Current Perspectives on Biological Therapy for COPD

Abstract Chronic obstructive pulmonary disease (COPD) is a chronic, complex, and heterogeneous condition with significant mortality, morbidity, and socioeconomic burden. Given the heterogeneity, the current management of COPD, which mainly relies on bronchodilators and corticosteroids, cannot consider all COPD populations. Moreover, the present treatment modalities are directed at minimizing symptoms and reducing the risk of a future attack, but they exhibit few meaningful anti-inflammatory activities in preventing and reducing disease progression. Therefore, new anti-inflammatory molecules are needed to manage COPD better. Use of targeted biotherapy may obtain better results by increasing understanding of the underlying inflammatory process and identifying new biomarkers. In this review, we focus briefly on study of the underlying inflammatory process in the pathogenesis of COPD for better identification of novel target biomarkers, and we describe a novel class of anti-inflammatory biologics that are already under evaluation for their use in managing COPD.


Introduction
The term "chronic obstructive pulmonary disease" (COPD) refers to a heterogeneous lung condition that is characterized by persistent, frequently progressive airflow obstruction and chronic respiratory symptoms (dyspnea, cough, sputum production, exacerbations).These symptoms are caused by abnormalities of the airways (bronchitis, bronchiolitis) and/ or alveoli (emphysema).COPD is a chronic, complex, and heterogeneous condition and develops over several years with different mechanisms.The third largest cause of death in the world today, COPD has a significant socioeconomic impact and is a serious concern for the healthcare system [1].The common etiologies for COPD are tobacco smoking, air pollution, and genetic factors [2].Among these, chronic cigarette smoking is the most predominant etiology, accounting for about 90% of all COPD populations in western countries [2,3] .The physiological hallmark currently required for diagnostic confirmation of COPD is irreversible airflow obstruction, dyspnea, cough, and exercise limitation.Sometimes acute worsening of these symptoms occurs, which is termed an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and may require hospitalization [4].
It is now understood that COPD is characterized by different biological pathways known as endotypes leading to the occurrence of the distinct features of the disease, and which are finally accountable for specific clinical characteristics known as phenotypes [5].These unique clinical presentations, the underlying pathophysiology, disease progression, and response to therapy make COPD a heterogeneous condition [6].Present-day available treatment options focus primarily on symptom control with bronchodilation and encompass long-acting beta-agonists(LABA) and antimuscarinics (LAMA).Inhaled corticosteroids (ICS) are indicated for severe COPD [7,8].Nonetheless, these drugs are not always efficacious in controlling symptoms and exacerbations.At present, corticosteroids are the main class of anti-inflammatory drugs used in COPD management.However, they also can induce severe adverse effects, including an increased risk of pneumonia, with chronic administration at high doses, even by inhalation [9].In view of the unsatisfactory status of existing treatment modalities for COPD, there is an urgent need to develop an alternative, safer and effective therapeutic approach that will not only be confined to relieving the symptoms but can also reduce disease progression.Given that COPD is a chronic inflammatory disorder, and without a potent and safer anti-inflammatory agent, the disease may progress continuously, as with the treatment of asthma.Patients with COPD may need biotherapy to modify the airway inflammation to delay the progression of the disease.Following the advancement in understanding of the inflammatory process underlying COPD, research is focused on deactivation and inhibiting the recruitment of inflammatory cells with the use of biological agents against specific cytokines and their receptors.Accordingly, some biologics (monoclonal antibodies) have been assessed recently in the management of COPD, and others are at different stages of evaluation.
With this understanding, in this review we give an overview of the status of novel biological therapies currently in clinical development for the treatment of COPD and discuss how these agents can modify pulmonary inflammation and remodeling in COPD.

