Proteomics Gears Up!
Five years ago, when Australian postdoc Marc Wilkins coined the
term proteome, it struck many observers as impossibly grandiose.
At the time, few researchers were even contemplating a wholesale
protein discovery effort on the scale of the Human Genome
Project. Yet more rare was a business model for proteomics, and,
in fact, only one real proteomics company (Large Scale Biology)
existed.
Today, it's a very different picture. The term proteomics has
entered the lexicon of biology and the field's aspirations have
gained legitimacy, if not widespread acceptance. Moreover,
dedicated proteomics companies have popped up all over the globe
-- there were seven at last count, including one co-founded by
Wilkins.
But for proteomics to become the new century's superhighway to
biological knowledge, rather than a blind alley, it must first
acquire or invent the technology to fit its grand aspirations. And
timing is critical. With the Human Genome Project in its
culminating phase, proteomics must either seize the moment or
risk watching something else become the Next Big Thing. It's
happened before.
Back in 1980, years before the Human Genome Project was
even a wisp of an idea, Congress seriously considered a Human
Proteome Project. The term proteome, which refers to the
proteins expressed by a genome, didn't, of course, yet exist, but
the Human Protein Index, as it was called then, seemed like the
logical next step in biology. Since proteins direct virtually all
biological functions, didn't it make sense to systematically
catalogue and classify them, and to learn how they change
during disease?
But shifting political winds and the rise of genomics cut short the
project before it got started. "We proposed it, probably, too
soon," says proteomics pioneer Leigh Anderson. "Then the DNA
revolution got in between. But I believe we're going back to it."
(Anderson, then at Argonne National Laboratory, now heads
Large Scale Biology Corp.)
In fact, in a research paper that appeared last year in the
scientific journal Electrophoresis, Anderson predicted that "by
the turn of the millennium, if not much sooner, we will see a
dramatic shift in emphasis from DNA sequencing and mRNA
profiling to proteomics."
That hasn't happened yet. "I may have missed it by a couple of
years," Anderson now says. "But the trend is definitely there.
The interest of the pharmaceutical and diagnostic industries is
ten-fold what it was a few years ago."
A handful of biotech companies are now exploiting that interest.
There were seven dedicated proteomics companies at last count
(see table), and at least two genomics companies -- Myriad
Genetics Inc. and CuraGen Corp. -- have added proteomics
capabilities to their repertoires. "Our revenue is doubling every
six months, probably," says Mary Lopez, vice president of
proteomics research and development at Genomic Solutions
Inc.{GNSL}, which sells automated proteomics systems and services.
"It's tremendous. Our growth is very, very fast."
It's dawning on government grant study sections -- and drug
companies -- that mass sequencing of genomic DNA, and
spotting cDNA onto chips, may not lead to the promised land.
Snazzy as these technologies are, they have a major
shortcoming: They don't take into account pre-translational
events and post-translational modifications of proteins. Protein
activity -- particularly receptor activity -- relies heavily on
phosphorylation, for example. DNA and mRNA reveal nothing
about whether a given protein is active, and can badly deceive
when it comes to estimating how much is there. Anderson has
demonstrated that the correlation between mRNA and protein
abundance is less than 0.5. "There doesn't seem to be any
controversy over how weak this correlation is," says Anderson.
"Everybody agrees it's pretty poor."
Measure proteins, not mRNA, evangelizes Anderson. Chip
companies, in his view, offer clues as opposed to answers.
"There are no drugs that are mRNAs, there are no targets that
are mRNAs," he says. "The only purpose [of mRNA] is to tell you
about proteins."
But proteomics remains a cottage industry. When Anderson
recently sold his fourteen-year-old company, Large Scale
Biology, to Biosource Technologies, Inc., it had only thirty
employees. Genomic Solutions{GNSL} has about fifty involved in
proteomics. Lopez admits the field is "in an embryonic stage,
getting close to toddlerhood, maybe." At a time when mRNA
expression arrays are spreading like cell phones and Palm Pilots
in big pharma and in academia, systems for large-scale protein
analysis are still novelties.
The problem: No one can agree on the best technology for
proteomics -- or even if it exists yet. "There are a lot of
companies out there...trying to develop technologies and saying,
'We have the solution,' " says University of Michigan proteomics
practitioner Phil Andrews. "I haven't seen a solution, something
that solves all the problems."
