Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, The Netherlands.
PLoS One. 2018 Dec 11;13(12):e0208922. doi: 10.1371/journal.pone.0208922. eCollection 2018.
TNF-α-neutralizing antibodies, such as infliximab (IFX) and adalimumab (ADA), are effective in the treatment of inflammatory bowel diseases (IBD), but they are expensive and become ineffective when patients develop anti-IFX or anti-ADA antibodies (ATI and ATA, respectively). Second-generation anti-TNF-α antibodies, such as Golimumab, Etanercept, Certolizumab-pegol and IFX biosimilars, may solve these issues.
To determine the neutralizing capacity of first- and second generation anti-TNF-α antibodies and to determine whether ATI show cross-reactivity with the IFX biosimilar CT-P13 (Inflectra).
TNF-α neutralization was measured using a quantitative TNF-α sensor assay consisting of HeLa 8D8 cells that express the Green Fluorescence Protein (GFP) under control of a NF-кB response element. All available anti-TNF-α drugs and the IFX biosimilar CT-P13 (Inflectra) were tested for their TNF-α-neutralizing capacity. In addition, patient sera with ATI were tested for their potential to block the activity of IFX, IFX (F)ab2-fragment, biosimilar CT-P13 (Inflectra) and ADA.
TNF-α strongly induced GFP expression in Hela 8D8 cells. Higher concentrations of first-generation anti-TNF-α drugs were required to neutralize TNF-α compared to the second-generation anti-TNF-α drugs. Serum of IBD patients with proven ATI blocked TNF-α-neutralizing properties of IFX biosimilar CT-P13 (Inflectra), whereas such sera did not block the effect of ADA.
The second-generation anti-TNF-α drugs show increased TNF-α-neutralizing potential compared to first-generation variants. ATI show cross-reactivity toward IFX biosimilar CT-P13 (Inflectra), consequently patients with ATI are unlikely to benefit from treatment with this IFX biosimilar.
TNF-α 中和抗体，如英夫利昔单抗（IFX）和阿达木单抗（ADA），在治疗炎症性肠病（IBD）方面非常有效，但当患者产生抗 IFX 或抗 ADA 抗体（ATI 和 ATA）时，它们会变得无效。第二代抗 TNF-α 抗体，如戈利木单抗、依那西普、 Certolizumab-pegol 和 IFX 生物类似药，可能会解决这些问题。
确定第一代和第二代抗 TNF-α 抗体的中和能力，并确定 ATI 是否与 IFX 生物类似药 CT-P13（Inflectra）发生交叉反应。
使用包含表达绿色荧光蛋白（GFP）的 HeLa 8D8 细胞的定量 TNF-α 传感器测定法测量 TNF-α 中和，GFP 的表达受 NF-кB 反应元件的控制。所有可用的抗 TNF-α 药物和 IFX 生物类似药 CT-P13（Inflectra）都进行了 TNF-α 中和能力的测试。此外，还测试了具有 ATI 的患者血清，以确定其是否有能力阻断 IFX、IFX（F）ab2 片段、生物类似药 CT-P13（Inflectra）和 ADA 的活性。
TNF-α 可强烈诱导 Hela 8D8 细胞中的 GFP 表达。与第二代抗 TNF-α 药物相比，第一代抗 TNF-α 药物需要更高的浓度才能中和 TNF-α。具有已证实 ATI 的 IBD 患者的血清可阻断 IFX 生物类似药 CT-P13（Inflectra）的 TNF-α 中和特性，而此类血清不能阻断 ADA 的作用。
与第一代变体相比，第二代抗 TNF-α 药物显示出更高的 TNF-α 中和潜力。ATI 对 IFX 生物类似药 CT-P13（Inflectra）表现出交叉反应性，因此，具有 ATI 的患者不太可能从这种 IFX 生物类似药的治疗中获益。
