Download Therapeutic MAbs: Saving Lives and Making Billions Monoclonal

Therapeutic MAbs: Saving Lives and Making Billions Monoclonal
antibodies spur a lucrative new period in biomedicine | By
Kelli Miller Stacy Adam Benton/Kromekat Digital Art & Design
In 1895 two French physicians attempted a radical departure
from the standard cancer treatment regimen. Instead of
surgery, Charles Richet and Jules Hericourt administered an
antiserum derived from dogs to patients with advanced cancer.1
Some patients improved, although significant immunogenicity
problems occurred. Lacking specificity and purity, the
formulation cured no one.
Now, after a century of setbacks and intermittent successes,
therapeutic antibodies – or more specifically, therapeutic
monoclonal antibodies (MAbs) – are finally coming into their
own. More than 100 such drugs are in clinical trials, and 18
have been approved for use in the United States. Those
therapies generated between $5 billion and $6 billion in
revenue in 2003, a number that is predicted to triple in the
next five years. By one estimate, MAbs will account for 32% of
all revenues in the biotech market by 2008.2
"We're really unraveling the understanding of the biology of
diseases," says Hal Barron, chief medical officer at Genentech
in South San Francisco. "The more we understand, the more
likely we are to identify various proteins and receptors that
play a pivotal role in a disease. Therefore, the opportunity
to create monoclonal antibodies that block those pathways is
quite substantial," he adds. Genentech has brought three
anticancer MAbs (Herceptin, Avastin, and Rituxan) to market.
Together they earned nearly $2.7 billion in 2004.
Such success must have been unimaginable in the early years of
the 20th century. For decades, many tried but failed to create
safe and effective therapeutic antibodies. It became apparent
that Richet and Hericourt's antiserum was actually an antibody
soup, containing antibodies that targeted antigens on both
diseased and healthy cells. Effective disease treatment would
depend on a single antibody targeted to a specific antigen,
but researchers lacked a reliable way to generate and
mass-produce such molecules.
That roadblock was removed in 1975, when César Milstein and
Georges J.F. Köhler developed a way to produce MAbs.3 (See
related story, p. 14.) Suddenly scientists had the ability to
create tools that could target cancerous cells with pinpoint
accuracy.
FROM MOUSE TO HUMAN Milstein and Köhler shared (with Niels
Jerne) the Nobel Prize in medicine in 1984, nine years after
their breakthrough. But it would be another 13 years before a
drug manufacturer was able to parlay hybridoma technology into
an anticancer drug that would pass US Food and Drug
Administration (FDA) muster. That drug was Rituxan
(rituximab), an antibody to the B-cell marker CD-20 that is
intended to combat non-Hodgkin lymphoma.
Paradoxically, the delay is largely attributable to the
recipients' immune systems, which recognized the antibodies –
produced in mice – as foreign and inevitably attacked them.
"Mouse MAbs never really proved to be very successful
therapeutics for chronic indications, because they were highly
antigenic," says Alejandro Aruffo, president of the Abbott
Bioresearch Center and Immunoscience Development Center at
Abbott Laboratories in Boston. "A single dose triggered a
strong immune system response that neutralized the activity of
the antibodies."
Several rounds of "humanization" ensued, in which researchers
tried to reengineer the mouse antibodies to make them ever
more human. First, using recombinant DNA technology,
scientists fused the mouse variable regions (VH and VL) to the
human immunoglobulin (Ig)-constant domain. Two-thirds human
and one-third mouse, these chimeric molecules substantially
alleviated human-anti-mouse antibody (HAMA) responses, yet
they still produced unwanted immune activity. The chimeric
drugs Rituxan and Remicade (infliximab), for example, have
been associated with serious allergic reactions.
Next, scientists inserted just the mouse
complementary-determining regions (CDRs) – those regions of
the antibody that bind antigen – into a human antibody
framework. The resulting "humanized" antibodies (90% to 95%
human) produced far fewer HAMA responses but did not eliminate
them. Other drawbacks were also evident: Designing humanized
antibodies is technically demanding, and humanization can
produce antibodies with reduced affinities for their targets.
FULLY HUMAN ANTIBODIES Manufacturing hurdles and the
persistence of adverse immune effects among certain chimeric
and humanized MAbs have sparked an effort to create fully
human antibodies, which promise to evade the human immune
response. Scientists have developed two different approaches
to the problem: Either they can change the mouse, or avoid it
all together.
Abgenix of Fremont, Calif., was the first company to turn an
ordinary mouse into a human antibody factory. Called
XenoMouse, it is a transgenic animal in which native antibody
genes have been replaced with their human counterparts.
Abgenix has used the platform both for internal drug
development and in partnership with other drug developers,
including Amgen in Thousand Oaks, Calif., Human Genome
Sciences in Rockville, Md., and Chiron in Emeryville, Calif.
