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.

Eosinophilic Asthma, Phenotypes-Endotypes and Current Biomarkers of Choice

“…All subtypes of asthma were initially considered to be eosinophilic; however, over time, a thorough understanding of its pathogenesis led to the recognition of phenotypes associated with the underlying type of inflammation [ 11 , 19 ]. The complex role of eosinophils in the pathogenesis of asthma has been extensively investigated in the past two decades.…”

“…In the airways, ILC2s generate Th2 inflammatory responses by producing IL-5 and IL-13. IL-5, IL-3, IL-4, IL-9, and IL-13 are the most important eosinophilic cytokines, and their function is to stimulate eosinophilic production, bone marrow extrusion, proliferation, and differentiation factors [ 11 , 19 , 29 , 30 , 31 ].…”

“…TAC2 and TAC3 are not associated with Th2 inflammation. TAC2 is characterized by elevated INFγ, ΤΝF-α, and inflammasome-associated genes, whereas TAC3 indicates metabolic and mitochondrial clusters [ 19 , 105 , 106 ].…”

“…Omalizumab binds to the third constant region of IgE, preventing its binding to the FcεRI receptor, which is expressed primarily on basophils and mast cells. The eligibility criteria for this biologic include poor asthma control on conventional therapy, sensitization to inhaled allergen(s) on skin prick testing or specific IgE, increased total serum IgE, a body weight within the local dosing range, and more than a specified number of exacerbations within the past year [ 19 , 27 , 30 , 105 ]. The results from numerous randomized clinical trials (RCTs) and real-life studies have demonstrated that omalizumab has a good safety profile, improves asthma control, lung function, and quality of life, and reduces exacerbations, emergency visits, hospitalizations, and the use of oral corticosteroids [ 19 , 27 , 30 , 105 , 113 ].…”

Severe asthma and personalized approach in the choice of biologic

“…Two asthma immune endotypes can be identified in asthma: type 2 high inflammation (or T2), the most common endotype, characterized by a distinct cytokine profile (T2 profile: IL-4, IL-5, IL-13) and type 2 low inflammation (or T1) (Fig. 1) [14,15].…”