Animal Testing of a Blocking Antibody of PcrV

PcrV 阻断抗体的动物试验

• 批准号: 6444270
• 负责人: TEIJI SAWA
• 金额: $ 20.88万
• 依托单位: INTERMUNE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444270
• 关键词: Pseudomonas aeruginosa; antibacterial antibody; bacterial pneumonia; bacterial proteins; blocking antibody; chemoprevention; drug screening /evaluation; hemodynamics; immunologic substance development /preparation; laboratory rabbit; monoclonal antibody; passive immunization; respiratory gas level; respiratory infections

DESCRIPTION (provided by applicant): This grant will determine the efficacy of a humanized monoclonal antibody in treating a lethal Pseudomonas-induced lung injury. We have shown that the airspace instillation of a strain of Pseudomonas aeruginosa that contains the type Il system predictably causes lung necrosis, sepsis and death (J Clin Invest 1999). We have also shown that the systemic administration of polyclonal antibody raised against recombinant PcrV, a type III bacterial protein involved in translocating the bacterial toxins into eukaryotic cells, prevented lung injury and death in mice pretreated with the antibody (Nature Med 1999). More recently, we have identified a mouse antiPcrV monoclonal antibody that when administered prior to the bacterial instillation, prevented mortality in mice airspace-infected with the virulent Pseudomonas. The proposed experiments will determine whether the systemic or lung administration of a humanized monoclonal antibody after the airspace instillation of the virulent Pseudomonas improves hemodynamics, gas exchange and/or improves the septicemia in airspace-infected, anesthetized rabbits. These results will be critical for deciding how to plan a clinical trial; the results will determine whether the antibody should be utilized as a therapy or as a prophylactic treatment. PROPOSED COMMERCIAL APPLICATIONS: Pseudomonas aeruginosa is a major cause of hospital infection, accounting for 20% of nosoconual pneumonias, 10-15% of nosocomial urinary tract infections, and 10% of sepsis. In addition, P. aeruginosa infection is the major cause of mortality in cystic fibrosis. Current treatment is associated with a high rate of antibiotic resistance and a 25-50% failure rate. The proposed treatment provides a novel approach to the prevention of P. aeruginosa infection in patients at high risk for this infection, including patients on ventilators, burn patients, patients with in-dwelling catheters, neutropenic patients, an patients with cystic fibrosis.

描述（由申请人提供）：该补助金将确定 人源化单克隆抗体治疗致死性假单胞菌肺 损伤我们已经证明，空气中滴注一种假单胞菌 含有II型系统的铜绿假单胞菌可预测地引起肺坏死， 败血症和死亡（J Clin Invest 1999）。我们还表明，系统 施用针对重组PcrV的多克隆抗体， III参与将细菌毒素转运到 真核细胞，防止肺损伤和死亡的小鼠预处理与 抗体（Nature Med 1999）。最近，我们发现了一种小鼠抗PcrV 当在细菌滴注之前施用时， 预防了感染有毒假单胞菌的小鼠的死亡率。 拟议的实验将确定是否全身或肺部 在空域之后施用人源化单克隆抗体 注入有毒的假单胞菌可以改善血液动力学，气体交换 和/或改善呼吸道感染的麻醉兔的败血症。 这些结果对于决定如何规划临床试验至关重要; 结果将决定抗体是否应用作治疗或 作为预防性治疗。 拟议的商业应用： 铜绿假单胞菌是医院感染的主要原因，占医院感染性肺炎的20%，医院尿路感染的10-15%，以及败血症的10%。此外，铜绿假单胞菌感染是囊性纤维化死亡的主要原因。目前的治疗与高抗生素耐药性和25-50%的失败率有关。所提出的治疗提供了一种新的方法来预防铜绿假单胞菌感染的高风险患者，包括使用呼吸机的患者、烧伤患者、留置导管的患者、血小板减少症患者、囊性纤维化患者。

项目成果

Polymorphisms in the Pseudomonas aeruginosa type III secretion protein, PcrV - implications for anti-PcrV immunotherapy.

• DOI: 10.1016/j.micpath.2010.02.008
• 发表时间: 2010-06
• 期刊: Microbial pathogenesis
• 影响因子: 3.8
• 作者: Lynch SV;Flanagan JL;Sawa T;Fang A;Baek MS;Rubio-Mills A;Ajayi T;Yanagihara K;Hirakata Y;Kohno S;Misset B;Nguyen JC;Wiener-Kronish JP
• 通讯作者: Wiener-Kronish JP