FUSION PROTEINS: APPLICATIONS AND CHALLENGES - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 4

FIGURE 1.2 The triple T paradigm of fusion proteins. Most fusion proteins are composed of
mixtures of these modules to combine two functionalities. The multifunctional natural prototype is an
antibody combining the constant Fc part that can contribute to half-life extension and toxicity. The
Fab part is contained in many fusion proteins for targeting and binding purposes. LRF, ligand receptor
fusion; CTP, C-terminal peptide; XTEN, XTENylation; ELP, elastin-like peptide; PAS, PASylation;
GILT, glycosylation independent lysosomal targeting; ApoA1, apolipoprotein A1; ADEPT, anti-
body-directed enzyme prodrug therapy; TNF, tumor necrosis factor family.

simplifies manufacture and drug delivery. Two molecules
combined into one will automatically have identical bio-
distribution profiles instead of two separate molecules that
might have a very different distribution. Furthermore, new
functionalities can be created that are lacking in natural or
separate proteins. This includes the modification of half-life
or targeting specificity. Even economic opportunities such as
life cycle extension of products with expired patents are
possible. This includes also the generation of novel intellec-
tual property for new and non-natural combinations of
proteins. Therapeutic benefits derived from reduced side
effects or longer dosing intervals and improved activity are
strong drivers to promote the generation of fusion proteins.
But besides all these important advantages, there are also
a number of challenges. The combination of unrelated
proteins might prove difficult to manufacture because in
some cases, the fusion partners have noncompatible proper-
ties. This can cause aggregation or misfolding of one domain
while the conditions might be perfect for the other domain.
Despite the fact that some modules of fusion proteins are
elements of other well-proven molecules such as antibodies,
the established platform processes might not be applicable
because other features shield the required property. This can

go so far that formulation is not possible due to conflicting
stability requirements. Furthermore, it will be difficult to
control and tune the relative amounts of each component
thus complicating dosing for optimal efficacy and safety.
Probably most important challenge is the high potential for
immunogenicity due to the formation of novel epitopes at
the junction between the fusion partners even if only fully
human proteins are connected.

1.3 PATENTING

The first generation biologics that represented a true copy of
human proteins used for therapeutic applications have
already lost or are about to lose their patent protection
[15]. In many cases second generation molecules, for exam-
ple, with improved half-life, are taking their place. A
number of them are fusion proteins that are patented as well.
To be able to file a patent for an invention, three character-
istics must be achieved novelty, nonobviousness, and utility or
enablement [16]. In the postgenome era, the discovery of
novel proteins, at least of human origin, will be difficult. This
challenges the first critical parameter on the way to a patent,