Anthrax toxin is a critical virulence factor of Bacillus anthracis. The toxin comprises protective antigen (PA) and two enzymatic moieties, edema factor (EF) and lethal factor (LF), forming bipartite lethal toxin (LT) and edema toxin (ET). PA binds cellular surface receptors and is required for intracellular translocation of the enzymatic moieties. For this reason, anti-PA antibodies have been developed as therapeutics for prophylaxis and treatment of human anthrax infection. Assays described publicly for the control of anti-PA antibody potency quantify inhibition of LT-mediated cell death or the ET-induced increase in c-AMP levels. These assays do not fully reflect and/or capture the pathological functions of anthrax toxin in humans. Herein, we report the development of a cell-based gene reporter potency assay for anti-PA antibodies based on the rapid LT-induced degradation of c-Jun protein, a pathogenic effect that occurs in human cells. This new assay was developed by transducing Hepa1c1c7 cells with an AP-1 reporter lentiviral construct and has been qualified for specificity, accuracy, repeatability, intermediate precision, and linearity. This assay not only serves as a bioassay for LT activity, but has applications for characterization and quality control of anti-PA therapeutic antibodies or other products that target the AP-1 signaling pathway.

2010-01-01·Biologie aujourd'hui

Review

作者: Vidal, Dominique ; Pelat, Thibault ; Thullier, Philippe ; Paucod, Jean-Charles

Recombinant antibodies are a highly successful class of therapeutic molecules, they are well adapted for use against bio-weapons (BW) as they act immediately, are often synergistic with other therapeutic molecules, have a long half-life and are well tolerated. Anthrax is regarded at high risk of being used as BW, and its pathogenic properties depend on toxins, which might be neutralized by antibodies. These toxins are made of three different types of sub-units (PA, LF, EF). Several anti-PA have been developed, including an original approach by our team. We have developed an anti-LF, as recommended by experts. Our anti-PA antibody, and to a lesser extend our anti-LF antibody, will be presented here.

PloS one3区 · 综合性期刊

Patient-Specific Modeling of Regional Antibiotic Concentration Levels in Airways of Patients with Cystic Fibrosis: Are We Dosing High Enough?

3区 · 综合性期刊

ArticleOA

作者: de Backer, Jan W ; Tiddens, Harm A W M ; Vos, Wim G ; van Holsbeke, Cedric ; Janssens, Hettie M ; van Westreenen, Mireille ; Bos, Aukje C

BACKGROUND:

Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient-specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF.

METHODS:

In- and expiratory CT-scans of children with CF (5-17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses.

RESULTS:

In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations.

CONCLUSIONS:

CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved.

100 项与 Anthraxumab 相关的药物交易

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