Pathology and pathophysiology of COPD
Previously, several studies demonstrated the presence of chronic inflammation throughout the airways, lung parenchyma, and pulmonary vasculature in patients with COPD [10][11][12][13][14].The most recent definition of COPD highlights a better knowledge of the inflammatory process, required for understanding the pathogenesis and selecting treatment.Smoking, pollutants, allergens, and pathogens promote airway inflammation and lung tissue damage [6,15].The airflow obstruction and development of emphysema in patients with COPD result from airway inflammation, remodeling, and lung parenchymal damage with loss of alveolar attachments because of complex host-environment interaction.Chronic inflammation in the airways provokes disruption and loss of cilia, squamous metaplasia, goblet cell hyperplasia, enlargement of mucous glands, smooth muscle hyperplasia and hypertrophy, airway wall fibrosis, and infiltration of inflammatory cells [10,16].The inflammatory profile in patients with COPD is strongly associated with increased numbers of neutrophils, macrophages, T lymphocytes, and B lymphocytes in the airwany lumen [17][18][19], or through dendritic cell activation [20].Noxious particles or gases inhaled into the airways might activate macrophages and stimulate the pulmonary epithelium to release several chemotactic mediators (chemokines), which attract neutrophils, monocytes, lymphocytes, and eosinophils to the lung.Some cytokines and chemokines involved in the pathophysiology of COPD include tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1b), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 8 (IL-8, chemokine ligand 8, CXCL8), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 33 (IL-33), thymic stromal lymphopoietin (TSLP), etc.

Neutrophils
Neutrophils are rich sources of inflammatory mediators and act via the release of proteases and small cationic peptides to destroy overwhelming pathogens, including associted tissues, ultimately activating other inflammatory cells and leading to chronic inflammation [21][22][23][24][25].Many studies have observed the raised level of neutrophils in sputum, bronchoalveolar lavage fluid (BALF), lung biopsy, and blood serum of patients with COPD [26,27].Various mediators such as IL8 and CXCL2 are found to be driver chemoattractants for the mobilization of neutrophils in damaged lung parenchyma leading to their increased numbers in COPD [28][29][30][31][32][33].Thus, in the pathogenesis of COPD, neutrophils are regarded as the initiator of the inflammatory process and producers of several other attractants and epitopes for further support of the inflammatory procedure.

Eosinophils
Many recent studies have observed elevated levels of eosinophils in the blood, bronchial mucosa, sputum, and BALF, which also have positive predictive value in patients with COPD [34][35][36][37].This process becomes activated upon exposure to proinflammatory mediators such as IL3 and IL5 [38][39][40].Their lung migration is controlled by specific chemotactic factors [40][41][42].The detection of raised eosinophil levels and associated proinflammatory mediators in the airways and blood of patients with COPD suggests that eosinophils actively contribute to inflammatory processes in the pathogenesis of COPD [43][44][45].In one study, the inflammatory profile associated with the eosinophilic cluster included sputum IL5 and serum CXCL11, IL5, etc [35].Evidence also supports a correlation between high eosinophils levels and AECOPD [46,47].

Macrophages
Alveolar macrophages in COPD show a marked reduction in their ability to clear apoptotic cells, which activates more and more alveolar macrophages leading to their increased number in the airways [48][49][50][51][52].It is well established that the numbers of alveolar macrophages in BALF, sputum, airway, and lung parenchyma of patients with COPD are several times higher than in the normal population and are greatly co-rrelated with the disease severity [26,27,53].The number of blood-derived monocytes, which act as the progenitor of alveolar macrophages, in patients with COPD is also high compared with healthy populations [54].The alveolar macrophages exert their pathogenic effect in the disease process of COPD by producing a range of matrix metalloproteins, cathepsins, and chemokines such as TNF alpha and IL8 [22,27].The IL8 secreted by activated alveolar macrophages is a potent chemoattractant for neutrophil recruitment in the airway, thus enhancing COPD progression.

