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Author Spotlight: Studying Host-Virus Interactions with Pseudotyped Viruses
Published on: November 21, 2023
Anti-PcrV antibody strategies against virulent Pseudomonas aeruginosa
Teiji Sawa1, Emi Ito, Vinh Huu Nguyen
1a Department of Anesthesiology ; Kyoto Prefectural University of Medicine ; Kyoto , Japan.
Abstract:
Pseudomonas aeruginosa is an opportunistic bacterial pathogen that causes fatal acute lung infections in critically ill individuals. Its pathogenesis is associated with bacterial virulence conferred by the type III secretion system (TTSS), through which P. aeruginosa causes necrosis of the lung epithelium and disseminates into the circulation, resulting in bacteremia, sepsis, and mortality. TTSS allows P. aeruginosa to directly translocate cytotoxins into eukaryotic cells, inducing cell death. The P. aeruginosa V-antigen PcrV, a homolog of the Yersinia V-antigen LcrV, is an indispensable contributor to TTS toxin translocation. Vaccination against PcrV ensures the survival of challenged mice and decreases lung inflammation and injury. Both the rabbit polyclonal anti-PcrV antibody and the murine monoclonal anti-PcrV antibody, mAb166, inhibit TTS toxin translocation. mAb166 IgG was cloned, and a molecular engineered humanized anti-PcrV IgG antigen-binding fragment, KB001, was developed for clinical use. KB001 is currently undergoing Phase-II clinical trials for ventilator-associated pneumonia in France and chronic pneumonia in cystic fibrosis in USA. In these studies, KB001 has demonstrated its safety, a favorable pharmacokinetic profile, and promising potential as a nonantibiotic strategy to reduce airway inflammation and damage in P. aeruginosa pneumonia.
Insights
Pseudomonas aeruginosa lung infections are deadly, but targeting its type III secretion system (TTSS) with antibodies like KB001 shows promise. This nonantibiotic therapy may reduce inflammation and damage in pneumonia patients.
Area of Science:
- Microbiology
- Immunology
- Pulmonology
Background:
- Pseudomonas aeruginosa is an opportunistic pathogen causing severe lung infections.
- The type III secretion system (TTSS) is crucial for P. aeruginosa virulence, mediating cytotoxin delivery and host cell death.
- PcrV is a key component of the TTSS, essential for toxin translocation.
Purpose of the Study:
- To investigate the therapeutic potential of targeting PcrV in P. aeruginosa lung infections.
- To evaluate the efficacy and safety of a humanized anti-PcrV antibody fragment, KB001.
Main Methods:
- Development of KB001, a humanized IgG antigen-binding fragment targeting PcrV.
- Preclinical studies involving vaccination against PcrV and antibody-mediated inhibition of TTSS.
- Phase-II clinical trials evaluating KB001 in ventilator-associated pneumonia and cystic fibrosis-associated pneumonia.
Main Results:
- Vaccination against PcrV improved survival and reduced lung inflammation and injury in mice.
- Anti-PcrV antibodies, including mAb166 and KB001, inhibit TTSS toxin translocation.
- KB001 demonstrated safety and a favorable pharmacokinetic profile in clinical trials.
Conclusions:
- PcrV is a viable therapeutic target for P. aeruginosa infections.
- KB001 represents a promising nonantibiotic strategy for managing P. aeruginosa pneumonia.
- Further clinical evaluation of KB001 is warranted for its potential to reduce airway inflammation and damage.
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