Effects of monoclonal anti-PcrV antibody on Pseudomonas aeruginosa-induced acute lung injury in a rat model

Faure, Karine; Fujimoto, Junichi; Shimabukuro, David; Ajayi, Temitayo; Shime, Nobuaki; Moriyama, Kiyoshi; Spack, Edward G.; Wiener-Kronish, Jeanine P.; Sawa, Teiji

doi:10.1186/1476-8518-1-2

Cited by 76 publications

(20 citation statements)

References 30 publications

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“…As a comparator MAb for these studies, we expressed a version of MAb166, the well-characterized anti-PcrV MAb and progenitor of the clinical candidate KB001-A, which has been shown to inhibit the P. aeruginosa T3SS in vitro and in vivo (18,19). The MAb166 VH and VL coding sequences (27) were fused in frame to mouse IgG2a Fcand C-kappa-coding regions to generate MAb166.2a.…”

Section: Resultsmentioning

confidence: 99%

“…This drug candidate is based on the PcrV-specific mouse monoclonal antibody MAb166. While effective in blocking P. aeruginosa T3SS in vitro, MAb166 requires relatively high antibody doses for protection in animal models (18,19). Whether this is due to its modest PcrV-binding affinity (11) or results from the mechanism by which its specific binding to PcrV inhibits the T3SS is unclear.…”

mentioning

confidence: 99%

“…The P. aeruginosa T3SS is a well-validated target for intervention in infections caused by this opportunistic pathogen. Both active vaccination with T3SS component proteins and passive immunotherapy targeting PcrV strongly attenuate P. aeruginosa disease in animal models (18)(19)(20)(21)(22). In fact, a pegylated Fab fragment of an anti-PcrV MAb is currently in development for preventing P. aeruginosa respiratory infections in mechanically ventilated patients (11,23).…”

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confidence: 99%

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A Novel Anti-PcrV Antibody Providing Enhanced Protection against Pseudomonas aeruginosa in Multiple Animal Infection Models

Warrener¹,

Varkey²,

Bonnell³

et al. 2014

Antimicrob Agents Chemother

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Pseudomonas aeruginosa is a major cause of hospital-acquired infections, particularly in mechanically ventilated patients, and it is the leading cause of death in cystic fibrosis patients. A key virulence factor associated with disease severity is the P. aeruginosa type III secretion system (T3SS), which injects bacterial toxins directly into the cytoplasm of host cells. The PcrV protein, located at the tip of the T3SS injectisome complex, is required for T3SS function and is a well-validated target in animal models of immunoprophylactic strategies targeting P. aeruginosa. In an effort to identify a highly potent and protective monoclonal antibody (MAb) that inhibits the T3SS, we generated and characterized a panel of novel anti-PcrV MAbs. Interestingly, some MAbs exhibiting potent inhibition of T3SS in vitro failed to provide protection in a mouse model of P. aeruginosa infection, suggesting that effective in vivo inhibition of T3SS with anti-PcrV MAbs is epitope dependent. V2L2MD, while not the most potent MAb as assessed by in vitro cytotoxicity inhibition assays, provided strong prophylactic protection in several murine infection models and a postinfection therapeutic model. V2L2MD mediated significantly (P < 0.0001) better in vivo protection than that provided by a comparator antibody, MAb166, a well-characterized anti-PcrV MAb and the progenitor of a clinical candidate, KB001-A. The results described here support further development of a V2L2MD-containing immunotherapeutic and may suggest even greater potential than was previously recognized for the prevention and treatment of P. aeruginosa infections in high-risk populations.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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A Novel Anti-PcrV Antibody Providing Enhanced Protection against Pseudomonas aeruginosa in Multiple Animal Infection Models

Warrener¹,

Varkey²,

Bonnell³

et al. 2014

Antimicrob Agents Chemother

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“…PcrV has garnered some attention in the past because it is surface displayed, and antisera directed against PcrV are protective in an animal model (41)(42)(43)(44).…”

