title: Target-Agnostic Identification of Functional Monoclonal Antibodies Against Klebsiella pneumoniae Multimeric MrkA Fimbrial Subunit.
abstract: The increasing incidence of Klebsiella pneumoniae infections refractory to treatment with current broad-spectrum antibiotic classes warrants the exploration of alternative approaches, such as antibody therapy and/or vaccines, for prevention and treatment. However, the lack of validated targets shared by spectrums of clinical strains poses a significant challenge. We adopted a target-agnostic approach to identify protective antibodies against K. pneumoniae Several monoclonal antibodies were isolated from phage display and hybridoma platforms by functional screening for opsonophagocytic killing activity. We further identified their common target antigen to be MrkA, a major protein in the type III fimbriae complex, and showed that these serotype-independent anti-MrkA antibodies reduced biofilm formation in vitro and conferred protection in multiple murine pneumonia models. Importantly, mice immunized with purified MrkA proteins also showed reduced bacterial burden following K. pneumoniae challenge. Taken together, these results support MrkA as a promising target for K. pneumoniae antibody therapeutics and vaccines.
authors.affiliation: Department of Infectious Disease and Vaccines.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: Chew-Shun
authors.initials: CS
authors.lastname: Chang
authors.affiliation: Department of Infectious Disease and Vaccines.
authors.forename: Meghan
authors.initials: M
authors.lastname: Pennini
authors.affiliation: Department of Infectious Disease and Vaccines.
authors.forename: Mark
authors.initials: M
authors.lastname: Pelletier
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Department of Infectious Disease and Vaccines.
authors.forename: Jingying
authors.initials: J
authors.lastname: Zha
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Infectious Disease and Vaccines.
authors.forename: Romana
authors.initials: R
authors.lastname: Cvitkovic
authors.affiliation: Department of Infectious Disease and Vaccines.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sadowska
authors.affiliation: Department of Analytical Biochemistry, MedImmune, Gaithersburg, Maryland.
authors.forename: Jenny
authors.initials: J
authors.lastname: Heidbrink Thompson
authors.affiliation: Department of Analytical Biochemistry, MedImmune, Gaithersburg, Maryland.
authors.forename: Hung
authors.initials: H
authors.lastname: Yu Lin
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: Arnita
authors.initials: A
authors.lastname: Barnes
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: Susan
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Department of Infectious Disease and Vaccines.
authors.forename: C Kendall
authors.initials: CK
authors.lastname: Stover
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: William F
authors.initials: WF
authors.lastname: Dall'Acqua
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: Partha S
authors.initials: PS
authors.lastname: Chowdhury
authors.affiliation: Department of Antibody Discovery and Protein Engineering.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D001428:Bacterial Vaccines / Q000276:immunology; D018441:Biofilms; D003602:Cytotoxicity, Immunologic; D036781:Fimbriae Proteins / Q000276:immunology*; D006801:Humans; D006825:Hybridomas; D007710:Klebsiella Infections / Q000517:prevention & control; D007711:Klebsiella pneumoniae / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019151:Peptide Library; D010587:Phagocytosis; D020545:Respiratory Mucosa / Q000382:microbiology
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D001428:Bacterial Vaccines; D019151:Peptide Library; D036781:Fimbriae Proteins
keywords: Klebsiella pneumoniae; MrkA; biofilm; functional screening; hybridoma; monoclonal antibodies; opsonophagocytic killing (OPK); organ burden; phage display; vaccine