Intersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma

doi:10.1016/S0140-6736(19)33005-3

The Lancet

Volume 395, Issue 10221, 1–7 February 2020, Pages 371-383

https://doi.org/10.1016/S0140-6736(19)33005-3 Get rights and content

Summary

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.

Introduction

Asthma is a chronic airway disease that inflicts between 300 million and 400 million people worldwide.¹ A diagnosis of asthma requires verifying the presence of reversible airflow obstruction,² which is accomplished by showing either airflow limitation that improves following bronchodilator administration or worsening airflow obstruction in the setting of airway provocation.³ The disease is characterised by coughing, shortness of breath, chest tightness, and wheezing.⁴ These symptoms result from impaired airway inflammatory responses that cause mucus hypersecretion, bronchial hyper-responsiveness, and activation of airway granulocytes.⁵ Mouse models of asthma were used to identify pivotal roles for the cytokines interleukin-4 (IL-4), IL-5, and IL-13 in driving the pathophysiological features of allergic asthma.6, 7, 8, 9 Because T-helper-2 (Th2) cells were believed to be the principle source of these signalling molecules they were originally named Th2 cytokines,¹⁰ but other cells, including innate lymphocytes, can also produce these proteins, and the research community has since migrated to the broader term of type 2 (or T2) cytokines. Confirming the pathological role of these factors in human asthma would take nearly 25 years as initial human trials of targeted therapies returned negative results.11, 12, 13 In fact, establishing the efficacy of these cytokines for asthma in humans required a convergence of two concepts. First, that asthma was a complex heterogeneous disease, and second, that biologic therapies needed to target the population of asthma patients with elevated type 2 cytokine activity in their airways.14, 15, 16

Section snippets

Type 2-high asthma

Inspired by observations that allergic inflammation in mice was driven by Th2 cytokine activity8, 9 and that these cytokines were measured at high concentrations in the lungs of patients with asthma,17, 18, 19, 20 multiple monoclonal antibodies were developed to inhibit type 2 inflammation. Unfortunately, the first clinical trials testing the inhibition of IL-5 (and IL-4) with these antibodies were profoundly disappointing.11, 12, 13 Proving the efficacy of type 2 cytokine inhibition would have

Omalizumab

Although patients and asthma physicians are excited about the type 2-targeted biologics, the first approved biologic for asthma (omalizumab) was infact targeted to immunoglobulin E (IgE). Multiple reviews have discussed in detail the use of omalizumab as a treatment for asthma.35, 36 Free or circulating IgE binds to high-affinity IgE receptors (FcɛRI) expressed on the surface of basophils and mast cells, leading to their cellular activation. Omalizumab is a monoclonal antibody that binds to

Eosinophils and IL-5 inhibition

Eosinophils are granulocytes that release a variety of proinflammatory mediators, including proinflammatory cytokines following activation, major basic protein, eosinophil peroxidase, eosinophil cationic protein, eosinophil-derived neurotoxin, and galactin-10 or Charcot-Leyden crystals (figure 1).⁷ Some patients with asthma show increases in airway eosinophilia, which has been appreciated for over 100 years.45, 46 This observation prompted a considerable amount of research focused on

Adverse effects of IL-5 inhibition

The most severe adverse reaction observed with the IL-5 inhibitors was anaphylaxis. This reaction was more common with the intravenously administered reslizumab than the other IL-5 antagonists and occurred in 0·3% of patients⁶¹—the US Food and Drug Administration (FDA) has given the drug a black box warning in this regard (table 2). This frequency is similar to that seen with the subcutaneous anti-IgE monoclonal antibody (omalizumab).⁶² Hypersensitivity reactions were slightly less frequent

IL-4RA inhibition

The cytokines, IL-4 and IL-13, are complementary both in their biologic roles and in their signalling machinery. Namely, the primary receptor for IL-4 is IL-4RA, which upon binding with IL-4, complexes with the common γ-chain (γ_c) to signal via intracellular JAK1 or JAK3 pathways (type 1 receptor).⁷¹ IL-13 also uses the IL-4RA receptor through a heterodimerisation with IL-13RA1 that signals via JAK1, JAK2, and TYK2 (type 2 receptor).71, 72 Thus, blocking IL-4RA inhibits the primary signalling

Adverse effects of IL-4RA inhibition

Dupilumab is relatively well tolerated and the most common adverse events are injection site reactions. In addition, treatment with dupilumab increased the frequency of a poorly characterised conjunctivitis (about 10%) in the atopic dermatitis studies, an effect not yet seen in the asthma trials.⁹² As with the anti-IL-5 monoclonal antibodies, there was a reported increase in herpes-related events, and IL-4RA inhibition also increased blood eosinophil counts after treatment, peaking at 1–2

