Biomedical Engineering Reference
In-Depth Information
potentially contribute to breaking self-tolerance, particularly if combined with any of the
circumstances outlined in the surrounding bulleted points.
•
Genetic and/or immunological factors.
Some individuals may display underlining or in-
duced immunological abnormalities, rendering them more susceptible to breakdown of self-
tolerance. For example, some blood factor and hormone preparations isolated by direct ex-
traction from human serum or tissue stimulated an immunological response in a proportion
of human patients receiving them. This may be triggered by some immune defi ciency in the
patients themselves, although the presence of product impurities or structural altered product
forms may also be contributing factors.
Even if a biopharmaceutical triggers an immune response, it does not automatically follow
that the response will be clinically signifi cant or undesirable. In some instances, anti-product
antibodies have no effect upon safety or effi cacy. In other instances, antibody binding may
alter the product's pharmacokinetic properties or directly neutralize the biopharmaceutical's
biological activity. Even more seriously, antibodies raised against the product could poten-
tially cross-react with the endogenous form of the protein, neutralizing it. Eprex provides an
example of this latter phenomenon. Antibodies formed against the product cross-reacted with
endogenous EPO, causing shutdown of (EPO-stimulated) red blood cell production, triggering
antibody-mediated pure red cell aplasia.
A number of approaches may be adopted in an attempt to reduce or eliminate protein im-
munogenicity. Protein engineering (Chapter 3), for example, has been employed to humanize
monoclonal antibodies (Chapter 13). An alternative approach entails the covalent attachment
of polyethylene glycol (PEG) to the protein backbone. This can potentially shield immunogenic
epitopes upon the protein from the immune system.
distribution profi le. The approach taken usually relies upon protein engineering, be it alteration of
amino acid sequence, alteration of a native post-translational modifi cation (usually glycosylation)
or the attachment of a chemical moiety to the protein's backbone (often the attachment of PEG,
i.e. PEGylation). Specifi c examples of therapeutic proteins engineered in this way are discussed in
detail within various subsequent chapters, and are summarized in Table 4.3.
4.12.3 Protein mode of action and pharmacodynamics
Different protein therapeutics bring about their therapeutic effect in different ways (Figure 4.8).
Hormones and additional regulatory molecules invariably achieve their effect by binding to a
specifi c cell surface receptor, with receptor binding triggering intracellular signal transduction
event(s) that ultimately mediate the observed physiological effect(s). Many antibodies, on the
other hand, bring about their effect by binding to their specifi c target molecule, which either
inactivates/triggers destruction of the target molecule or (in the case of diagnostic applications)
effectively tags the target molecules/cells. Therapeutic enzymes bring about their effect via a
catalytic mechanism. The mode of action of many specifi c biopharmaceuticals will be outlined in
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