Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α antagonists

Tumor necrosis factor (TNF)-alpha is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-alpha therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-alpha, full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-alpha antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-alpha agents on neutralization of soluble TNF-alpha, each anti-TNF-alpha agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-alpha agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-alpha, and lymphotoxin, (2) effects toward transmembrane TNF-alpha-expressing cells, (3) effects toward Fc gamma receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-alpha agents to enhance the clinical efficacy in inflammatory diseases. (C) 2016 Elsevier Ltd. All rights reserved.