Treatment Efficacy of MEDI3902 in Pseudomonas aeruginosa Bloodstream Infection and Acute Pneumonia Rabbit Models

Le, Hoan N.; Tran, Vuvi G.; vụ, Trang tin tổng hợp nhất Công nghiệp dịch; Gras, Emmanuelle; Le, Vien T. M.; Pinheiro, Marcos Gabriel; Aguiar-Alves, Fábio; Schneider-Smith, Erika; Carter, Henry Clay; Sellman, Bret R.; Stover, C. Kendall; DiGiandomenico, Antonio; Diep, Binh An

doi:10.1128/aac.00710-19

Cited by 21 publications

(19 citation statements)

References 13 publications

(12 reference statements)

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“…The resistance rates of PA are increasing in many parts of the world: recent studies reported the widespread presence of extreme drug-resistant (XDR) high-risk clones in healthcare settings [5]. Therefore, several evolving translational strategies are being explored for the control and therapy of PA, including immunotherapy [6], phage therapy [7] and vaccination. Several types of vaccines have been developed and tested in Phases I-III clinical trials [8]; however, currently there is no approved option for use in humans.…”

Section: Introductionmentioning

confidence: 99%

A live auxotrophic vaccine confers mucosal immunity and protection against lethal pneumonia caused by Pseudomonas aeruginosa

et al. 2020

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Pseudomonas aeruginosa is one of the leading causes of nosocomial pneumonia and its associated mortality. Moreover, extensively drug-resistant high-risk clones are globally widespread, presenting a major challenge to the healthcare systems. Despite this, no vaccine is available against this high-concerning pathogen. Here we tested immunogenicity and protective efficacy of an experimental live vaccine against P. aeruginosa pneumonia, consisting of an auxotrophic strain which lacks the key enzyme involved in D-glutamate biosynthesis, a structural component of the bacterial cell wall. As the amounts of free D-glutamate in vivo are trace substances in most cases, blockage of the cell wall synthesis occurs, compromising the growth of this strain, but not its immunogenic properties. Indeed, when delivered intranasally, this vaccine stimulated production of systemic and mucosal antibodies, induced effector memory, central memory and IL-17A-producing CD4 + T cells, and recruited neutrophils and mononuclear phagocytes into the airway mucosa. A significant improvement in mice survival after lung infection caused by ExoU-producing PAO1 and PA14 strains was observed. Nearly one third of the mice infected with the XDR high-risk clone ST235 were also protected. These findings highlight the potential of this vaccine for the control of acute pneumonia caused by this bacterial pathogen.

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Section: Introductionmentioning

confidence: 99%

A live auxotrophic vaccine confers mucosal immunity and protection against lethal pneumonia caused by Pseudomonas aeruginosa

et al. 2020

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“…Like the other Hu-mAb from AstraZeneca PLC, this product was also dosed i.v., excluded patients on antibiotics, and only patients positive for P. aeruginosa were enrolled. Multiple animal models led to the development of this Hu-mAb [55,59], and aside from the anti-virulence mechanism of action, it was recently shown in vitro that MEDI3902 can steer neutrophils through a "dead zone" to reach and destroy biofilm generated by P. aeruginosa [60], which highlights another positive aspect of infection remediation.…”

Section: Previous Failures Lead To Current Successmentioning

confidence: 99%

“…Finally, there are some that have said that the efficacy of Hu-mAb therapeutics is not significant enough but, again, this criticism will be addressed in the future as technology improves and more targets are added either via a cocktail or by multivalent antibody engineering. It has already been shown that the addition of just one target with a bispecific antibody improves Hu-mAb efficacy [55,59,60]. Further, there are now pentavalent antibodies and mAb cocktails that are also being explored to improve efficacy [73,74].…”

Section: Future and Conclusionmentioning

confidence: 99%

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

2020

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In the beginning of the 21st century, the frequency of antimicrobial resistance (AMR) has reached an apex, where even 4th and 5th generation antibiotics are becoming useless in clinical settings. In turn, patients are suffering from once-curable infections, with increases in morbidity and mortality. The root cause of many of these infections are the ESKAPEE pathogens (Enterococcus species, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli), which thrive in the nosocomial environment and are the bacterial species that have seen the largest rise in the acquisition of antibiotic resistance genes. While traditional small-molecule development still dominates the antibacterial landscape for solutions to AMR, some researchers are now turning to biological approaches as potential game changers. Monoclonal antibodies (mAbs)—more specifically, human monoclonal antibodies (Hu-mAbs)—have been highly pursued in the anti-cancer, autoimmune, and antiviral fields with many success stories, but antibody development for bacterial infection is still just scratching the surface. The untapped potential for Hu-mAbs to be used as a prophylactic or therapeutic treatment for bacterial infection is exciting, as these biologics do not have the same toxicity hurdles of small molecules, could have less resistance as they often target virulence proteins rather than proteins required for survival, and are narrow spectrum (targeting just one pathogenic species), therefore avoiding the disruption of the microbiome. This mini-review will highlight the current antibacterial mAbs approved for patient use, the success stories for mAb development, and new Hu-mAb products in the antibacterial pipeline.

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“…Active immunization with recombinant PcrV also improved acute lung injury and mortality in P. aeruginosa pneumonia models [64][65][66]. In recent years, more researchers have reported the clinical application of anti-PcrV antibodies, which have been developed using different approaches [67][68][69][70].…”

Section: Blocking Effects Of Antibodies Against the Bacterial Type IImentioning

confidence: 99%

“…Antibodies 2019, 8, 52 6 of 13 recent years, more researchers have reported the clinical application of anti-PcrV antibodies, which have been developed using different approaches [67][68][69][70].…”

Section: V-antigen Homologsmentioning

confidence: 99%

Immunoglobulin for Treating Bacterial Infections: One More Mechanism of Action

et al. 2019

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The mechanisms underlying the effects of immunoglobulins on bacterial infections are thought to involve bacterial cell lysis via complement activation, phagocytosis via bacterial opsonization, toxin neutralization, and antibody-dependent cell-mediated cytotoxicity. Nevertheless, recent advances in the study of the pathogenicity of Gram-negative bacteria have raised the possibility of an association between immunoglobulin and bacterial toxin secretion. Over time, new toxin secretion systems like the type III secretion system have been discovered in many pathogenic Gram-negative bacteria. With this system, the bacterial toxins are directly injected into the cytoplasm of the target cell through a special secretory apparatus without any exposure to the extracellular environment, and therefore with no opportunity for antibodies to neutralize the toxin. However, antibodies against the V-antigen, which is located on the needle-shaped tip of the bacterial secretion apparatus, can inhibit toxin translocation, thus raising the hope that the toxin may be susceptible to antibody targeting. Because multi-drug resistant bacteria are now prevalent, inhibiting this secretion mechanism is an attractive alternative or adjunctive therapy against lethal bacterial infections. Thus, it is not unreasonable to define the blocking effect of anti-V-antigen antibodies as the fifth mechanism for immunoglobulin action against bacterial infections.

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Treatment Efficacy of MEDI3902 in Pseudomonas aeruginosa Bloodstream Infection and Acute Pneumonia Rabbit Models

Cited by 21 publications

References 13 publications

A live auxotrophic vaccine confers mucosal immunity and protection against lethal pneumonia caused by Pseudomonas aeruginosa

A live auxotrophic vaccine confers mucosal immunity and protection against lethal pneumonia caused by Pseudomonas aeruginosa

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

Immunoglobulin for Treating Bacterial Infections: One More Mechanism of Action

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