Biologic Drugs: A New Target Therapy in COPD?

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with significant morbidity and mortality. Current diagnostic criteria based on the presence of fixed airflow obstruction and symptoms do not integrate the complex pathological changes occurring within the lung and they do not define different airway inflammatory patterns. The current management of COPD is based on ‘one size fits all’ approach and does not take the importance of heterogeneity in COPD population into account. The available treatments aim to alleviate symptoms and reduce exacerbation frequency but do not alter the course of the disease. Recent advances in molecular biology have furthered our understanding of inflammatory pathways in pathogenesis of COPD and have led to development of targeted therapies (biologics and small molecules) based on predefined biomarkers. Herein we shall review the trials of biologics in COPD and potential future drug developments in the field.

KEYWORDS:

• COPD
• biologics
• eosinophil
• anti-IL5
• benralizumab
• mepolizumab
• anti-TNFα
• anti-IL8
• anti-IL1β, IL33, IL13
• TSLP

Introduction

Chronic obstructive pulmonary disease (COPD) is defined by airflow obstruction that is not fully reversible and that is usually progressive (1). Cigarette smoke is the main causative agent, although other exposures (e.g. air pollution, occupational and biomass fuel) are increasingly being recognised as important (2–4). COPD is characterized by persistent symptoms punctuated by episodes of worsening symptoms beyond day-to-day variability known as exacerbations.

COPD is common and causes significant morbidity and mortality. There are approximately 400 million cases of COPD worldwide (5) and it is predicted to become the 3^rd leading cause of mortality worldwide by 2030 (4). In the United Kingdom it is responsible for approximately 30,000 deaths per year and for >£800 million per year in direct health care costs (6).

COPD is a heterogeneous condition with respect to clinical presentation, underlying pathophysiology, disease progression and response to therapy (7). Current therapies alleviate symptoms and reduce exacerbations, but have little or no effect upon disease progression and follow a broadly ‘one size fits all’ approach to the disease. Greater understanding of the inflammatory mechanisms in COPD has led to advances in targeted biologic therapies for specific cytokines or their receptors. The success of such approaches is predicated on selection of a patient group in which the intervention will be both safe and effective and that the therapy will be affordable. We shall consider herein the heterogeneity of the underlying airway inflammation and remodeling and the success and failures of biological therapy to date in COPD.

Pathophysiology

COPD is a heterogeneous disease, which is a consequence of complex host-environment interactions over time as summarized in Figure 1. Smoking together with other pollutants, pathogens and in some cases allergens insult the lung promoting airway inflammation and damage in a susceptible host (7,8). This chronic airway inflammation and remodeling leads to small airway obliteration and emphysema, which in turn cause airflow obstruction and clinical expression of the disease.

Figure 1. COPD is a heterogeneous complex disease as a consequence of complex host-environment interactions across spatial scales within the host over time.

Airway inflammation

The presence of airway inflammation in both stable COPD and exacerbation episodes is well recognised, with severity of airflow obstruction correlating with airway inflammation (8). The inflammatory profile in COPD is typically associated with increased CD8+ T-cells and neutrophils (9,10). In some cases the neutrophilic response is a consequence of chronic airway infection particularly a predominance of proteobacteria such as Hemophilus Influenzae (11). In a subgroup of 15–40% COPD patients there is eosinophilic inflammation (12). Eosinophils have been found in sputum, Broncho-Alveolar Lavage (BAL) fluid and tissue (12). An increase in the number of eosinophils has been found during exacerbations (13). In asthma this is predominately due to allergic mediated type-2 immunity with a possible contribution independent from allergy mediated by type-2 innate lymphoid cells (14). In COPD the cause of eosinophilic inflammation is uncertain. The possible triggers and cytokine networks involved in neutrophilic versus eosinophilic COPD are described in Figure 2.

Figure 2. Cytokine networks in COPD, in those with eosinophilic disease or non-eosinophilic predominately neutrophilic disease. Biologics that have shown promise and are in phase 3 are shown in blue boxes, those that are in early phase trials in green boxes and those that have been unsuccessful are in orange boxes.

