Preclin. Test of Biodefense Drug for SEB Toxin Exposure

描述（由申请方提供）：葡萄球菌肠毒素B（SE B）是食物中毒的主要原因，也是一种超抗原，可在创伤或手术葡萄球菌伤口感染后引起中毒性休克。除了是一个主要的公共卫生威胁外，SEB还被认为是10种最危险的生物战剂之一。SEB被认为是某些国家生物武器库的一部分，构成了真实的生物恐怖主义威胁。目前还没有获得许可的药物或疫苗可用于保护人类免受SEB的毒性作用。 我们的假设是Vpr蛋白的性质表明它可能具有控制毒素诱导的细胞因子风暴的功效，从而防止SEB毒血症的致死效应。我们公司的方法关闭细胞因子风暴后SEB毒素结合。非常需要开发可以在毒素结合后使暴露个体受益的试剂。 我们开发了VGX-750（重组Vpr蛋白），作为SEB毒素暴露的潜在新疗法。我们相信VGX-750具有重要的治疗质量相关的SEB毒血症的发病机制。我们公司在使用重组Vpr蛋白治疗毒血症和其他炎症性疾病方面拥有多样化的专有专利。此外，许多基于重组蛋白的药物已被批准，并已成为现代医学中最重要的药物之一。这些I期研究的成功完成将证明使用重组Vpr蛋白作为治疗毒素结合后SEB暴露的新药的可行性。我们建议通过以下三个具体目标来检验这一重要假设： 目标1：建立VGX-750（重组Vpr蛋白）的扩大生产工艺，VGX-750是一种潜在的SEB毒素暴露新疗法。 目的2：在啮齿动物中进行VGX-750的GLP临床前毒性和药代动力学试验。 目的3：在恒河猴中的致死SEB毒素攻击模型中测试VGX-750的保护作用。 本项目将检验VGX-750在恒河猴激发系统中有效预防毒素诱导的细胞因子风暴和脓毒症的发病率和死亡率的假设。我们的计划是使用提议的IV猕猴研究来支持我们进行恒河猴吸入研究的计划（与R。Ulrich和美国陆军）在该SBIR应用的第二阶段部分。此外，预期将Vpr蛋白纳入临床评价，我们将在小鼠中进行GLP临床前毒性和药代动力学研究，作为I期SBIR研究的一部分。随着VGX-750在I期研究中的保护作用的成功表征，我们计划在SBIR申请的II期资助部分期间尽可能方便地将该产品投入临床评价。 从长远来看，我们也认为VGX-750也可能是一种治疗SEB和其他致热超抗原细菌毒素引起的中毒性休克的新方法。VGX-750也可能对其他炎症性疾病有效。这种候选药物如此广泛的潜在适用性增加了VGXO-50对遭受生物恐怖主义的人群和普通人群都具有相当大价值的可能性。

DESCRIPTION (provided by applicant): Staphylococcal enterotoxin B (SEB), a primary cause of food poisoning, is also a superantigen that can cause toxic shock after traumatic or surgical Staphylococcal wound infections. In addition to being a major public health threat, SEB is regarded as one of 10 most dangerous BW agents. SEB is believed to be a part of the biological weapons arsenals of certain countries, and to pose a real bioterrorism threat. At the present there are no licensed drugs or vaccines available to protect humans against the toxic effects of SEB. Our Hypothesis is that the properties of Vpr protein suggest that it may have efficacy in controlling toxin-induced cytokine storm thus preventing the lethal effects of SEB toxemia. Our company's approach shuts down cytokine storm post-SEB toxin binding. There is a significant need to develop agents, which may benefit exposed individuals post-toxin binding. We have developed VGX-750 (recombinant Vpr protein), as a potential novel therapy for SEB Toxin Exposure. We believe VGX-750 has important therapeutic qualities relevant to the pathogenesis of SEB toxemia. Our company has a diverse and proprietary patent position on the use of recombinant Vpr protein to treat toxemia and other inflammatory diseases. In addition, many recombinant protein based drugs have been approved and have become some of the most important drugs in modern medicine. Successful completion of these Phase I studies will result in the demonstration of feasibility for using recombinant Vpr protein as a novel drug to treat post-toxin binding SEB exposure. We propose to test this important hypothesis through the following three specific aims: Aim 1: Establish a scale-up manufacturing process for VGX-750 (recombinant Vpr protein), a potential novel therapy for SEB toxin exposure. Aim 2: Perform GLP preclinical toxicity and pharmacokinetics testing of VGX-750 in rodents. Aim 3: Test the protective effects of VGX-750 in a lethal SEB toxin challenge model in rhesus macaques. This project will test the hypothesis that VGX-750 will be effective at preventing morbidity and mortality from toxin induced cytokine storm and sepsis in a rhesus macaque challenge system. Our plan is to use the proposed IV macaque studies to support our plan to conduct rhesus inhalation studies (in collaborations with R. Ulrich and the US Army) in the Phase II portion of this SBIR application. Furthermore, in anticipation of carrying the Vpr protein into clinical evaluation, we will perform GLP pre-clinical toxicity and pharmacokinetics studies in mice as a part of the Phase I SBIR studies. With successful characterization of the protective effects of VGX-750 in Phase I, we plan to focus on bringing this product to clinical evaluation as expediently as possible during the Phase II funding portion of the SBIR application. In the long run, we also feel that VGX-750 could also be a novel treatment for toxic shock due to SEB and other pyrogenic superantigen bacterial toxins. It is also possible that VGX-750 could be effective against other inflammatory diseases. Such a broad potential applicability of this drug candidate increases the likelihood that VGXO-50 could have a considerable value for both a population subject to bioterrorism and the general population.