Department of Immunopathology, Sanquin Research, Amsterdam, and Landsteiner Laboratory, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, The Netherlands.
Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands.
Clin Exp Rheumatol. 2020 Mar-Apr;38(2):306-313. doi: 10.55563/clinexprheumatol/nlr4r8. Epub 2019 Aug 30.
Tumour necrosis factor (TNF) inhibitors like certolizumab, elicit an immunogenic response leading to the formation of anti-drug antibodies (ADAs). We sought to mechanistically investigate the relationship between certolizumab concentrations, ADAs, and the effective TNF neutralising capacity in sera of rheumatoid arthritis (RA) patients. TNF neutralising capacity of certolizumab was compared to the neutralising capacity of adalimumab.
Serum samples were collected from 40 consecutive certolizumab-treated RA patients at baseline and 4, 16, 28 and 52 weeks after treatment initiation [Dutch Trial Register NTR (Nederlands Trial Register) Trial NL2824 no. 2965]. Certolizumab concentration and ADA titre were measured with a certolizumab bridging enzyme-linked immunosorbent assay (ELISA) and a drug-tolerant radioimmunoassay (RIA), respectively. TNF neutralisation by certolizumab and adalimumab, in presence or absence of ADAs, was analysed with the TNF-sensitive WEHI bioassay.
Despite a high incidence of ADAs during one year of follow-up (65%; 26/40 patients), certolizumab levels of >10 μg/ml were measured in most patients. The capacity for TNF neutralisation highly correlated with certolizumab serum concentration, whereas no association with ADAs was observed. Similar results were obtained for adalimumab. The relative in vitro neutralising potency was higher for certolizumab compared to adalimumab.
Anti-certolizumab antibodies were detected in a large proportion of patients, but in most cases where ADAs were detected, certolizumab was also present in high concentrations, directly correlating with in vitro neutralising capacity. These results indicate that measurement of certolizumab drug levels, rather than ADAs, have direct clinical significance.
肿瘤坏死因子（TNF）抑制剂，如certolizumab，会引起免疫反应，导致形成抗药物抗体（ADA）。我们旨在从机制上研究 certolizumab 浓度、ADA 和类风湿关节炎（RA）患者血清中有效 TNF 中和能力之间的关系。比较了 certolizumab 与阿达木单抗的 TNF 中和能力。
从 40 例连续接受 certolizumab 治疗的 RA 患者的基线和治疗开始后 4、16、28 和 52 周采集血清样本[荷兰试验注册处（Nederlands Trial Register）试验 NL2824 编号 2965]。使用 certolizumab 桥接酶联免疫吸附试验（ELISA）和药物耐受放射免疫测定（RIA）分别测量 certolizumab 浓度和 ADA 效价。在存在或不存在 ADA 的情况下，用 TNF 敏感 WEHI 生物测定法分析 certolizumab 和阿达木单抗的 TNF 中和作用。
尽管在一年的随访中有很高的 ADA 发生率（65%，40 例患者中有 26 例），但在大多数患者中仍测量到 >10 μg/ml 的 certolizumab 水平。TNF 中和能力与 certolizumab 血清浓度高度相关，而与 ADA 无关。阿达木单抗也得到了类似的结果。与阿达木单抗相比，certolizumab 的体外相对中和效力更高。
在很大一部分患者中检测到抗 certolizumab 抗体，但在大多数检测到 ADA 的情况下，certolizumab 也以高浓度存在，与体外中和能力直接相关。这些结果表明，测量 certolizumab 药物水平而不是 ADA 具有直接的临床意义。
