Optimization of therapeutic mAbs to carbapenem resistant Klebsiella clone ST258

Document text

Principal Investigator: Bettina  Fries
Organization: NORTHPORT VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs

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

Terms: <Adjuvant Therapy><Affinity><Animal Model><Animal Models and Related Studies><Anti-Infective Agents><Anti-Infective Drugs><Anti-Infectives><Anti-infective Preparation><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibodies><Antigenic Determinants><Applications Grants><Armed Forces Personnel><Assay><Bacteria><Binding><Binding Determinants><Bioassay><Biological Assay><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Calymmatobacterium><Capsules><Clinical Treatment Moab><Collaborations><Communities><Data><Diagnosis><Disease><Disorder><Donovania><Encapsulated><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Epitopes><Exhibits><Extended-spectrum beta-lactamase><Extended-spectrum β-lactamase><Funding><GAR-936><Glycans><Goals><Grant Proposals><Healthcare><Heterogeneity><Hospital Admission><Hospitalization><Hospitals><Hour><Human><In Vitro><Infection><Inflammatory Response><Injury><K pneumoniae><K. pneumoniae><Klebsiella><Klebsiella pneumoniae><Laboratories><Lead><Life><Lung><Lung Respiratory System><Lung infections><MAb Therapeutics><MDR organism><MDR pathogen><Methods><Mice><Mice Mammals><Military><Military Personnel><Miscellaneous Antibiotic><Modality><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Monoclonal Antibody Therapy><Multiple Anti-bacterial Drug Resistance><Multiple Anti-bacterial Drug Resistant><Multiple Bacterial Drug Resistance><Murine><Mus><Nebulizer><Patients><Pb element><Persons><Pneumonia><Polymyxins><Polysaccharides><Prevalence><Proteins><Publishing><Rehabilitation Centers><Renal function><Reporting><Resistance><Resistance to Multiple Anti-bacterial Drug><Resistant to Multiple Anti-bacterial Drug><Risk><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Sepsis><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Soldier><Solid><Specificity><State Hospitals><Testing><Texas><Therapeutic Monoclonal Antibodies><United States><Urinary tract infection><Urinary tract infectious disease><Vaccines><Variant><Variation><Veterans><Wound Infection><adjuvant treatment><aerosolized><alternative treatment><blood infection><bloodstream infection><capsule><carbapenem resistance><carbapenem resistant><co-morbid><co-morbidity><combat><communicable disease control agent><comorbidity><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><emerging pathogen><epidemiologic investigation><epidemiology study><experience><health care><heavy metal Pb><heavy metal lead><in vivo><infected wound><injuries><intraperitoneal><kidney function><lead candidate><lead optimization><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><mAB-based therapy><mAb therapy><mAb-based therapeutics><mAbs><military population><model of animal><monoclonal Abs><monoclonal antibody drugs><mortality><multi-drug resistant bacteria><multi-drug resistant organism><multi-drug resistant pathogen><multidrug resistant bacteria><multidrug resistant organism><multidrug resistant pathogen><multiple drug resistant organism><multiple drug resistant pathogen><murine mAb><murine monoclonal antibody><mutant><nebulization><nebulize><new pathogen><novel><novel pathogen><pathogen><patient population><pneumonia therapy><pneumonia treatment><preservation><prevent><preventing><protective efficacy><pulmonary><pulmonary infections><rehabilitative center><resistance in K pneumoniae><resistance in K. pneumoniae><resistance in Klebsiella pneumoniae><resistance to carbapenem><resistant><resistant K pneumoniae><resistant K. pneumoniae><resistant Klebsiella pneumoniae><resistant to carbapenem><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><therapeutic mAbs><tigecycline><treat pneumonia><urinary infection>