Anti-capsule human monoclonal antibodies protect against hypervirulent and pandrug-resistant Klebsiella pneumoniae

Emanuele Roscioli; Vittoria Zucconi Galli Fonseca; Soraya Soledad Bosch; Ida Paciello; Giuseppe Maccari; Giulia Cardinali; Giampiero Batani; Samuele Stazzoni; Giusy Tiseo; Cesira Giordano; Yuwei Shen; Laura Capoccia; Dario Cardamone; Matteo Ridelfi; Marco Troisi; Noemi Manganaro; Chiara Mugnaini; Concetta De Santi; Annalisa Ciabattini; Linda Cerofolini; Marco Fragai; Danilo Licastro; Kelly L. Wyres; Laurent Dortet; Simona Barnini; David P. Nicolau; Francesco Menichetti; Marco Falcone; Kamilia Abdelraouf; Claudia Sala

doi:10.1038/s41586-025-09391-3

MicrobiologyNatureOct 1, 2025

Peer-reviewed journal article

Anti-capsule human monoclonal antibodies protect against hypervirulent and pandrug-resistant Klebsiella pneumoniae

Emanuele Roscioli iD, Vittoria Zucconi Galli Fonseca iD, Soraya Soledad Bosch iD, Ida Paciello iD, Giuseppe Maccari iD, Giulia Cardinali iD, Giampiero Batani iD, Samuele Stazzoni iD, Giusy Tiseo iD, Cesira Giordano iD, Yuwei Shen iD, Laura Capoccia iD, Dario Cardamone iD, Matteo Ridelfi iD, Marco Troisi iD, Noemi Manganaro iD, Chiara Mugnaini, Concetta De Santi iD, Annalisa Ciabattini iD, Linda Cerofolini iD, Marco Fragai iD, Danilo Licastro iD, Kelly L. Wyres iD, Laurent Dortet iD, Simona Barnini iD, , Rino Rappuoli iD

Abstract

The silent pandemic caused by antimicrobial resistance (AMR) requires innovative therapeutic approaches. Human monoclonal antibodies (mAbs), which are among the most transformative, safe and effective drugs in oncology and autoimmunity, are rarely used for infectious diseases and not yet used for AMR. Here we applied an antigen-agnostic strategy to isolate extremely potent human mAbs against Klebsiella pneumoniae (Kp) sequence type 147 (ST147), a hypervirulent and pandrug-resistant clonotype which is spreading globally. Isolated mAbs target the bacterial capsule and the O-antigen. Surprisingly, although both capsule- and O-antigen-specific mAbs displayed bactericidal activity in the picomolar range in vitro, only the capsule-specific mAbs were protective against fulminant ST147 bloodstream infection. Protection correlated with in vitro bacterial uptake by macrophages and enchained bacterial growth. Our study describes the only drug able to protect against pandrug-resistant Kp and provides a strategy to isolate mAbs and identify correlates of protection against AMR bacteria.

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