Personalized medicine with biologics for severe type 2 asthma : current status and future prospects

Asthma affects more than 300 million people worldwide and poses a large socioeconomic burden, particularly in the 5% to 10% of severe asthmatics. So far, each entry of new biologics in clinical trials has led to high expectations for treating all severe asthma forms, but the outcome has only been successful if the biologic, as add-on treatment, targeted specific patient subgroups. Indeed, we now realize that asthma is a heterogeneous disease with multiple phenotypes, based on distinct pathophysiological mechanisms, called endotypes. Thus, asthma therapy is gradually moving to a personalized medicine approach, tailored to individual's asthma endotypes identified through biomarkers. Here, we review the clinical efficacy of antibody-related therapeutics undergoing clinical trials, or those already approved, for the treatment of severe type 2 asthma. Biologics targeting type 2 cytokines have shown consistent efficacy, especially in patients with evidence of type 2 inflammation, suggesting that the future of asthma biologics is promising

A bispecific antibody strategy to target multiple type 2 cytokines in asthma

Background: Asthma is a chronic inflammatory airway disease in which innate and adaptive immune cells act together to cause eosinophilic inflammation, goblet cell metaplasia (GCM), and bronchial hyperreactivity (BHR). In clinical trials using biologicals against IL-4 receptor (IL-4R) alpha or IL-5, only a subset of patients with moderate-to-severe asthma responded favorably, suggesting that distinct pathophysiologic mechanisms are at play in subgroups of patients called endotypes. However, the effect of multiple cytokine blockade using bispecific antibodies has not been tested. Objective: We sought to target simultaneously the IL-4, IL-13, and IL-5 signaling pathways with a novel IL-4R alpha/IL-5-bispecific antibody in a murine house dust mite (HDM) model of asthma. Methods: Two mAbs neutralizing IL-4R alpha and IL-5 were generated by using a llama-based antibody platform. Their heavy and light chains were then cotransfected in mammalian cells, resulting in a heterogeneous antibody mixture from which the bispecific antibody was isolated by using a dual anti-idiotypic purification process. C57BL/6J mice were finally sensitized and challenged to HDM extracts and treated during challenge with the antibodies. Results: We successfully generated and characterized the monospecific and bispecific antibodies targeting IL-4R alpha and IL-5. The monospecific antibodies could suppress eosinophilia, IgE synthesis, or both, whereas only the IL-4R alpha/IL-5-bispecific antibody and the combination of monospecific antibodies additionally inhibited GCM and BHR. Conclusion: Type 2 cytokines act synergistically to cause GCM and BHR in HDM-exposed mice. These preclinical results show the feasibility of generating bispecific antibodies that target multiple cytokine signaling pathways as superior inhibitors of asthma features, including the difficult-to-treat GCM

Atomic-resolved depth profile of strain and cation intermixing around LaAlO 3 /SrTiO 3 interfaces

International audienceNovel behavior has been observed at the interface of LaAlO 3 /SrTiO 3 heterostructures such as two dimensional metallic conductivity, magnetic scattering and superconductivity. However, both the origins and quantification of such behavior have been complicated due to an interplay of mechanical, chemical and electronic factors. Here chemical and strain profiles near the interface of LaAlO 3 /SrTiO 3 heterostructures are correlated. Conductive and insulating samples have been processed, with thicknesses respectively above and below the commonly admitted conductivity threshold. The intermixing and structural distortions within the crystal lattice have been quantitatively measured near the interface with a depth resolution of unit cell size. A strong link between intermixing and structural distortions at such interfaces is highlighted: intermixing was more pronounced in the hetero-couple with conductive interface, whereas in-plane compressive strains extended deeper within the substrate of the hetero-couple with the insulating interface. This allows a better understanding of the interface local mechanisms leading to the conductivity

Travailler l'organisation spatiale par des manipulations

peer reviewedCet article propose quelques séquences destinées à l’enseignement maternel, axées sur l’organisation spatiale et la géométrie. Le premier thème aborde, par des activités de codage et décodage, des questions de topologie comme l’intérieur et l’extérieur, les itinéraires, les notions au-dessus et en dessous. Par un travail sur des assemblages de cartes et des empreintes, le second thème amène les enfants à repérer des symétries dans des figures et à reconnaître, assembler et comparer des formes géométriques simples. Parallèlement à la description des activités, nous nous attacherons à mettre en évidence l’aspect mathématique des concepts abordés.Maths et Manips : favoriser l'apprentissage des mathématiques par des manipulation