Proteomics' workhorse technology, powerful but frustrating, is
two-dimensional (2-D) gel electrophoresis. 2-D separates a cell's
proteins on a gel based on their charge and mass, yielding a
sheet of dark spots -- proteins -- suspended in a thin layer of
acrylamide jello. When 2-D first arrived in the 1970s, "people
thought it would revolutionize biology," says Andrews.
Researchers thrilled at having a cell's protein complement
physically separated out and seemingly ripe for the picking. "The
problem was, we didn't know what these spots were, and to
identify them took a tremendous amount of work," says Andrews.
"And you could only get to the abundant ones."
A detailed section of an F344 rat liver 2-D protein pattern.
Courtesy Large Scale Biology Corp.
A lot has happened since then. For protein identification, the
traditional, slow system of Edman sequencing has mostly given
way to mass spectrometry (MS). MS, in fact, now drives
progress in proteomics. In the same way that the whole vast
enterprise of genome sequencing ultimately rests on two
machines (the Applied Biosystems 3700 and the Molecular
Dynamics MegaBACE), so proteomics is utterly dependent on
new generations of mass spectrometers from companies like
Micromass, Finnigan, and PerSeptive Biosystems.
These instrumentation companies are making progress. After
decades of frustration, they learned in the early '80s to transform
peptides in solid or liquid form to gas, making direct mass
analysis possible. The year 1989 marked the arrival of MALDI, or
Matrix Assisted Laser Desorption/Ionization, and electrospray
ionization (ESI), both greatly expanding the range of proteins
that could be analyzed with MS. In 1993 a fast, efficient way to
identify proteins from MS was unveiled: protein mass
fingerprinting. (Proteins are selectively cut with an enzyme,
usually trypsin, and the fragment masses compared to
theoretical peptides, from protein databases, similarly "digested"
by computer.) If mass fingerprinting doesn't nail the protein, then
the peptides can be further fragmented and analyzed in a
second, "tandem" MS, or "MS/MS."
But proteomics technology still has a long way to go. Mapping
the human genome was a trivial exercise compared to the sheer
complexity that proteomics is facing. For example, most human
genes express multiple distinct proteins, when one takes into
consideration post-translational modifications and mRNA
splicing. "It has been estimated that the number of actual
proteins generated by the human genome, which is all the
proteins of the proteome, if you will, is on the order of ten to
twenty million," says Andrews.
Ways around this complexity are to work with the smaller model
organisms like yeast (6,000 genes) and E. coli (4,500), or to just
take a narrow look at individual pathways involving human
proteins. But 2-D systems have other problems. Unlike DNA,
proteins vary in abundance tremendously in a given cell -- by five
or more orders of magnitude. And since there's no PCR for
proteins, the scarce ones can't be amplified, and neither 2-D nor
any other existing system can detect anything but a fraction in
one snapshot. The scarce proteins are often critical control
elements like protein kinases, or other important enzymes like
telomerase.
And membrane proteins are hard to separate because they're
insoluble without detergents. These proteins are often involved in
cell-cell signaling, and make ideal drug targets, so their detection
is critical. Finally, on a mechanical level, 2-D is labor-intensive,
slow, and prone to contamination.
That's not a big deal, says Genomic Solutions' Lopez. "It's an
erroneous perception that the problem and difficulty in
proteomics is running 2-D gels," she says. "Even though the
process up front takes time, the amount of information that can
be generated is tremendous." Three thousand proteins or more
can be seen on a single gel, and they can be quantified.
"The real bottleneck is not 2-D gels," says Lopez. "The real bottleneck is gel analysis and mass spectrometry." (Loading proteins onto an MS plate, generating spectra, and searching protein databases like SWISS-PROT for matches takes time.) To speed things up, Genomic Solutions-{GNSL} (and competitors like Oxford GlycoSciences plc, Large Scale Biology and Proteome Systems Ltd.) have automated the entire process, from extracting proteins from the gel through protein identification and quantification. One
system can now plow through 200 proteins or more in a day.
But that may still not be good enough for high-throughput
proteomics. To gauge the effect of knocking out all 4,500 genes
in E. coli one by one, for example, assuming each one causes
a change in twenty proteins, would mean identifying 90,000
spots. For a single system, that's still a multi-year task. (And
automated image analysis software and robotic systems aren't
foolproof.) Running multiple systems in parallel, of course, would
add speed. But at some point cost becomes a barrier; a MALDI
mass spectrometer will run between $200,000 and $350,000.
