Biomedical Engineering Reference
In-Depth Information
The purifi ed product is presented as a solution and contains sodium citrate, EDTA, sodium chloride
and polysorbate 80 as excipients. A daily (s.c.) injection of 100 mg is recommended for patients
with rheumatoid arthritis. This infl ammatory condition is (not surprisingly) characterized by the
presence of high levels of IL-1 in the synovial fl uid of affected joints. In addition to its pro-infl am-
matory properties, IL-1 also mediates additional negative infl uences on the joint/bone, including
promoting cartilage degradation and stimulation of bone resorption.
An additional approach to IL-1 down-regulation could entail development of inhibitors of the
proteolytic enzymes that release the active interleukin from its inactive precursor. Moreover, such
inhibitors could probably be taken orally and, thus, would be suitable to treat chronic infl amma-
tion (the alternatives outlined above would be administered parenterally).
The enzyme that releases active IL-1
from its 31 kDa precursor has been identifi ed and stud-
ied in detail. Termed IL-1β converting enzyme (ICE), it is a serine protease whose only known
physiological substrate is the inactive IL-1
β
β
precursor. ICE cleaves this precursor between Asp 116
and Ala 117, releasing the active IL-1β.
ICE is an oligomeric enzyme (its active form may be a tetramer). It contains two distinct
polypeptide subunits, p20 (20 kDa) and p10 (10 kDa). These two subunit types associate very
closely, and the protease's active site spans residues from both. p10 and p20 are proteolytically
derived from a single 45 kDa precursor protein.
9.4 Interleukin-11
IL-11 is an additional cytokine that has gained approval for general medical use. This cytokine,
produced largely by IL-1-activated bone marrow stromal cells and fi broblasts, functions as a hae-
matopoietic growth factor. It stimulates (a) thrombopoiesis (the production of platelets formed by
the shedding of fragments of cytoplasm from large bone marrow cells called megakaryocytes;
Chapter 10) and (b) growth/differentiation of bone marrow cells, derived from stem cells that have
become committed to differentiate into macrophages.
IL-11 is a 23 kDa, 178 amino acid polypeptide. Its receptor appears to be a single-chain 150 kDa
transmembrane protein. Binding of IL-11 results in tyrosine phosphorylation of several intracel-
lular proteins, which, in turn, somehow promote the observed biological activities of IL-11.
The rationale for assessing IL-11 as a potential therapeutic agent relates mainly to its ability to
induce platelet synthesis. Platelet counts can be signifi cantly lowered due to certain disease condi-
tions and in patients undergoing cancer chemotherapy. Trials in patients receiving chemotherapy
illustrated that s.c. administration of IL-11, at levels above 25 µg per kilogram body weight per
day, did stimulate platelet production, at least partially offsetting the chemotherapeutic effects.
When administered at levels of 50 µg kg 1 day 1 , a signifi cant increase in the bone marrow meg-
akaryocyte population was noted. At levels in excess of 75
g kg 1 day 1 , side effects, including
fatigue and oedema (tissue swelling due to accumulation of fl uid), were also noted.
Neumega is the tradename given to the IL-11-based product approved for the prevention
of thrombocytopenia. The product is produced in engineered E. coli cells and is presented
as a purifi ed product in freeze-dried format. Excipients include phosphate buffer salts and
glycine. It is reconstituted (with water for injections) to a concentration of 5 mg ml 1 before
s.c. administration.
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