According to Abgenix's Web site, 11 XenoMouse-generated
antibodies have moved into clinical trials, including ABX-EGF
(panitumumab), an anticancer drug targeting the epidermal
growth-factor receptor. Developed in partnership with Amgen,
panitumumab is currently in Phase II trials for metastatic
colorectal cancer.
Medarex, based in Princeton, NJ, has also developed a fully
human transgenic mouse platform. Medarex's HuMab-Mouse
technology allows for faster production of fully human MAbs.
"It's simple and straightforward," says company president and
CEO Don Drakeman. The company and its partners have more than
150 fully human MAbs in development, including MDX-010, an
anti-CTLA-4 compound now in Phase III clinical trials for
metastatic melanoma. The drug is being developed in
collaboration with Bristol-Myers Squibb.
UK-based Cambridge Antibody Technology skips the mouse
altogether, isolating human monoclonal antibodies via a test
tube-based phage-display system instead. Phage display reduces
antibody production time from months to weeks. "It is somewhat
like fishing," explains David Glover, chief medical officer.
"You have a pool of antibodies and go fishing with the antigen
as the bait. Some antibodies will bite; the ones that don't
are thrown away. You sort your catch to find the ones that
bind the best and have the highest specificity." The company
houses a library of more than 100 billion distinct phage
antibodies.
Eleven human MAbs originating at Cambridge Antibody Technology
have entered clinical trials, including Humira (adalimumab),
the first fully human MAb approved for sale in the US.
Developed in collaboration with Abbott and targeting tumor
necrosis factor (TNF)-a, Humira was approved for the treatment
of rheumatoid arthritis in 2002 and is currently being
investigated for other inflammatory diseases; it garnered $852
million in sales in 2004.
Cambridge, Mass.-based Dyax has an automated phage-display
discovery tool that allows scientists to rapidly select the
best antibody, small protein, or peptide binders from
libraries containing billions of candidates. "We have a speed
and throughput that is greater than the vast majority of
hybridoma-based approaches," says Clive Wood, Dyax's chief
scientific officer. "We can select, in a short period,
antibodies that bind with a potency and selectivity that
outstrips what medicinal chemists can normally achieve."
Human Genome Sciences also houses it own collection of
proprietary antibody targets. In 2000, the company purchased
rights to technology that allows it to produce human
antibodies for clinical trials without the help of an outside
pharmaceutical company. The company's human MAb, LymphoStat-B
(isolated at Cambridge Antibody Technology), recognizes and
inhibits the B-lymphocyte stimulator, typically found in high
levels among patients with lupus and rheumatoid arthritis.
On February 1, 2005, MorphoSys, based near Munich, Germany,
announced that the first fully human therapeutic candidate
based on its HuCAL technology entered clinical trials in
Europe. Munich-based GPC Biotech is conducting the Phase I
trial of ID09C3, an anti-MHC class II monoclonal, in patients
with B-cell lymphomas. MorphoSys' HuCAL GOLD combinatorial
library contains more than 10 billion members; therapeutic
candidates are selected using phage display.
Currently Approved Therapeutic Monoclonal Antibodies
Click for larger version MONOCLONALS FOR CANCER Therapeutic
MAbs have opened a completely new field of biomedical research
and have clearly illustrated the immune system's power to
fight chronic disease, especially cancer. "MAbs really
represent the first concerted examples of success in targeted
therapy," says Louis M. Weiner, chair of the department of
medical oncology at Fox Chase Cancer Center in Philadelphia.
"They have forced researchers and clinical oncologists to
change their thinking. Instead of blowing apart a cancer's DNA
with classical chemotherapy, cancer biology is telling us
where to attack."
Now some drug developers are moving beyond the standard
antibody molecule structure to improve both potency and
effectiveness. The approach involves conjugating "payloads" –
for example, chemotherapeutic agents, radioactive particles,
or other toxins – to the antibodies. And it gives oncologists
the ability to target highly toxic treatments precisely where
they are needed. Some say this is the only means to move
therapeutic MAbs into the future.
In 2002, Cambridge, Mass.-based Biogen Idec's (formerly IDEC
Pharmaceuticals) Zevalin (90Y ibritumomab tiuxetan) became the
first radioimmunoconjugate approved for cancer treatment. It
combines the chimeric antibody Rituxan with the metal
chelator, MD-DTPA, which provides stability when used for
radionucleotide tumor imaging and chemotherapy. Because
murine-oriented MAbs exit the body faster than those with a
higher human content, the chimeric Zevalin offers a rare
advantage: It allows for swift removal of radiation from the
body.