Lymphocytes
Peripheral airway inflammation in a patient with COPD mainly involves increased CD8+ T lymphocytes and B lymphocytes [19].An increased number of predominantly T lymphocytes, especially CD + cytotoxic T cells, in the bronchial mucosa of patients with COPD has been observed in several studies [55][56][57][58].Although traditionally, CD8+ cytotoxic T lymphocytes may initiate airway epithelial damage by excessive recruitment to the lung parenchyma in response to repeated viral infection, increased accumulation is also found in the lungs of patients with COPD, due to an autogenic response induced by smoking in the absence of a stimulus such as viral infection [59].The connection between CXCR3, which is generated by CD8+ cytotoxic T cells in patients with COPD, and CXCL10 (a ligand for CXCR3) increases the synthesis of a significant amount of matrix metalloproteinase-12 (MMP12) by macrophages, which is crucial for the destruction of lung tissue and the onset of emphysema [60] (Figure 1).

Current management of COPD
Reducing symptoms, frequency, and severity of exacerbations, improving exercise tolerance and health status, preventing accelerated decline in lung function, and reducing mortality are goals of the recent pharmacological therapy of COPD.In clinical practice, the management of COPD follows the recommendations of the global initiative for chronic obstructive lung disease (GOLD).In general, bronchodilators such as long-acting β2 agonists (LABA) and long-acting muscarinic antagonist (LAMA), along with anti-inflammatory agents (inhaled corticosteroids, ICS), are the two main groups of drugs used in managing COPD in the current scenario.There is also a considerable advancement in the development and use of fixed-dose combination inhalers containing LABA and LAMA and, more recently, triple inhaler therapy containing LABA, LAMA, and ICS for the management of COPD.However, current treatment guidelines suggest an individualized treatment regimen based on symptom scores from instruments such as the modified British Medical Research Council (mMRC), the COPD assessment test (CAT), and the clinical COPD questionnaire (CCQ) along with the future risk of disease progression and exacerbation [61][62][63].Additionally, a bifunctional dimer molecule muscarinic antagonist/beta2-agonist (MABAs) is a new advancement in the bronchodilator groups of molecules used in the treatment of COPD [64,65].

Potential targets and use of biological agents in the management of COPD
Given that COPD is a chronic inflammatory disorder, biological therapy may alter airway inflammation to delay disease progression.This new concept has led to the (mmP9:matrix metalloproteinase-9, COb: chronic obstructive bronchitis, rOs: reactive oxygen species, CtGf: connective tissue growth factor, tGf-β:transforming growth factor beta, CCr2: cc chemokine receptor2) development of biological therapies that target a particular component of disease pathophysiology.We focus below on mentioned newly discovered targets and pathways that inhibit the recruitment and activation of inflammatory cells and mediators in the pathogenesis of COPD.

Anti-TNF alpha
TNF alpha is a highly potent pro-inflammatory cytokine implicated in the pathophysiology of COPD, as evidenced by its elevated expression in patients with COPD [66,67].In a TNF receptor knockout study, Churge.et al. suggested that TNF may account for 70 percent of smoke-induced emphysema in a mouse model [68].Stimulation of TNFR induces synthesis and release of tens of inflammatory mediators including broad spectrum pro-inflammatory cytokines (TNF alpha, IL-1, etc), chemokines (CXCL-8, MCP-1), proteases (MMP-9, MMP-12) and several adhesion molecules [69,70].In various studies, TNF alpha was associated with metaplasia of airway mucous cells, with increased secretion, reduction in epithelial binding, and desmosome formation in epithelial cells, which enhances cell death leading to emphysematous change and airway remodeling [71][72][73][74].Hence, antagonization of the effect of TNF alpha is a potential target for the treatment of COPD.
Although TNF alpha inhibitors have been found to induce a synergistic effect with corticosteroids in controlling airway remodeling and retrieving corticosteroids insensitivity by reducing the debilitating impact of corticosteroids on inflammation as suggested in some preclinical studies, TNF alpha inhibitors have shown limited clinical efficacy in the management of COPD [75,76].
In an exploratory randomized controlled trial (RCT) on 22 patients with mild to moderate COPD, infliximab(a monoclonal antibody which forms a stable complex with the human soluble and membrane forms of TNF, resulting in termination of the effect of TNF) was found to have no overall beneficial effects on sputum neutrophils, lung function, resting energy expenditure and quality of life.There was also no increase in adverse events in the infliximab treatment group [77].A similar efficacy result was observed in another two RCTs where infliximab failed to show any significant improvement in health and inflammation status in patients with moderate to severe COPD [78,79].However, Rennard et al. observed a higher risk of development of pneumonia (10 vs. 1) and cancers (12 vs. 3) as an adverse event in the infliximab treatment group when compared with placebo [79].Conversely, another TNF alpha inhibitor, etanercept (a receptor blocker that binds to free-floating and cell-bound TNF) was found to reduce COPD-related hospitalization over infliximab.However, in this study, only 16 out of 1205 patients were on etanercept, and 21 were on infliximab [80].In another study evaluating the effect of etanercept versus prednisolone on AECOPD, the authors found no beneficial effect of treatment favoring etanercept over prednisolone [81].These poor safety and efficacy profiles marked anti-TNF-alpha as a failure in treating COPD.Therefore, no further studies are ongoing to assess the antagonism of TNF-alpha in COPD.

