Biomedical Engineering Reference
In-Depth Information
PEPTIDE-Fc FUSION THERAPEUTICS: APPLICATIONS
AND CHALLENGES
C
HICHI
H
UANG
1
AND
R
ONALD
V. S
WANSON
2
1
Biologics Research, Centocor R&D, A Division of Johnson & Johnson
Pharmaceutical Research & Development, Radnor, PA, USA
2
Biologics Research, Centocor R&D, A Division of Johnson & Johnson
Pharmaceutical Research & Development, San Diego, CA, USA
8.1 Introduction
8.2 Peptide drugs
8.3 Technologies used for reducing in vivo clearance of
therapeutic peptides
8.4 Fc-Fusion proteins in drug development
8.5 Peptide-Fc-fusion therapeutics
8.6 Considerations and challenges for engineering peptide-Fc-
fusion therapeutics
8.7 Conclusions
Acknowledgments
References
account for one in four submissions for FDA approval. Over
130 proteins or peptides have been approved to date for
clinical use, and this number is growing rapidly. The top
seven major biological drugs, including Remicade
1
,
Enbrel
1
, Avastin
1
, Rituxan
1
, Humira
1
, Herceptin
1
,
and Lantus
1
, generated over $40 billion in 2010 [1-3].
Much of the success of biopharmaceuticals comes from
recombinant monoclonal antibodies (mAbs), thanks to their
favorable biological and pharmacological properties. Four
of the top 10 therapeutic drugs of 2010 by sales are mAbs,
including Remicade, Avastin, Rituxan, and Humira [3].
It has been predicted that by 2014, five mAbs will be in
the top 10 list and that the sales of these mAbs will be over
$45 billion [4]. Despite the great success antibody drugs
have enjoyed, their utility has mainly been limited to antago-
nism, in concordance with what antibodies have evolved to
do: to neutralize the function and accelerate the clearance of a
foreign antigen. Many existing native peptides and receptor
ligands are potent agonists, however, and represent a rich
source of therapeutic potential. Although there are several
successful exceptions such as the GLP-1-analog peptide drug
Exanatide, unmodified naturally existing peptides have not
traditionally made good drugs.
Several key issues arise when contemplating peptides as a
source of drug candidates. Many peptides are very flexible
and have lower binding affinity owing to their loss of
significant amounts of entropy while binding to targets.
Peptides also have a very short half-life owing to rapid renal
clearance and proteolytic degradation in the blood, kidneys,
or liver. They are typically cleared from the bloodstream
8.1
INTRODUCTION
In 1982, the FDA approved the first recombinant protein
drug, Humulin-R, a recombinant form of insulin developed
for the treatment of diabetes. This approval is one of the
most important milestones in the history of biotechnology
and protein therapeutics. Since then, the development and
use of biological drugs, including peptides, proteins, recom-
binant proteins with native or modified sequences, and
fusion proteins, have undergone tremendous growth for
the treatment of a wide variety of diseases. More than
300 distinct biopharmaceuticals (around 40% of all drug
candidates) are in clinical trials for various disease indica-
tions including cancer, Alzheimer's disease, and chronic
inflammation. In the United States, biopharmaceuticals now
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