Researchers at the American College of Rheumatology's (ACR) 65th Annual Meeting will soon discuss several new molecular approaches for the control and regulation of B cell mediated autoimmune diseases, highlighting the need for innovative treatments for debilitating diseases such as lupus, rheumatoid arthritis and other conditions.

Dr. Jane Gross, a Principal Scientist at ZymoGenetics Inc, will present recent research findings and preclinical studies demonstrating the potential utility of the company's TACI receptor as an inhibitor of B cell activation and auto-antibody production, key mediators involved in development of autoimmune disease.

TACI-Ig, a soluble recombinant receptor developed by ZymoGenetics scientists, binds two key growth factors, termed BLyS and APRIL, which trigger the development of B cells and the production of self-destructive auto-antibodies. By competing with naturally occurring B cell receptors to bind these molecules, TACI-Ig has been shown to reduce symptoms in animal models of systemic lupus erythematosus (SLE) and rheumatoid arthritis.

Scientists at ZymoGenetics will present two posters on related research in autoimmune disease intervention. The first presentation focuses on the recent discovery of a novel receptor, called zTNFR12. Like TACI, the zTNFR12 receptor is found on B cells and binds the growth factor BLyS. The second poster outlines the use of TACI-Ig to moderate disease progression in a mouse model of rheumatoid arthritis. Through these studies and other ongoing research, ZymoGenetics is building its portfolio of protein therapeutics for the treatment of a broad range of human autoimmune disorders.

ZymoGenetics recently announced that the company has entered into an exclusive co-development and commercialization agreement with Serono S.A. focused on TACI and a second preclinical product candidate, termed BCMA. Both product candidates are derived from ZymoGenetics' discovery research. Using a genomics-driven approach, ZymoGenetics' scientists identified the two receptor molecules as key regulators of the human immune system. 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.

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 "auto-antibodies." These auto-antibodies 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 may provide a novel opportunity to improve patient outcomes.

TACI is a receptor found on B cells, that when stimulated, induces the development of those cells and the potential production of auto-antibodies. By using the receptor portions of TACI responsible for binding B cell 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 molecule thus prevents binding of the growth factors to the B cells, regulating the development of mature B cells and antibody production.

Scientists at ZymoGenetics have demonstrated, for example, that transgenic mice engineered to over-express a soluble form of the TACI receptor produce fewer mature B cells and show 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 activity of BLyS and APRIL growth factors and consequently avert production of destructive auto-antibodies, it may be possible to limit the extent of tissue damage observed in patients with autoimmune disease. In animal models of SLE, treatment with a modified, soluble form of TACI receptor was effective in limiting progression of the disease. Similarly, in a mouse model of collagen-induced arthritis, soluble TACI receptor was able to inhibit the development of collagen-specific antibodies and the incidence of disease. ZymoGenetics has published data in Nature and Immunity demonstrating these preclinical findings.