Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction.

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33) and oxidized IL-33 (IL-33) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 10 M s, to effectively neutralize IL-33 following rapid release from damaged tissue.

Sputum biomarkers during acute severe asthma attacks in children-a case-control study.

Aim: To study sputum mediator profiles pattern in children with acute severe asthma, compared with stable asthma and healthy controls. The mechanisms of acute severe asthma attacks, such as biomarkers cascades and immunological responses, are poorly understood.

Methods: We conducted a prospective observational case-control study of children aged 5 to 17 years, who presented to hospital with an asthma attack.

Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophilus-predominant subgroup.

Background: Airway ecology is altered in asthma and chronic obstructive pulmonary disease (COPD). Anti-microbial interventions might have benefit in subgroups of airway disease. Differences in sputum microbial profiles at acute exacerbation of airways disease are reflected by the γProteobacteria:Firmicutes (γP:F) ratio.

Severe exacerbations in moderate-to-severe asthmatics are associated with increased pro-inflammatory and type 1 mediators in sputum and serum.

Background: Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events.

Methods: We recruited 102 adults and 34 children with asthma.

Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles.

Background: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous.

Objective: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations.

Methods: Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center.

IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells.

Innate lymphoid cells (ILCs) represent a distinct branch of the lymphoid lineage composed of 3 major subpopulations: ILC1, ILC2, and ILC3. ILCs are mainly described as tissue-resident cells but can be detected at low levels in human blood. However, unlike mouse ILCs, there is still no consistent methodology to purify and culture these cells that enables in-depth analysis of their intrinsic biology.

Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis.

Background: Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level.

Objective: We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators.

Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation.

In response to infections and irritants, the respiratory epithelium releases the alarmin interleukin (IL)-33 to elicit a rapid immune response. However, little is known about the regulation of IL-33 following its release. Here we report that the biological activity of IL-33 at its receptor ST2 is rapidly terminated in the extracellular environment by the formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site.

Strategies targeting the IL-4/IL-13 axes in disease.

IL-4 and IL-13 are pleiotropic Th2 cytokines produced by a wide variety of different cell types and responsible for a broad range of biology and functions. Physiologically, Th2 cytokines are known to mediate host defense against parasites but they can also trigger disease if their activities are dysregulated. In this review we discuss the rationale for targeting the IL-4/IL-13 axes in asthma, atopic dermatitis, allergic rhinitis, COPD, cancer, inflammatory bowel disease, autoimmune disease and fibrotic disease as well as evaluating the associated clinical data derived from blocking IL-4, IL-13 or IL-4 and IL-13 together.

Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial.

Background: Interleukin 13 is a central mediator of asthma. Tralokinumab is a human interleukin-13 neutralising monoclonal antibody. We aimed to assess the efficacy and safety of two dosing regimens of tralokinumab in patients with severe uncontrolled asthma.

Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease.

Background: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases.

Objective: We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis.

Methods: We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD.

A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma.

The critical role played by IgE in allergic asthma is well-documented and clinically precedented, but some patients in whom IgE neutralization may still offer clinical benefit are excluded from treatment with the existing anti-IgE therapy, omalizumab, due to high total IgE levels or body mass. In this study, we sought to generate a novel high affinity anti-IgE antibody (MEDI4212) with potential to treat a broad severe asthma patient population. Analysis of body mass, total and allergen-specific IgE levels in a cohort of severe asthmatics was used to support the rationale for development of a high affinity IgE-targeted antibody therapeutic.

Development of a mouse model mimicking key aspects of a viral asthma exacerbation.

Viral respiratory tract infections are known triggers of asthma exacerbations in both adults and children. The current standard of care, inhaled CS (corticosteroids) and LABAs (long-acting β2-adrenoceptor agonists), fails to prevent the loss of control that manifests as an exacerbation. In order to better understand the mechanisms underlying viral asthma exacerbations we established an in vivo model using the clinically relevant aeroallergen HDM (house dust mite) and the viral mimetic/TLR3 (Toll-like receptor 3) agonist poly(I:C).

Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma.

Rationale: The relationship between airway inflammation and obesity in severe asthma is poorly understood.

Objectives: We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma.

Methods: Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index.

A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma.

Pre-clinical data demonstrate a pivotal role for interleukin (IL)-13 in the development and maintenance of asthma. This study assessed the effects of tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, in adults with moderate-to-severe uncontrolled asthma despite controller therapies. 194 subjects were randomised to receive tralokinumab (150, 300 or 600 mg) or placebo subcutaneously every 2 weeks.

A predictive model of human myelotoxicity using five camptothecin derivatives and the in vitro colony-forming unit granulocyte/macrophage assay.

Purpose: Many promising anticancer drugs are limited by myelosuppression. It is difficult to evaluate human myelotoxicity before a Phase I study because of the susceptibility of humans and animals to hematotoxicity. The purpose of this study was to establish a reliable method to predict the human maximum tolerated dose (MTD) of five camptothecin derivatives: SN-38, DX-8951f, topotecan, 9-aminocamptothecin, and camptothecin.

Measurement of eotaxin (CCL11) in induced sputum supernatants: validation and detection in asthma.

Background: Induced sputum is widely used in asthma research; however, for many mediators, the detection methods have not been validated.

Objective: We sought to optimize the method of detection of eotaxin, an important chemokine acting through the CCR3 receptor on eosinophils, basophils, and T(H)2 cells.

Methods: Induced sputum from normal and asthmatic subjects was processed with dithioerythritol (DTE) or PBS; recovery of eotaxin was assessed by means of ELISA before and after spiking with recombinant eotaxin.

Fractionation, structural studies, and immunological characterization of the semi-synthetic Quillaja saponins derivative GPI-0100.

Unfractionated GPI-0100 (UFGPI-0100) containing semi-synthetic derivatives of deacylated Quillaja saponins (DS saponins) modified at the glucuronic acid residue was resolved by reverse phase low-pressure liquid chromatography (RP-LPLC) into two fractions, RP18-1 and RP18-2, with different compositions and adjuvanticity. The fraction RP18-1 contained DS saponin adducts of N-dicyclohexylurea, and stimulated Th2 immunity with production of IgG1, while the RP18-2 fraction contained the dodecylamide derivatives of DS saponins and stimulated Th1 immunity with production of IgG2a, IFN-gamma, IL-2, and CTL. The strong immune stimulatory properties of RP18-2, relative to RP18-1, and the formation of RP18-1/RP18-2 mixed micelles may account for the effective stimulation of Th1 immunity by UFGPI-0100.

Degradation of Quillaja saponaria Molina saponins: loss of the protective effects of a herpes simplex virus 1 subunit vaccine.

Quillaja saponins (Q. saponins) are readily hydrolyzed at neutral pH to yield degraded deacylated saponins (DS-saponins). Degradation of Q.