Background: Anti–tumor necrosis factor α (anti-TNF-α) 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-α but also the effect on transmembrane TNF-α is important mechanisms of action of anti-TNF-α agents. This study investigated the cytotoxic effects of new anti-TNF-α agents, certolizumab pegol and golimumab, which are mediated by transmembrane TNF-α.
Methods: Transmembrane TNF-α–expressing Jurkat T cells that did not express TNF receptors were used. The binding ability of each anti-TNF-α agent to transmembrane TNF-α, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and the apoptotic effect were examined.
Results: Certolizumab pegol and golimumab bound to transmembrane TNF-α. 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-α–expressing cells. Golimumab induced a weaker apoptotic effect than infliximab and adalimumab.
Conclusions: The cytotoxic effects of anti-TNF-α agents on TNF-α–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-α–producing cells may contribute to its clinical efficacy in Crohn's disease. Golimumab may be less effective for granulomatous diseases.
Article first published online 28 March 2013
*Department of Medicine and Biosystemic Science, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
†Department of Internal Medicine, Saga University, Saga, Japan
‡Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan
§Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Reprints: Hiroshi Tsukamoto, MD, PhD, Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (e-mail: email@example.com).
The authors have no conflicts of interest to disclose.
Supported in part by grants from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Received August 10, 2012
Accepted August 24, 2012