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Interleukin 21
(IL-21)
Overview
Cytokines are natural proteins that regulate
the immune system and have been used to
treat a variety of cancers and infectious
diseases. This type of therapy, known
as immunotherapy, stimulates the normal
immune response to fight disease. ZymoGenetics
discovered interleukin 21 (IL-21), a new
cytokine that has potent regulatory effects
on cells of the immune system, including
cytotoxic T cells (CTL) and Natural Killer
(NK) cells, that can destroy malignant
or infected cells (1, 2). In preclinical
studies, IL-21 increases activity of NK
cells and disease-specific CTLs and decreases
the number of tumors in animal models
of cancer. The Company is developing IL-21
as an immunotherapeutic agent for treatment
of malignant melanoma and renal cell carcinoma.
Cytokines
and Their Role in Treating Disease
Given the enormous power of the immune
system to fight cancers and infectious
diseases, there has been significant interest
in finding ways to use the immune system
itself as a tool to treat disease. For
decades scientists around the world have
searched for factors that help to initiate,
sustain or enhance an immune response,
leading to the identification of several
dozen cytokines that serve as the communication
network among cells of the immune system.
While some cytokines help to enhance the
immune response, other cytokines help
to keep the immune system from running
out of control.
A number of approved cytokine immunotherapies
are on the market today. These include
erythropoietin, for the treatment of anemia;
granulcyte-macrophage colony stimulating
factor (G-CSF), for the stimulation of
white blood cell formation; interleukin
2, for the treatment of cancer; interferon-alpha,
for anti-viral therapy and, interferon-beta,
for the treatment of multiple sclerosis.
The cytokines approved for the treatment
of cancer and viral disease are not effective
in all patients and in many cases have
significant side effects that result in
cessation of therapy. A challenge in new
cytokine therapies is finding agents that
have broad applicability and acceptable
side effect profiles.
Immunology and cytokine biology are key
areas of research and development at ZymoGenetics.
The Company's efforts have led to the
identification of a number of novel cytokines
and cytokine receptors. One of these cytokines,
IL-21, is a novel protein that regulates
a variety of cell types that include CTLs
and NK cells, cell types involved in the
body's ability to fight diseases, including
certain cancers.
Discovery of IL-21
Based on structural similarities among
members of a cytokine receptor family,
ZymoGenetics developed computer algorithms
to screen DNA sequence databases for novel
cytokine receptors. This database mining
approach identified a new member of the
Class I cytokine receptor family, now
designated interleukin 21 receptor (IL-21R).
IL-21R appears to be expressed in bone
marrow cells and in defined subsets of
B-cells, T-cells and NK cells that circulate
in blood (1, 2). This tissue-specific
restriction suggested that IL-21R might
be a key component in the differentiation
or activation pathway of the immune system.
Using IL-21R as a target, ZymoGenetics
identified the protein that binds to the
receptor. This protein ligand, now known
as IL-21, binds to cells that have the
IL-21 receptor on their surface and activates
cells to divide. IL-21 has structural
similarity with interleukin 2 (IL-2),
a cytokine approved as a therapy for several
cancers.
Rationale for IL-21 Therapy
Initial investigations with IL-21 suggested
that the cytokine was a potent stimulator
of NK cells and CTLs. These cell types
are key in eliminating malignant or virally
infected cells from the body. ZymoGenetics
then conducted a series of preclinical
studies to assess the efficacy of IL-21
in animal models of cancer.
In an animal model of metastatic melanoma,
IL-21 suppressed tumor growth (3). Treatment
with IL-21 led to a significant reduction
in the number of lung metastases relative
to untreated controls. IL-21 was also
found to have potent inhibitory activity
in other animal models of cancer. These
models demonstrated that the in vivo effects
of IL-21 were mediated through the activation
of CTLs and NK cells (3).
IL-21
Development Plan
Based on the mechanism of action of IL-21
and its effectiveness to inhibit tumor
growth in animal models of metastatic
cancer, ZymoGenetics is developing IL-21
as an immunotherapy for treatment of solid
tumors. IL-21 is the second development
candidate derived from ZymoGenetics' bioinformatics-driven
discovery strategy.
ZymoGenetics initiated clinical development with IL-21 in 2004. In 2006, ZymoGenetics and partner Novo Nordisk completed and presented data from Phase 1 monotherapy trials of IL-21 in patients with metastatic melanoma or metastatic renal cell carcinoma. These data demonstrated a satisfactory toxicity profile and, evidence of anti-tumor activity in several patients treated with this agent was observed. Also in 2006, ZymoGenetics initiated a Phase 1 trial combining IL-21 with Rituxan® for treatment of patients with non-Hodgkin’s lymphoma and started a Phase 1/2 trial combining IL-21 with Nexavar® for treatment of patients with renal cell carcinoma. ZymoGenetics and Novo Nordisk started a Phase 2 clinical trial of IL-21 monotherapy for the treatment of patients with metastatic melanoma in July 2006.
Market Opportunity
There are 100,000 new cases of melanoma
per year worldwide with approximately
50% of the cases occurring in North America.
Melanoma is the cause of 8,000 deaths
per year in North America. Melanoma has
also become one of the leading cancers
in women between the ages of 25-34. There
are approximately 100,000 new cases of
renal cell carcinoma per year worldwide
with 36,000 new cases in North America.
Renal cell carcinoma results in approximately
12,000 deaths per year in North America.
There is a demonstrated need for new and
improved therapies for both types of cancer.
References:
- Parrish-Novak J.,
S. R. Dillon, et al. Interleukin 21
and its receptor are involved in NK
cell expansion and regulation of lymphocyte
function. Nature 2000, 408:57-63.
- Parrish-Novak J,
Foster DC, Holly RD, Clegg CH: Interleukin
21 and IL21 Receptor: Novel effectors
of NK and T cell responses. J. Leuk.
Biol. 2002, 72:856-863.
- ZymoGenetics; unpublished
data.
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