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Development of a Therapeutic for Staphylococcal Enterotoxin B

葡萄球菌肠毒素 B 治疗药物的开发

基本信息

批准号：
8083295
负责人：
David M. Kranz
金额：
$ 63.97万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-02 至 2012-08-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8083295
关键词：
Affinity Animal Disease Models Animal Model Area Binding Biochemical Biochemistry Biological Assay Biotechnology Blood Cells Businesses Clinical Clinical Research Contracts Development Drug Kinetics Engineering Escherichia coli Exposure to Fc Receptor Goals Government Hour Human Human Cell Line IgG1 IgG4 Illinois Immunoglobulin Domain Immunoglobulins In Vitro Inflammatory Institution Intellectual Property Knowledge Lead Lung Lung diseases MHC Class II Genes Mediating Military Personnel Minnesota Modeling Molecular Mus Oryctolagus cuniculus Phase Production Property Proteins Pump Reaction Research Personnel Serum Staphylococcal Enterotoxin B Structure Superantigens Systemic disease T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Agents Time Tissues Toxic Shock Syndrome Toxic effect Toxin Transgenes Universities Wild Type Mouse Work cGMP production comparative efficacy effective therapy experience immunogenicity improved in vitro Assay in vitro testing in vivo milligram pre-clinical product development receptor research study respiratory scale up

项目摘要

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 ï¿½ domain (Vï¿½) 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 Vï¿½ G5-8 can be improved by fusion to immunoglobulin (Ig) Fc regions, and to begin the scale-up production of Vï¿½ 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 Vï¿½ 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 Vï¿½ domains and Vï¿½-immunoglobulin fusions that bind to SEB with picomolar affinity; (2) To perform in vitro testing of the soluble Vï¿½ domains and immunoglobulin fusions that bind to SEB with picomolar affinity; (3) To determine pharmacokinetics and compare the efficacy of soluble Vï¿½ 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.

40多年来，美国军方已经认识到毒素SE B（葡萄球菌肠毒素B）构成了严重的致残和致命威胁。在过去的15年里，各种生化和分子研究表明，SEB作为一种超抗原，刺激大量的T细胞反应，导致一种称为中毒性休克综合征的全身性疾病。呼吸道和其他组织特异性炎症反应也使接触SEB成为一种严重的威胁。随着我们现在对SEB的结构、生物化学和作用机制的了解，我们假设我们可以通过设计高亲和力中和剂来开发针对SEB暴露的特异性和有效的治疗方法。我们的目标是进一步开发一种名为G5-8的针对SEB的领先治疗剂。G5-8是一种可溶性T细胞受体，是一种14 kDa的可变T细胞半结构域（V细胞半结构域），先前已被工程化以皮摩尔亲和力结合SEB。动物模型的结果表明，G5-8在全身性SEB介导的疾病和肺暴露于SEB中均具有疗效。本项目的目的是确定是否可以通过融合至免疫球蛋白（IG）Fc区来改善VEGF 1/2 G5-8的药代动力学特性，并在当前药品生产质量管理规范条件下开始VEGF 1/2 G5-8或其IG融合衍生物的规模化生产。该项目将涉及四个机构的协调合作：伊利诺伊大学厄巴纳-尚潘分校（UIUC），明尼苏达大学（UMN），生物技术公司ImmuVen和合同生物制剂制造公司Cangene。ImmuVen的成立是为了通过汇集商业，知识产权，科学和产品开发专业知识来开发该产品用于临床。Cangene是一家加拿大公司，是参与美国政府生物制剂领域合同工作的最大和最有经验的公司之一。他们的专业知识对于cGMP生产足够的水平用于额外的临床前研究和最终的I期临床研究至关重要。伊利诺伊大学和明尼苏达大学提供蛋白质表征，受体生物化学，T细胞测定和SEB引起疾病的动物模型方面的专业知识。本项目的具体目标是：（1）表达和纯化可溶性VEGF 1/2结构域和VEGF 1/2-免疫球蛋白融合体，它们以皮摩尔亲和力与SEB结合;（2）对可溶性VEGF 1/2结构域和免疫球蛋白融合体进行体外测试，它们以皮摩尔亲和力与SEB结合;（3）测定药代动力学并比较可溶性VEGF 1/2结构域和免疫球蛋白融合体的功效。SEB毒性动物模型中的1/2结构域和免疫球蛋白融合。描述了G5-8或其衍生物产品开发道路沿着的各种里程碑，最终目标是为暴露于SEB的个体提供治疗。