2-D is still evolving. Andrews is developing a system, called
"virtual 2-D," that promises much faster performance. By using
MALDI to scan proteins separated in only one dimension
(charge), protein identification is incredibly fast. But the system
can't yet quantitate proteins, and will be hard to use for complex
organisms. Andrews is also working on loading 2-D gels directly
into a mass spectrometer for reading. "Imagine a machine where
you could map a thousand proteins an hour by MS," he says.
Unfortunately, 2-D gels are not stable in the high vacuum of the
mass spectrometer long enough to collect data. "We're working
on ways to get around that problem," says Andrews. "And I think
we'll get there."
Even if direct mass analysis of 2-D gels ends up working,
anyone using 2-D faces a fundamental quandary: The system
won't show many low-abundance proteins, because the spots
are invisible, but pre-separation, or "fractionation" --which can
resolve these spots -- makes quantitation impossible.
High-abundance proteins can be removed in advance -- "peeling
an onion to get down to the nifty ones inside," in Anderson's
words. But there's never a clean cut, and any protein lost will
skew measurements of relative quantity.
The quantitation dilemma is another reason that 2-D isn't ideal
for high-throughput, "global" proteomics. Although the future
promises better methods, such as high-performance liquid
chromatography (HPLC) and capillary electrophoresis,
researchers are stuck with 2-D for now. "It'll be an important part
of proteomics for the next three or four years, at least," says
Andrews. "I don't see an alternative. We don't have anything
better than 2-D gels; it's the highest resolution technique we
have."
Fortunately, technology is not standing still. Ruedi Aebersold, a
proteomics practitioner at the University of Washington
(Seattle), has devised an ingenious method for measuring the
relative quantities of proteins using mass spectrometry. (See
Gygi, S. et al. Nature Biotechnology. 17:994-999 [1999] for
details.)
Aebersold and Steve Gygi took two cell extracts, labeled them
differently using stable isotopes, mixed them together, and
separated proteins. Then they loaded them into a mass
spectrometer, and measured the ratio of the two labels (and thus
the relative mass). An interference phenomenon called ion
suppression normally prevents this, but because the protein
pairs being compared are virtually identical chemically, they're
equally affected by ion suppression, so it doesn't matter. This
system may also solve the pre-fractionation problem, since for
pre-mixed proteins the relative ratio stays the same no matter
how much protein is thrown out during fractionation. The
technique, dubbed "ICAT" (Isotope Coded Affinity Tags) "is one
of the most elegant things I've seen in proteomics since its
inception," says Andrews.
Its impact remains to be seen. In theory, ICAT could make any
separation technology, including HPLC and capillary
electrophoresis, quantitative. (So far they're not.) It also promises
to make 2-D gel electrophoresis more useful, by allowing
pre-fractionation with quantitation.
One new separation technology -- already earning customer
raves and generating income -- is protein arrays. Ciphergen
Biosystems Inc., a three-year-old Palo Alto biotech firm, sells a
system based on an aluminum chip spotted either with
chemicals to bind proteins or with known antibodies to snare
antigens. A cell extract is placed on the chip, the target proteins
bind, the rest are washed off. Then the chip goes into a
specialized mass spectrometer, the "ProteinChip Reader," for
analysis. Ciphergen marketing director Gary Holmes says the
system offers "a significant improvement in speed and
sensitivity" compared to other technologies.
But protein arrays have their limitations, too. "That technology
has a lot of promise," says Mary Lopez. "But working with
proteins is not as easy as working with nucleic acids." She
points out that proteins, when they interact with a chemically
treated surface, unfold and otherwise change the way they're
shaped. So they behave differently. "It's not an absolute
limitation, but it's a concern," she says. "The interaction that
happens on a chip may not represent what happens in vivo. It's
potentially fraught with artifacts."
