title: The cytotoxic effects of certolizumab pegol and golimumab mediated by transmembrane tumor necrosis factor α.
abstract: 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.
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Naoyasu
authors.initials: N
authors.lastname: Ueda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mitoma
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ayano
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Ohta
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Arinobu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Takahiko
authors.initials: T
authors.lastname: Horiuchi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D000068582:Certolizumab Pegol; D003165:Complement System Proteins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D009154:Mutation / Q000235:genetics; D011092:Polyethylene Glycols / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D003165:Complement System Proteins; C529000:golimumab; D020169:Caspases; D000068582:Certolizumab Pegol