Soluble high-affinity T cell receptors prevent MRSA lethality

描述（由申请人提供）：耐甲氧西林金黄色葡萄球菌（MRSA）和甲氧西林敏感金黄色葡萄球菌（MSSA）是高度严重的人类健康威胁，可导致一系列疾病。最近，美国疾病控制和预防中心及其同事报告说，MRSA是美国严重感染和传染病死亡的最重要原因。MRSA和MSSA致命的一个主要因素是分泌的毒素，被称为超级抗原。由于美国军方在1969年终止的旧生物武器计划下储存了大量葡萄球菌肠毒素B (SEB)，这些超级抗原的致命性已经被认识了几十年。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症细胞因子的大量释放而在细胞外起作用。我们设计了可溶性T细胞受体，使其与超级抗原具有高亲和力结合，以防止毒素相关的致死性。该提案的目标是建立在I期成功的基础上，在肺内兔模型中，使用新的治疗方法（可溶性，高亲和力T细胞受体，称为IMV-01）能够中和MRSA分泌的SEB。II期研究的假设是，治疗药物的产量可以提高，IMV-01和两种可溶性T细胞受体导联（IMV-02和IMV-03）已经针对其他临床重要的超级抗原（SEC和TSST-1）进行了改造，可以作为鸡尾酒共同给药，以中和这些毒素，并防止由MRSA引起的肺炎致死。具体目的是：1)确定最佳产率和纯度优化条件。-TCRs IMV-01、IMV-02和IMV-03；2)在万古霉素存在或不存在的兔肺内模型中，分别确定IMV-01、IMV-02或IMV-03对MRSA菌株产生的各自毒素的有效剂量和时间；3)确定IMV-01、IMV-02和IMV- 03作为鸡尾酒，在万古霉素存在或不存在的情况下，对三种不同MRSA菌株（分别分泌SEB + SEC、SEB + TSST-1或SEC + TSST-1）肺内攻击导致家兔死亡的保护效果。

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 super antigens. The lethality associated with these super antigens 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. We have engineered soluble T cell receptors for high-affinity binding to super antigens to prevent toxin-associated lethality. The objective of this proposal is to build on the success of work completed in Phase I where treatment with the novel therapeutic (soluble, high-affinity T cell receptor, called IMV-01) was able to neutralize SEB secreted from MRSA in an intrapulmonary rabbit model. The hypotheses of the Phase II work are that yields of the therapeutics can be improved, that IMV-01 and two soluble T cell receptor leads (IMV-02 and IMV-03) already engineered against the other clinically important super antigens (SEC & TSST-1) can be co-administered as a cocktail to neutralize these toxins, and prevent lethality due to pneumonia caused by MRSA. The Specific Aims are: 1) To determine the best conditions for optimizing the yield and purity of the V?-TCRs IMV-01, IMV-02 and IMV-03; 2) To determine the effective dose and timing of IMV-01, IMV-02 or IMV-03 individually to neutralize their respective toxins produced by MRSA strains in an intrapulmonary rabbit model in the presence or absence of vancomycin; and 3) To determine the efficacy of using IMV-01, IMV-02 and IMV- 03 as a cocktail to protect rabbits from death due to intrapulmonary challenge with three different MRSA strains secreting either SEB + SEC, SEB + TSST-1 or SEC + TSST-1, in the presence or absence of vancomycin.