Optimization of therapeutic mAbs to carbapenem resistant Klebsiella clone ST258

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Carbapenem resistant Klebsiella pneumoniae (CR-Kp) bacteria are 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. Mortality of invasive CR-Kp infections is high and commonly over 50%. One problem is that most CR-Kp infections are diagnosed too late and empiric treatment with antibiotics like polymyxin is toxic and also compromised by emerging resistance even to these antibiotics. The goal of this application is to optimize two existing lead monoclonal antibodies (mAbs) that bind to the diverse polysaccharide capsule (CPS) of CR-Kp. Both clade 1 and clade 2 CPS-specific IgG mAbs are available and are expected to cover the majority of CR-Kp strains especially those that belong to the more virulent clade 2 of the clonal group CG258 group. Based on others and our published experience we propose several strategies to test these mAbs. Three aims are proposed. In Aim 1 we propose to generate isotype switch variants of CR-Kp specific mAbs and investigate relevance of FcɣR binding in vivo. In Aim 2 we will identify the epitopes of the lead mAbs, and identify the best isotypes of the candidate mAbs with respect to protective efficacy. We will also test combinations of CR-Kp specific mAbs with antibiotics for optimal protection. Finally, in Aim 3 we will use a murine gut colonization model to investigate if antibiotic-induced dissemination in colonized mice can be prevented by treatment with CPS- specific mAbs.