Optimization of therapeutic mAbs to carbapenem resistant Klebsiella clone ST258

Optimization of therapeutic mAbs to carbapenem resistant Klebsiella clones Carbapenem resistant Klebsiella pneumoniae (CR-Kp) bacteria continue to be the most common gram- negative multidrug-resistant bacteria in US hospitals. CR-Kp cause predominantly pneumonia, sepsis, and urinary tract infections and, in military personnel, complicated invasive wound infections as well. Most patients acquire this pathogen in health care-associated settings. Soldiers are at risk because they commonly have prolonged stays in hospitals and rehabilitation centers when they recover from injuries they sustained in combat. The mortality of invasive CR-Kp infections is high despite the introduction of novel antibiotics. Monoclonal antibodies that bind to the capsule of CR-Kp are protective. One problem is that most CR-Kp infections are diagnosed late and in patients with multiple comorbidities. One barrier to generating monoclonal antibodies to the polysaccharide capsule is the heterogeneity of the polysaccharide capsule. The goal of this application is to continue to optimize lead monoclonal antibodies (mAbs) that bind to the diverse polysaccharide capsule (CPS) of CR-Kp. We now have a cross-protective monoclonal antibody that binds to both clade 1 and clade 2 CR-Kp strains. Although the majority of CR-Kp strains belong to the clonal group CG258 group, there is also another GC307 clone emerging, which expresses a unique wzi173 capsule type. Based on others and our published experience we propose several strategies to optimize mAb therapy to combat CR-Kp infections. Three aims are proposed. In Aim 1 we propose to characterize in vitro and in vivo efficacy of humanized 24D11 (HU-24D11) which will be generated. In Aim 2 we will generate new mAbs that bind to the capsule (wzi173) of ST307. Finally, in Aim 3 we will explore aerosilization as a novel delivery method to use CR-Kp-specific mAbs. 1