Airway remodeling

Airway remodeling refers to structural changes that occur in small and large airways. Remodeling changes that occur in COPD include disruption and loss of cilia, squamous metaplasia of the respiratory epithelium, goblet cell hyperplasia and mucous gland enlargement, bronchiolar smooth muscle hyperplasia and hypertrophy, airway wall fibrosis and inflammatory cell infiltration (15,16). Small airways are the major site of airway obstruction in COPD. The airways obstruction in COPD is due to a combination of remodeling and accumulation of inflammatory exudates within the airway lumen (17,18). There is some evidence that a reduction in number and luminal area of distal airways is the cause of increased peripheral airway resistance in COPD (19).

Cigarette smoke is a key trigger for tissue damage^{Figure 1} and is also implicated in the abnormal lung repair processes seen in COPD (20). Amongst the multiple effects of cigarette smoking, smoking causes increased epithelial permeability (21) and can activate epidermal growth factor (EGF) receptors. Increased EGF and EGF receptor (EGFR) expression is seen in bronchial epithelium in COPD and has been implicated in the remodeling processes (22–25). Activation of EGFR can lead to mucin synthesis and goblet cell hyperplasia, and EGF is also a stimulator of airway smooth muscle proliferation (26). It has been shown that there is a negative correlation between smooth muscle in the small airways and Forced Expiratory Volume in 1 second (FEV1) (27,28).

Epithelial changes observed in COPD include small airway squamous metaplasia, which increases with increasing COPD severity (29). These squamous cells express increased Interleukin 1 beta (IL-1β) which induces a fibrotic response in adjacent airway fibroblasts and is implicated in activation of transforming growth factor (TGF)-β. TGF-β is a potent fibrogenic factor that is increased in the small airway epithelial cells in COPD. This activation of TGF-β correlates with disease severity and small airway thickening in COPD (30,31). The EGF and TGF-β released from small airways may be involved in fibroblast activation and proliferation. Increased bronchial deposition of extracellular matrix proteins including collagens, fibronectin and laminin is observed with deposition increased on the epithelial basement membrane at sites of damage. The negative correlation between bronchial extracellular matrix deposition and FEV₁ supports the view that bronchial deposition of extracellular matrix is related to airway remodeling (32).

Lung damage

In emphysema activated neutrophils release neutrophil elastase, a proteinase that can destroy elastin (33). In healthy individuals, elastase is neutralized by alpha-1-antitrypsin, a proteinase inhibitor that protects lung tissue from neutrophil elastase damage. Alpha-1-antitrypsin deficiency leads to an imbalance between proteinases and anti-proteinases, which in turn leads to uncontrolled elastin destruction resulting in parenchymal lung destruction (34).

Macrophages and neutrophils are found in greater numbers in COPD airways (35), and they release elastolytic proteinases (e.g. matrix-metalloproteinases, cathepsins and collagenases) when activated, which lead to degradation of the extra-cellular matrix.

Current pharmacological therapies in stable COPD

The two main approaches^{Table 1} for current drugs in management of stable COPD are bronchodilators (e.g. β₂ agonists, antimuscarinics, and methylxanthines) and anti-inflammatories (e.g. corticosteroids). Current recommendations base treatment decisions on COPD control determined by symptoms scores e.g. Modified Medical Research Council (mMRC), COPD Assessment Tool (CAT) and Clinical COPD Questionnaire (CCQ) and future risk of disease progression and exacerbations predicted by current lung function and exacerbation frequency (1). Phenotype-specific approaches to management of COPD are used in clinical practice as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations as shown in Figure 3, but do not include measures of underlying pathobiology.

Figure 3. Summary of drug treatment based on GOLD disease classification. (SABA = short acting beta agonist, LAMA = long acting muscarinic antagonist, LABA = long acting beta agonist, ICS = inhaled corticosteroid.)

As described above, eosinophilic inflammation is present in a subset of COPD patients and an elevated sputum eosinophil count is associated with a greater response to inhaled and oral corticosteroids in stable disease in terms of improvement in lung function, health status and walking distance (36–38). Management directing corticosteroid therapy in stable disease to minimize eosinophilic inflammation has led to reduced hospitalization as observed also in asthma (39). Interestingly the blood eosinophil count is consistently correlated with the sputum eosinophil count and an increased blood eosinophil count is associated with greater improvements to inhaled corticosteroids in stable disease and oral corticosteroids in acute exacerbations (40,41). Thus, it is likely in the near future that this measure will become part of standard-of-care in directing corticosteroid therapy in COPD.

