Over the past two decades, the number of new antimicrobials being developed has experienced a greater than 60% decline, while the number of antibiotic resistant microorganisms has been steadily increasing. Only one new antibacterial drug with a novel mechanism of action (linezolid) has been introduced during this period making the long term outlook for sustained infection control increasingly precarious. One particularly concerning example is a Gram negative bacterium called Pseudomonas aeruginosa in which 30% of clinical isolates from ICU (intensive care unit) or nursing home patients were reported to be resistant to 3 or more drugs. The Infectious Diseases Society of America (IDSA) also identified P. aeruginosa as one of six "superbugs" on the top priority "hit list" of dangerous pathogens that are becoming increasingly drug resistant. P. aeruginosa poses a particularly deadly threat for lung infections in hospital acquired pneumonia (HAP), particularly ventilator associated pneumonia (VAP) cases and in cystic fibrosis (CF) patients. The major hypothesis to be tested in this application is whether a human monoclonal antibody (mAb) targeted against a prevalent cell surface carbohydrate (alginate) on P. aeruginosa can be used clinically to treat P. aeruginosa lung infections resulting in improvement in lung function and a reduction in morbidity and mortality. Preliminary data indicate that these human mAbs recognize an epitope on alginate that is expressed on a broad array of P. aeruginosa clinical isolates. The mAb kills these isolates through an immune mediated process called opsono-phagocytosis and can be used therapeutically to protect animals from lethal lung infections. In this application, we propose to scale-up the manufacturing process for the mAb and produce clinical material for future clinical trials. We propose to test the clinical material in toxicity studies in animals according to Good Laboratory Procedures (GLP) to demonstrate that the mAb is safe to administer to people in human clinical testing. Finally, we propose to schedule a pre-IND (investigational new drug) meeting with the FDA to present and discuss the Mab preclinical data and our proposed clinical plan. Incorporating feedback from the FDA, we will then file an IND application.
The proposed studies will result in further development of a human monoclonal antibody for the treatment of severe bacterial lung infections due to Pseudomonas aeruginosa in patients with hospital acquired pneumonia and cystic fibrosis. Clinical material will be produced, safety data in animals will be generated and an IND will be filed with the FDA.