Biomedical Engineering Reference
In-Depth Information
within minutes after administration. As a result, there can be
insufficient exposure in the target tissue to have a pharma-
codynamic effect [5]. Although transformation of a meta-
bolically labile peptide into a drug remains challenging,
considerable efforts and advances have been made
to increase the in vivo stability and circulating half-life
of peptides. Several approaches, have been developed,
including conjugation of polyethylene glycol (PEG) to a
peptide to increase its hydrodynamic radius and reduce
kidney filtration, fusion with albumin-binding peptides,
proteins, or lipids to attach to serum albumin, chemical
conjugation of peptides to covalently link to human serum
albumin (HSA) or other long circulating proteins, including
site-specific covalent attachment of peptides to an antibody,
genetic fusion of peptides to Fc domains of human IgG,
HSA, or transferrin. Among these approaches, Fc fusion is
the most advanced and currently the most successful
approach. Seven Fc-fusion drugs have been developed
and approved for treating patients, and many more targeted
at a variety of different disease areas are in the pipeline.
In this chapter, we review the successes and limitations of
therapeutic drugs, the technologies developed in the last 20
years for improving peptide stability and serum half-life, and
the key for the success of peptide therapeutics, including the
Fc-fusion platform. However, the main focus of the discus-
sion is on current approaches in which peptide- Fc-fusion
proteins are used as receptor agonist biotherapeutics. Exam-
ples of peptide-Fc-fusion proteins that have been on the
market or in clinical trials are discussed in detail. In order for
an Fc-fusion protein to become a successful therapeutic, it is
often necessary to optimize its biological, biophysical, and
pharmacological properties, including activity, stability,
solubility, heterogeneity, and PK profiles. In this chapter,
we discuss in detail the challenges faced in the design and
development of Fc-fusion drugs and provide some examples
of how we dealt with these challenges in specific cases.
be elucidated. Some very important peptides in biological
process, such as glucagon, corticotrophin,
a
- and
b
-mela-
notropin, oxytocin, vasopressin, and angiotensin, were iso-
lated and their sequences were determined. So far, a large
number of naturally existing peptides in our body with their
functions in the central and peripheral nervous systems,
immunological processes, cardiovascular system, and the
intestine were identified [6]. Their potent functions as neuro-
transmitters, neuromodulators, and hormones involved in a
number of physiological processes, including metabolism,
pain, reproduction, and immune response give them great
potential as sources of therapeutic drugs.
8.2.1 The Limitations of Native Endogenous Peptides
in Drug Development
Despite several successful examples, such as the GLP-1-
analog peptide drug Exanatide developed by Amylin and Eli
Lilly, unmodified peptides have not traditionally made good
drugs. Several key issues have prevented peptides from
becoming a major source of drug candidates in their native
form. Many peptides are very flexible and have lower
binding affinity owing to their loss of significant amounts
of entropy upon binding to targets. The flexible conforma-
tion of peptides renders them easily accessed and cleaved in
tissue or cellular compartments by specific endopeptidases
and in the systemic circulation by less specific exopeptidases
(amino- and carboxy-peptidases). In addition, owing to their
very small hydrodynamic radius, peptides are rapidly
removed from the circulation by glomerular filtration (renal
clearance). Protease susceptibility and rapid clearance are
the major reasons that native peptides typically have for their
very short serum half-life; these attributes are important
physiologically for the inactivation of the peptides after they
have exerted their functions. They are usually cleared from
the bloodstream within minutes after administration. As a
result, there can be insufficient time for them to reach and act
in the target tissue to have a pharmacodynamic effect.
Although transformation of a metabolically labile natural
peptide into a drug remains challenging, considerable
advances have been made to increase the in vivo stability
and circulating half-life of peptides.
8.2 PEPTIDE DRUGS
One traditional definition of a peptide is a polypeptide chain
that is short enough to be chemically synthesized as distin-
guished from a protein. With the rapid progress of peptide
synthesis techniques, especially the development of peptide
ligation technology, a polypeptide with hundreds of amino
acids long can now be synthesized. Therefore, the size that
used to distinguish a peptide from a protein on the basis of
synthesis can be ambiguous. An arbitrary definition that a
peptide is a chain shorter than 50 amino acids is widely
accepted and is used here.
Native endogenous peptides play many very important
physiological and biochemical roles in humans. The devel-
opment of sensitive analytical techniques for isolation,
purification, and identification of peptides allowed the
many important functional roles of peptides to begin to
8.2.2 Chemical Modification of Peptides to Reduce
Proteolytic Degradation
In the last several decades, chemical modifications of peptides
have been proven very successful in improving resistance to
protease cleavagewhile preserving the potency and selectivity
of the bioactive natural peptides [7]. One commonly used
approach is chemically modifying the N- or C-terminus or
both ends by N-terminal acetylation or C-terminal amidation.
Other terminal modifications, for example, addition of carbo-
hydrate chains such as glycosylation: glucose, xylose, hexose,
and so on, have also been used. The modifications of the
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