Biomedical Engineering Reference
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associated proteins are likely to become activated, thus mediating additional downstream
events that eventually trigger characteristic TNF molecular responses. The downstream events
are complex and varied. Experimental evidence from various studies implicates a variety of
mechanisms, including phosphorylation events, as well as activation of various phospholi-
pases, resulting in the generation of messengers such as diacylglycerol, inositol phosphates and
arachidonic acid.
9.5.5 Tumour necrosis factor: therapeutic aspects
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
fi rmly 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 F
c
(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 purifi cation and excipient addition
(mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treat-
ment 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-infl ammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell
surface receptors. The antibody F
c
component of the hybrid protein confers an extended serum
half-life on the product, increasing it by fi vefold 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. re-
lease) of TNF-α 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 thera-
peutic agents remains to be determined by future clinical trials.
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