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，称为超级抗原。几十年来，这些超级抗原的致命性一直受到重视，因为美国军方在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）。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。我们已经设计了可溶性T细胞受体，用于与超级抗原高亲和力结合，以防止毒素相关的致死性。该提案的目的是建立在I期完成的工作的成功基础上，其中用新型治疗剂（可溶性高亲和力T细胞受体，称为IMV-01）治疗能够中和肺内兔模型中MRSA分泌的SEB。II期工作的假设是，可以提高治疗剂的产量，IMV-01和已经针对其他临床上重要的超级抗原（SEC和TSST-1）工程化的两种可溶性T细胞受体先导物（IMV-02和IMV-03）可以作为混合物共同施用以中和这些毒素，并防止由于MRSA引起的肺炎而导致的致死性。具体目的是：1）确定最佳条件，以优化V？-的收率和纯度。2）确定IMV-01、IMV-02或IMV-03在存在或不存在万古霉素的肺内兔模型中单独中和由MRSA菌株产生的它们各自的毒素的有效剂量和时间;和3）确定使用IMV-01、IMV-02和IMV- 03作为混合物保护兔免于由于用分泌SEB + SEC的三种不同MRSA菌株肺内攻击而死亡的功效，SEB + TSST-1或SEC + TSST-1，存在或不存在万古霉素。

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.