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  • Review Article
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The potential of biologics for the treatment of asthma

Nature Reviews Drug Discovery volume 11, pages 958–972 (2012)Cite this article

Subjects

Key Points

  • The recent advances in the knowledge of asthma pathobiology are substantially contributing to the characterization of the various phenotypes of this complex and heterogeneous disease. Such advances can affect the development of novel anti-asthma treatments.

  • Biological therapies have the potential to be very useful for the phenotype-driven treatment of severe asthma.

  • Immunoglobulin E and pro-inflammatory cytokines are currently the main targets of biological drugs for the treatment of asthma.

  • The immunoglobulin E-targeted monoclonal antibody omalizumab is the first — and so far the only — biologic approved for the treatment of asthma. In patients with difficult-to-treat allergic asthma, omalizumab reduces disease exacerbations, emergency hostpital visits and hospitalizations.

  • Other promising biologics for the treatment of inadequately controlled asthma include monoclonal antibodies that target interleukin 5 (IL-5), such as mepolizumab, and those that target IL-13, such as lebrikizumab.

  • Antibodies that target other pro-infammatory cytokines are also in clinical development or preclinical studies.

Abstract

Recent advances in the knowledge of asthma pathobiology suggest that biological therapies that target cytokines can be potentially useful for the treatment of this complex and heterogeneous airway disease. The use of biologics in asthma has been established with the approval of the humanized monoclonal immunoglobulin E-targeted antibody omalizumab (Xolair; Genentech/Novartis) as an add-on treatment for inadequately controlled disease. Furthermore, evidence is accumulating in support of the efficacy of other biologics, such as interleukin-5 (IL-5)- and IL-13-specific drugs. Therefore, these new developments are changing the scenario of asthma therapies, especially with regard to more severe disease. The variability among patients' individual therapeutic responses highlights that it will be necessary to characterize the different asthma subtypes so that phenotype-targeted treatments based on the use of biologics can be implemented.

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Figure 1: Pathobiology of asthma.
Figure 2: Mechanism of action of biological therapies for asthma.

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Authors and Affiliations

  1. Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Campus Universitario S. Venuta Viale Europa, Località Germaneto, Catanzaro, 88100, Italy

    Girolamo Pelaia & Rosario Maselli

  2. Department of Respiratory Medicine, University of Salerno, Via Salvator Allende, Baronissi, 84081, Salerno, Italy

    Alessandro Vatrella

Authors
  1. Girolamo Pelaia
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  2. Alessandro Vatrella
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  3. Rosario Maselli
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Corresponding author

Correspondence to Girolamo Pelaia.

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FURTHER INFORMATION

ClinicalTrials.gov website

Rigel website (R343 — Asthma)

University of Southampton website — “Positive results in Southampton-led patient trial for new asthma treatment” (19 April 2012 press release)

Glossary

Corticosteroids

A class of steroid hormones that generally inhibit inflammation and immunity.

Eosinophilia

The accumulation of eosinophils (white blood cells that produce cytokines, cationic proteins and reactive oxygen species) in tissue or blood.

Dyspnoea

Shortness of breath that causes discomfort.

Airway hyperresponsiveness

An exaggerated contractile response of airway smooth muscle that has been exposed to potentially bronchoconstrictive stimuli.

Antigen presentation

An immunological event that is mediated by antigen-presenting cells. These cells internalize and process antigens, then display antigenic peptidic fragments on their surface, together with co-stimulatory molecules that are required for the activation of the cognate lymphocytes.

TH1 polarization

Interleukin 12 (IL-12)-driven expansion of T helper 1 (TH1) cells, which produce large amounts of TH1 cytokines (such as interferon-γ and IL-2), activate macrophages and are essential for the defence against intracellular pathogens.

TH2-adaptive responses

A type of adaptive immunity mediated by T helper 2 (TH2) cells; a TH cell subset that produces TH2 cytokines (for example, interleukin 4 (IL-4), IL-5 and IL-13), which are involved in atopic immune responses.

Immunoglobulin class switching

Interleukin-4 (IL-4)- and IL-13-mediated induction of B cells to perform immunoglobulin class recombination, resulting in prevalent production of immunoglobulin E.

CD4+ T cell

A subset of helper T lymphocytes expressing the cell surface glycoprotein called CD4.

Neutrophilic inflammation

A type of inflammation that is mediated by the recruitment and activation of neutrophils (white blood cells that produce pro-inflammatory cytokines, proteases and reactive oxygen species).

IL-17

Interleukin-17; a T helper 17 (TH17) cell-derived cytokine that induces neutrophil recruitment.

Adaptive immunity

The ability of the immune system to recognize and remember a specific pathogen, causing the host to induce a strong immune response every time that pathogen is encountered.

Epithelial shedding

Epithelial detachment from the basement membrane, which results in the loss of ciliated cells from the layer of epithelial cells in the airway.

Goblet cell

A modified columnar epithelial cell that produces and secretes mucus.

Epithelial reticular basement membrane

(RBM). A histological structure that is underneath epithelial cells in the airway.

Mesenchyme

Embryological tissue from which all types of connective tissue are derived.

Long-acting β2-adrenergic receptor agonists

A class of inhaled drugs that act by providing a prolonged bronchodilation, which is mediated by the stimulation of β2-adrenergic receptors expressed by airway smooth muscle cells.

Complementarity-determining region

A specific region of an antibody that consists of a highly variable amino acid sequence and confers antigen-binding specificity.

Fcɛ receptor I

A high-affinity receptor for immunoglobulin E that is expressed by mast cells, basophils and a variety of other cell types, and is essential for several biological functions of immunoglobulin E.

Early-phase asthmatic responses

Bronchoconstrictive reactions that occur within minutes of the airway being exposed to allergens.

Late-phase asthmatic responses

Bronchoconstrictive reactions that occur several hours after allergens have been inhaled.

Cɛ3 domain

The third domain of the constant region of immunoglobulin E that contains the Fcɛ receptor I (FcɛRI)-binding function.

Peak expiratory flow

(PEF). An individual's maximum speed of expiration that acts as an indicator of changes in the functioning of the airway.

Asthma Control Questionnaire

(ACQ). A list of questions that are used to assess how well a patient's asthma is controlled; includes questions about symptoms during the day and at night, limitations in daily activity, airway functioning and the use of rescue bronchodilators.

Atopic status

The propensity to generate allergic responses to antigens, mediated by an exaggerated production of immunoglobulin E.

Rescue bronchodilators

Rapidly acting inhaled drugs, which provide immediate relief of bronchoconstriction.

Forced vital capacity

(FVC). A spirometric indicator of lung function.

FEV1/FVC ratio

A ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC). A decrease in this ratio from normal values indicates that a patient has limitations in airflow through the bronchi.

IgG4κ

A subclass of immunoglobulin G4 that has a structure characterized by the presence of κ light chains.

Nasal polyposis

Mucosal protrusions that contain oedema fluid and variable levels of eosinophils.

Area under the curve

A pharmacokinetic parameter that estimates drug bioavailability. It is extrapolated from the area under the graph of drug plasma concentration plotted against time after administration.

Volume of distribution

The amount of drug in the body divided by the concentration of the drug in blood or plasma; the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce its desired blood concentration.

Innate immune responses

Rapid and non-specific cellular responses to pathogens and/or tissue injury, which stimulate and influence the relatively slow development of specific adaptive immune responses.

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Pelaia, G., Vatrella, A. & Maselli, R. The potential of biologics for the treatment of asthma. Nat Rev Drug Discov 11, 958–972 (2012). https://doi.org/10.1038/nrd3792

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