Earlier this month the New England Journal of
Medicine published a single group, open-label phase II trial of
another conjugated monoclonal, 131I-tositumomab (Bexxar), in
patients with late-stage follicular lymphoma. Three-quarters
of the study's 76 patients had a complete response, defined as
"the disappearance of all disease for at least one month" or
no change in x-ray findings for at least six months.4
But therapeutic antibodies aren't just for cancer. Last
November, the FDA approved Biogen Idec's natalizumab (Tysabri,
formerly Antegren), a humanized MAb for the treatment of
multiple sclerosis. MAbs targeting immunoglobulin, such as
Genentech's omalizumab (Xolair), have had an enormous impact
on the treatment and management of asthma and other
inflammatory diseases. Unlike standard asthma therapies that
treat symptoms, MAbs for asthma target the underlying cause.
Cambridge Antibody Technology's CAT-354, a human anti-IL-13
monoclonal antibody for the treatment of severe asthma, is in
early-stage clinical trials. Other human antibodies targeting
inflammation include Abbott's ABT-874, an IL-12 inhibitor for
the treatment of multiple sclerosis and other autoimmune
diseases, and ABT-328, an IL-18 inhibitor for lupus.
FUTURE CHALLENGES Fully human MAbs have significantly improved
efficacy and reduced toxicity, but roadblocks remain.
Anti-TNF-a agents such as Humira have been associated with an
increased risk of infection, including tuberculosis. And while
MAbs are revolutionizing cancer care, they are not applicable
to all patients, as only some tumors overexpress the receptor
or antigen of interest. Tumors can also shed the desired
antigen into the bloodstream, essentially putting MAb therapy
onto an unproductive detour that never reaches the cancer
site.
Other drawbacks are apparent. One is that MAbs can't enter
cells; they attach to proteins or molecules only on the
surface. This limits the number of targets one can pursue and,
thus, the types of diseases that can be treated. InNexus
Biotechnology of Vancouver, British Columbia, has addressed
that problem with its so-called SuperAntibody Technology
(SAT).
InNexus' SAT platforms combine site-specific chemical
conjugation and genetically engineered fused proteins to
improve MAb potency, avidity, and affinity, and promote
intracellular transit. Early proof-of-principle studies
suggest that coupling a synthetic peptide, called a
membrane-translocator sequence, to an MAb allows it to
penetrate cells and target antigens from within.5 The company
is now developing SuperAntibody conjugates for the treatment
of plaque associated with coronary artery disease.
The cost of MAb therapeutic agents is also a concern. Drug
developers often must pay royalties to those who hold key
intellectual property in MAb production and target
identification. Such payments can mean considerable cash for
the companies holding the patents, but for pharmaceutical
companies marketing a drug based on someone else's platform,
it can be a financial burden, and one that inevitably is
passed onto the patient.
Moreover, drugs currently must be injected. Technology for
making oral or inhaled formulations could come sometime in the
future, says Medarex's Drakeman, but "it's not there yet."
Perhaps the biggest challenge facing antibody developers today
lies in maintaining a full drug pipeline. Five years ago, with
the decoding of the human genome, the number of potential
therapeutic targets seemed limitless. But in practice, working
with the new targets provided by the Human Genome Project is
proving to be difficult and taking longer than expected.
Few clinically validated targets have been identified, says
Glover. "In terms of when there will be enough good-quality
targets to make good antibodies against them is a difficult
question," he explains. "After this present flush of
antibodies, there will be new targets that come along, and
there may be ways to improve, but one could argue that the
major growth phase has already passed."
Not everyone agrees. "There are thousands of more targets that
have not been appreciated," says Ivor Royston, a pioneer in
the field of monoclonal antibodies and a managing member of
San Diego-based Forward Ventures. "I believe MAbs will be the
single, fastest growing sector of biopharmaceuticals for the
indefinite future," says Drakeman.
Whatever the case, 30 years after their invention, monoclonal
antibodies have finally established a firm beachhead in the
clinic. "What we're really seeing now is an understanding of
how to use these agents," says Abbott's Aruffo. "For a long
time people were skeptical about whether they could deliver on
their promise. Now, with MAbs like Humira, we see they can be
used for chronic disease, and provide a lot of patient
benefit."
References
1. J Hericourt, C Richet "'Physiologie Pathologique' – de la
serotherapie dans la traitement du cancer," Comptes Rendus
Hebd Seanc Acad Sci 1895, 121: 567.
2. Monoclonal Antibody Therapies 2004: Entering a New
Competitive Era Minneapolis: Arrowhead Publishers 2004.,
3. G Köhler, C Milstein "Continuous cultures of fused cells
secreting antibody of predefined specificity," Nature 1975,
256: 495-7. [PubMed Abstract]
4. MS Kaminski et al, "131I-Tositumomab therapy as initial
treatment for follicular lymphoma," N Engl J Med 352: 441-9.
[Publisher Full Text] Feb. 3, 2005
5. Y Zhao et al, "MTS-conjugated-antiactive caspase 3
antibodies inhibit actinomycin D-induced apoptosis," Apoptosis
2003, 8: 631-7. [PubMed Abstract][Publisher Full Text]