Recombinant blood products and therapeutic enzymes - Pharmaceutical Biotechnology: Concepts and Aapplications - page 355

The thrombolytic ability of (recombinant) staphylokinase has been evaluated in initial clini-
cal trials with encouraging results. Some 80 per cent of patients suffering from acute myocardial
infarction who received staphylokinase responded positively (10 mg staphylokinase was admin-
istered by infusion over 30 min). The native molecule displays a relatively short serum half-life
(of 6.3 min), although covalent attachment of PEG reduces the rate of serum clearance, hence
effectively increasing the molecule's half-life signifi cantly. As with streptokinase, patients admin-
istered staphylokinase develop neutralizing antibodies. A number of engineered (domain-deleted)
variants have been generated that display signifi cantly reduced immunogenicity.

12.4.7 α 1 -Antitrypsin

The respiratory tract is protected by a number of defence mechanisms, including:

• particle removal in the nostril/nasopharynx;

• particle expulsion (e.g. by coughing);

• upward removal of substances via mucociliary transport;

• presence in the lungs of immune cells, such as alveolar macrophages;

• production/presence of soluble protective factors, including α 1 -antitrypsin, lysozyme, lactofer-

rin and interferon.

Failure/ineffective functioning of one or more of these mechanisms can impair normal respira-
tory function. Emphysema, for example, is a condition in which the alveoli of the lungs are dam-
aged. This compromises the lung's capacity to exchange gases, and breathlessness often results.
This condition is often promoted by smoking, respiratory infections or a defi ciency in the produc-
tion of serum α 1 -antitrypsin.

α 1 -Antitrypsin is a 394 amino acid, 52 kDa serum glycoprotein. It is synthesized in the liver and
secreted into the blood, where it is normally present at concentrations of 2-4 g l 1 . It constitutes
in excess of 90 per cent of the α 1 -globulin fraction of blood.
The α 1 -antitrypsin gene variants

have been described. Their gene products can be distinguished by their differential mobility upon
gel electrophoresis. The normal form is termed M, but point mutations in the gene have gener-
ated two major additional forms, i.e. S and Z. These mutations result in a greatly reduced level of
synthesis and secretion into the blood of the mature

α 1 -antitrypsin gene is located on chromosome 14. A number of

α 1 -antitrypsin. In particular, persons inherit-
ing two copies of the Z gene display greatly reduced levels of serum α 1 -antitrypsin activity. This
is often associated with the development of emphysema (particularly in smokers). The condition
may be treated by the administration of purifi ed α 1 -antitrypsin. This protein constitutes the major
serine protease inhibitor present in blood. It is a potent inhibitor of the protease elastase, which
serves to protect the lung from proteolytic damage by inhibiting neutrophil elastase. The product
is administered on an ongoing basis to sufferers, who receive up to 200 g of the inhibitor each
year. It is normally prepared by limited fractionation of whole human blood, although the large