF-TNFi 复合物在不同 TNFi 清除中的作用存在争议。此外，缺乏对 TNF-TNFi 复合物结构方面和生物学意义的机制见解。我们假设 Fc 介导的 TNF-TNFi 免疫复合物清除起作用。因此，我们研究了在缺乏 certolizumab Fc 尾部的情况下与阿达木单抗、戈利木单抗、英夫利昔单抗和依那西普治疗相比，循环中的 TNF-TNFi 复合物。
开发了药物耐受 ELISA，并用于在炎症性关节炎或溃疡性结肠炎患者中定量测定阿达木单抗、戈利木单抗、依那西普、certolizumab 和英夫利昔单抗治疗期间的 TNF，最大随访时间为 1 年。对所有五种 TNFi 进行了体外 TNF 产生和 Fc 介导的 TNF-TNFi 复合物摄取的影响。
与阿达木单抗相比，在 certolizumab 治疗期间循环 TNF 浓度高 20 多倍，高达 23.1ng·ml-1。巨噬细胞内吞 TNF-TNFi 复合物取决于 Fc 价数，全抗体 TNFi（三个 Fc 尾部）具有有效的摄取，但依那西普和 certolizumab（分别为一个和零 Fc 尾部）摄取很少或没有。TNF 产生不受 TNFi 影响。总 TNF 负荷不影响总 TNFi 的清除率。
TNFi 结构的差异极大地影响了 TNF 的清除，而 TNF 本身不太可能对 TNFi 的靶向介导药物处置有显著贡献。
