Biomedical Engineering Reference
In-Depth Information
Pharmacokinetic studies indicate the product displays two-compartment behaviour, with a
distribution phase (half-life 2-5 min) and a terminal phase (half-life 70-80 min). Development
of antibodies to the product signifi cantly impacts upon clearance rates.
The major clinical study underpinning product approval was a randomized, double blind
study in which 71 CTCL patients were administered the product at one of two dosage levels (9
or 18 µg kg
1
day
1
); overall, 30 per cent of patients experienced an objective tumour response.
Serious side effects potentially associated with product administration include acute hypersen-
sitivity-type reactions, vascular leak syndrome and visual impairment. Additional adverse re-
actions include fl u-like symptoms, headache, hyper- or hypo-tension, as well as digestive upset.
Ontak is manufactured by Seragen Inc. and is distributed by Ligand Pharmaceuticals.
9.3 Interleukin-1
IL-1 is also known as lymphocyte-activating factor (LAF), endogenous pyrogen and catabolin. It
displays a wide variety of biological activities and has been appraised clinically in several trials.
Two distinct forms of IL-1 exist: IL-1
. Although different gene products, and ex-
hibiting only 20 per cent amino acid sequence homology, both of these molecules bind the same
receptor and induce similar biological activities. The genes coding for IL-1
α
and IL-1
β
both reside
on human chromosome number 2, and display similar molecular organization, both containing
seven exons.
IL-1
α
and -1
β
are expressed as large (30 kDa) precursor molecules from which the mature
polypeptide is released by proteolytic cleavage. Neither IL-1
α
and -1
β
possess any known secre-
tory signal peptide, and the molecular mechanism by which they exit the cell remains to be char-
acterized. Neither interleukin appears to be glycosylated.
IL-1
α
and -1
β
is initially synthesized as a 271 amino acid precursor, with the mature form containing
159 amino acids (17.5 kDa). This molecule appears to remain associated with the extracellular
face of the cell membrane. IL-1
α
, initially synthesized as a 269 amino acid precursor, is released
fully from the cell. The mature form released contains 153 amino acids and displays a molecular
mass in the region of 17.3 kDa.
X-ray diffraction analysis reveals the three-dimensional structure of both IL-1 molecules to be
quite similar. Both are globular proteins, composed of six strands of antiparallel
β
β
pleated sheet
forming a 'barrel' that is closed at one end by a further series of
sheets.
A wide range of cells are capable of producing IL-1 (Table 9.4). Different cell types produce the
different IL-1s in varying ratios. In fi broblasts and endothelial cells, both are produced in roughly
similar ratios, whereas IL-1
β
β
is produced in larger quantities than IL-1
α
in monocytes. Activated
macrophages appear to represent the major cellular source for IL-1.
The IL-1s induce their characteristic biological activities by binding to specifi c cell surface
receptors present on sensitive cells. Two distinct receptors, type I and II, have been identifi ed.
Both IL-1
can bind both receptors. The type I receptor is an 80 kDa transmem-
brane glycoprotein. It is a member of the IgG superfamily. This receptor is expressed predomi-
nantly on fi broblasts, keratinocytes, hepatocytes and endothelial cells. The type II receptor is a
60 kDa transmembrane glycoprotein, expressed mainly on B-lymphocytes, bone marrow cells
and polymorphonuclear leukocytes. It displays a very short (29 amino acid) intracellular domain,
α
and IL-1
β
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