Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa

Alexander Simonis; Christoph Kreer; Alexandra Albus; Katharina Rox; Biao Yuan; Dmitriy Holzmann; Joana A Wilms; Sylvia Zuber; Lisa Kottege; Sandra Winter; Meike Meyer; Kristin Schmitt; Henning Gruell; Sebastian J Theobald; Anna-Maria Hellmann; Christina Meyer; Meryem Seda Ercanoglu; Nina Cramer; Antje Munder; Michael Hallek; Gerd Fätkenheuer; Manuel Koch; Harald Seifert; Ernst Rietschel; Thomas C Marlovits; Silke van Koningsbruggen-Rietschel; Florian Klein; Jan Rybniker

doi:10.1016/j.cell.2023.10.002

Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa

Cell. 2023 Nov 9;186(23):5098-5113.e19. doi: 10.1016/j.cell.2023.10.002. Epub 2023 Nov 1.

Authors

Alexander Simonis¹, Christoph Kreer², Alexandra Albus³, Katharina Rox⁴, Biao Yuan⁵, Dmitriy Holzmann³, Joana A Wilms³, Sylvia Zuber³, Lisa Kottege², Sandra Winter³, Meike Meyer⁶, Kristin Schmitt³, Henning Gruell⁷, Sebastian J Theobald³, Anna-Maria Hellmann⁸, Christina Meyer³, Meryem Seda Ercanoglu², Nina Cramer⁹, Antje Munder¹⁰, Michael Hallek³, Gerd Fätkenheuer¹¹, Manuel Koch¹², Harald Seifert¹³, Ernst Rietschel⁶, Thomas C Marlovits⁵, Silke van Koningsbruggen-Rietschel⁶, Florian Klein¹⁴, Jan Rybniker¹⁵

Affiliations

¹ Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany. Electronic address: alexander.simonis@uk-koeln.de.
² Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
³ Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
⁴ Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany; German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, 38124 Braunschweig, Germany.
⁵ Institute of Structural and Systems Biology, University Medical Center Hamburg-Eppendorf (UKE), 22607 Hamburg, Germany; Centre for Structural Systems Biology (CSSB), 22607 Hamburg, Germany; Deutsches Elektronen-Synchrotron Zentrum (DESY), 22607 Hamburg, Germany.
⁶ CF Centre, Pediatric Pulmonology and Allergology, University Children's Hospital Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Centre for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.
⁷ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
⁸ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Department of Experimental Pediatric Oncology, University Children's Hospital Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.
⁹ Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany.
¹⁰ Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany.
¹¹ Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany.
¹² Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
¹³ German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany; Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50935 Cologne, Germany.
¹⁴ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany; Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
¹⁵ Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany. Electronic address: jan.rybniker@uk-koeln.de.

PMID: 37918395
DOI: 10.1016/j.cell.2023.10.002

Abstract

Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B cell and antibody response to the virulence-associated type III secretion system (T3SS) in a cohort of patients chronically infected with PA. Single-cell analytics revealed a diverse B cell receptor repertoire directed against the T3SS needle-tip protein PcrV, enabling the production of monoclonal antibodies (mAbs) abrogating T3SS-mediated cytotoxicity. Mechanistic studies involving cryoelectron microscopy identified a surface-exposed C-terminal PcrV epitope as the target of highly neutralizing mAbs with broad activity against drug-resistant PA isolates. These anti-PcrV mAbs were as effective as treatment with conventional antibiotics in vivo. Our study reveals that chronically infected patients represent a source of neutralizing antibodies, which can be exploited as therapeutics against PA.

Keywords: Pseudomonas aeruginosa; anti-virulence therapy; antibacterial antibodies; antimicrobial resistance; monoclonal antibodies; patient-derived antibodies; type III secretion system.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Bacterial* / pharmacology
Antibodies, Neutralizing*
Cryoelectron Microscopy
Humans
Immunoglobulins / metabolism
Pseudomonas Infections* / drug therapy
Pseudomonas aeruginosa* / drug effects
Pseudomonas aeruginosa* / physiology

Substances

Antibodies, Bacterial
Immunoglobulins
Antibodies, Neutralizing