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

Background: Inhibitors of tumor necrosis factor a (TNF alpha) have demonstrated significant efficacy in chronic inflammatory diseases, including Crohn's disease (M). To further elucidate the mechanisms of action of these agents, we compared the anti-TNF alpha agents certolizumab pegol, infliximab, adalimumab, and etanercept in several in vitro systems. Methods: The ability of each anti-TNF alpha agent to neutralize soluble and membrane-bound TNFa; 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 beta production by human monocytes was measured in vitro. Results: All 4 agents neutralized soluble TNFa and bound to and neutralized membrane TNF alpha. 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 beta production was inhibited by certolizurnab pegol, infliximab, and adalimumab, but only partially inhibited by etanercept. Conclusions: In contrast to the other anti-TNFa agents tested, certolizurnab 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-TNFa agents in CD. As certolizurnab pegol, infliximab, and adalimumab, but not etanercept, almost completely inhibited LPS-induced IL-1 beta release from monocytes, inhibition of cytokine production may be important for efficacy of anti-TNF alpha agents in CD.