ZymoGenetics and Serono to Collaborate on a Novel Therapeutic Approach For Autoimmune Disease
Co-development of Products to Regulate B-lymphocyte Activity
SEATTLE, and GENEVA, Sept. 4 /PRNewswire/ -- ZymoGenetics and Serono S.A. (SWX Swiss Exchange: SEO and NYSE: SRA) announced that they have entered into an exclusive co-development and commercialization agreement focused on two preclinical product candidates derived from ZymoGenetics' discovery research. Using a genomics-driven approach, ZymoGenetics' scientists identified the two molecules, termed TACI and BCMA, as key regulators of the human immune system. These two proteins are cell-surface receptors found on B-lymphocytes, cells involved in the production of antibodies.
The companies intend to focus their activities on the development of one or more products based on these receptors for the treatment of autoimmune diseases where there is an over production of autoantibodies (antibodies that attack one's own cells). Serono has extensive experience in the research and treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, where there remain significant unmet medical needs.
snip
Under the terms of the agreement, ZymoGenetics could receive license fees and milestone payments of up to $52.5 million linked to the development and approval of products. The two companies will share research and development expenses worldwide, excluding Japan where Serono will cover all expenses. ZymoGenetics retains an option to co-promote products with Serono in North America. If ZymoGenetics exercises this option the two companies will share commercialization expenses and profits equally. Serono will have exclusive rights to market products in the remainder of the world, for which ZymoGenetics will receive undisclosed royalties. Serono will manufacture all products for both clinical trials and commercial sale.
snip
BACKGROUND INFORMATION
Autoimmune Disease Progression
One of the key components of the autoimmune disease process is the development of antibodies to an individual's own healthy tissues. When normal immune function goes awry due to altered development, inherited disorders or
environmental factors, the body's B cells (B lymphocytes) produce "autoantibodies." These autoantibodies then attack the individual, leading to destruction of specific tissues. Depending upon the type of autoimmune disorder, targeted tissues may be the kidney, as in systemic lupus erythematosus (SLE); the muscle system, as in myasthenia gravis; the nervous system, as in multiple sclerosis; or portions of the joint, as in rheumatoid arthritis. Currently available treatments for these conditions are often limited due to toxic side effects, including their overall suppressive effects on the human immune system. New therapies that act specifically on destructive B cell pathways provide a novel opportunity to improve patient
outcomes.
TACI and BCMA Product Candidates
The two product candidates, TACI and BCMA, are receptors found on B cells, that when stimulated, induce the production of antibodies. In the case of autoimmune disease these are autoantibodies (antibodies that attack one's own cells). Using their bioinformatics gene discovery platform, scientists at ZymoGenetics initially identified a growth factor called BlyS (also known as BAFF, TALL-1, THANK and zTNF4) that is a key mediator in regulating the human immune system. This factor was found to bind to B cells, stimulating the replication and survival of these cells, and inducing their production of antibodies.
Using their expertise in pairing growth factors with their corresponding receptors, the ZymoGenetics scientists subsequently identified two receptors, TACI and BCMA, that are found on the surface of B cells and that bind BLyS. These receptors also bind a second growth factor called APRIL. The importance of this pathway for regulating B cell function is demonstrated in a recent publication from ZymoGenetics(1) where the gene for BLyS was eliminated in mice, thereby preventing the production of BLyS protein. These mice had virtually no mature B cells present and had reduced serum antibody response to immunization. ZymoGenetics scientists further showed that mice genetically engineered to over express the gene for BlyS develop symptoms of the autoimmune disease systemic lupus erythematosus (SLE), including the generation of autoantibodies(2). Reports from ZymoGenetics and others have also demonstrated an association between elevated levels of circulating BLyS and autoimmune disease, including SLE in mice and humans and rheumatoid arthritis in humans.
By using the receptor portions of TACI and BCMA responsible for binding the growth factors, ZymoGenetics researchers have produced antagonist proteins that can ``mop up'' increased BLyS and APRIL growth factor present in the blood. Such a soluble TACI- or BCMA- molecule thus prevents binding of the growth factors to the B cells, regulating the development of mature B cells and antibody production. In published studies(1), scientists at ZymoGenetics demonstrated that in TACI transgenic mice, mice that have been genetically engineered to over express a soluble form of the TACI receptor, there are fewer mature B cells and reduced levels of circulating antibody. Similar results were observed in normal mice treated with soluble TACI receptor.
Through the ability of soluble receptors to bind to and eliminate the BLyS and APRIL growth factors and consequently avert production of destructive autoantibodies, it may be possible to limit the extent of tissue damage observed in patients with autoimmune disease. In animal models of SLE, for example, scientists at ZymoGenetics demonstrated that a soluble form of TACI- receptor was effective in limiting progression of the disease (2). Similarly, in a mouse model of collagen-induced arthritis, ZymoGenetics scientists demonstrated that treatment with soluble TACI-receptor was able to inhibit the development of collagen-specific antibodies and the incidence of disease (1).
1. Immunity, 15;289-302,2001
2. Nature 404;995-999, 2000
snip |
