Biomedical Engineering Reference
In-Depth Information
Box 4.1
Protein immunogenicity
Most traditional pharmaceuticals are relatively low molecular weight substances and generally
escape the attention of the immune system. Proteins, on the other hand, are macromolecules
and display molecular properties that can potentially trigger a vigorous immune response. Dur-
ing its formation our immune system develops tolerance to self-antigens. Such immunological
tolerance is generally maintained throughout our lifetime by various regulatory mechanisms
that either (a) prevent B- and T-lymphocytes from becoming responsive to self-antigens or (b)
that inactivate such immune effector cells once they encounter self-antigens.
Based on the above principles, it might be assumed that a therapeutic protein obtained by
direct extraction from human sources (e.g. some antibody preparations) or produced via re-
combinant expression of a human gene/cDNA sequence (e.g. recombinant human hormones
or cytokines) would be non-immunogenic in humans whereas 'foreign' therapeutic proteins
(e.g. non-engineered monoclonal antibodies) would stimulate a human immune response. This
general principle holds in many cases, but not all. So why do therapeutic proteins of human
amino acid sequences have the potential to trigger an immune response? Potential reasons can
include:
•
Differences in post-translational modifi cation (PTM) detail.
Human therapeutic proteins
produced in several recombinant systems (e.g. yeast-, plant- and insect-based systems;
Chapter 5) can display altered PTM detail, particularly in the context of glycosylation
(Chapter 2). Some sugar residues/motifs characteristic of these systems can be highly
immunogenic in humans.
•
Structural alteration of the protein during processing or storage.
Suboptimal product
processing or formulation can result in partial degradation, denaturation, aggregation or pre-
cipitation of the therapeutic protein. Epitopes normally shielded from immune surveillance
may be exposed as a result, triggering an immune response.
•
Some modes of administration
. In particular, s.c. injection may trigger protein aggregation
or cause prolonged contact between the protein and immune system cells, thereby enhanc-
ing the potential for an immune response. An interesting example of this is provided by the
recombinant human EPO-based product 'Eprex'. In the late 1990s the product's formulation
was changed, with the removal of HSA as an excipient and its replacement with glycine and
polysorbate 80. The product was being administered subcutaneously. The formulation change
coincided with the product becoming immunogenic in a proportion of recipient humans. It
is believed that the underlining immunogenicity was triggered by the association of multiple
EPO molecules on polysorbate-generated micellar surfaces, with concurrent prolonged expo-
sure to immune system cells. A switch from s.c. to i.v. administration relieved the problem.
•
Dosage levels and duration of treatment.
High dosage levels (well above normal physiologi-
cal ranges), in particular if a product is administered on an ongoing and regular basis, may
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