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

Abstract

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.

Keywords: asthma; biologic; biomarker; cytokine; personalized medicine.

Figure 1.

Simplified schematic representation of four different types of airway inflammation in asthmatic patients. (A) Type 2 consists of allergic and nonallergic eosinophilic asthma. (a) In allergic eosinophilic asthma, T-helper type 2 (T_H2) cell lymphocytes and mast cells drive eosinophilic airway inflammation in an allergen-specific, immunoglobulin E (IgE)-dependent manner. (b) In nonallergic eosinophilic asthma, innate lymphocytes such as natural killer T cells (NKT cells) and innate lymphoid cells type 2 (ILC2) cells might contribute to airway eosinophilia via the production of interleukin (IL)-5, in response to pollutants or infectious agents. (B) Non-type 2 consists of neutrophilic and paucigranulocytic asthma. (c) The mechanisms underlying neutrophilic asthma need to be elucidated, but the IL-17 pathway and CXCL8 have been associated with the airway neutrophilia. More precisely, IL-17A and IL-17F play important roles in host responses to extracellular pathogens via the upregulation of antimicrobial proteins and induction of cytokines and chemokines involved in neutrophil expansion (e.g., GM-CSF) and recruitment (e.g., CXCR ligands). (d) Paucigranulocytic asthma has been poorly studied. It is thought to be not inflammatory and is characterized by the absence of increased numbers of inflammatory cells, suggesting the involvement of non-inflammatory mechanisms mediated by airway remodeling responses that lead to extensive airway narrowing. The biologics being evaluated in clinical trials or already approved as add-on treatment, on top of high-doses inhaled corticosteroid (ICS) and a short- or long-acting β₂-adrenergic agonist (LABA), for (C) allergic and (D) nonallergic eosinophilic asthma are depicted in light grey. CRTH₂: prostaglandin D2 receptor 2; CXCL8: C-X-C motif chemokine ligand 8; CXCR: C-X-C chemokine receptor; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; FcεRI: Fc epsilon receptor I; GM-CSF: granulocyte-macrophage colony-stimulating factor; ICS: inhaled corticosteroid; IgE: immunoglobulin epsilon; ILC2: innate lymphoid cell type 2; IL: interleukin; IL-4Rα: interleukin-4 receptor alpha; IL-5Rα: interleukin-5 receptor alpha; IL-9R: interleukin-9 receptor; IL-25R: interleukin-25 receptor; IL-33R: interleukin-33 receptor; LABA: long-acting β₂-adrenergic; MHC: major histocompatibility complex; NKT: natural killer T; PGD₂: prostaglandin D2; TCR: T-cell receptor; T_H2: T-helper type 2 cell; T_H17: T-helper type 17 cell; TSLP: thymic stromal lymphoietin; TSLPR: thymic stromal lymphoietin receptor.

Figure 2.

Simplified schematic representation of targeted T_H2 and T_H17 cytokines therapies that can lead to amplification of activity of the opposing pathway in a murine house dust mite model of asthma. (A) With suppression of T_H2 activity by targeted therapy or corticosteroids, a T_H17-permissive environment exists. A direct relationship between T_H17 and T_H2 disease exists, whereby, through mutual cross regulation, T_H17 asthma may represent a transition or switch away from T_H2-mediated disease. Thus, by treating T_H2 patients with corticosteroids, T_H17 asthma may have been promoted. (B) Combination therapy targeting T_H2 cytokine, such as interleukin-13, and T_H17 cytokine, such as interleukin-17, in patients expressing either a T_H2 or T_H17 signature may provide additional efficacy over single T_H2 or T_H17 inhibition. T_H2: T-helper type 2 cell; T_H17: T-helper type 17 cell.