Biomedical Engineering Reference
In-Depth Information
meaning that a poly ethylene glycol (PEG) moiety is specii cally attached to the protein such that it
does not interfere with the protein interactions (see also Chapter 4). The resulting molecule has an
increased size and renal clearance of the molecule is decreased, thereby extending the half-life of
the molecule.
22.5.2 M ONOCLONAL A NTIBODIES
Monoclonal antibodies (mAbs) are artii cial antibodies against a particular target (the “antigen”)
and are produced in the laboratory. The original method involved hybridoma cells (a fusion of two
different types of cells) that acted as factories for antibody production. A major advance in this i eld
was the ability to convert these antibodies, which originally were made from mouse hybridomas, to
“humanized” antibodies that more closely resemble our natural antibodies. mAbs have been widely
used in scientii c studies of cancer, as well as in cancer diagnosis. They are now used as a very
successful molecular format in treatment of several diseases where there is a high unmet medical
need and where targets are the so-called nondruggable, i.e., it has not been successful to make
small molecules against the target. The format is highly attractive due to the relatively long in vivo
half-life of the antibodies and the fact that we have high levels of antibodies circulating so the body
does not see them as foreign entities and the risk of immunogenic effects is therefore reduced. The
primary drawback of using antibodies is that so far have to be delivered as injectibles either by the
intravenous or subcutaneous administration.
22.5.3 C YTOKINES
Cytokines are relatively small proteins that play a major role in modulating the immune system.
Among the large number of cytokines are the IFNs, TNF, and the interleukins. Cytokines are manu-
factured and released by cells of the immune system and perform a variety of functions including
cell activation, inl ammation, tissue breakdown, and repair as well as cell death. Various different
cytokines send different complex signals to other cells including: calling immune system cells to
the site of the infection, telling endothelial (blood vessel “lining”) cells to let these cells through and
telling immune system cells to activate themselves.
Using the body's own immunomodulators is becoming an exciting possibility to target inefi cient
or misdirected immune responses that result in diseases. The potential benei ts in terms of treat-
ment of human diseases are enormous and still largely unexplored. Thus, using cytokines and their
antagonists as therapeutic agents is an emerging and growing area of research.
22.5.3.1 Interferons
IFNs belong to the cytokine protein family. They are produced by white blood cells in the body
(or in the laboratory) in response to infection, inl ammation, or stimulation. They have been used
as a treatment for certain viral diseases, including hepatitis B and C as well as MS. IFNs can be
divided into three groups, IFN-
, respectively. Sub-variants of each group have
been developed as therapeutic agents in the form of recombinant proteins for injection.
IFNs regulate cell function in the immune system by blocking cell growth and differentiation
and stimulating monocytes and macrophages. In MS, IFN-
α
, IFN-
β
, and IFN-
γ
works indirectly on the central nervous
system (CNS) by reducing the inl ammatory reaction. The exact mechanism is unknown but it is
believed that IFN-
β
can improve the activity of regulatory T cells, reduce the production of proin-
l ammatory cytokines such as, TNF-
β
, IL-6, IL-1, and IL-8. They have been shown to downregu-
late antigen presentation and the mobility of the activated T cells in the CNS.
IFN-
α
was one of the i rst cytokines to show an antitumor effect, and it is able to slow tumor
growth di rectly, as well as help to activate the im mune system. I F N-
α
has been approved by the FDA
and is now commonly used for the treatment of a number of cancers, including multiple myeloma,
chronic myelogenous leukemia, hairy cell leukemia, and malignant melanoma.
α
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