Anti-IL-6
IL-6 is another proinflammatory cytokine implicated in the pathophysiology of COPD, which has been found to be associated with activation, growth, differentiation, and survival of T cells along with antibody synthesis from B cells [82][83][84].In addition, several studies have reported that its concentration in BALF, induced sputum, exhaled breath, and plasma is raised in patients with COPD, especially during exacerbation [85][86][87][88][89][90].This evidence makes it a potential target for the treatment of COPD.However, despite the development of several monoclonal antibodies against IL-6(tocilizumab, sirukumab, siltuximab, olokizumab, and clazakizumab), none of them have yet been tested in patients with COPD.

Anti-IL-8 and anti-CXCR
CXCL8 (IL-8) is a crucial mediator cytokine for neutrophil and monocyte chemotaxis, degranulation, and activation occurs via CXCR1 and CXCR2 receptors during an inflammatory response [84].It is also involved in angiogenesis, wound healing, epithelial proliferation, and endothelial migration via the CXCR2 receptor [91,92].TNF alpha, cigarette smoke, and some endotoxin can stimulate overexpression on mesenchymal, structural, and inflammatory cells.Elevated levels of IL-8 and the receptors in induced sputum and BALF from patients with COPD support their crucial role in pathogenesis and make them a potential target in treating COPD [27,93,94].
In a preclinical study in a murine model of lung inflammation, PA401 or dnCXCL8 (modified recombinant human CXCL8 distinguished by a higher affinity for glycosaminoglycans that empowers the displacement of CXCL8 at the site of inflammation from glycosaminoglycans) was found to reduce BALF neutrophils and systemic inflammatory markers [95].
In a double-blind placebo-controlled multicenter trial on 109 patients with mild to moderate COPD, Mahler et al. examined the safety and efficacy of ABX IL-8 (a human monoclonal antibody against IL-8).The authors found a small but significant improvement in dyspnea, measured using the transitional dyspnea index (TDI) [96].However, no notable distinction between groups was observed for lung function, health status, 6 min walking distance (6-MWD), and adverse events.This biologic was not progressed but gave the motivation to test inhibition of CXCR2 with small molecule inhibitors.
Accordingly, Rennard et al. performed a dose-ranging proof of concept trial of MK-7123/navarixin (a CXCR2 receptor antagonist) on 616 patients with moderate to severe COPD.They found that treatment with 50 mg MK-7123 resulted in a significant improvement in forced expiratory volume in 1 s (FEV1) versus placebo.This suggested clinically significant anti-inflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because absolute neutrophilic count (ANC) decreases with MK-7123.There was also a decrease in the probability of an exacerbation in current smokers when compared with placebo [97].The development of clinically significant neutropenia and increased predisposition to infection are major concerns with this target,however, and were evaluated by Kirsten et al. in a four-week study on patients with 87 COPD.They investigated the safety and tolerability of AZD5069 (a CXCR2 antagonist) and found neutropenia and AECOPD as major adverse events.However, there was no increase in subsequent infection in the intervention arm [98].