Comparing clinical efficacy and differing trial designs of phase 3 trials

Comparing clinical efficacy between medications requires a randomised blinded trial design directly testing the medications in a head-to-head analysis. To our knowledge, no such trial has been done and would probably require large numbers of patients. Furthermore, because study populations and analysis plans differed greatly between the type 2 biologic clinical trials, directly comparing the treatment effect sizes for each drug is difficult.⁹⁴ For example, the threshold to discriminate

Fevipiprant

Although it is not a monoclonal antibody, fevipiprant is an oral medication that blocks the binding of prostaglandin D2 to its receptor, the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or PTGDR2). As the name implies, this receptor is commonly expressed on Th2 cells, and would therefore be expected to work in patients with type 2-high asthma. However, clinical trials of fevipiprant have shown mixed results, with the most consistent finding showing a small

Biomarkers of treatment response

Blood eosinophil counts are a predictor of response for each of the type 2 biologic agents.54, 90, 97, 98 Patients with blood eosinophil counts of 300 cells per μL or higher have approximately a 50% reduction in asthma exacerbation when treated with either anti-IL-5 or anti-IL-4RA therapies, whereas the clinical benefit in patients with blood eosinophil counts of less than 300 cells per μL is considerably reduced.90, 98 However, blood eosinophilia does not uniformly predict treatment response,

Indications for treatment

The American Thoracic Society and the European Respiratory Society's definition of severe asthma is the presence of poor asthma control despite maximal treatment with high doses of inhaled corticosteroids and one additional controller medication.42, 103 The relatively small percentage of patients with severe asthma (5–10%) contributes to the majority of asthma-associated health-care costs.¹⁰⁴ The cost of health care for each patient helps to justify the high expense of these new biologic

New therapies for severe non-eosinophilic or type 2-low asthma

Treatment options for patients with type 2-low severe asthma remain limited, and aggressive efforts to identify non-type 2 treatment options remain scarce. Multiple cytokines with roles that overlap with the prototypical type 2 cytokines have been tested in asthma with mixed results. An early phase 2B trial with an inhibitor of the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) have been positive, with tezepelumab decreasing asthma exacerbation by 60–70%.¹⁰⁶ By contrast,

Future directions and remaining controversies

Although the results of the clinical trials do not provide evidence that inhibition of IL-5 is superior or inferior to inhibiting IL-4RA, there are clues that heterogeneity in type 2 inflammatory-immune processes might eventually define pathobiological subgroups of patients with type 2 asthma who respond better to inhibition of one pathway versus the other. For example, airway eosinophilia can be induced by activation of Th2 cells or type 2 innate lymphoid cells. Type 2 innate lymphoid cells

Conclusion

The emergence of type 2 biologics for the treatment of severe asthma is a welcomed and much needed advance in the management of patients with asthma. Although a cure for asthma remains elusive, many patients with severe asthma show a robust and sustained response to this new class of medication. Critical needs remain regarding better biomarkers to identify patients that are most likely to respond to these drugs and a deeper understanding for how airway type 2 inflammation develops in airway

Search strategy and selection criteria

We evaluated the biological target and clinical efficacy of type 2 monoclonal antibodies in asthma. References for this Review were identified through searches of PubMed for articles published between Jan 1, 1950, and Oct 31, 2019 (last searched Nov 7, 2019). The search terms “Asthma/drug therapy” [MeSH], “Antibodies, monoclonal/therapeutic use” [MeSH], “Clinical Trial” [publication type], “Eosinophilia/drug therapy” [MeSH], “Asthma/immunology” [MeSH], “Th2 Cells/immunology” [MeSH], and “asthma

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Exposure to toluene diisocyanate (TDI) can cause pulmonary diseases such as asthma. Inhibition of high mobility group box 1 protein (HMGB1) has been found to be protective against the toxic effects of TDI on human bronchial epithelial (HBE) cells. Here, we evaluated the in vivo positive roles of HMGB1 in the TDI-caused asthma mice and explored its underlying mechanisms in HBE cells. We found that suppression of HMGB1 obviously alleviated airway inflammation, airway hyperresponsiveness, and airway remodeling in the lung tissue of the asthma mice. The in vitro results showed that inhibition of HMGB1 ameliorated TDI-induced reactive oxygen species (ROS) release, inflammatory response, and activation of autophagy in HBE cells. At the molecular level, inhibition of HMGB1 decreased the expressions of HMGB1, Toll-like receptor 4, Vimentin and matrix metalloproteinase-9 proteins, activated NF-κB and NOD-like receptor protein 3 (NLRP3) inflammasome, and increased E-cadherin expression. Importantly, activation of autophagy could lead to the overactivation of NLRP3 inflammasome in TDI-induced asthma. These results suggest that inhibition of HMGB1 can alleviate TDI-induced asthma through ROS/AMPK/autophagy pathways, which may provide valuable evidence for the pathogenesis and therapeutic targets of TDI-induced asthma.
Identification of cough-variant asthma phenotypes based on clinical and pathophysiologic data
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Cough-variant asthma (CVA) may respond differently to antiasthmatic treatment. There are limited data on the heterogeneity of CVA.
We aimed to classify patients with CVA using cluster analysis based on clinicophysiologic parameters and to unveil the underlying molecular pathways of these phenotypes with transcriptomic data of sputum cells.
We applied k-mean clustering to 342 newly physician-diagnosed patients with CVA from a prospective multicenter observational cohort using 10 prespecified baseline clinical and pathophysiologic variables. The clusters were compared according to clinical features, treatment response, and sputum transcriptomic data.
Three stable CVA clusters were identified. Cluster 1 (n = 176) was characterized by female predominance, late onset, normal lung function, and a low proportion of complete resolution of cough (60.8%) after antiasthmatic treatment. Patients in cluster 2 (n = 105) presented with young, nocturnal cough, atopy, high type 2 inflammation, and a high proportion of complete resolution of cough (73.3%) with a highly upregulated coexpression gene network that related to type 2 immunity. Patients in cluster 3 (n = 61) had high body mass index, long disease duration, family history of asthma, low lung function, and low proportion of complete resolution of cough (54.1%). T_H17 immunity and type 2 immunity coexpression gene networks were both upregulated in clusters 1 and 3.
Three clusters of CVA were identified with different clinical, pathophysiologic, and transcriptomic features and responses to antiasthmatics treatment, which may improve our understanding of pathogenesis and help clinicians develop individualized cough treatment in asthma.
Cimifugin suppresses type 2 airway inflammation by binding to SPR and regulating its protein expression in a non-enzymatic manner
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Cimifugin is one of the main bioactive components of Yu-Ping-Feng-San, a well-known traditional Chinese medicine, which can effectively relieve Allergic asthma (AA) and atopic dermatitis and reduce recurrence in clinic. However, the underlying mechanism of cimifugin on AA is still unknown.
In the present study, we aimed to investigate the effect and mechanism of cimifugin on AA.
In vivo and in vitro experimental studies were performed.
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We found cimifugin effectively alleviated AA by reducing airway hyperresponsiveness, inhibiting type 2 cytokines-mediated airway inflammation, and restoring the expression of epithelial barrier proteins. Molecular docking predicted the direct binding ability of cimifugin to SPR, which was further verified by MST. Notably, the therapeutic effect of cimifugin on AA was dampened with SPR interfering, in contrast, the phenotypic features of AA were significantly alleviated with QM385 application both in vivo and in vitro. Interestingly, cimifugin showed no effect on the enzyme activity of SPR, as the level of its substrate sepiapterin was not affected with cimifugin treatment by cell-free enzyme activity assay. Furthermore, we found cimifugin could reduce SPR protein expression without affecting its mRNA expression probably through autophagosome pathway.
To our knowledge, we're reporting for the first time that cimifugin can suppresses type 2 airway inflammation to alleviate AA by directly binding to SPR and regulating its protein expression in a non-enzymatic manner.
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Ovalbumin (OVA) was used to construct asthmatic murine models. IgE, cytokines (e.g., IL-4, IL-5), fecal water content, colonic length, histopathologic appearance, and gut microbiota were evaluated in asthmatic mice treated with DCQD. Finally, we administered DCQD to antibiotic-treated asthmatic mice to measure the ILC2 in the small intestine and colon.
DCQD decreased pulmonary IgE, IL-4, and IL-5 levels in asthmatic mice. The fecal water content, the colonic length weight loss, and the epithelial damage of jejunum, ileum, and colon of asthmatic mice were ameliorated by DCQD. Meanwhile, DCQD greatly improved intestinal dysbiosis by enriching Allobaculum, Romboutsia and Turicibacter in the whole intestine, and Lactobacillus gasseri only in the colon. However, DCQD caused less abundant Faecalibaculum and Lactobacillus vaginalis in the small intestine of asthmatic mice. A higher ILC2 proportion in different gut segments of asthmatic mice was reversed by DCQD. Finally, significant correlations appeared between DCQD-mediated specific bacteria and cytokines (e.g., IL-4, IL-5) or ILC2. These findings indicate that DCQD alleviated the concurrent intestinal inflammation in OVA-induced asthma by decreasing the excessive accumulation of intestinal ILC2 in a microbiota-dependent manner across different gut locations.
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Interleukin-4 (IL-4) is a pleiotropic cytokine mainly known for its role in type 2 immunity. Therapies antagonizing or blocking IL-4 activity have been developed to counteract diseases such as atopic dermatitis and asthma. In contrast, other disorders experimentally benefit from IL-4-related effects and IL-4 recently demonstrated beneficial activity in experimental stroke, spinal cord injury and the animal model of multiple sclerosis. To exploit IL-4-related activity for therapeutic concepts, current experimental efforts include modifying the pathway without inducing type 2 immune response and targeting of the cytokine to specific tissues. Here, we review different activities of IL-4 as well as therapeutic strategies.
Leptin-producing monocytes in the airway submucosa may contribute to asthma pathogenesis
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Citation Excerpt :
Asthma is one of the most common chronic respiratory diseases, characterized by reversible airway obstruction and increased airway hypersensitivity caused by airway inflammation [1].
Obesity leads to an increase in the incidence and severity of asthma. Adipokines, such as leptin, secreted by adipocytes induce systemic inflammation, causing airway inflammation. We previously reported that leptin activates both inflammatory and structural cells, including lung fibroblasts. However, little is known about the differential leptin expression and responsiveness to leptin in asthmatic individuals and healthy controls (HC). In this study, we investigated the expression and origin of leptin in asthmatic airways. We also compared the effect of leptin on asthmatic and HC fibroblasts.
Lung specimens from asthmatic and non-asthmatic patients were analyzed by immunohistochemical staining using anti-leptin and anti-CD163 antibodies. Leptin mRNA and protein levels in human monocytes were detected by real-time PCR and western blotting and ELISA, respectively. We used flow cytometry to analyze asthmatic and HC lung fibroblasts for leptin receptor (Ob-R) expression. Further, we determined cytokine levels using cytometric bead array and ELISA and intracellular phosphorylation of specific signaling molecules using western blotting.
Asthma specimens displayed accumulation of leptin-positive inflammatory cells, which were also positive for CD163, a high-affinity scavenger receptor expressed by monocytes and macrophages. Leptin expression was observed at both transcript and protein levels in human blood-derived monocytes. No significant differences were observed between asthmatic and HC lung fibroblasts in Ob-R expression, cytokine production, and intracellular phosphorylation of p38 mitogen-activated protein kinase.
Our findings reveal similar responsiveness of control and asthmatic fibroblasts to leptin. However, the accumulation of inflammatory leptin-producing monocytes in the airway may contribute to the pathogenesis of asthma.