Des Math et manips autour des grandeurs

Publié partiellement en 2011 dans la revue Losanges, cet article, actualisé par les auteures pour Au fil des maths, présente des activités destinées à des élèves d’école primaire en Belgique (de 6 à 12 ans) pour favoriser l’apprentissage des grandeurs par des manipulations

Des puzzles en cycle 1

peer reviewedPublié dans la revue Losanges, cet article propose des Math & Manips autour de puzzles de formes géométriques, à partir de la Moyenne Section. Une utilisation en élémentaire est aussi envisageable, notamment avec des élèves en difficulté avec la notion d’aire. À vous de jouer !Maths et Manips : favoriser l'apprentissage des mathématiques par des manipulation

Dual anti-idiotypic purification of a novel, native-format biparatopic anti-MET antibody with improved in vitro and in vivo efficacy

Bispecific antibodies are of great interest due to their ability to simultaneously bind and engage different antigens or epitopes. Nevertheless, it remains a challenge to assemble, produce and/or purify them. Here we present an innovative dual anti-idiotypic purification process, which provides pure bispecific antibodies with native immunoglobulin format. Using this approach, a biparatopic IgG1 antibody targeting two distinct, HGF-competing, non-overlapping epitopes on the extracellular region of the MET receptor, was purified with camelid single-domain antibody fragments that bind specifically to the correct heavy chain/light chain pairings of each arm. The purity and functionality of the anti-MET biparatopic antibody was then confirmed by mass spectrometry and binding experiments, demonstrating its ability to simultaneously target the two epitopes recognized by the parental monoclonal antibodies. The improved MET-inhibitory activity of the biparatopic antibody compared to the parental monoclonal antibodies, was finally corroborated in cell-based assays and more importantly in a tumor xenograft mouse model. In conclusion, this approach is fast and specific, broadly applicable and results in the isolation of a pure, novel and native-format anti-MET biparatopic antibody that shows superior biological activity over the parental monospecific antibodies both in vitro and in vivo

Proinflammatory bacterial peptidoglycan as a cofactor for the development of central nervous system autoimmune disease

Upon stimulation by microbial products through TLR, dendritic cells (DC) acquire the capacity to prime naive T cells and to initiate a proinflammatory immune response. Recently, we have shown that APC within the CNS of multiple sclerosis (MS) patients contain peptidoglycan (PGN), a major cell wall component of Gram-positive bacteria, which signals through TLR and NOD. In this study, we report that Staphylococcus aureus PGN as a single component can support the induction of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for MS. Mice immunized with an encephalitogenic myelin oligodendrocyte glycoprotein peptide in IFA did not develop EAE. In contrast, addition of PGN to the emulsion was sufficient for priming of autoreactive Th1 cells and development of EAE. In vitro studies demonstrate that PGN stimulates DC-mediated processes, reflected by increased Ag uptake, DC maturation, Th1 cell expansion, activation, and proinflammatory cytokine production. These data indicate that PGN-mediated interactions result in proinflammatory stimulation of Ag-specific effector functions, which are important in the development of EAE. These PGN-mediated processes may occur both within the peripheral ly

Zilucoplan in patients with acute hypoxic respiratory failure due to COVID-19 (ZILU-COV) : a structured summary of a study protocol for a randomised controlled trial

Objectives: Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. Trial design: This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study. Participants: Adult patients (>= 18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows: 1) Inclusion criteria: a. Recent (>= 6 days and <= 16 days) SARS-CoV-2 infection. b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation. c. Acute hypoxia (defined as PaO2/FiO(2) below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen). d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those. 2) Exclusion criteria: e. Mechanical ventilation for more than 24 hours prior to randomisation. f. Active bacterial or fungal infection. g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways). Intervention and comparator: Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin.The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. Main outcomes: The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO2/FiO(2) ratio, P(A-a)O-2 gradient and a/A PO2 ratio.(PAO(2)= Partial alveolar pressure of oxygen, PaO2=partial arterial pressure of oxygen, FiO(2)=Fraction of inspired oxygen). Randomisation: Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap). Blinding (masking): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. Numbers to be randomised (sample size): A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm. Trial Status: ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date. Trial registration: The trial was registered on Clinical Trials.gov on May 11(th), 2020 (ClinicalTrials.gov Identifier: NCT04382755) and on EudraCT (Identifier: 2020-002130-33). Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol

Allergen Uptake, Activation, and IL-23 Production by Pulmonary Myeloid DCs Drives Airway Hyperresponsiveness in Asthma-Susceptible Mice

Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs “pro-asthmatic”, and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness