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Altus Pharmaceuticals: Turning Protein
Crystals into Therapeutic Gems
By
Laurie Sullivan
Synthetic
small-molecule drugs have long-been delivered in stable crystal forms.
Conversely, only one large biomolecule—insulin—has successfully been
crystallized for therapeutic delivery.
Altus
Pharmaceuticals is overcoming the boundaries that have heretofore hampered
the convenient delivery of large biomolecules such as proteins. Read how
Altus’ proprietary protein crystallization and cross-linking technology is
enabling proteins to withstand the degradative biochemical conditions of the
gastrointestinal tract for oral delivery to treat metabolic and
gastrointestinal diseases.
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Altus is unleashing proteins’ full potential to serve as
therapeutic agents, with the first technology allowing commercially
scalable, bulk protein crystallization. Alexey Margolin, Altus’ Senior Vice President, Research and Pre-clinical Development/Chief
Scientific Officer, quickly points
out that their technology is very different from X-ray crystallography.
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“As soon as you mention crystallization of proteins, people immediately
think X-ray crystallography,” he says. Whereas X-ray crystallography
requires a high-quality crystal to deduce structural information about
proteins, “Our goals are somewhat different,” Margolin explains. “We
use crystallization as a tool for purification, formulation, and
delivery.”
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Bigger Molecules,
Bigger Challenges
The
benefits of crystallization are well documented. Crystals’ advantages include stability, purity, greater concentration, ease of
handling and manufacturing, explaining why most classical, small-molecule
drugs are produced and delivered in crystal form. In stark contrast, of all
the biotechnology products (e.g., proteins and other large molecules) that
are on the market or in late-stage development, only one such compound is
produced in crystal form—insulin, which was crystallized 80 years ago
largely by accident.
Protein therapies have not been afforded the use of the
crystalline state because protein crystallization is believed to be
significantly more complex than small-molecule crystallization and for this
reason it has not historically been a commercially scalable process.
“Recognizing
this discrepancy, we developed technology to close the gap,” notes
Margolin. “While many large biomolecules have been crystallized, none has
been developed as a crystalline therapeutic product—that’s what
differentiates Altus.”
Image courtesy of Altus
Pharmaceuticals.
In addition to the aforementioned advantages, crystallization of large
molecules can give them an extended-release profile. For example, Altus’ investigational compound ALTU-238 is a once-a-week growth hormone; it is
also the subject of a large business development deal Altus
recently struck with Genentech. While there are many growth hormone products
already on the market, they are parenteral formulations requiring daily
injections. “Crystallizing a growth hormone enabled us to formulate
ALTU-238 for extended release, requiring delivery only once a week. So
it’s a very significant advancement in terms of compliance,” says
Margolin. “That’s only one example of what crystallization can give
you.”
Being
able to pack high concentration into a single dose, another of
crystallization’s perks, is particularly important in the development of
therapeutic antibodies, which currently represent an enormous area of
research and development. More than 20 antibodies have reached the market,
and hundreds more are in development. Antibodies are high-dose compounds,
meaning that therapeutic doses of antibodies must be in the range of 1–15
milligrams per kilogram of body weight. Such a high dose generally requires
intravenous delivery, “Because there is no way you can squeeze so much
protein into a small volume of a syringe—the protein would start
aggregating and losing activity,” Margolin explains. But crystallizing
proteins allows for the formulation of highly concentrated suspensions that
are capable of being delivered via subcutaneous injection. “Protein
crystallization thus offers the opportunity to move from intravenous to
subcutaneous delivery—that would be an enormous advance and advantage for
antibody-based drugs,” Margolin notes.
Altus’ lead program, ALTU-135,
is indicated for pancreatic insufficiency, exemplified by diseases like
cystic fibrosis or chronic pancreatitis. In these cases, the pancreas does
not produce enough enzymes, leading to a host of ill effects including
insufficient nutrition stemming from the inability to break down food
properly. Using its crystallization technique,
Altus
can stabilize protein enzymes to withstand low pH in the stomach and high
proteolysis in the intestines. “That means we can orally deliver a lipase
to hydrolyze fat as substitution therapy for the enzyme not being produced
by the pancreas,” Margolin explains. “For oral indications, the big
difference is that we are not only crystallizing the products, we are also
cross-linking them, which brings us to the second step of our process.”
Cross-Linking: An
Enabling Technology for Oral Delivery
Even
crystallized proteins can dissolve very quickly under harsh gastrointestinal
(GI) conditions (e.g., in response to changes in pH levels or salt
concentrations), necessitating further chemical modification to enhance
their stability in the gut. For parenteral formulations, it’s an
unnecessary step. But for oral indications, taking for example ALTU-135, the
protein lipase is not only crystalline but cross-linked too.
Cross-linking
offers a huge advance as it confers the stability against degradative GI
conditions necessary to enable the oral delivery of large protein molecules.
Yet a remaining hurdle is that the complexity of the protein molecule
precludes it from being absorbed through the intestinal wall and into
systemic circulation, as small molecules are. Because of this challenge, Altus
strategically focuses on diseases that can be treated with therapies that
exert a therapeutic effect in the lumen of the GI tract or which create a
gradient across the intestinal wall to facilitate removal of toxic
substances from the bloodstream through enterocirculation. “It’s very important to mention that normally, when people say oral
delivery, what they mean is that the compound is taken orally and it goes
into circulation in the bloodstream,” Margolin explains. “In our case,
we don’t want a protein to enter the bloodstream. The protein, in
cross-linked form, remains in the gut, exerting its therapeutic effect,
until it gets excreted.”
Moving Proteins into
Medicine
With
Genentech,
Altus
will jointly develop its second lead product, the once-weekly growth hormone
ALTU-238, in the
US
and potentially in other parts of the world. The company’s goal for its
lead product, ALTU-135, is to independently develop it in the US
and begin commercializing it through an internal sales force. “For our
earlier programs, we seek to retain commercial rights in the
US, but are more flexible in terms of the rest of the world,” Margolin adds.
Altus
has two additional
products in preclinical development. It hopes to start clinical trials for
its hyperoxaluria and kidney stones treatment, ALTU-237, within the next six
months. Altus
is hopeful that the clinical program will yield positive results.
“Millions of people suffer from kidney stones,” says Margolin. “Not
only is it a huge market, but one that is vastly underserved.” ALTU-237 is
an orally-delivered crystalline and cross-linked formulation of an
oxalate-degrading enzyme.
ALTU-236
is in preclinical development for the genetic disease, phenylketonuria;
afflicted individuals lack the enzyme needed to break down the amino acid
phenylalanine. Because phenylalanine is an essential amino acid found in
meat and most other protein foods, people with phenylketonuria must adhere
to a medical diet essentially from birth. ALTU-236 is an orally-administered enzyme
replacement therapy designed to reduce the long-term effects associated with
excess levels of phenylalanine.
The Commercial Canvas
In
total, Altus has crystallized more than 70 different proteins. The challenge faced by the
company is not a lack of targets—rather, it boils down to managing its
strategic planning process. The company is currently evaluating its
preclinical portfolio and deciding what will be internally developed
projects as well as deciding which projects can be outlicensed.
Margolin
says he is not aware of any other companies within the drug development or
biotechnology fields with similar technology; however, there are companies
working on large-scale crystallization in the industrial field. “The
source of competition would come from other companies using similar
technology to try to achieve the same goals—not from the technology
itself,” Margolin concludes.
Copyright 2007, Cambridge Healthtech Institute. All Rights Reserved.
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