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TherapeuticsIntersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma

Summary

Introduction

Section snippets

Type 2-high asthma

Omalizumab

Eosinophils and IL-5 inhibition

Adverse effects of IL-5 inhibition

IL-4RA inhibition

Adverse effects of IL-4RA inhibition

Comparing clinical efficacy and differing trial designs of phase 3 trials

Fevipiprant

Biomarkers of treatment response

Indications for treatment

New therapies for severe non-eosinophilic or type 2-low asthma

Future directions and remaining controversies

Conclusion

Search strategy and selection criteria

Pulm Pharmacol Ther

Lancet

Lancet

Lancet

Mucosal Immunol

J Allergy Clin Immunol

Lancet

Lancet

Lancet Respir Med

Lancet

Lancet

Lancet Respir Med

J Allergy Clin Immunol

Allergy Asthma Clin Immunol

Trends Parasitol

Mod Pathol

J Allergy Clin Immunol

J Allergy Clin Immunol

Immunity

Lancet Respir Med

Respir Med

Lancet Respir Med

Lancet Respir Med

Lancet Respir Med

Lancet

Lancet

J Allergy Clin Immunol

Lancet Respir Med

Lancet Respir Med

Global asthma prevalence in adults: findings from the cross-sectional world health survey

BMC Public Health

Reevaluation of diagnosis in adults with physician-diagnosed asthma

JAMA

Type 2 inflammation in asthma—present in most, absent in many

Nat Rev Immunol

Interleukin-5 and eosinophils induce airway damage and bronchial hyperreactivity during allergic airway inflammation in BALB/c mice

Immunol Cell Biol

Requirement for IL-13 independently of IL-4 in experimental asthma

Science

Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice

Am J Respir Cell Mol Biol

Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma

N Engl J Med

A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma

Am J Respir Crit Care Med

A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma

Am J Respir Crit Care Med

T-helper type 2-driven inflammation defines major subphenotypes of asthma

Am J Respir Crit Care Med

Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma

Thorax

Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics

Am J Respir Crit Care Med

Interleukin-13 and interleukin-4 are coexpressed in atopic asthma

Proc Assoc Am Physicians

Cytokine profiles of BAL T cells and T-cell clones obtained from human asthmatic airways after local allergen challenge

Allergy

Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids

Proc Natl Acad Sci USA

IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity

Am J Respir Crit Care Med

Alternative splicing of interleukin-33 and type 2 inflammation in asthma

Therapeutics
Intersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma