Mechanism of action of certolizumab pegol (CDP870): In vitro comparison with other anti-tumor necrosis factor a agents

• Published in: Inflammatory bowel diseases 2007-11, Vol.13 (11), p.1323-1332
• Main Authors: Nesbitt, Andrew, Fossati, Gianluca, Bergin, Marianne, Stephens, Paul, Stephens, Sue, Foulkes, Roly, Brown, Derek, Robinson, Martyn, Bourne, Tim
• Format: Article
• Language: English
• Subjects: Antibody-dependent cell-mediated cytotoxicity; Apoptosis; Crohn's disease; Cytotoxicity; Degranulation; etanercept; Inflammatory bowel diseases; infliximab; Interleukin 1; Intestine; Leukocytes (granulocytic); Lipopolysaccharides; Lymphocytes; Monoclonal antibodies; Monocytes; Peripheral blood; Tumor necrosis factor; Tumor necrosis factor- alpha
• ISSN: 1078-0998
• DOI: 10.1002/ibd.20225

Background: Inhibitors of tumor necrosis factor (TNF) 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-TNF agents certolizumab pegol, infliximab, adalimumab, and etanercept in several in vitro systems. Methods: The ability of each anti-TNF agent to neutralize soluble and membrane-bound TNF; 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)-1 production by human monocytes was measured in vitro. Results: All 4 agents neutralized soluble TNF and bound to and neutralized membrane TNF. 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-1 production was inhibited by certolizumab pegol, infliximab, and adalimumab, but only partially inhibited by etanercept. Conclusions: In contrast to the other anti-TNF 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-TNF agents in CD. As certolizumab pegol, infliximab, and adalimumab, but not etanercept, almost completely inhibited LPS-induced IL-1 release from monocytes, inhibition of cytokine production may be important for efficacy of anti-TNF agents in CD. (Inflamm Bowel Dis 2007).