Anti-IL-17
IL-17 is a superfamily that stimulates the synthesis of numerous chemokines for neutrophil and macrophage recruitment as part of "host defense" [99].It incorporates six members (IL-17A-17F) and five receptors (IL-17RA-17RE).Among them, IL-17A is the most potent member.It is synthesized by Th17 cells and other cells such as lymphoid tissue inducer cells, innate lymphoid cells, and natural killer cells.IL-17A can prompt the production of cytokines including IL-6, IL-8, granuloc yte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor, which are vital in neutrophil recruitment, survival, and activation.IL-17A plays essential roles in both the initial inflammatory response to cigarette smoke exposure and in alveolar epithelial cell damage, which are pathological processes associated with the development and progression of COPD [100].There is evidence that serum levels of IL-17 are elevated in patients with stable COPD, which correlates directly with the stage of COPD and inversely with the predicted FEV 1 percentage [99].
A preclinical study on a mouse model using non-typeable Haemophilus influenzae AECOPD showed that IL-17 mice and IL-17 neutralizing antibody-receiving mice were protected against enhanced airway neutrophilia [101].Similarly, in another in vitro study, the authors found that, after anti-IL-17 antibody injection into mice exposed to tobacco smoke, the level of IL-17 in lung tissue and neutrophil levels in the BALF were notably decreased.At the same time, the pathological score of small airway inflammation was alleviated [102].
Nevertheless, secukinumab (a neutralizing antibody against IL-17A) did not attenuate acute ozone-induced airway neutrophilia in healthy subjects [103].CNTO 6785 (a monoclonal antibody against IL-17A) resulted in a slight improvement in FEV1 in patients with moderate to severe COPD enrolled in a randomized, placebo-controlled, double-blind, multicenter, phase II study [104].However, there was no statistically and clinically significant variation in the primary and secondary endpoints in the placebo and intervention groups.Several anti-IL-17A and anti-IL17RA monoclonal antibodies are under development, intended to reduce the recruitment of inflammatory cells, especially neutrophils, and thus to decrease inflammation [105].However, most of the studies are directed against asthma rather than COPD.Given that IL-17 is crucial to host defense, neutralizing IL-17 activity may lead to severe complications from immunosuppression, which is a significant concern in patients with COPD and may increase susceptibility to lung infections and the risk of AECOPD.

Anti IL-5 and IL-5R
An association was found between airway eosinophilia and a higher risk of exacerbation, airway remodeling, and IL5 expression [2,36].Alarmin cytokines such as IL-33, IL-25, and TSLP, which are generated by bronchial epithelium in response to exposure to the noxious environment, including smoking, lead to the differentiation of naive T cells into Th2 cells for the production of IL-5, IL-13, and IL-4 through the initiation of an adaptive immune response.Eosinophil maturation from their progenitors depends greatly on IL-5, IL-3, and granulocyte-macrophage colony-stimulating factors, among which IL-5 is the most crucial [106].There is also an innate immune response to non-allergen triggered through stimulation of ILC 2 to produce IL5 and IL13 which leads to eosinophilic airway inflammation.This concept of both adaptive and innate immune responses may explain the eosinophilic airway inflammation in COPD, with an increased percentage of IL-5 expression found in the sputum of patients with COPD.Many studies are available to demonstrate the presence of a higher percentage of IL-5 and IL-5R in the sputum of patients with COPD and justify them as a potential target in treatment using biologics [107][108][109][110].
In a double-blind RCT, the authors found a significant increase in FEV1 in those COPD patients who received benralizumab (a humanized afucosylated monoclonal antibody that binds with IL-5Ralpha, thus inhibiting IL-5R signaling) as treatment.However, there was no improvement in the frequency of acute exacerbation and health status compared to the placebo [111].In subgroup analysis of COPD patients with evidence of eosinophilic inflammation (either sputum eosinophil count of more than 2% or blood eosinophil count of more than 250 cells/µL), there was a more significant improvement in lung function and health status, and a numerical reduction in exacerbation.The inability of benralizumab to lower the annualized rate of exacerbation overall in patients with moderate to severe COPD was also revealed in two recent phase 3 RCTs (GALATHEA and TERRANOVA) [112].More clinical trials are ongoing in different stages to evaluate the efficacy and safety of benralizumab with regard to the annual exacerbation rate of COPD and improvement in clinical response(NCT04053634, NCT04098718).
In another study, the authors evaluated the efficacy of mepolizumab (a humanized monoclonal antibody that blocks free IL-5) in a small pilot study on 18 patients with COPD [113].The study showed that despite a lack of clinical improvement, the sputum eosinophil count was reduced in those receiving mepolizumab versus placebo.Finally, in two recent phase 3 trials (METREX and METREO) on patients with moderate to very severe COPD, the authors found a decrease in exacerbation frequency in those with an eosinophilic phenotype who were treated with mepolizumab [114].However, such improvement was only seen in the METREX study, while no improvement in the annual exacerbation rate was documented in the METREO study.
The results from mepolizumab and benralizumab trials consistently show that the extent of benefit is associated with the magnitude of eosinophilic inflammation.Consequently, several trials are ongoing to confirm the benefits of mepolizumab treatment in optimization of COPD therapy and reduction in the rate of exacerbation (NCT04133909, NCT04075331).

