| ASCO 2007 atacicept B-CLL Phase 1b poster
ASCO 2007 atacicept B-CLL abstract
ACR 2006 atacicept RA abstract
ACR 2006 atacicept SLE abstract
Overview
Immunology and cytokine biology are key
areas of research and development at ZymoGenetics.
The Company's efforts in these areas have
led to the identification of many novel
cytokines and to an expanded understanding
of how various components of the immune
system interact in the process of normal
immune function as well as in the context
of immune diseases. One of the Company's
promising product opportunities is atacicept
(formerly known as TACI-Ig), a soluble
fusion protein that links part of a novel
cytokine receptor (TACI) to the Fc portion
of immunoglobulin (Ig). This product candidate
is being evaluated as a therapy for autoimmune
diseases that result at least in part
from inappropriate activity of B-lymphocytes,
a type of immune cell that produces antibodies
and also helps to regulate the activity
of other immune cells. B-cells are believed
to play a role in a broad array of autoimmune
diseases, including systemic lupus erythematosus
(SLE or lupus) and rheumatoid arthritis.
Clinical studies with atacicept are also being conducted in patients with advanced
B-cell malignancies.
The human immune system, the body's primary
defense against pathogens and cancer (foreign
antigens), consists of several types of
immune cells, each of which plays a specific
role in preventing or fighting an enormous
array of diseases. Working via a series
of complex and exquisitely regulated interactions,
the cells of the immune system are able
to raise a rapid and robust response to
foreign antigens, while at the same time
ignoring the thousands of proteins and
cells normally found in human tissue (also
known as self-antigens). B-cells (B lymphocytes)
are a class of immune cells that play
several significant roles in a normal
immune response. A primary function of
B-cells is the production of antibodies,
proteins that bind to their target antigens
and help to trigger the removal of those
antigens from the body.
In some cases, however, there is an inappropriate
response by the B-cells leading to the
development of autoimmune disease. One
of the key components of the autoimmune
disease process is the development of
antibodies to an individual's own healthy
tissues or “autoantibodies.” These autoantibodies
then attack normal cells, leading to destruction
of specific tissues. More than a dozen
autoimmune diseases exist and, depending
upon the type of autoimmune disorder,
the affected tissue may be the kidney,
as in lupus; the muscle system, as in
myasthenia gravis; the nervous system,
as in multiple sclerosis; or portions
of the joint, as in rheumatoid arthritis.
These diseases affect millions of people
worldwide and are a significant cause
of morbidity, mortality and health care
costs. Current treatments for these conditions,
such as steroids and chemotherapeutic
agents, are often limited due to toxic
side effects, including their overall
suppressive effects on the human immune
system. New therapies that act specifically
on B-cell mediated pathways may provide
a novel opportunity to improve patient
outcomes with fewer side effects.
BLyS and Autoimmune Disease
Applying its expertise in bioinformatics
and genomic database mining, ZymoGenetics
discovered a novel gene called BLyS (B-lymphocyte
stimulator, also known in the literature
as zTNF4, BAFF, TALL-1 and THANK) that
has been demonstrated to be a potent regulator
of B-cell function (1). This gene was
identified as a result of its sequence
homology to other members of the tumor
necrosis factor (TNF) family of cytokines.
BLyS is capable of stimulating B-cells
which leads to increased antibody production
and the expression of cell-surface proteins
essential for B-cell activity. Transgenic
mice engineered to express high levels
of BLyS exhibit immune cell disorders
and develop symptoms characteristic of
those seen in patients with SLE (1, 2).
These mice have increased numbers of B-cells
in the spleen and lymph nodes. The transgenic
mice also have elevated levels of serum
immunoglobulin, anti-DNA antibodies, protein
in their urine (proteinuria) and kidney
damage, symptoms that mirror key aspects
of human SLE (1, 2).
Similarly, increased levels of BLyS have
been measured in serum samples taken from
SLE patients and other patients with various
autoimmune diseases (3), extending the
association of BLyS and autoimmune disease
from animal models to humans. Elevated
levels of BLyS and APRIL, a second growth
factor related to BLyS, have also been
observed in the synovial fluid of patients
with inflammatory arthritis (4). In a
strain of mice that spontaneously develops
autoimmune-like symptoms, researchers
found elevated levels of BLyS correlated
with a secondary pathology reminiscent
of Sjogren's syndrome (5).
BLyS and APRIL Bind to Three Unique
Receptors
The family to which BLyS belongs has grown
in complexity as a result of the identification
of a second growth factor, APRIL (A proliferation-inducing
ligand), which is a close homolog to BLyS,
and is also a stimulator of B-cell activation
(6). Additionally, three receptors,
TACI (transmembrane activator and CAML [calcium-modulator
and cyclophilin ligand]-interactor), BCMA
(B-cell maturation antigen) and BAFF-R (for
B cell activating factor belonging to the
TNF family), have been identified and have
unique binding affinities for the two growth
factors (7, 8). TACI and BCMA
bind both BLyS and APRIL, while BAFF-R appears
capable of only binding BLyS with high affinity
(7, 8). As a result, BLyS is
able to signal through all three receptors,
while APRIL only appears capable of stimulating
B-cell activation through TACI and BCMA(9).
