RECOMBINANT ALBUMIN FUSION PROTEINS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 169

or the magnitude or duration of exposure to the fusion
protein. Moreover, in the Phase III clinical trial program,
the 1200 m g dose of alb-IFN was associated with a higher
rate of pulmonary complications and, in some cases, inter-
stitial pulmonary fibrosis [27]. As a result, this treatment
arm was eliminated from Phase III trials and all patients
receiving 1200 m g alb-IFN were switched to 900 m g every
2 weeks [27].
With regard to the barbourin-albumin fusion protein, in
vivo studies indicated that the protein was immunogenic in
rabbits, but the antibodies generated had no effect on platelet
aggregation [91]. Fewer non-neutralizing antibodies were
generated when smaller barbourin-derived peptides with
antiplatelet activity were fused to albumin [91]. Similarly,
the immunogenic risk with the albumin-hirudin fusion pro-
tein is not expected to be a major concern, based on previous
experiments with recombinant hirudin [92,93] and the expe-
rience with albumin-barbourin fusion proteins [91].
Despite the low inherent immunogenicity of rHA, the risk
of immunogenicity must be taken into account when devel-
oping recombinant albumin fusion proteins. Steps can be
taken to minimize the risk of immunogenicity during the
design process, such as avoiding peptides that bind to T cell
receptors or major histocompatibility complex class II mol-
ecules [94]. Adhering to certain production methods can also
limit immunogenicity; this includes selecting an appropriate
expression system, ensuring sufficient removal of poten-
tially immunogenic aggregates during downstream process-
ing, and minimizing denaturation during formulation [95].

because it is a well characterized, naturally occurring carrier
protein with an extraordinarily long half-life. The fact that
albumin is distributed widely and has no enzymatic activity
suggests that recombinant albumin fusion proteins are
unlikely to elicit unwanted immunogenicity or toxicity
through the albumin moiety. Recombinant albumin fusion
technology allows for high-quality production of a homog-
enous product while requiring fewer postexpression modifi-
cations and purification steps than other technologies such as
PEGylation. Compared to other fusion protein approaches,
such as fusion proteins using the Fc fragment of IgG,
recombinant albumin fusion proteins are more efficient to
produce. The use of a well-established yeast expression
system facilitates production using robust, reproducible,
and scalable processing methods; the same methods can
be applied to mammalian expression systems as needed.
Albumin fusion has been used to successfully extend the
half-life of various therapeutic proteins, including small
peptides (GLP-1), cytokines (IFN- a ), and complex proteins
(FVII and FIX). The improved pharmacokinetic properties
have generally translated into improved pharmacodynamic
effects. Clinical studies evaluating recombinant albumin
fusion proteins are underway that will help further define
the potential of recombinant albumin fusion technology to
enhance the clinical use of therapeutic proteins.

ACKNOWLEDGMENT

The authors gratefully acknowledge the editorial assistance
of Dr. Sandra Cox (Swiss Medical Press GmbH).

10.6 FUTURE PERSPECTIVES

REFERENCES

Among the many fusion protein technologies currently
being pursued, recombinant albumin fusion technology
represents a promising area of research. Numerous recom-
binant albumin fusion proteins are in various stages of
preclinical and clinical development, demonstrating that
this approach is feasible and can extend the half-life of
therapeutic proteins while retaining their biological activity.
The wide spectrum of current research on recombinant
albumin fusion proteins indicates that these fusion proteins
have the potential to positively impact treatment in a broad
range of diseases. Future applications for recombinant
fusion proteins are therefore likely to expand well beyond
the established areas of oncology, immunology, hemostasis,
and inflammation.

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10.7 CONCLUSION

Recombinant albumin fusion technology represents a simple
yet flexible platform for the production of proteins with an
extended half-life. Albumin is an ideal fusion partner