Biologics in COPD

With the neutrophil and pro-inflammatory cytokines implicated in the pathogenies of COPD the first biologics in COPD have targeted this element of the inflammatory response. The efficacy has been disappointing and inhibiting these cytokines has led to adverse events which has diminished enthusiasm for biologics in COPD (42–44). In contrast, targeting eosinophilic inflammation in those with evidence of this phenotype has demonstrated efficacy without an increase in adverse events (45,46). These data are more promising and have begun to pave a way forward for biologics in COPD. The Phase 2 and 3 studies of biologics in COPD that have completed and reported their findings are as shown in Table 1 and how they map onto the cytokine networks is as shown in Figure 2.

Table 1. Completed and reported phase 2 and 3 trials of biologics in COPD (Anti-IL8 = anti-interleukin 8, Anti-TNF-α = anti- tumour necrosis factor alpha, Anti-IL1 = Anti- interleukin 1, IL5 = Interleukin 5, CRQ = Chronic respiratory questionnaire, TDI = Transitional Dyspnoea Index, SGRQ-C = St. George's Respiratory Questionnaire for COPD).

Drug, Dose & Duration	Population	Primary outcome	Secondary outcome
Anti- Pro-inflammatory, neutrophilic, non-T2 inflammation
Anti-IL8	Mod-severe COPD (n = 109)	↓ Severity of dyspnoea as measured by TDI	↔ Health status, lung function, 6-min walk test, rescue use of albuterol
800 mg loading dose, 400 mg/month for 2 months, 5 month follow-up (47)	>50 years, MRC ≥1
	>20 pack year smoking history
Anti-TNFα (Etanercept)	≥35 years old (n = 81)	↔ FEV1 over 14 days from exacerbation onset	↔ 90-day treatment failure, dyspnoea, health status
50 mg, 90 days (42)	Enrolled at exacerbation onset
Anti-TNFα (Infliximab)	Mild-mod COPD (n = 22)	↔ Sputum inflammatory cells	↔ FEV1, SGRQ
5mg/kg, 8 weeks (50)	Current smokers
Anti-TNFα (Infliximab)	Mod-severe COPD (n = 234)	↔ CRQ	↔ FEV1, 6-min walk test, TDI
3 mg/kg or 5 mg/kg, 44 weeks (43)	>40 years, CRQ<120		↑ Malignancy, pneumonia
Anti-IL1 (MEDI 8968)	Mod-very severe COPD (n = 324)	↔ Moderate-to-severe exacerbations	↔ SGRQ-C
300 mg every 4 weeks, 52 weeks (53)	45–75 years, ≥2 exacerbations in past year
Anti- eosinophilic, T2 inflammation
Benralizumab/ IL-5	Mod-severe COPD (n = 101)	↔ Moderate-to-severe exacerbations	↑ FEV1 in intervention group
100 mg every 4 weeks (3 doses) then every 8 weeks (5 doses), 56 week (45)	40–85 years, ≥1 exacerbation in past year		↔ health status
	Sputum eosinophils ≥3%		↓ Blood and sputum eosinophils
Mepolizumab/ IL5	Mod-severe COPD (n = 18)	↓ Sputum eosinophils	↓ Blood eosinophil
750 mg/month, 6 months (62)	Sputum eosinophils >3%		↔ FEV1, CAT, CRQ, exacerbations
	≥1 exacerbation in previous year
Mepolizumab/ IL-5	Mod-very severe COPD, (n = 836)	↓ Exacerbations in pre-specified eosinophilic group	↓ Time to first exacerbation
100 mg or 300 mg every 4 weeks, 52 weeks (46)	>40 years, ≥2 moderate or ≥1 severe exacerbation in previous year		↔ FEV1, SGRQ, CAT
Mepolizumab/ IL-5	Mod-very severe COPD, (n = 674), >40 years, ≥2 moderate or ≥1 severe exacerbation in previous year, blood eosinophils >150/µL	↓ Exacerbations	↓ Time to first exacerbation
100 mg or 300 mg every 4 weeks, 52 weeks (55)			↔ FEV1, SGRQ, CAT

Anti- Pro-inflammatory, neutrophilic, non-T2 inflammation

Anti-IL8 and anti-CXCR

The chemokine C-X-C Ligand 8 (CXCL8) (IL-8) is produced by a variety of cells, including monocytes, macrophages and neutrophils. It mainly attracts and activates neutrophils during an inflammatory response (44). It binds to CXC chemokine receptor 1 (CXCR1) and CXCR2 members of the G-protein coupled receptor family. CXCR2 is present on the surface of neutrophils and is involved in their recruitment to the lung (44).