In addition, circulating heterotrimer
complexes of BLyS and APRIL (groupings
of three proteins, containing one or two
copies each of BLyS and APRIL) have been
identified in serum samples taken from
patients with systemic immune-based rheumatic
diseases (6). Heterotrimer complexes of
BLyS and APRIL have also been shown to
induce B cell proliferation in vitro.
In vitro studies with Ig-fusion proteins
for all three receptors demonstrated that
only the TACI fusion protein was able
to block the biological activity of the
heterotrimeric complexes (6).
Development of Atacicept as an Antagonist
The observation that over-expression of
BLyS correlates with the onset and severity
of autoimmune disease in animal models suggests
that an antagonist to BLyS may have therapeutic
utility. By using the portions of TACI responsible
for binding BLyS, and fusing it to the Fc
portion of human IgG, ZymoGenetics has produced
atacicept, an antagonist protein that can
prevent binding of BLyS and APRIL to the
B-cells, thus regulating the development
of mature B cells and antibody production.
ZymoGenetics has demonstrated that transgenic
mice engineered to over-express a soluble
form of the TACI receptor in the blood produce
fewer mature B cells and show reduced levels
of circulating antibody (10).
Similar results were observed in normal
mice treated with atacicept protein (10).
The ability of atacicept to bind to and
block BLyS and APRIL, and the resultant
inhibition of autoantibody production, suggest
that atacicept may have therapeutic utility
to limit the extent of tissue damage observed
in patients with autoimmune disease. In
animal models of SLE, treatment with atacicept
inhibited the development of proteinuria
and prolonged the survival of the animals
(1). Similarly, in a mouse model
of collagen-induced arthritis, soluble atacicept
was able to inhibit the development of collagen-specific
antibodies and reduce both the incidence
of inflammation and the rate of occurrence
of disease (10). These data suggest
that atacicept may provide a novel approach
to treat autoimmune disease.
Atacicept
as a Novel Treatment for B-Cell Malignancies
An
expanding body of literature suggests
that atacicept may prove to be an effective
treatment for a variety of B-cell cancers.
Researchers from multiple labs in the
U.S. and in France have shown that malignant
B-cells from essentially all patients
with B-cell neoplasms examined to date
express one or more of the three known
receptors for BLyS and APRIL (TACI, BCMA
and BAFF-R). Furthermore, these malignant
B-cells also often abnormally express
BLyS and APRIL proteins themselves, while
normal B-cells do not. These findings
seem to suggest that malignant B-cells
can both produce and consume the BLyS
and APRIL growth factors, leading to their
autonomous survival in patients. In fact,
BLyS and APRIL levels are usually elevated
in the serum of patients bearing these
B-cell tumors. Studies from Mayo Clinic
suggest that lymphoma patients in whom
high levels of BLyS are present in blood
samples fare worse than those in whom
levels are lower. Thus, BLyS and/or APRIL
appear to enhance the survival of malignant
B-cells. In support of this theory, scientists
have shown that the addition of BLyS or
APRIL to cultured cells from non-Hodgkin's
lymphoma and multiple myeloma patients
enables these cancer cells to survive
for extended periods of time. Inhibition
of BLyS and APRIL using atacicept causes
the cultured malignant B-cells to die
rapidly. These results suggest that atacicept
might represent an important new cancer
therapeutic, specifically targeting malignant
B-cells.
Market Potential and Competition
Autoimmune diseases affect millions of
people worldwide, resulting in serious
unmet medical needs. ZymoGenetics believes
that atacicept may have significant potential
in addressing a number of these disorders,
including SLE and rheumatoid arthritis.
There are over 1 million patients with
some form of lupus in the US; ninety percent
of these patients are women. There are
approximately 100,000 patients with a
severe form of the disease that would
likely be eligible for treatment with
a drug such as atacicept. The standard
care for SLE consists of steroid therapy
and immunosuppressive drugs, treatments
that may have severe side effects.
The development of atacicept by ZymoGenetics
provides an alternative approach to inhibit
the pathogenic effects of B-cells in the
development of SLE and other autoimmune
diseases. Preclinical data generated in
animal models of disease, coupled with
the mode of action through which atacicept
works, suggests that atacicept may provide
a novel approach to treat autoimmune diseases,
such as SLE, for which no new therapies
have been approved in the past 40 years.
Several Companies Developing Products
Aimed at Same Market
Atacicept
is distinguished from other products in
development by its ability to block both
APRIL and BLyS and by its effect being
limited to mature B cells. There is evidence
that both BLyS and APRIL are involved
in disease, so it is possible there is
an advantage to blocking both cytokines.
It also seems desirable to minimize the
impact of therapy on the patients' immune
systems. Therefore, an agent like atacicept
that only impacts mature B cells but leaves
the earlier parts of the immune system
intact may pose less risk for the patients.
Clinical Development Partnership
ZymoGenetics has an exclusive
co-development and commercialization agreement
with Merck Serono for the development of products based
upon the receptors TACI and BCMA. ZymoGenetics and Merck Serono have completed Phase 1 clinical
studies with atacicept in patients with systemic lupus erythematosus,
rheumatoid arthritis and advanced B-cell malignancies. The companies have started two Phase 2/3 registrational studies in systemic lupus erythematosus and have initiated Phase 2 trials in rheumatoid arthritis and multiple sclerosis.
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