Section: A Pcrv Mutant Secretes Exos Constitutivelymentioning

confidence: 99%

ExsE, a secreted regulator of type III secretion genes in Pseudomonas aeruginosa

Rietsch

Vallet-Gély

Dove

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

348

349

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Type III secretion systems are toxin delivery systems that are present in a large number of pathogens. A hallmark of all type III secretion systems studied to date is that expression of one or more of their components is induced upon cell contact. It has been proposed that this induction is controlled by a negative regulator that is itself secreted by means of the type III secretion machinery. Although candidate proteins for this negative regulator have been proposed in a number of systems, for the most part, a direct demonstration of their role in regulation is lacking. Here, we report the discovery of ExsE, a negative regulator of type III secretion gene expression in Pseudomonas aeruginosa. Deletion of exsE deregulates expression of the type III secretion genes. We provide evidence that ExsE is itself secreted by means of the type III secretion machinery and physically interacts with ExsC, a positive regulator of the type III secretion regulon. Taken together, these data demonstrate that ExsE is the secreted negative regulator that couples triggering of the type III secretion machinery to induction of the type III secretion genes.contact-dependent secretion ͉ pathogenesis ͉ virulence

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“…Animal model studies of P. aeruginosa pneumonia have demonstrated the involvement in virulence of proteases, flagella, pili and LPS O side chains as well as the delivery of the extracellular toxins ExoS, ExoT and ExoU via a type III secretion system (T3SS). For example, administration of anti-pcrV antibodies blocking the T3SS has been shown to offer protection against acute P. aeruginosa pneumonia when tested in animal studies (Faure et al, 2003;Shime et al, 2001). …”

Section: Hospital-associated Pneumoniamentioning

confidence: 99%

Pseudomonas aeruginosa – Pathogenesis and Pathogenic Mechanisms

Alhazmi

2015

IJB

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Pseudomonas aeruginosa is a common bacterium, Gram-negative opportunistic pathogen capable of infecting humans with compromised natural defenses and causing severe pulmonary disease. It is one of the leading pathogen associated with nosocomial infections. It has a vast arsenal of pathogenicity factors that are used to interfere with host defenses. Pathogenesis in P. aeruginosa facilitates adhesion, modulate or disrupt host cell pathways, and target the extracellular matrix. The propensity of P. aeruginosa to form biofilms further protects it from antibiotics and the host immune system. P. aeruginosa is intrinsically resistant to a large number of antibiotics and can be acquired resistance to many others, making treatment difficult. P. aeruginosa provokes a potent inflammatory response during the infectious process. The majority of mortalities in immunocompromised patients; cystic fibrosis, can be attributed to the progressive decline of lung function resulting from chronic infection by pathogens such as P. aeruginosa. Antibiotic treatment of chronic P. aeruginosa infections may temporarily suppress symptoms; however, they do not eradicate the pathogen. Lung diseases caused by P. aeruginosa are a leading cause of death in immunocompromised individuals as well as in children. Although immunocytes recruitment is critical to augment the host defense, excessive neutrophil accumulation results in life-threatening diseases, such as acute lung injury, as well as acute respiratory distress syndrome. Several virulence factors have been studied for their roles as potential vaccine candidate, although there is currently no clinically accepted vaccine. Understanding host-pathogen interaction is critical for the development of effective therapeutic strategies to control the damage in the lung.

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Effects of monoclonal anti-PcrV antibody on Pseudomonas aeruginosa-induced acute lung injury in a rat model

Abstract: Background: The effects of the murine monoclonal anti-PcrV antibody Mab166 on acute lung injury induced by Pseudomonas aeruginosa were analyzed in a rat model.

Cited by 76 publications

References 30 publications

A Novel Anti-PcrV Antibody Providing Enhanced Protection against Pseudomonas aeruginosa in Multiple Animal Infection Models

A Novel Anti-PcrV Antibody Providing Enhanced Protection against Pseudomonas aeruginosa in Multiple Animal Infection Models

ExsE, a secreted regulator of type III secretion genes in Pseudomonas aeruginosa

Pseudomonas aeruginosa – Pathogenesis and Pathogenic Mechanisms

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