Animal Testing of a Blocking Antibody of PcrV

描述(由申请人提供)：这项资助将决定 人源化单抗治疗致死性假单胞菌肺 受伤。我们已经证明，一株假单胞菌的空域灌输 含有Il系统的铜绿假单胞菌可以预测会导致肺坏死， 败血症与死亡(J Clin Invest 1999)。我们还表明，系统性的 重组PcrV A型多克隆抗体的免疫接种 参与细菌毒素转运的细菌蛋白 真核细胞，预防预先处理的小鼠肺损伤和死亡 抗体(《自然医学》1999年)。最近，我们发现了一种小鼠抗PcrV 当在细菌滴注之前给药时， 防止小鼠空域死亡-感染毒力假单胞菌。 拟议中的实验将确定是全身还是肺部 空域后人源化单抗的应用 滴注致病假单胞菌可改善血流动力学、气体交换 和/或改善空域感染的麻醉兔的败血症。 这些结果将是决定如何计划临床试验的关键； 结果将决定抗体是否应该被用作治疗或 作为一种预防性治疗。 建议的商业应用： 铜绿假单胞菌是医院感染的主要原因，占院内肺炎的20%，院内尿路感染的10%~15%，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。目前的治疗与较高的抗生素耐药率和25%-50%的失败率有关。拟议的治疗方法为预防铜绿假单胞菌感染的高危患者提供了一种新的方法，这些患者包括使用呼吸机的患者、烧伤患者、居家导管患者、中性粒细胞减少患者、囊性纤维化患者。

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.