Anti-IL13/anti-IL4
IL-4 is primarily synthesized by Th2 and mast cells, while IL-13 is synthesized by Th2 cells, mast cells, eosinophils, and basophils, but they share a common receptor, IL-4R alpha, and the STAT 6 signaling pathway.IL-4 affects chemokine production by Th2 cell development and production and B cell isotype switching, while IL-13 affects hematopoietic cells, bronchial epithelium, smooth muscle, fibroblasts, and endothelial cells and promotes an allergic phenotype of inflammation.Overexpression of IL-13 along with interferon-gamma in murine lungs was found to be associated with over-expression of MMPs and cathepsin, resulting in the development of emphysema, which makes this cytokine a possible target for treatment of COPD [115,116].
On the above basis, the efficacy, safety, and tolerability of dupilumab (a humanized monoclonal antibody against IL-4Ralpha) are now being assessed in patients with moderate to severe COPD in some ongoing pivotal studies (NCT03930732 and NCT04456673).On the other hand, preliminary data from a study(NCT02546700) evaluating the efficacy of lebrikizumab (a monoclonal antibody against IL-13) in patients with COPD suggests that it has no influence on the rate of AECOPD when compared with placebo [107].The study's complete findings, however, have not yet been released.

Anti-IL-33/anti ST2
IL-33 is an alarmin, acts as a proinflammatory endogenous danger signal and is expressed by many cells and tissues, including bronchial epithelium, fibroblasts, smooth muscle, macrophages, and dendritic cells [117].The biological activity of IL-33 is mediated by its interaction with the ST2 receptor and IL1 receptor accessory protein.Recently it was demonstrated that IL-33 was a crucial cytokine for driving viral infection and induction of AECOPD [118].Moreover, overexpression of IL-33 was observed in the plasma and bronchial epithelium of patients with COPD [119].
Considering the above evidence, a phase 2 study was conducted to evaluate the impact of itepekimab (a humanized anti-IL33 monoclonal antibody) on the annual rate of AECOPD [120].The authors found a significant reduction in the rate of exacerbation in those with former smoker status with COPD; however, there were no significant differences in the rate in all enrolled patients when compared with placebo.More trials in different phases of the study are underway to evaluate the efficacy of itepekimab with regard to the annual frequency of AECOPD(NCT04701983 and NCT04751487).
MSTT1041A/Astegolimab (an anti-ST2 receptor monoclonal antibody) did not significantly reduce the exacerbation rate but improved the overall health status compared with placebo when tested in a 48-week phase 2a RCT in patients with moderate to severe COPD [121].The mean difference in the St George's respiratory questionnaire for COPD (SGRQ-C) between the treatment and placebo groups was −3.3 (95% CI −6.4 to −0.2; p = 0.039), while the mean difference in FEV 1 between the two groups was 40 ml.
Moreover, MEDI 3506 is another anti-IL-33 monoclonal antibody being assessed in a phase 2 proof of concept trial for its effects on pulmonary function test (PFT) in patients with moderate to severe COPD (NCT04631016).

