Differences Among TNF Antagonists

There may be clinically important differences among TNF antagonists. Immunogenicity is directly related to the structure of protein therapeutics and may result in increased adverse effects and diminished efficacy. Antibodies to adalimumab, a fully human monoclonal IgGj antibody indistinguishable from naturally occurring IgG1, were observed in 5 % of patients with rheumatoid arthritis (Humira prescribing information, 2005). This low level of immunogenicity is reflective of the natural process of anti-idiotypic antibody formation to endogenous antibodies characteristic of the natural immune network (Jerne 1974). Certolizumab is a polyethylene glycolated Fab' fragment of a humanized anti-TNF monoclonal antibody. It led to the formation of anticer-tolizumab antibodies in approximately 12 % of patients in a phase 2 trial (Schreiber et al. 2005). In contrast, inf-liximab, a chimeric antibody developed by recombinant fusion of murine and human antibody components, can be immunogenic in a high proportion of patients, especially when administered episodically, unless immunosuppressive drugs are administered concomitantly (Anderson 2005; Baert et al. 2003; Maini et al. 1998). Problems encountered during clinical experience with infliximab include infusion reactions, loss of response, and serum sickness-like delayed reactions, which limit its long-term use.

Pharmacokinetic differences between the TNF antagonists also are apparent. Because of their longer half-lives, adalimumab and certolizumab are adminis tered subcutaneously on an intermittent dosing schedule. In contrast, infliximab is administered by infrequent intravenous infusion, which produces peak concentrations significantly higher and trough concentrations significantly lower than those administered sub-cutaneously (Granneman et al. 2003; Maini et al. 1998; Zhou et al. 2004). Although the clinical implications of these substantial fluctuations in concentration are unknown, subcutaneously administered products are more convenient for patients and healthcare providers in comparison with intravenously administered products. Infusion-related resource and monitoring costs also are a consideration with intravenously administered products, such as infliximab.

Finally, although no head-to-head clinical trials have been performed, clinical data suggest that there may be differences in efficacy among the TNF antagonists, as seen in CD. These differences in efficacy among TNF antagonists may at least partially be related to the ability of infliximab and adalimumab to induce apoptosis of T cells (Shen et al. 2005). Although it is accepted that both infliximab and adalimumab bind to membrane TNF on transfected cells, in vitro data on binding and initiation of Fc-mediated effector functions such as complement activation or antibody-dependent cellular cytotoxicity (ADCC) by normal human cells are inconsistent (Fossati and Nesbitt 2005b; Scallon et al. 1995; van den Brande et al. 2003). There also are conflicting in vitro data regarding the induction of apoptosis in T cells, monocytes, or other cells by etanercept (Catrina et al. 2005; Fossati and Nes-bitt 2005a; Mitoma et al. 2005; Shen et al. 2005; van den Brande et al. 2003; van Deventer et al. 2003). The recent demonstration of certolizumab efficacy in CD (Schreiber 2005) and data showing no induction of apoptosis, complement-dependent cytotoxicity or ADCC by cer-tolizumab in vitro (Fossati and Nesbitt 2005a, 2005b) raises questions about the relevance of these mechanisms to the efficacy of TNF antagonists in CD.

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