Biologics in Asthma: A Molecular Perspective to Precision Medicine

Abstract

Recent developments in therapeutic strategies have provided alternatives to corticosteroids as the cornerstone treatment for managing airway inflammation in asthma. The past two decades have witnessed a tremendous boost in the development of anti-cytokine monoclonal antibody (mAb) therapies for the management of severe asthma. Novel biologics that target eosinophilic inflammation (or type 2, T2 inflammation) have been the most successful at treating asthma symptoms, though there are a few in the drug development pipeline for treating non-eosinophilic or T2-low asthma. There has been significant improvement in clinical outcomes for asthmatics treated with currently available monoclonal antibodies (mAbs), including anti-immunoglobulin (Ig) E, anti-interleukin (IL)-4 receptor α subunit, anti-IL-5, anti-IL-5Rα, anti-IL-6, anti-IL-33, and anti-thymic stromal lymphopoietin (TSLP). Despite these initiatives in precision medicine for asthma therapy, a significant disease burden remains, as evident from modest reduction of exacerbation rates, i.e., approximately 40-60%. There are numerous studies that highlight predictors of good responses to these biologics, but few have focused on those who fail to respond adequately despite targeted treatment. Phenotyping asthmatics based on blood eosinophils is proving to be inadequate for choosing the right drug for the right patient. It is therefore pertinent to understand the underlying immunology, and perhaps, carry out immune endotyping of patients before prescribing appropriate drugs. This review summarizes the immunology of asthma, the cytokines or receptors currently targeted, the possible mechanisms of sub-optimal responses, and the importance of determining the immune make-up of individual patients prior to prescribing mAb therapy, in the age of precision medicine for asthma.

Keywords: T2 inflammation; eosinophil; monoclonal antibodies; severe asthma; treatment response.

FIGURE 1

Targets of current therapy in severe asthma. There are numerous targets that have been identified for the management of severe asthma. In particular, the differentiation of eosinophil progenitors (EoP) into eosinophils, and subsequent activation of eosinophils can be targeted by anti-Siglec-8 (AK002), dexpramipexole, as well as anti-IL-5 therapies. The secretion of alarmin cytokines (TSLP, IL-33) from epithelial cells and activation of downstream ILC2s and Th2 cells can be inhibited by anti-TSLP and anti-IL-33 agents, such as tezepelumab and etokimab, respectively. The downstream action of Th2 cytokines, such as IL-4 and IL-13, produced primarily from Th2 cells, ILC2s and basophils can be inhibited by dupilumab. The cross-linking of IgE on FcεR1 receptors on mast cells and basophils can be inhibited by omalizumab, and thus prevent degranulation of leukotrienes, histamine, and prostaglandins (PGDs). PGDs play an important role in binding to CRTH2 on ILC2s and Th2 cells, promoting their migration and activation within the airways. This can be targeted by anti-CRTH2 agents such as fevipiprant. There are few identified targets for Th2-low inflammation but anti-TSLP is a potential biologic acts on this pathway. Abbreviations: AA: Autoantibodies; EoP: Eosinophil Progenitors; ILC2s: Innate Lymphoid Type 2 Cells; INF: Interferon; PGDs: Prostaglandins; TNF: Tumor necrosis factor; TSLP: Thymic Stromal Lymphophoietin.

FIGURE 2

Factors affecting optimal biologic response and clinical ramifications. The schematic addresses the primary factors that alone or in combination can lead to sub-optimal treatment response to currently approved monoclonal antibodies (mAbs) in severe asthma. The sub-optimal responses to mAbs can result in undesired clinical manifestations via, persistence and worsening of asthma symptoms, exacerbations, infections and decline in lung functions. Abbreviations: mAb: Monoclonal anitbody; MCS: Maintenance corticosteroids.