Development of a Therapeutic for Staphylococcal Enterotoxin B

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For over 40 years, the U.S. military has recognized that the toxin SEB (staphylococcal enterotoxin B) poses a serious incapacitating and lethal threat. In the past 15 years, various biochemical and molecular studies have shown that SEB acts as a superantigen, stimulating a massive T cell response that leads to a systemic disease called toxic shock syndrome. Respiratory and other tissue specific inflammatory reactions have also made exposure to SEB a serious threat as a bioweapon. With the knowledge we now have of the structure, biochemistry, and mechanism of action of SEB, it is our hypothesis that we can develop specific and effective treatments for SEB exposure by engineering high-affinity neutralizing agents. The goal is to further develop a lead therapeutic agent called G5-8 against SEB. G5-8 is a soluble T cell receptor, a 14 kDa variable � domain (V�) that has been previously engineered to bind to SEB with picomolar affinity. Results in animal models have shown that G5-8 has efficacy in both systemic SEB-mediated disease and pulmonary exposure to SEB. The goals of the present project are to determine if the pharmacokinetic properties of the V� G5-8 can be improved by fusion to immunoglobulin (Ig) Fc regions, and to begin the scale-up production of V� G5-8, or its Ig fusion derivatives, under current Good Manufacturing Practice conditions. The project will involve a coordinated partnership of four institutions: University of Illinois, Urbana- Champaign (UIUC), University of Minnesota (UMN), ImmuVen, a biotechnology company, and Cangene, a contract biologics manufacturing company. ImmuVen was founded in order to develop this product for clinical use by bringing together business, intellectual property, scientific, and product development expertise. Cangene, a Canadian company, is among the largest and most experienced companies involved in US government contract work in the area of biologics. Their expertise is critical for the cGMP production of V� G5- 8 at levels sufficient for additional pre-clinical studies, and ultimately, Phase I clinical studies. The University of Illinois and the University of Minnesota provide expertise in protein characterization, receptor biochemistry, T cell assays, and animal models of diseases caused by SEB. The specific aims of the project are: (1) To express and purify soluble V� domains and V�-immunoglobulin fusions that bind to SEB with picomolar affinity; (2) To perform in vitro testing of the soluble V� domains and immunoglobulin fusions that bind to SEB with picomolar affinity; (3) To determine pharmacokinetics and compare the efficacy of soluble V� domains and immunoglobulin fusions in animal models of SEB toxicity. Various milestones along the product development path for G5-8, or its derivatives, are described, with the ultimate goal of providing a therapeutic for individuals who are exposed to SEB.