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The need for improved half-life extension technologies
January 2013
SHARING OPTIONS:
Today's pharmaceutical market is facing a number of
pressures, in particular relating to moving drugs through clinical trials and
to market faster and more cost-effectively. This stems from ever-shrinking
budgets and growing financial burdens throughout the industry. In recent
years,
the industry has witnessed a significant increase in the investment into the
development of targeted, biological drugs, with companies looking
to take these
tailored, novel therapies to market faster than ever before. The increased
interest into these therapies is as a result of their
decreased side effects
for patients, which makes them ideal for treating conditions where medication
needs to be administered frequently, such as
chronic diseases.
However, biological drugs are often hampered by their
characteristically short half-lives, which
means that once administered, they
can be cleared from the body in a matter of minutes. As a result of this short
half-life, patients with chronic
conditions such as diabetes, hemophilia and
neutropenia are often required to administer higher dosages more regularly,
leading to likelihood of
reduced compliance, higher costs and greater risks of
side effects. Drugs with a promising therapeutic value are often limited by
this factor. For this
reason, the pharmaceutical and biotech sectors are paying
increasing attention to half-life extension strategies, with a number of
research institutes
and academic papers noting the growing trend in developing
technologies that extend and improve the circulatory half-life of peptides and
proteins.
Responding to this issue, many researchers have concentrated
their efforts in recent years into developing half-
life extension technologies
that modulate the serum half-life of protein-based therapeutics to desired
specifications. However, while researchers have
managed to successfully extend
the actual serum half-life, they have not been able to design flexible protein
half-lives to deliver the required
pharmacokinetics.
Current strategies used for extending half-life are those
that increase hydrodynamic volume
(PEGylation) or those that use FcRn-mediated
recycling (albumin fusions). Although real progress has been made in the
creation of novel technologies
that modulate serum half-life, the market is
still actively searching for a solution that will allow companies to tailor
their therapies in line with
specific medical indications.
Recent advances in
albumin fusion technology
Recent enabling half-life extension technologies are based
on serum albumin, a natural, non-immunogenic plasma carrier
protein. Albumin is
an optimal material upon which to base half-life extension technologies due to
its naturally long half-life of 19 days in humans,
in comparison to protein
therapeutics that are often cleared from the body in as little as hours. Apart
from its size, it is the pH-dependent recycling
through the neonatal FcRn
receptor that protects albumin from renal clearance and is responsible for its
extended half-life. Like IgGs, albumin is
taken up by cells through nonspecific
pinocytosis and is protected from intracellular degradation through pH-dependent
binding to the FcRn receptor in
acidic endosomes. This interaction allows
albumin to then be recycled back to the cell surface where it is released into
circulation due to the
physiological pH of the blood.
It is the pH-dependent interaction between albumin fusion and
the FcRn receptor
that provides the basis for the latest advancements in
albumin fusion technology. The understanding of its impact on albumin fusion
half-life has
enabled the engineering of this interaction with the potential to
modulate albumin's half-life. Previous studies that altered this interaction
have
been shown to impact the pharmacokinetics of the IgG.
Applying these same
kinetic principles, enabling half-life
extension technologies are able to
modulate protein half-life through construction of albumin variants with
altered binding affinity to FcRn. With the
ability to modulate albumin
half-life, researchers are provided with the opportunity to tailor therapeutics
to specific disease states and fine-tune
their drug design, holding significant
benefits for drug developers and patients alike.
Enabling technologies also
produce more stable blood levels
in patients, and a reduced risk of side effects at the associated lower dose
rate means that the toxicity level of the
protein may not be reached. Instead,
these technologies allow the drug dose to remain within the therapeutic range,
increasing the patient's tolerance
to the drug.
Broad platform
applicability
The
current approach when using albumin as a half-life
extension technology is to conjugate, or genetically fuse. Both of these
methods can be equally as
effective, depending on specific drug delivery
requirements. Lysine, tyrosine and the free thiol residues of the albumin
molecule are used for chemical
conjugation to the drug product, with the free
thiol at position 34 of albumin the most widely used conjugation route. This
approach is particularly
useful for peptides containing maleimide groups that
specifically react with the free thiol, allowing for the formation of a stable
thioether bond
between albumin and the peptide.
Alternatively, proteins can be
genetically fused to the N- or C-terminus or even to
both ends of the albumin
variant. Using a contiguous cDNA of the target protein or peptide with DNA
encoding the albumin variant of choice allows the
generation of protein fusions
exhibiting the required binding characteristics. A yeast expression system
provides a high-quality, consistent and
reliable supply of the protein of
interest when a genetic fusion is applied.
In recent studies, a
range of albumin protein fusions has
been generated to test that the albumin variants maintain their modified FcRn
binding affinity when fused to a
protein or peptide. The variants chosen
displayed a range of binding affinities from low affinity albumins (HSA K500A)
to albumins with a 15-fold
increase in receptor binding (HSA K573P). Antibody
fragments fused at the C-terminus, N-terminus or bivalent forms, as well as
fusions to small or
large peptides were compared to unfused albumin variants
for FcRn affinity by SPR using Biocore technology. All albumin fusions tested
presented
different receptor affinities, correlating to their unfused variants.
Each showed the same differences in ScRn binding as the control rHSA variant.
As a result of the technology, proteins and peptides can be
bound at either the C- or N-terminus or both. This
creates fusion molecules
with monovalent, bivalent or bispecific affinity. In addition to protein- or
peptide-based drugs, the technology also serves
as a delivery vehicle for small
molecules, providing a broad scope of usability. It also enables construction
of albumin variants with altered binding
affinity to FcRn, making it possible
to modulate half-life extension of a fused target protein, while offering drug
developers enhanced flexibility and
control.
Minutes to hours,
hours to days
While the market demand for technologies that allow the
development of drugs with novel properties continues to grow, researchers must
develop
solutions that provide manufacturers with competitive solutions. Due to
the limited number of biological drugs available on the market, researchers are
now looking to adapt and improve upon those that are available to them. In
recent years, significant work has been dedicated to studying the half-life
of
drugs, and while researchers have been successful in lengthening the half-life
of proteins and peptides, they have yet to find a way to tailor the
pharmacokinetics of certain drugs to specific medical needs. Enabling half-life
extension technologies provide a solution to these issues by proving a
platform
in which drug developers are able to fine-tune the half-lives of drugs to
certain therapeutic conditions.
Commercially, the latest advancements in half-life extension
technologies offer drug manufacturers the opportunity to establish a niche
position
in the market with flexible products that offer improved performance
throughout the drug lifecycle. The ability to modulate and tailor the
half-lives
of drugs offers the potential to significantly improve quality of
life for patients with chronic conditions through lower and less frequent
dosage
levels. This can lead to increased patient compliance and the
possibility for patients to administer their own drugs. By realizing the
relationship
between albumin and its receptors for the first time, these
enabling technologies have the potential to revolutionize the wider healthcare
industry by
increasing a protein's half-life from minutes to hours, and hours
to days.
Mark Perkins is the customer
solution manager at Novozymes
Biopharma and
works with partners who are evaluating Novozymes Biopharma's
recombinant albumin products and associated technologies in the areas of
biopharmaceutical formulation and half-life extension. He is a formulation
chemist with a doctoral degree in pharmaceutical sciences from the University of
Nottingham.
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