Ciphergen has worked to minimize that problem. "We try to use
conditions where we maintain native [protein] conformation,"
says Holmes. Whatever its limitations, Ciphergen's system has
already proven useful. "In every case where we've tried to find
uniquely expressed proteins, disease versus normal sample,"
says Holmes, "we've been able to find them."
signalsmag.com
Subject 34842
ragingbull.com
Recombinant protein-based medicines have already proved their value in the marketplace. Several have even surpassed the
magic $1 billion mark, making them blockbusters in every sense of the word. That's a good reason for a company to devote its
resources to creating the next protein therapeutic -- but is it sufficient? Are there other incentives for sticking with proteins in this
era of computer-aided drug design and small molecule mimetics? Yes -- and lots of them. Just ask ZymoGenetics, or
Wyeth-Ayerst Research, or Johnson & Johnson's subsidiary Centocor. All three have compelling arguments -- and they're not the
same.
With all the sophisticated drug discovery and development tools available to researchers today, why would a company
choose to focus on protein-based therapeutics rather than turn its sights to small molecule drugs? If it's possible to use
structure-based drug design to create an exquisitely specific, and entirely unique, compound that binds only to the target of
interest, why would any firm opt for generating a recombinant version of the natural molecule? After all, if its precise role in
the body's biochemical pathways isn't understood, even a nature-identical molecule might act in unpredictable, and
undesirable, ways. And, since proteins can't be administered orally -- they get chewed up by gastric secretions before they
even have a chance to get into the bloodstream -- why bother with them at all?
Well, there are lots of reasons. First, gaining a patent on a recombinant version of a naturally occurring protein offers
exclusivity. Second, these proteins are by themselves unique: There IS only one erythropoietin, for instance. Third, clinical
trials on such proteins, which act as positive effectors in a biological setting, can take less time to demonstrate efficacy
than do trials involving purely synthetic compounds. (Experience has shown that this isn't always the case, however, since
protein drugs are dosed at non-natural concentrations.) Also, it's possible that proteins can be dosed orally or even inhaled
if they are protected via some form of delivery vehicle or mechanism; there are even needleless injection devices under
development that could allow individuals to inject themselves with a protein drug, eliminating visits to the hospital or clinic.
Moreover, protein drugs have a successful history at the FDA: Nearly 86 percent of the 77 biotechnology medicines
approved by the FDA are recombinant human proteins (others include polyclonal antibodies, purified natural interferon,
vaccines, modified natural enzymes and various cell and tissue therapies). (The tables scattered throughout this article list
many, although not all, of the FDA-approved recombinant proteins. They include the date of first approval [and indication]
as well as subsequent approvals for additional indications.)
Lastly, and perhaps the main factor influencing a company's decision to stick with proteins, is the sales potential.
Handsome profits can be made off recombinant protein-based therapeutics. In fact, you'll find a table below that lists the
annual sales figures for some of these medicines -- including Amgen's blockbusters Epogen and Neupogen, as well as
Genentech's two hot cancer therapies Herceptin and Rituxan. Also included are the sales figures for two insulin products --
Eli Lilly and Co.'s Humulin and Novo Nordisk A/S's Novolin -- which will give you an idea of the ever-increasing market size
for a medicine to treat a very common disease, one which affects more individuals each year.
Of the many companies that are developing recombinant medicines, however, we'll focus on only three in this article:
Genetics Institute Inc., Centocor Inc. and ZymoGenetics Inc. These three share some common traits: They were all
stand-alone biotech companies in the 1980s; they've all been acquired by big pharma; and all three have been responsible
for the development of products that are on the market today. But there the similarity ends.
If there was ever a dark horse in the biotech product development race, it's ZymoGenetics. Those of you who've been
following the biotech industry for the last 25 years may remember the small Seattle-based company, but newcomers have
probably never heard of it. That's about to change.
ZymoGenetics, which was founded in 1981 by three university professors, established its reputation by developing
yeast-based expression and production systems (thus the company's name) for recombinant proteins. It was especially
well-known for platelet-derived growth factor (PDGF), a tricky molecule that several biotech firms were working on at the
time. ZymoGenetics licensed its PDGF technology to Chiron Corp. and Chiron's partner the R.W. Johnson Pharmaceutical
Research Institute (a unit of Johnson & Johnson). Today, Ortho McNeil Pharmaceuticals Inc. (also a Johnson & Johnson
company) sells that product as Regranex Gel, which the FDA approved in December 1997 for treating diabetic foot ulcers.
But ZymoGenetics wasn't slated to remain independent for very long. In 1988, following a collaboration with Danish
pharmaceutical giant Novo Nordisk on recombinant insulin (now sold as Novolin), the latter bought the Seattle firm for
about $30 million in cash. The companies had also partnered to develop a yeast-based production system for recombinant
Factor VIIa (now marketed as NovoSeven for treating hemophilia).
