Soluble high-affinity T cell receptors prevent MRSA lethality

性状（由申请方提供）：耐甲氧西林金黄色葡萄球菌（MRSA）和甲氧西林敏感性葡萄球菌。金黄色葡萄球菌（MSSA）是引起一系列疾病的高度显著的人类健康威胁。最近，CDC及其同事报告说，MRSA是美国严重感染和传染病死亡的最重要原因。参与MRSA和MSSA致死性的主要因素是分泌的毒素，称为超抗原。几十年来，随着美国军方在1969年终止的旧生物武器计划下储存了大量的葡萄球菌肠毒素B（SE B），与这些超抗原相关的致命性一直受到重视。毒素的作用机制是众所周知的-它们通过与T细胞上的T细胞受体结合并刺激炎性细胞因子的大量释放而在细胞外起作用。这项工作的目的是测试使用一种新的潜在药物的可行性，这种药物是一种可溶性T细胞受体蛋白（G5-8），它被设计成与SEB具有非常高的亲和力结合，以防止致命性。将检查SEB诱导致死性的两种家兔模型，即肺部单独暴露于毒素（如生物恐怖主义事件中发生的）或肺部感染产生SEB的MRSA菌株。I期工作的假设是，可以提高工程化V2蛋白G5-8的产量，并且可以确定将降低与SEB暴露相关的肺部疾病的严重程度的给药剂量和时间。具体目标是：1）确定优化V2-TCR G5-8蛋白的产量和长期储存的最佳条件; 2）确定使用G5-8保护兔免于由于SEB肺内攻击而死亡的功效;和3）确定使用G5-8保护兔免于由于SEB+ CA-MRSA USA 400菌株肺内攻击而死亡的功效。在第二阶段的工作中，ImmuVen将测试长期储存的G5-8是否可以防止暴露于其他SEB+ MRSA菌株的家兔的致死性，以及G5-8是否可以以雾化形式使用。ImmuVen还将开始开发cGMP工艺，用于其他临床前和临床研究。G5-8和其他S.金黄色葡萄球菌外毒素（SEC，TSST-1）代表了治疗由MRSA和MSSA引起或恶化的许多疾病的临床和商业机会。 公共卫生相关性：耐抗生素金黄色葡萄球菌分离株经常通过细菌在呼吸道粘膜和皮肤上的定殖，随后分泌被称为超抗原的强效毒素而引发严重的人类疾病。疾病包括严重的病毒感染后肺炎、过敏性皮肤病和伤口愈合延迟，在美国每年影响数千人。分泌的毒素直接参与疾病的影响，包括死亡。本申请研究了一种新的基于蛋白质的药物，其作用是阻断支气管给药的超抗原（如生物恐怖剂中的情况）和耐药链球菌感染的致病作用。金黄色。

DESCRIPTION (provided by applicant): Methicillin resistant Staphylococcus aureus (MRSA) and methicillin sensitive S. aureus (MSSA) are highly significant human health threats that are responsible for a range of diseases. Recently, the CDC and colleagues reported that MRSA are the most significant causes of serious infections and infectious disease deaths in the United States. A major factor involved in the lethality of MRSA and MSSA are secreted toxins, known as superantigens. The lethality associated with these superantigens has been appreciated for decades, as the U.S. military stockpiled large amounts of staphylococcal enterotoxin B (SEB) under its old bioweapons program that was terminated in 1969. The mechanism of action of the toxins is well known - they act extracellularly by binding to the T cell receptor on T cells and stimulating massive release of inflammatory cytokines. The objective of the proposed work is to test the feasibility of using a novel potential drug, a soluble T cell receptor protein (G5-8) that has been engineered for very high-affinity binding to SEB, to prevent lethality. Two rabbit models of SEB-induced lethality will be examined, pulmonary exposure to the toxin alone (as would occur in a bioterrorism incident) or pulmonary infection with a strain of MRSA that produces SEB. The hypotheses of the Phase I work are that yields of the engineered V2 protein G5-8 can be improved, and that the doses and timing of administration that will reduce the severity of pulmonary diseases associated with SEB exposure can be determined. The Specific Aims are: 1) To determine the best conditions for optimizing the yield and long-term storage of the V2-TCR G5-8 protein; 2) To determine the efficacy of using G5-8 to protect rabbits from death due to intrapulmonary challenge with SEB; and 3) To determine the efficacy of using G5-8 to protect rabbits from death due to intrapulmonary challenge with an SEB+ CA-MRSA USA400 strain. In Phase II work, ImmuVen would test whether long-term stored G5-8 prevents lethality in rabbits exposed to additional SEB+ MRSA strains, and whether the G5-8 can be used in nebulized form. ImmuVen will also begin development of a cGMP process for additional pre-clinical and clinical studies. G5-8 and similar proteins in development for other S. aureus exotoxins (SEC, TSST-1) represent clinical and commercial opportunities to treat a host of diseases caused or worsened by MRSA and MSSA. PUBLIC HEALTH RELEVANCE: Antibiotic-resistant Staphylococcus aureus isolates frequently initiate serious human diseases through the bacterium's colonization of respiratory mucosa and skin, followed by secretion of potent toxins referred to as superantigens. Illnesses include serious post- viral pneumonias, allergic skin diseases, and delayed wound healing that affect thousands of individuals each year in the United States. The secreted toxins are directly involved in the disease effects, including death. This application studies a novel protein- based drug that acts to block the disease-causing effects of bronchially-administered superantigens (as would be the case in a bioterrorism agent) and of infections with antibiotic-resistant S. aureus.