McRae Bradford L, Levin Alon D, Wildenberg Manon E, Koelink Pim J, Bousquet Peter, Mikaelian Igor, Sterman Annette Schwartz, Bryant Shaughn, D'Haens Geert, Kamath Rajesh, Salfeld Jochen, van den Brink Gijs R
Abbvie Bioresearch Center, Worcester, MA, USA.
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
J Crohns Colitis. 2016 Jan;10(1):69-76. doi: 10.1093/ecco-jcc/jjv179. Epub 2015 Oct 1.
Anti-tumour necrosis factor [TNF] monoclonal antibodies [infliximab, adalimumab] induce complete mucosal healing in a proportion of patients with Crohn's disease whereas a TNF receptor fusion protein [etanercept] is not effective and the anti-TNF F[ab']2 fragment [certolizumab] shows a very low rate of complete mucosal healing. In contrast, all four TNF-neutralising drugs have demonstrated efficacy in the treatment of rheumatoid arthritis. These observations suggest that factors other than neutralisation of TNF may contribute to clinical outcomes in Crohn's disease. Here we tested the hypothesis that Fc receptor [FcR]-mediated effects may contribute to the therapeutic response of anti-TNF antibodies in inflammatory bowel disease.
We modified an IgG2c mouse anti-TNF antibody that binds the high-affinity FcRs to generate an IgG1 isotype with strongly diminished binding. We examined the therapeutic effects of both antibodies in the T cell transfer model of inflammatory bowel disease and the collagen-induced arthritis model.
The IgG2c anti-TNF antibody prevented colonic inflammation in the T cell transfer model of colitis, whereas the IgG1 anti-TNF did not. Conversely, both the IgG2c and IgG1 anti-TNFs were similarly effective in reducing the severity of articular inflammation in mouse collagen-induced arthritis.
These data support the concept that the mechanism of action for TNF-neutralising drugs may differ across immune-mediated diseases and, potentially, between therapeutics within a particular disease. Our data suggest a specific role of Fc-mediated immune regulation in the resolution of intestinal inflammation by anti-TNF monoclonal antibodies.
抗肿瘤坏死因子（TNF）单克隆抗体（英夫利昔单抗、阿达木单抗）可使部分克罗恩病患者实现完全黏膜愈合，而TNF受体融合蛋白（依那西普）无效，抗TNF F(ab')2片段（赛妥珠单抗）显示完全黏膜愈合率极低。相比之下，所有这四种TNF中和药物在类风湿关节炎治疗中均已证明有效。这些观察结果表明，除TNF中和作用外的其他因素可能对克罗恩病的临床疗效有影响。在此，我们检验了如下假设：Fc受体（FcR）介导的效应可能有助于抗TNF抗体在炎症性肠病中的治疗反应。
我们对一种能结合高亲和力FcR的IgG2c小鼠抗TNF抗体进行改造，以生成一种结合力大幅降低的IgG1同种型。我们在炎症性肠病的T细胞转移模型和胶原诱导的关节炎模型中研究了这两种抗体的治疗效果。
在结肠炎的T细胞转移模型中，IgG2c抗TNF抗体可预防结肠炎症，而IgG1抗TNF抗体则不能。相反，在小鼠胶原诱导的关节炎中，IgG2c和IgG1抗TNF抗体在减轻关节炎症严重程度方面同样有效。
这些数据支持了这样一种概念，即TNF中和药物的作用机制可能在不同免疫介导疾病之间存在差异，并且在特定疾病的不同治疗药物之间也可能存在差异。我们的数据表明Fc介导的免疫调节在抗TNF单克隆抗体解决肠道炎症方面具有特定作用。
