Biomedical Engineering Reference
In-Depth Information
STRUCTURAL ASPECTS OF FUSION PROTEINS
DETERMINING THE LEVEL OF COMMERCIAL SUCCESS
G
ILES
S
OMERS
Datamonitor, London, UK
3.1 Classification of FPs
3.2 Factors for commercial success
References
Additionally, FPs produced in the body via administration
of a gene or cell therapy are also excluded.
We classified the components of each FP as one of three
different functional groupings (Figure 3.1). Allowing for
homogenous combinations, a two-component FP could, there-
fore, have any of six different combinations. The first compo-
nent type is “activity.” To alter the symptoms or processes
behind a medical condition, pharmacological treatments must
convey some form of activity. Although this activity compo-
nent can be fused to another, in the vast majority of FPs the
partner instead serves to aid delivery of the active moiety to
site of action. This can be achieved by either altering the
locations to which the protein is distributed (targeting), or by
rising the duration for which it remains active (half-life). A
particular protein will be predisposed to distribute to certain
areas of the body, giving variable levels of activity throughout.
We defined targeting moieties as those that have a primary
purpose of selectively delivering an activity partner, thereby
increasing its concentration and potency at desired sites, while
reducing side effects at others. The physical properties of a
protein also dictate the rate at which it is broken down or
removed from the body. Half-life moieties can be included in
an FP to alter the duration for which a partner protein remains
active and thereby able to modulate target sites.
The three FP component types (activity, targeting, and
half-life) are shown in Figure 3.1. A linker or spacer
peptide can also be included to aid folding of the proteins
and/or biologic activity. Of note, this chapter is primarily
focused on significant secondary and tertiary structural
differences or component combinations rather than the fine
tuning of specific proteins, such as through sequence
modifications.
The previous chapter described the commercial outlook for
marketed and upcoming fusion proteins (FPs). In this
chapter, we look in more detail at the structural aspects
of FPs, drawing out the factors that play a key role in
determining the level of commercial success that a product
will attain.
3.1 CLASSIFICATION OF FPs
3.1.1 Pharmacokinetic, Targeting, and Activity
FP Components
Awide range of FPs exists and in order to better understand
their commercial potential, it is useful to investigate their
differences in terms of structure and function. In this chapter,
FPs have been defined as non-native proteins produced from a
genetic fusion of sequences encoding two or more protein
components, which unless specified otherwise include whole
proteins, protein fragments, and short peptides. The FP
components must be combined in gene expression, rather
than being chemically joined at a later time. The analysis does
not include products consisting only of fused antigens, such as
multiepitope vaccines. However, for reference, we identified
five such products in Phase II development or beyond.
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