Biotechnology Healthcare - June 2008 - (Page TNF3) TABLE 2 Functional attributes of tumor necrosis factor (TNF) inhibitors Human soluble receptor (etanercept) • TNF-α • TNF-β (LT-α) • Bioactive/trimer TNF-α • No large protein complexes • Unstable with rapid dissociation • Apoptosis: • Monocytes in RA Monoclonal antibodies (infliximab, adalimumab) • TNF-α • Bioactive/trimer TNF-α • Inactive/monomer TNF-α* • Large protein complexes • Stable with slow dissociation • Apoptosis: • Monocytes in RA and CD* • T-cells in CD • Lysis • Reduction in TB-responsive T-cells • Suppressed production Attributes Binding targets TNF-α binding selectivity Complex formation with TNF-α TNF-α binding stability Induction of cytotoxic responses Impact on INF-γ activity * Data available only for infliximab • Lesser effect CD=Crohn’s disease, INF= interferon, LT=lymphotoxin, RA=rheumatoid arthritis, TB=tuberculosis. SOURCES: MANUFACTURERS’ PRESCRIBING INFORMATION, SCALLON 2002, KOHNO 2007, SANTORA 2001, LUGERING 2006, FURST 2006, SALIU 2006 TNF-α has been implicated in the inflammatory cycle (Heresbach 2005). Owing to their structural differences, TNF inhibitors display fundamentally diverse TNF-α binding characteristics. First, etanercept targets only the bioactive form of TNF-α, which is a trimer (Scallon 2002). In contrast, infliximab has been shown to bind not only to the trimeric form of TNF-α, but also to its inactive monomeric precursors (Scallon 2002). It is suspected that adalimumab also binds to both forms of TNF-α. Binding to the TNF monomers may interfere with the formation of the bioactive trimeric TNF (Scallon 2002). Second, the mAbs have been shown to form large complexes with the TNF-α molecules, which may lead to antibody- and complementdependent cellular cytotoxicity (Kohno 2007). Third, the TNF dissociates from etanercept at a significantly faster rate than that seen with the mAbs (Scallon 2002, Santora 2001). When the TNF dissociates from etanercept, it remains bioactive (Scallon 2002). Thus, it has been suggested that in comparison with etanercept, the mAbs have a greater potential for neutralization of the TNF. As mentioned previously, sufficient levels of TNF-α are needed to sustain normal immune response. Activity at the points of impact A comparison of the binding profiles of the TNF inhibitors helps to highlight the potentially important functional differences among these agents. First, the potential to induce cellular apoptosis may vary (Lugering 2006), and the role of cellular mediators and the mechanisms of action underlying their therapeutic effects may vary with each disease state. For instance, unlike etanercept, the anti-TNF mAbs have demonstrated induction of apoptosis in monocytes and lymphocytes extracted from patients with Crohn’s disease (Van den Brande 2003, Shen 2005). However, in a study involving cells extracted from the joints of patients with RA (Catrina 2005), etanercept and infliximab showed similar effects — both agents induced apoptosis in monocytes, but not lymphocytes . TNF inhibitors also may have different propensities for lysing cells that express TNF on their membranes (Strand 2007, Furst 2006). It is believed that when bound to the transmembrane TNF, the mAbs can lead to cellular lysis. In contrast, etanercept has not shown to induce lysis in vitro in the presence or absence of complement. Although the clinical significance of this difference is unknown, lysis of cells with transmembrane TNF may be associated with a greater susceptibility to granulomatous infections (Furst 2006). It should be noted that TNF-expressing cells include monocytes, macrophages, and lymphocytes, all of which play a critical role in the formation of granulomas (Wallis 2005). Conclusion In an effort to control utilization of TNF inhibitors, MCOs may be compelled to apply traditional category management techniques, including the selection of a preferred agent. Given the significant differences among 3
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