For the next 12 years or so -- until May 2000 -- ZymoGenetics disappeared off almost everyone's radar screens. But just
because its parent company wasn't talking about R&D projects doesn't mean that ZymoGenetics was idling. Far from it:
The firm's technology underlies five marketed products -- not only Regranex Gel , Novolin and NovoSeven, but also
Glucagen (for treating severe hypoglycemia; also sold by Novo Nordisk) and a recombinant tissue plasminogen activator
sold in Japan by a Japanese partner. Together, these represent about $1.5 billion in annual worldwide sales, according to
Bruce Carter, ZymoGenetics' president. (See the table of product sales for details.) Also, Amgen Inc. and Kirin Brewery
Co. Ltd. have licensed ZymoGenetics' thrombopoietin (TPO), which is in development.
The main reason that we now know what ZymoGenetics has been up to all these years is because its parent company,
Novo Nordisk, is spinning it off. The spin-off strategy is certainly not unusual in the biotech world (see the Signals article
"Biotech Spin-Offs Seek New Orbits," for examples), but spinning off an acquisition is fairly unique. The move, which is
scheduled to be completed by the end of this year, is expected to be accomplished through a huge private financing --
reportedly as much as $200 million, garnered from a group of private investors with very deep pockets.
Some of that cash will no doubt go to rebuilding ZymoGenetics' product development capabilities, which it forsook about
five years ago in favor of a research-intensive staff. One project on the near horizon is to ramp up activities at the
company's fermentation/manufacturing facilities.
Novo Nordisk will retain a small stake in ZymoGenetics (which has yet to be determined), but it will no longer have control.
The parent company will, however, retain the option to license ZymoGenetics' protein therapeutics outside North America
and plans on taking two board seats. (Also joining ZymoGenetics' board will be two of biotech's founding fathers -- George
Rathmann and Edward Penhoet.)
Now that ZymoGenetics is re-emerging as a biotech player, it's also upfront about where it stands. Carter's presentation at
the Allicense 2000 meeting in Basel in May was the first time that the firm's strategy and strengths were outlined in a public
forum. The strength and the strategy are the same -- protein-based therapeutics.
In fact, ZymoGenetics has amassed a stack of patents on recombinant proteins. According to Carter, that
amounts to 173 issued U.S. patents, and hundreds more pending. All together, ZymoGenetics has filed patents
on about 500 proteins. And, more often than not, it's been the first company to do so, Carter said. For instance,
between 1993 and August 1998, ZymoGenetics was first to file on more patent applications for possible protein
therapeutics than any other company save Human Genome Sciences Inc. (Genentech Inc. was third; Genetics
Institute Inc. was fourth.) Moreover, since 1996, he added, ZymoGenetics has filed first the most often, followed
by Genentech and Human Genome Sciences.
Why proteins? Because, protein therapeutics provide exclusivity, and "Exclusivity is the holy grail of the pharmaceutical
industry," Carter said. Small molecule drugs afford only limited patent protection, and it's relatively easy to synthesize
variants, or "me toos" (thus quickly eroding market share). "In the last 10 years, these drugs [new chemical entities, or
NCEs] have been very rapidly copied. For instance, there must be 20 ACE inhibitors on the market today," he said. "When
a small molecule comes off patent, it can lose up to 80 percent of its sales within one year."
Proteins, on the other hand, have unique modes of action and they can be protected by composition-of-matter, use and/or
production patents. "There's only one erythropoietin," Carter said. "This exclusivity has allowed Amgen to build a company
with a huge market cap." Still, even in the realm of biological molecules it's possible to find competitors in the marketplace
today (there are several recombinant tissue plasminogen activators on the market, for instance, and the number of alpha
interferons is even higher). But, according to Carter, that's all in the past. "We won't see this situation in the future." That's
because a patent can be written such that it covers not only the protein per se, but also proteins that are "substantially
homologous" in composition, he continued.
