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.

An Official American Thoracic Society Workshop Report: Evaluation and Management of Asthma in the Elderly

“…Phenotypes, the outward manifestation of an individual's underlying genetics, have been widely accepted as a way to characterize patients with asthma (76)(77)(78)(79)(80)(81) and include clinical, physiologic, inflammatory, and molecular features. Stratification of asthma subtypes by phenotype and endotype (i.e., specific biologic mechanisms) represents the cutting edge for advancing asthma treatment.…”

Genetics of Allergic Asthma and Current Perspectives on Therapeutic Management

“…Over the last 40 years, there has been a marked increase in the development of targeted treatments for asthma-anti-leukotrienes, anti-IgE, anti-interleukins, and anti-TNF-α [115]. Obviously, as more of the biological basis of asthma is uncovered, more effective targeted asthma treatments might be developed.…”

IgE+ B cells in the pathogenesis of allergic asthma: fundamental but often forgotten

“…Omalizumab (Xolair®) is a humanized monoclonal antibody that binds to free, circulating IgE. This prevents IgE binding to high (FcεRI) and low affinity (FcεRII) IgE receptors on mast cells and basophils, thereby inhibiting the degranulation and release of inflammatory mediators (8). A systematic review by Rodrigo et al (9) found that omalizumab therapy was able to reduce the rate of asthma exacerbations by up to 50% and significantly improve quality of life scores of allergic asthmatics (9).…”

“…Another alternative, quilizumab, which targets M1-prime (a protein specific to membrane bound IgE+ B cells), has been shown to reduce the production of IgE after allergen inhalation challenge (11). Despite the therapeutic potential of anti-IgE, major drawbacks of antibody therapies are their cost and that they must be taken regularly for long-term treatment as their effects are known to wane following the termination of treatment (8). Additionally, anti-IgE therapies are prescribed to a small proportion of patients with moderate-severe allergic asthma.…”