Biomedical Engineering Reference
In-Depth Information
has mainly been limited to antagonism, the majority of the
peptide therapeutics in clinical trials or on the market acts as
receptor agonists. For example, Lupron (leuprolide), a small
nine amino acid peptide analog of Gonadotropin-releasing
hormone (GnRH), is an agonist of pituitary GnRH receptors.
By stimulating its receptors, Lupron downregulates the
secretion of the gonadotropins, luteinizing hormone (LH),
and follicle-stimulating hormone (FSH), leading to a dra-
matic reduction in estradiol levels. The drug is approved for
treating prostate and breast cancers [15]. Zoladex (Goserelin
acetate), developed by AstraZeneca, is another GbRH ana-
log approved in 1989 for suppressing the production of the
sex hormones, testosterone and estrogen, for treating breast
and prostate cancers [16]. Sandostatin or Octreo 1 (Octreo-
tide), developed by Novartis Pharmaceuticals and New
Medicon Pharma, is an octapeptide analog of somatostatin
which down regulates growth hormone, glucagon, and insu-
lin by stimulating the somatostatin receptor for the treatment
of acromegaly [17]. The drug is also used for reducing
watery diarrhea and flushing episodes caused by cancerous
tumors [18]. Forteo (Teriparatide), a recombinant form of
the first 34 amino acids of PTH, is another receptor agonist,
developed by Eli Lilly. The drug was approved in 2002 for
treating osteoporotic men and postmenopausal women who
are at high risk of having a fracture [19]. Byetta (Exenatide,
exendin-4), a 39 amino acid peptide isolated from saliva
of the Gila monster, is an agonist of the GLP-1 receptor.
The drug, developed by Amylin Pharmaceuticals and Eli
Lilly, was approved for the treatment of type 2 diabetic
patients in 2005.
More than 60% of approved peptide drugs target mem-
bers of the G-protein coupled receptor (GPCR) family which
includes around 800 different receptors predicted from
genome sequence analysis (about 4% of the entire pro-
tein-coding genome codes for GPCRs). GPCRs activate
many cellular responses, such as estrogen secretion, neuro-
peptide signaling, opiate receptivity and vision pathways
(class A GPCRs), calcium and glucose metabolism, growth
hormone secretion, and gastrointestinal tract function (class
B GPCRs) [14]. Almost 30% of all drugs target GPCRs and
most of the peptide drugs targeting them are receptor
agonists [20].
The success of peptide drugs acting as receptor agonists
highlights several advantages over both small molecules and
large protein drugs such as antibodies and receptor-Fc-
fusion proteins. The peptide drugs are significantly larger
than traditional small molecules, enabling them to more
specifically bind targets with higher affinity due to the larger
available contact surface; therefore, peptides usually have a
more favorable off-target toxicity profile relative to small
molecules [21]. Compared to antibodies or soluble recep-
tors, on the other hand, they are much smaller and have the
potential to penetrate deeper into tissues and exhibit better
bioavailability. They can be generally less immunogenic and
can have higher solubility and better stability during the
storage and transport. More importantly, many peptide drugs
naturally regulate crucial biological processes functioning
as agonists, which have proven very difficult for both large
recombinant protein therapeutics, such as mAbs and
receptor-Fc fusions, and small molecules to achieve.
8.3 TECHNOLOGIES USED FOR
REDUCING IN VIVO CLEARANCE
OF THERAPEUTIC PEPTIDES
Although chemical modification of peptides can signifi-
cantly improve the pharmacokinetic profiles by increasing
the serum half-life fromminutes to hours, treatment of many
chronic diseases requires single or multiple injections daily.
As a comparison, the circulating half-life of many mAb
drugs is not hours or days but weeks. Rapid clearance of
peptides after administration from the circulation via the
kidneys is mainly because of their small size (
5 kDa). A
number of techniques have been developed to reduce the
renal clearance by fusing or attaching peptides to molecules
with larger molecular weight (generally
<
>
50 kDa) to retard
excretion through the kidneys.
8.3.1 PEGylation
One of the most widely accepted methods to improve
pharmacokinetic properties of peptides is to conjugate
them to polyethylene glycol (PEG) [22]. Often, a single
large PEG (e.g., 40 kDa) or multiple small PEGs (e.g.,
5 kDa) molecules are used to increase the peptide size.
The PEG can be conjugated to peptides on either terminus
or can be conjugated to cysteine or lysine residues at internal
positions in the peptide [23]. The conjugation of PEG not
only increases the hydrodynamic size of the peptides thus
reducing their clearance, but can also protect them from
peptidase cleavages in vivo by masking sensitive sites [24].
By carefully selecting the conjugation sites and testing
different PEG conjugates, a properly conjugated peptide,
which retains most of its activities while increasing its serum
half-life from minutes to tens of hours, can be identified.
PEGylation of peptides can also confer additional positive
attributes such as reducing immunogenicity and improving
solubility [25-27].
8.3.2 Human Serum Albumin Fusions
Human serum albumin (HSA), comprising about half of the
blood serum protein, is the most abundant protein in human
blood plasma. It has good solubility and is widely distributed
in vivo. It has a long circulatory half-life (up to 19 days in
humans). It is a monomer with molecular weight of 67 kDa.
Similar
to Fc-fusion proteins,
the idea of
improving
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