There's another advantage to proteins over small molecules, Carter said. Proteins positively affect biological processes
that occur in the body; small molecules usually act in a negative manner -- by inhibiting biological activity. "The drug
industry was founded on chemistry, and chemistry is good at stopping processes (through the action of inhibitors, blockers
or antagonists). Proteins, on the other hand, act positively, as effectors." Thus, it can be easier to study proteins in the
clinic. "With a biologic, you can find out sooner whether the product is going to work," Carter said. And, the sooner a
company can decide whether to forge ahead with large-scale trials or to terminate clinical development, the more
cost-effective it is.
ZymoGenetics uses a genomics-based approach to identify its potential product candidates. It's been a subscriber to Incyte
Genomics Inc.'s EST sequence database since August 1995 and it's also developed an extensive in-house sequence
database. "We use bioinformatics to look for DNA sequences that are similar to proven ones," Carter said. "We search for
sequence homology and structural motifs." Since only about one to two percent of the genes in the human genome code
for "plausible protein therapeutics," it's not such a huge search. At ZymoGenetics, that search includes about "30 different
families [of genes]," he said. "The challenge is to clone and patent only those that look interesting." As well, starting with
the gene and then determining its function -- rather than the other way around -- allows a company to take a more
opportunistic approach to product development, defining therapeutic areas as it goes. Now, armed with a hefty patent
portfolio, ZymoGenetics is ready to make good on its heritage.
While ZymoGenetics may be the dark horse in the protein patent and product race, there are lots of other contenders that
have captured the crown time after time. Take Genetics Institute: The company has also been extremely active in its efforts
to protect its intellectual property, ranking right up there with ZymoGenetics, Human Genome Sciences and Genentech in
the number of protein patents filed between 1993 and 1998. As well, in its current guise, the company's been responsible,
either directly or indirectly, for the market introduction of seven recombinant protein therapeutics, explained L. Patrick
Gage, president of Wyeth-Ayerst Research. "We're marketing more recombinant protein products than any other company
except Genentech," he said. Plus, Wyeth-Ayerst sells a number of recombinant protein-based vaccines and it's in the final
stages of filing for regulatory approvals in both the U.S. and Europe on BMP-2 (recombinant human bone morphogenic
protein; for repairing long-bone fractures and dental/craniofacial surgery), he added.
What one has to take into account, however, is Genetics Institute's history -- plus that of its sister company Immunex Corp.
and their parent organization, American Home Products Corp. (AHP). Genetics Institute was acquired by AHP in
December 1996 for about $1.25 billion, but the big pharma already owned 60 percent of the biotech, which it bought in
1991. (At that time, this "60 percent solution" was a popular means for big pharmas to take significant stakes in leading
biotech firms without acquiring them lock, stock and barrel. Roche did it with Genentech; Sandoz did it with SyStemix).
Also, in 1994 AHP acquired a stake in Immunex through its acquisition of American Cyanamid (which had merged its
Lederle oncology business with Immunex the previous year). By the spring of 1998, Genetics Institute had been integrated
into AHP's Wyeth-Ayerst Research division, with Gage at the helm. Gage had been at Genetics Institute since 1989, and
was its COO and president at the time of the acquisition.
Thus, the products developed by these entities -- which all fall under AHP's marketing umbrella -- include EPO
(recombinant human erythropoietin, Genetics Institute's product that is blocked from the U.S. market by Amgen but was
approved in Japan and Europe in 1990, where it is sold as Epogin and Recormon, respectively); Recombinate; Neumega;
BeneFIX; Refacto; Enbrel; and Mylotarg. (Please refer to the tables scattered throughout this article for the details on these
products).
Why has Genetics Institute -- in both former and current incarnations -- chosen to work with protein therapeutics? Simply
put, "Proteins make great drugs," Gage said. He cited a number of reasons why this is true. First, and especially because
of the genome sequencing efforts, there's now a massive amount of data on new genes. And, since genes code for
proteins, there's an immediacy to turning these new discoveries directly into marketed products.
"We can go very quickly from the gene to a protein product, without the steps of target identification, screening, picking
lead compounds, optimization and testing. We can go from a new gene to a drug in three to four years," he claimed. "It's
the fast way to take advantage of the explosion of new genetic information."
"Until small molecule mimetics are developed, it's the only way to address some of the opportunities presented
by genes," he explained. "We can't do this [yet] through small molecules. For instance, researchers are still
struggling to develop an oral formulation of EPO, but in the meantime [the recombinant protein] is a great drug."
(AHP, of course, also develops and sells small molecule drugs and vaccines.) |
