Preclin. Test of Biodefense Drug for SEB Toxin Exposure

Preclin。

• 批准号: 7072317
• 负责人: J. Joseph Kim
• 金额: $ 64.09万
• 依托单位: VIRAL GENOMIX, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072317
• 关键词: Macaca mulatta; antibacterial agents; bacterial proteins; bacterial toxins; bioterrorism /chemical warfare; cytokine; drug design /synthesis /production; drug screening /evaluation; flow cytometry; immunoaffinity chromatography; laboratory mouse; nonhuman therapy evaluation; pharmacokinetics; recombinant proteins; septic shock; septicemia; staphylococcal enterotoxin

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.

描述（由申请人提供）：食物中毒的主要原因是葡萄球菌肠毒素B（SEB），也是一种超抗原，它可能在创伤或手术葡萄球菌伤口感染后引起有毒休克。除了成为主要的公共卫生威胁外，SEB还被视为10位最危险的BW特工之一。 SEB被认为是某些国家的生物武器库的一部分，并构成了真正的生物恐怖威胁。目前，尚无持牌药物或疫苗可保护人类免受SEB的毒性作用。 我们的假设是，VPR蛋白的特性表明，它可能在控制毒素诱导的细胞因子风暴中具有疗效，从而阻止了SEB毒血症的致命作用。我们公司的方法关闭了SEB毒素后的Cytokine Storm。有很大的需求开发药物，这可能会使毒素后结合后暴露的个体受益。 我们已经开发了VGX-750（重组VPR蛋白），作为SEB毒素暴露的一种潜在新型治疗。我们认为，VGX-750具有与SEB毒血症的发病机理有关的重要治疗特性。我们公司在使用重组VPR蛋白来治疗毒血症和其他炎症性疾病方面具有多样化且专有的专利立场。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一些最重要的药物。成功完成这些I期研究将导致证明使用重组VPR蛋白作为一种新型药物来治疗毒素后结合SEB暴露的可行性。我们建议通过以下三个特定目标来检验这一重要假设： AIM 1：为VGX-750（重组VPR蛋白）建立扩大制造过程，这是一种潜在的新型SEB毒素暴露疗法。 AIM 2：对啮齿动物中VGX-750进行GLP临床前毒性和药代动力学测试。 AIM 3：测试VGX-750在恒河猕猴中致命的SEB毒素挑战模型中的保护作用。 该项目将检验以下假设：VGX-750将有效预防恒河猴猕猴挑战系统中毒素诱导的细胞因子风暴和败血症的发病率和死亡率。我们的计划是利用拟议的IV猕猴研究来支持我们在本SBIR应用程序的第二阶段部分进行恒河神吸入研究（与R. Ulrich和美国陆军的合作）。此外，为了期待将VPR蛋白携带到临床评估中，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在第一阶段的保护作用的成功表征，我们计划专注于在SBIR应用程序的II期资金部分中尽可能地将该产品尽可能地进行临床评估。 从长远来看，我们还认为VGX-750也可能是SEB和其他热原性超抗原细菌毒素引起的毒性休克的新型治疗方法。 VGX-750也有可能对其他炎症性疾病有效。这种候选药物的如此广泛的潜在适用性增加了VGXO-50可能对受生物恐怖主义和普通人群的人群具有相当大的价值。