title: Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents.
abstract: BACKGROUND
  Inhibitors of tumor necrosis factor alpha (TNFalpha) have demonstrated significant efficacy in chronic inflammatory diseases, including Crohn's disease (CD). To further elucidate the mechanisms of action of these agents, we compared the anti-TNFalpha agents certolizumab pegol, infliximab, adalimumab, and etanercept in several in vitro systems.
  
  
  METHODS
  The ability of each anti-TNFalpha agent to neutralize soluble and membrane-bound TNFalpha; mediate cytotoxicity, affect apoptosis of activated human peripheral blood lymphocytes and monocytes; induce degranulation of human peripheral blood granulocytes, and modulate lipopolysaccharide (LPS)-induced interleukin (IL)-1beta production by human monocytes was measured in vitro.
  
  
  RESULTS
  All 4 agents neutralized soluble TNFalpha and bound to and neutralized membrane TNFalpha. Infliximab and adalimumab were comparable in their ability to mediate complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and to increase the proportion of cells undergoing apoptosis and the level of granulocyte degranulation. Etanercept generally mediated these effects to a lesser degree, while certolizumab pegol gave similar results to the control reagents. LPS-induced IL-1beta production was inhibited by certolizumab pegol, infliximab, and adalimumab, but only partially inhibited by etanercept.
  
  
  CONCLUSIONS
  In contrast to the other anti-TNFalpha agents tested, certolizumab pegol did not mediate increased levels of apoptosis in any of the in vitro assays used, suggesting that these mechanisms are not essential for the efficacy of anti-TNFalpha agents in CD. As certolizumab pegol, infliximab, and adalimumab, but not etanercept, almost completely inhibited LPS-induced IL-1beta release from monocytes, inhibition of cytokine production may be important for efficacy of anti-TNFalpha agents in CD.
authors.affiliation: Inflammation Discovery, UCB Celltech, Slough, UK. Andrew.Nesbitt@celltech.UCB-group.com
authors.forename: Andrew
authors.initials: A
authors.lastname: Nesbitt
authors.forename: Gianluca
authors.initials: G
authors.lastname: Fossati
authors.forename: Marianne
authors.initials: M
authors.lastname: Bergin
authors.forename: Paul
authors.initials: P
authors.lastname: Stephens
authors.forename: Sue
authors.initials: S
authors.lastname: Stephens
authors.forename: Roly
authors.initials: R
authors.lastname: Foulkes
authors.forename: Derek
authors.initials: D
authors.lastname: Brown
authors.forename: Martyn
authors.initials: M
authors.lastname: Robinson
authors.forename: Tim
authors.initials: T
authors.lastname: Bourne
mesh_terms: D000068879:Adalimumab; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D001773:Blood Cells; D002478:Cells, Cultured; D000068582:Certolizumab Pegol; D004341:Drug Evaluation; D000068800:Etanercept; D006098:Granulocytes / Q000187:drug effects; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D000069285:Infliximab; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D009000:Monocytes; D011092:Polyethylene Glycols / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept; D000068582:Certolizumab Pegol