The Drug development process - Pharmaceutical Biotechnology: Concepts and Aapplications - page 79

lysosome

Cell

biopharmaceutical

(a) (b)

or

(c) (d)

Figure 4.7 The process of receptor-mediated endocytosis. Binding of ligand, in this case a therapeutic
protein, to its cell surface receptor (a) triggers invagination of the immediately surrounding area of plasma
membrane, internalizing the receptor and its ligand in an intracellular vesicle (b). This is usually followed by
fusion of the internalized vesicle with a lysosome and, therefore, degradation of both ligand and receptor
by lysosomal hydrolases (c). In some cases, however, a variation can occur in which the ligand disassociated
from the receptor (due to a lower pH in the vesicle), with subsequent budding off a small receptor-contain-
ing section of the vesicle, which returns the receptor to the cell surface. In this situation, only the ligand is
available for degradation upon subsequent vesicular fusion with the lysosome (d)

• Immunogenicity. Many, if not most, therapeutic proteins are potentially immunogenic when

administered to humans. The likelihood that non-human proteins (e.g. murine monoclonal an-
tibodies; Chapter 13) are immunogenic in humans is an obvious one. However, human proteins
can also be potentially immunogenic, as discussed in Box 4.1. Antibodies raised in this way can
bind the therapeutic protein, neutralizing its activity and/or affecting its serum half-life.

• Sugar profi le of glycoproteins. Expression of a therapeutic glycoprotein in different eukaryotic ex-

pression systems results in a product displaying differences in exact glycosylation detail (Chapter 2).
The exact glycosylation pattern can infl uence protein activity and stability in vivo , and some sugar
motifs characteristic of yeast-, insect- and plant-based expression systems are immunogenic in man.

4.12.2 Tailoring of pharmacokinetic profi le

A number of different approaches may be used in order to alter a protein's pharmacokinetic profi le.
This can be desirable in order to achieve a predefi ned therapeutic goal, such as generating a faster-
or slower-acting product, lengthening a product's serum half-life or altering a product's tissue