Biomedical Engineering Reference
In-Depth Information
Box 9.2
Product case study: Beromun
-1a produced by recom-
binant means in E. coli . The recombinant product is identical to the native human protein,
with three 17.3 kDa, 157 amino acid polypeptides forming the biologically active homotrimer.
It gained approval for use within the EU in 1999. Beromun is indicated for the treatment of
soft-tissue sarcoma (STS) in the limbs, mainly so as to prevent or delay amputation. It is usu-
ally used in combination with the chemotherapeutic drug melphalan. STS is a relatively rare
malignancy (0.6 per cent of newly diagnosed cancers) and only some 10 per cent of sufferers
require amputation or severely debilitating surgery.
After initial cell fermentation and product extraction from the producer cells, the crude
preparation is subject to multiple chromatographic steps, including ion-exchange, hydrophobic
interaction chromatography and gel-fi ltration chromatography. The purifi ed product is pre-
sented in lyophilized form in vials (1 mg active/vial) and excipients include a phosphate buffer,
sodium chloride and serum albumin.
The product (reconstituted in sterile physiological saline to a concentration of 0.2 mg ml 21 )
is administered by isolated limb perfusion in which 3-4 mg of product is circulated through
the limb over 90 min via a perfusion circuit divorced from general body circulation. The exact
mechanisms by which the product induces haemorrhagic necrosis in tumours remain to be elu-
cidated. Pharmacokinetic studies indicate that TNF administered systemically has a relatively
short terminal half-life (20-30 min). Studies indicate some systemic leakage will occur during
the procedure and/or that some TNF will enter systemic circulation upon restoration of circula-
tion to the isolated limb subsequent to the procedure. Common (systemic) side effects include
nausea, cardiac arrhythmias and liver toxicity, whereas regional side effects (in the isolated
limb) can include oedema, nerve injury and infection. Clinical trials verifi ed that beromun
delays/prevents the need for whole limb amputation in a majority of patients treated.
Beromun (tradename, also known as tasonermin) is human TNF-
α
Table 9.7 Some diseases in which TNF is known to mediate many of the symptoms
Disease
Symptoms induced by TNF
Cancer
Cachexia
Stimulation of growth of some tumours
Septic shock
Vascular leakage
Tissue necrosis
Hypotension
Activates blood clotting
Rheumatoid arthritis
Tissue infl ammation
Possible role in destruction of joints
MS
Infl ammation
Diabetes
Death of pancreatic islet cells induces insulin resistance
 
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