The initial interest in utilizing TNF as a general anti-cancer agent has diminished, largely due to the realization that:
• many tumours are not susceptible to destruction mediated by TNF (indeed, some tumours produce TNF as an autocrine growth factor);
• tumour cell necrosis is not TNF's major biological activity;
• severe side effects usually accompany systemic administration of therapeutically relevant doses of this cytokine.
One such product (tradename Beromun) has been approved for general medical use (Box 9.2). Most clinical interest in TNF, however, now centres around neutralizing its biological effects in situations where overexpression of TNF induces negative clinical effects. TNF has been firmly implicated in mediating many of the adverse effects associated with dozens of diseases (Table 9.7). Administration of anti-TNF monoclonal antibodies or soluble forms of the TNF receptor should help reduce the severity of many of the symptoms of these diseases.
Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone.
More recently, an additional approach to preventing TNF toxicity has been proposed. Several metalloprotease inhibitors (most notably hydroxamic acid) prevent proteolytic processing (i.e. release) of TNF-a from producer cell surfaces. Such inhibitors may also prove useful in preventing TNF-induced illness. The extent to which TNF (and inhibitors of TNF) will serve as future therapeutic agents remains to be determined by future clinical trials.
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