The Cytotoxic Effects of Certolizumab Pegol and Golimumab Mediated by Transmembrane Tumor Necrosis Factor &agr;

Background:Anti–tumor necrosis factor &agr; (anti-TNF-&agr;) agents have been successfully applied for the treatment of rheumatoid arthritis, Crohn's disease, and other chronic inflammatory diseases. Not only the neutralization of soluble TNF-&agr; but also the effect on transmembrane TNF-&agr; is important mechanisms of action of anti-TNF-&agr; agents. This study investigated the cytotoxic effects of new anti-TNF-&agr; agents, certolizumab pegol and golimumab, which are mediated by transmembrane TNF-&agr;. Methods:Transmembrane TNF-&agr;–expressing Jurkat T cells that did not express TNF receptors were used. The binding ability of each anti-TNF-&agr; agent to transmembrane TNF-&agr;, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and the apoptotic effect were examined. Results:Certolizumab pegol and golimumab bound to transmembrane TNF-&agr;. Golimumab induced antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, which was comparable to infliximab and adalimumab. However, certolizumab pegol did not induce antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity. Certolizumab pegol directly induced nonapoptotic cell death in transmembrane TNF-&agr;–expressing cells. Golimumab induced a weaker apoptotic effect than infliximab and adalimumab. Conclusions:The cytotoxic effects of anti-TNF-&agr; agents on TNF-&agr;–expressing cells are considered to be associated with the clinical effect of these agents on granulomatous diseases. The direct cytotoxic effect of certolizumab pegol on TNF-&agr;–producing cells may contribute to its clinical efficacy in Crohn's disease. Golimumab may be less effective for granulomatous diseases.

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