Tailored therapy for severe asthma

Abstract

Patients with severe asthma or COPD have often a suboptimal symptom control due to inadequate treatment. A better understanding of pathogenetic mechanisms, phenotypes, endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen, or to open a way for new therapeutic target options. At the moment, the only biologic drug available in clinical practice is omalizumab. To overcome the limits of omalizumab, the research has focused on new monoclonal antibodies presenting higher avidity for IgE (e.g. ligelizumab and lumiximab) and ability to interact also with low affinity IgE receptor (FcϵRII). At present, many new biological drugs with different mechanisms of action and targets are matter of research. It is very important to identify the asthmatic phenotype in order to select the most appropriate drug for the individual patient. The most promising agents are targeted against cytokines of Th2 pattern and related receptors, such as IL-2 (daclizumab) and IL-13 (lebrikizumab) or IL-5 in patients with hypereosinophilia (mepolizumab, reslizumab and benralizumab). Other interesting drugs have as a target TNF-α or its soluble receptor (infliximab, golimumab and etanercept) or IL-1 (canakinumab), a cytokine with an important systemic proinflammatory action. Finally, the discovery of increased levels of C5a in the airways of asthmatic patients has led to the synthesis of a specific monoclonal antibody (eculizumab). Further help should come from the identification of biomarkers that can guide in choosing the best treatment for the individual patient, such as IgE for omalizumab or periostin for lebrikizumab.

Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives

“…The ongoing EXCELS study (Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma) will shed more information on the natural history of severe asthma and the efficacy of omalizumab [75]. Moreover, there is increasing interest in developing new monoclonal antibodies presenting higher avidity for IgE, such as ligelizumab and lumiliximab, and the ability to interact with low-affinity IgE receptors [76]. Further studies are needed to fully elucidate the exact mechanisms through which anti-IgE treatment benefits patients with severe allergic asthma.…”

Tumor Necrosis Factor-alpha and Transforming Growth Factor-beta Synergistically Upregulate Endothelin-1 Expression in Human Bronchial Epithelial Cells BEAS-2B

“…However, asthma is a disease encompassing multiple different phenotypes 11,12 , and cytokines, such as TNF-and TGF-, might also play an important role in certain phenotypes of severe asthma. TNF-is a pleiotropic cytokine that upregulates the expression of adhesion molecules, cytokines, and chemokines in the bronchial mucosa of patients with asthma, implicating an important role for TNF-in the pathogenesis of severe asthma 13,14 . Recent data also showed that TNFinhibits eosinophil apoptosis 15 , and that the TNF-pathway could be associated with airway hyper-responsiveness in obesity, one of the risk factors for the severity of asthma 16 .…”

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“…However, despite these studies, the treatment options for asthma remain limited, and steroids are the predominant type of medication [25]. The discovery of different inflammatory phenotypes in patients with BA and the related molecular phenotyping, thanks to new technologies in the field of molecular biology and immunogenetics, have made it possible to synthesize specific monoclonal antibodies, including anti-cytokine antibodies [26]. Anti-IL monoclonal antibodies should reduce airway inflammation and prevent eosinophilic activation [27].…”