Mahler and colleagues undertook a 3-month pilot study of an IL-8 monoclonal antibody in 109 subjects with COPD (47). Neutralization of IL-8 led to small but significant improvements in dyspnea measured using the transitional dyspnea index (TDI). The study was not powered to detect differences in exacerbation rate between the groups. This biologic was not progressed but gave encouragement to test inhibition of CXCR2 with small molecule inhibitors. The major concern with this target is whether it might cause clinically important neutropenia and subsequent predisposition of infection. Kirsten and colleagues undertook a 4-week study in 87 COPD subjects to investigate the safety and tolerability of a CXCR2 antagonist (AZD5069) (44). The main adverse events reported were neutropenia (<1× 10⁹/L) in intervention arm (3 patients in 50-mg arm and 1 patient in 80-mg arm), and COPD exacerbations (1 in 50-mg arm and 1 in 80-mg arm). However, there was no increase in infection in those receiving anti-CXCR2 versus placebo. Rennard and colleagues undertook a 6-month dose-ranging proof-of-concept study of the CXCR2 antagonist MK-7123 in 616 subjects with moderate-to-severe COPD (43). They found a small significant improvement in FEV1 in those receiving the highest dose of anti-CXCR2 (50 mg daily) versus placebo. The benefit was observed in those that were current smokers with an improvement above placebo of 160 mL. There was also a reduction in the likelihood (hazards ratio 0.5) of exacerbation in current smokers compared to placebo. Importantly, there was no statistically significant difference in FEV₁ or exacerbations between ex-smokers in the intervention arm and placebo. The study was terminated early at 12 months because not enough patients continued with the study to the scheduled 18 months. There was no difference in rate of infection between the two groups at 6 months, however, in patients who continued with treatment beyond 6 months, the frequency of total infection and respiratory infections was higher in intervention arm compared to placebo, 47% versus 35% and 40% versus 28% respectively. Thus, the efficacy of CXCR2 inhibition was small and the potential of increased adverse events has meant this target has not progressed in COPD.

Tumor necrosis factor –alpha (TNF-α)

TNF-α is a potent pro-inflammatory mediator and plays a major role in driving inflammation in COPD exacerbations (43). The level of TNF-α in sputum rises significantly during an exacerbation (42). It is mainly produced by monocytes and lymphocytes. It is secreted in response to various stimuli. It exerts its effect via TNF-α receptor 1 and TNF-α receptor 2 by activation of nuclear factor-kappa B (NF-kB), which in turn leads to up regulation of inflammatory genes. It stimulates leucocyte accumulation and differentiation at the site of infection, as well as necrosis, apoptosis and oxidative stress. Biologics targeting TNF-α have been very successful and indeed transformed treatment of several chronic inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease (48).

In an observational study by Suissa and colleagues, etanercept but not infliximab reduced COPD hospitalisation in a group of patients who had rheumatoid arthritis and COPD (49). The relative risk of COPD hospitalisation with the use of etanercept was 0.47 and with infliximab 1.14. In this study, only 16 out of 1205 patient were on etanercept and 21 were on infliximab. Patients were identified from insurance claim data base, and therefore, it is not certain all the patients had lung function confirmed COPD. Notwithstanding this limitation, this provides some further support to study biologics against TNF-α in COPD.

Van der Vaart and colleagues undertook the first study of infliximab for 8 weeks in 22 subjects with COPD (50). There was no increase in adverse events in those receiving infliximab but also no benefits in lung function nor health status were observed. This led to a larger study of infliximab in 234 subjects with COPD. In this study, there was no improvement in health status, lung function, symptoms nor exacerbation frequency in those receiving infliximab versus placebo. Importantly there were more adverse events in those receiving infliximab with an increase in incidences of cancer (12 versus 3; 6 lung cancers, 2 head and neck cancers, 1 breast cancer, 1 renal cell cancer, 1 Hodgkin's lymphoma, 1 liver or pancreatic cancer versus 2 prostate cancer, 1 cervical cancer) and pneumonia (10 versus 1). This difference in cancer risk during the study did not persist in the long-term follow-up of patients after the treatment cessation. However, the poor efficacy for anti-TNF-α in stable disease and the increased cancer and infection risk has stopped progress of this biologic as maintenance therapy.

