Development of antibodies to capsule of carbapenem resistant Klebsiella pneumonia

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DESCRIPTION (provided by applicant): Carbapenem resistant Klebsiella pneumonia (CR-Kp) isolates are emerging worldwide including in the US. The CDC has reported an increase in prevalence from 1.6% in 2001 to 10.4% in 2011. CR-Kp causes predominantly pneumonia, sepsis and urinary tract infections. Most patients acquire this pathogen in health care associated settings but infections with CR-Kp have also been observed in healthy people from the community. One problem is that many of the CR-Kp isolates retain full virulence and often become resistant even to aminoglycosides. The 2nd line reserve antibiotics such as Tycycline or Polymyxin either have low efficacy or are very toxic especially in patients with compromised renal function. As a result, the mortality of invasive Cr-Kp infections is high and ranges from 50-80%. New effective drug classes against gram-negative bacteria are not in sight hence alternative treatment regimens have to be explored. This application proposes to generate mAbs to the capsular polysaccharide (CPS) of CR-Kp. Molecular capsule typing of 40 CR-KP isolates demonstrates that despite a common ST258 clonal background the CPS in these isolates is heterogeneous and therefore cross-reactive mAbs will have to be generated in order to successfully cover the variability of clinical isolates. In aim 1 we propose several strategies o generate cross-reactive mAbs and to also increase the number of hybridomas that produce IgG as this isotype is the preferred isotype. In aim 2 we propose to characterize the mAbs with respect to their ability to bind to diverse capsule-types of Cr-Kp and effectively enhance the host response to diverse Cr-Kp isolates. The goal is to generate a rank list of best candidates that are then humanized and further developed.