Novel, Broadly Reactive Anticapsular Antibodies against Carbapenem-Resistant Klebsiella pneumoniae Protect from Infection

• Published in: mBio 2018-04, Vol.9 (2)
• Main Authors: Diago-Navarro, Elizabeth, Motley, Michael P, Ruiz-Peréz, Gonzalo, Yu, Winnie, Austin, Julianne, Seco, Bruna M S, Xiao, Guozhi, Chikhalya, Aniska, Seeberger, Peter H, Fries, Bettina C
• Format: Article
• Language: English
• Subjects: adjuvant therapy; Agglutination Tests; Animal Structures - microbiology; Animals; antibiotic resistance; Antibodies, Bacterial - administration & dosage; Antibodies, Bacterial - isolation & purification; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - isolation & purification; carbapenem resistance; Carbapenem-Resistant Enterobacteriaceae - immunology; Cells, Cultured; Disease Models, Animal; Immunoglobulin G - administration & dosage; Immunoglobulin G - isolation & purification; infection protection; Klebsiella Infections - therapy; Klebsiella pneumoniae; Klebsiella pneumoniae - immunology; Macrophages - immunology; Macrophages - microbiology; Mice; monoclonal antibodies; Neutrophils - immunology; Neutrophils - microbiology; Phagocytosis; Polysaccharides, Bacterial - immunology; Treatment Outcome
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.00091-18

Carbapenem-resistant (CR) sequence type 258 (ST258) has become an urgent health care threat, causing an increasing number of high-mortality infections. Its resistance to numerous antibiotics and threat to immunocompromised patients necessitate finding new therapies to combat these infections. Previous successes in the laboratory, as well as the conservation of capsular polysaccharide (CPS) among the members of the ST258 clone, suggest that monoclonal antibody (MAb) therapy targeting the outer polysaccharide capsule of could serve as a valuable treatment alternative for afflicted patients. Here, we isolated several IgG antibodies from mice inoculated with a mixture of CR CPS conjugated to anthrax protective antigen. Two of these MAbs, 17H12 and 8F12, bind whole and oligosaccharide epitopes of the CPS of clade 2 ST258 CR , which is responsible for the most virulent CR infections in the United States. These antibodies were shown to agglutinate all clade 2 strains and were also shown to promote extracellular processes killing these bacteria, including biofilm inhibition, complement deposition, and deployment of neutrophil extracellular traps. Additionally, they promoted opsonophagocytosis and intracellular killing of CR by human-derived neutrophils and cultured murine macrophages. Finally, when mice were intratracheally infected with preopsonized clade 2 CR , these MAbs reduced bacterial dissemination to organs. Our data suggest that broadly reactive anticapsular antibodies and vaccines against clade 2 ST258 CR are possible. Such MAbs and vaccines would benefit those susceptible populations at risk of infection with this group of multidrug-resistant bacteria. Carbapenem-resistant is an enteric bacterium that has been responsible for an increasing number of deadly outbreaks and hospital-acquired infections. The pathogen's resistance to numerous antibiotics, including new drugs, leaves few therapeutic options available for infected patients, who often are too sick to fight the infection themselves. Immunotherapy utilizing monoclonal antibodies has been successful in other medical fields, and antibodies targeting the outer polysaccharide capsule of these bacteria could be a valuable treatment alternative. This study presents two anticapsular antibodies, 17H12 and 8F12, that were found to be protective against the most virulent carbapenem-resistant clinical strains. These antibodies are shown to promote the killing of these strains through several extracellular an