Even though the poor safety of anti-TNF-α precludes its use in stable COPD, Aaron and colleagues undertook an acute study of etanercept at the onset of an exacerbation versus prednisolone in 81 subjects with COPD. They found no increase in adverse events but neither did they find benefit in favor of etanercept. No further studies of anti-TNF-α in COPD are ongoing.

Anti-interleukin 1 (anti- IL1)

IL-1 has been described as the master cytokine of inflammation and affects most cells and organs (51). In COPD IL-1 is increased in sputum, serum and BAL at stable state and exacerbation. IL-1 is primarily produced by macrophages, monocytes and fibroblasts. IL-1A and IL-1B genes encode IL-1 α and IL-1 β, respectively (52). Both exert their effect by binding to IL-1 receptor 1 (IL-1R1), which is expressed in almost all cells. Unlike most other pro-inflammatory cytokines, IL-1 exerts its effects at receptor and nucleus level. It stimulates local and systemic inflammation by facilitating the recruitment of inflammatory cells. IL-1 antagonists have been used in treating rheumatological conditions with mixed results and is associated with improved outcomes following myocardial infarction (52). Blocking the effects of IL-1 α and IL-1 β is thus a potential treatment strategy for COPD patients.

Calverley and colleagues undertook a 1-year study of anti-IL-1R1 in 324 subjects with COPD (53). The intervention arm received a 600 mg loading of anti-IL-1 intravenously on day 1 followed by 300 mg subcutaneous every 4 weeks for a total of 14 doses. There was no reduction in exacerbation frequency nor improvements in lung function and health status in those receiving anti-IL-1R1 versus placebo. There were no differences in adverse events between the groups. In another study, 147 patients with moderate to very severe COPD were randomized to receive canakinumab, an IL1-1R1 antagonist or placebo for 1 year. No statistical analysis was provided at the completion of the study, but changes in lung function that are reported were very similar between those receiving canalinumab versus placebo (54). There were no deaths reported in the study and adverse events were similar between groups. No anti-IL-1 studies are currently ongoing.

Therefore, targeting neutrophilic inflammation via anti-IL-8 and anti-CXCR2 has led to small clinical benefit with evidence of reduced blood neutrophil counts and possibly increased risk of infection. Targeting TNF-α and IL-1 has not been associated with efficacy and inhibiting TNF-α has led to substantial and clinically important adverse events. These findings have stopped progress of biological therapy against pro-inflammatory cytokines and neutrophilic inflammation in COPD.

Anti- eosinophilic, T2 inflammation

Biologics targeting T2-mediated inflammation has been successful in severe asthma and led to newly licensed therapies targeting IL-5 and its receptor (46,55–58). As described above although eosinophilic inflammation is common in asthma it is less frequent in COPD and not associated with increased atopy. Thus, the mechanisms of the cause of eosinophilic inflammation in COPD is poorly understood but does offer a potential therapeutic target.

Anti-IL-5 and anti-IL-5R

IL-5 is released by CD4+ T-helper cell type 2 (Th2) lymphocytes, innate lymphoid cells and eosinophils. Its receptor Interleukin 5 receptor (IL-5R) is expressed by eosinophils and basophil. IL-5 stimulates maturation and release of eosinophils from bone marrow and is an obligate survival factor for tissue eosinophils (59). In asthma, biologics neutralizing IL-5 (mepolizumab and reslizumab) substantially reduce blood and sputum eosinophil counts and attenuate bronchial submucosal eosinophils by about 50% (60). The afucosylated monoclonal antibody against the IL-5R, benralizumab, also induces antibody-mediated cell cytotoxicity and thus has a greater effect on reducing eosinophil number in the bronchial submucosa (61).

Brightling and colleagues undertook a study of anti-IL-5R (benralizumab) in 101 patients with moderate to severe COPD (45). Subjects were randomized in a 1:1 ratio to either receive benralizumab or placebo 4 weekly for the first 3 doses and then 8 weekly for the remaining 5 doses. The primary outcome, annual rate of acute exacerbations, was not met. The annual rate of acute COPD exacerbations in placebo group was 0.92 and in intervention group was 0.95. The FEV₁ was significantly increased in those receiving benralizumab versus placebo but no difference was observed in health status. In a post hoc analysis those who had evidence of eosinophilic inflammation at screening, either a sputum eosinophil count >2% or a blood eosinophil count >250 cells/μL, had a greater improvement in lung function, heath status and a numerical reduction in exacerbations. These findings perhaps suggesting greater efficacy in a more eosinophilic subgroup. There were no differences in adverse events between those receiving benralizumab versus placebo.

Dasgupta and colleagues undertook a small pilot study of mepolizumab in 18 COPD subjects (62). They found that the sputum eosinophil count decreased in those receiving mepolizumab versus placebo, but there were no clinical improvements in terms of lung function or health status. Pavord and colleagues undertook two recent phase III trials (METREX and METREO) in moderate to very severe COPD (46). Subjects were randomized to receive 100 mg mepolizumab or placebo in 1:1 ratio (METREX, n = 836), 100 mg mepolizumab, 300 mg mepolizumab or placebo in 1:1:1 ratio (METREO, n = 674) every 4 weeks for 52 weeks. Subject stratification into eosinophilic or non-eosinophilic phenotypes were based on blood eosinophil count of ≥150/µL on screening or ≥300/µL in previous year and blood eosinophil count of <150/µL on screening or <300/µL in previous year, respectively. In METREX they included eosinophilic and non-eosinophilic patients, whereas in METREO they only included eosinophilic patients. In METREX the mean annual rate of moderate or severe exacerbations in the mepolizumab group was 1.40 per year compared to 1.71 per year in the placebo group (rate ratio, 0.82). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group and 1.27 per year in the 300-mg mepolizumab group, compared to 1.49 per year in the placebo group (rate ratio [100 mg vs. placebo], 0.80; adjusted P = 0.07; rate ratio [300 mg vs. placebo], 0.86; adjusted P = 0.04). In a pre-planned post hoc analysis, those with eosinophilic phenotype who were treated with 100 mg mepolizumab had an annual rate of moderate to severe exacerbation that was 18–20% lower than placebo group. Higher dose of mepolizumab did not confer any additional benefit. The time to the first moderate or severe exacerbation was significantly longer with mepolizumab than with placebo in the modified intention-to-treat population with an eosinophilic phenotype (192 days versus 141 days; hazard ratio, 0.75; adjusted P = 0.04). In keeping with the smaller pilot study there were no improvements in lung function and health status in those receiving mepolizumab versus placebo and no differences in adverse events.

Mepolizumab is the first biologic to demonstrate a reduction in COPD exacerbations. The findings from the mepolizumab and benralizumab studies were consistent in showing that the magnitude of benefit was related to the intensity of eosinophilic inflammation (46). Importantly in both studies there was a poorer outcome in those with low blood eosinophil counts who received the biologic versus placebo. This is in contrast to asthma where there is a failure of benefit in those with low eosinophil counts but no difference compared with placebo. Whether anti-IL-5 or anti-IL-5R approaches increase risk of exacerbations in COPD subjects with low eosinophil counts needs to be further explored and the possible mechanisms elucidated.

Anti-IL-13

IL-13 is an archetypal Th2 cytokine produced by T-cells, mast cells and eosinophils and acts upon inflammatory cells and structural cells such as the bronchial epithelium and airway smooth muscle (63). Anti-IL-13 signals through interleukin 13 receptor type 1 (IL-13RI) and II with IL-13RI sharing the interleukin 4 (IL-4) receptor alpha chain subunit with the IL-4R interleukin 4 receptor (IL-4R). Biologics have been tested in asthma that either neutralize IL-13 or inhibit IL-4Rα and thus inhibit both IL-4 and −13. The former, lebrikizumab and tralokinumab, have consistently shown benefits compared to placebo with improved lung function but effects upon exacerbations have been inconsistent and too small to warrant further development (64,65). In contrast, anti-IL-4Rα has had more promising results in phase 3 in asthma (66). Of these three biologics, only lebrikizumab has been tested in COPD. The full results have not been reported but the headline result in a press release reported that in COPD exacerbations were not reduced in those receiving lebrikizumab versus placebo.

Future biologics in COPD

In view of the poor response to biologics targeting neutrophilic inflammation and pro-inflammatory cytokines versus the promising results in targeting eosinophilic inflammation attention in COPD is to initially explore other cytokines implicated in T2-mediated immunity and or eosinophilic inflammation.

Thymic stromal lymphopoietin (TSLP) is an IL-7 interleukin 7 (IL-7) like cytokine, which signals via IL-7 receptor alpha (IL-7Rα) and thymic stromal lymphopoietin receptor (TSLPR) (67). It stimulates thymocytes and B cell lymphopoiesis (68). TSLP is produced by airway epithelial cells and stromal cells during inflammation (69). TSLP orchestrates response to epithelial injury by acting on CD4, CD8 T cells, B cells, mast cells, basophils, eosinophils and innate lymphoid cells (70). There has been a great deal of interest in role of TSLP in pathogenesis of asthma and COPD due to its ability to activate pro-inflammatory cells. Studies have shown increased expression of TSLP in airways disease (71,72). Tezepelumab a monoclonal antibody that binds to TSLP and prevents it from attaching to TSLP receptor reduced asthma exacerbations, improved lung function and asthma control (73). It attenuated the peripheral blood eosinophil count although response was also observed in those without an elevated blood eosinophil count. Whether targeting TSLP has benefit in an unselected COPD population or in an eosinophilic subgroup is unknown and warrants further investigation. This reduction in exacerbation frequency was irrespective of eosinophil count. There has not been a similar study on the effect of anti-TSLP in COPD.

There is also increasing interest in IL-33 as a target particularly in asthma. IL-33 is an alarmin released from the epithelium following damage (74). IL-33 is an IL-1 family alarmin cytokine constitutively expressed at epithelial barrier surfaces where it is rapidly released from cells during tissue injury. IL-33 signals through a receptor complex of IL-1 receptor-like 1 (IL1RL1) (known as ST2) and IL-1 receptor accessory protein (IL1RAcP) to initiate Myeloid differentiation primary response 88 (MyD88)-dependent inflammatory pathways (75). IL-33 has been implicated in eosinophil recruitment to the airways and maturation in the bone marrow largely via its effects upon innate lymphoid cells (76). IL-33 increased following experimental cold in asthma and thus might play a role in the consequent inflammatory response and possible susceptibility to secondary bacterial infection in obstructive lung disease (77). The role of the IL-33/ST2 axis in COPD is uncertain. A correlation between blood eosinophil, smoking status and IL-33 in COPD has been reported and IL-33 levels in peripheral blood and airways of COPD patients are increased (78). Both eosinophilic inflammation and viral infection drive COPD exacerbations and therefore targeting the IL-33/ST2 axis might reduce COPD exacerbations. Clinical trials of anti-IL33 or anti-ST2 biologics in COPD are awaited.

Biologics might offer alternative strategies to target the exposome as well as the inflammatory response in the host. For example, biologics can be developed to target bacteria; inhibit virulence factors or block adhesion of viruses to cells and thus could be adjuncts to antimicrobial strategies.

Conclusion

The heterogeneity of COPD is beginning to be dissected and our understanding of the interaction between the host, chronic infection and other exposures is becoming clearer. This has provided insights but also underscored the complexity of these relationships overtime. Biological therapy in COPD has presented some surprises with respect to the lack of efficacy for treatments targeting neutrophilic inflammation and pro-inflammatory cytokines but has shown how blockade of these cytokines can lead to profound increases in adverse events. This is contrasted with the promising responses to biologics targeting eosinophilic inflammation although responses are more blunted than observed in asthma. These differences are possibly due to different underlying mechanisms driving the eosinophilic inflammation between asthma and COPD but are pointing towards the possibility of biological therapy for a subgroup with persistent eosinophilic inflammation. This will perhaps present other opportunities for biologics targeting more upstream molecules such as TSLP and IL-33. Biologics might also offer alternative strategies to targeting acute and chronic infection, which is problem in many subjects with COPD. Biologics have not yet entered the clinic for COPD but the likelihood is that the wait will be not much longer and then we shall need to better understand which biological therapy has value in which COPD patient to improve what outcome.

Declaration of interest

None.