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Anti-CD3 Mab (teplizumab)
MacroGenics is developing teplizumab, a humanized Fc-engineered monoclonal antibody also known as MGA031 and hOKT3γ1(Ala-Ala), as a novel treatment for autoimmune/inflammatory disease. Teplizumab represents a paradigm shift in the management of autoimmune disease that focuses on the induction of tolerance rather than broad spectrum immunosuppression. With early clinical development completed on this drug by experts affiliated with the Immune Tolerance Network (ITN) at the National Institutes of Health (NIH), MacroGenics is committed to advancing teplizumab as a commercially viable option to the management of autoimmune disease.
Type 1 diabetes. The American Diabetes Association reports that approximately one in every 400 to 500 children and adolescents will develop type 1 diabetes. Diabetic patients are prone to a variety of complications from the disease, including heart disease, high blood pressure, blindness, and kidney disease. Accordingly, treatments that aim to slow the progression of disease have the opportunity to substantially improve the health and quality of life of these patients. The development of type 1 diabetes is believed to proceed by a two-step process. In the first step, an environmental agent, possibly a virus, injures the insulin-producing beta cells of the pancreas. It is presumed that this initial injury to the beta cells precipitates a T-lymphocyte-dependent autoimmune attack on the beta cells in the pancreas, resulting in progressive destruction of the capacity to produce insulin and the signs and symptoms of diabetes.
In phase II trials, a single brief course of teplizumab delivered within the first six weeks following diagnosis was shown to improve c-peptide responses, reduce HbA1c levels and lower insulin requirements for at least two years (Herold, et al. Diabetes. Vol 54, June 2005: 1763-1769). This translated into better metabolic control for the treated individuals for the two-year duration of the study.
These findings are being further studied in the Protege trial, a global, Phase II/III pivotal trial and the clinical trials listed below.
In addition to the research described above, prior research indicates that reprogramming an islet cell transplant recipient's immune system may be important to prevent the recurrence of an autoimmune attack on the transplanted islets. Previous studies of teplizumab have supported the view that prolonged transplant tolerance may be possible. Ongoing clinical trials in this area include a Phase II trial sponsored by NIDDK and led by Dr. Bernhard Hering of the University of Minnesota.
Other autoimmune/inflammatory disease applications. T-lymphocyte-dependent autoimmune attack can also contribute to a host of other autoimmune/inflammatory diseases. There is human clinical data available to support development of anti-CD3 therapy in other autoimmune/inflammatory indications and so teplizumab has potential applications in a wide range of immunological diseases including systemic lupus, multiple sclerosis, arthritis, psoriatic arthritis, ulcerative colitis and psoriasis. For example, a previous phase I/II study in psoriatic arthritis showed that teplizumab reduced joint inflammation and pain in patients with advanced disease.
Anti-CD16 (FcyRIII) Mab
The low affinity activating receptor, CD16, is expressed on macrophages, natural killer cells and other immune effector cells. Stimulation of CD16 through engagement via the Fc regions of complexed antibodies triggers activation of effector cell functions. MacroGenics believes that prevention of CD16/Fc engagement is an effective means to treat antibody mediated autoimmune diseases such as rheumatoid arthritis, lupus, and idiopathic thrombocytopenic purpura (ITP). MacroGenics developed a humanized antibody that binds CD16 receptor directly thereby blocking access to Fc regions that would normally engage and activate CD16. This product candidate, GMA161, is being developed by Genzyme Corporation.
sFcR
Solube Fc receptors that bind to the Fc regions of antibodies thereby preventing CD16 engagement also are being co-developed with Genzyme Corporation.
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