Anti-TSLP
Thymic stromal lymphopoietin is an IL-7-like cytokine that interacts with IL-7R alpha and TSLPR and stimulates thymocytes and B-cell lymphopoiesis [122].It is an epithelial cell-derived cytokine produced by airway epithelial cells and stromal cells during inflammations.Several studies have shown its increased expression in airway diseases [123,124].In addition, evidence suggests that its overproduction in a viral infection leads to AECOPD [125].
Tezepelumab (a humanized monoclonal antibody that binds with TSLP) is under evaluation for its efficacy and safety in a phase 2a trial in patients who have had having moderate to severe COPD and having two or more documented AECOPD in the previous 12 months.(NCT04039113).

Anti-IL-1
IL-1 beta is a potent activator of alveolar macrophages in COPD pathogenesis.Rusznak et al. in a study of bronchial epithelial cell culture, found an escalated release of IL-1 beta after exposure to cigarette smoke [126].In various animal models, the authors found IL-1 beta to be an essential cytokine in the pathogenesis of pulmonary inflammation and emphysema [127,128].
A pre-clinical study reported that airway inflammation in mice given multiple exposures to tobacco smoke was inhibited after receiving treatment with anti-IL-1 beta monoclonal antibody [129].Similarly, another pre-clinical study  found that IL-1-receptor-knockout mice have significantly reduced emphysema after multiple exposures to tobacco smoke [130].However, in a phase 2 RCT on 324 patients with COPD, the authors found that MEDI8968 (a fully human monoclonal antibody that bound selectively to IL-1R1, inhibiting the action of IL-1) did not produce any statistically significant improvement in AECOPD rate, lung function, and quality of life [131].A similar result was reported in another RCT on the use of canakinumab (an IL-1R1 antagonist) to treat 147 patients with moderate to severe COPD.At the end of the trial, no statistically significant difference was observed in change from baseline in FEV 1 , forced vital capacity (FVC), slow vital capacity (SVC), or forced expiratory flow 25% to 75% [132].These studies demonstrate that IL-1 targeting has not been associated with effective COPD therapy (Tables 1 and 2).

Conclusion
The effective management of COPD has become a point of discussion.Although encouraging, the use of biological agents in COPD has not had the clinical impact that has been seen in asthma.As detailed in this review, many biologics studied so far have failed to provide a substantial clinical benefit or disease modification.Therefore, no novel targeted biologics are currently cleared for their use in COPD.However, biologics targeting T2 inflammation have shown some small but promising effects in the eosinophilic phenotype subgroup of COPD.This suggests that targeting biologics according to a particular phenotype of the disease may improve outcomes.We need more trials that should look into the best route of administration, optimal dosage and duration of treatment, appropriate outcome measures, and patient selection to determine the efficacy of biologics in managing COPD.

Figure 1 .
Figure 1. the inflammatory process in the pathogenesis of COPD.

2 .
a randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Pivotal study estimated total = 924 ongoing nCt04456673 assessing the efficacy, safety, and tolerability of Dupilumab in COPD with type 2 inflammation anti-il-33/anti st2 itepekimab 1. randomized, Double-blind, Placebo-controlled, Parallel Group Phase 3 study estimated total = 930 ongoing nCt04701983 evaluating the efficacy of itepekimab on an annualized rate of aeCOPD in former smokers 2. randomized, Double-blind, Placebo-controlled, Parallel-group Phase 3 study estimated total = 1170 ongoing nCt04751487 the annualized rate of moderate or severe acute exacerbation of COPD (aeCOPD) in former smokers meDi3506 Phase ii, randomized, Double-blind, Placebo-controlled study estimated total = 144 ongoing nCt04631016 assessing the efficacy, safety, and tolerability of meDi3506 in Participants With moderate to severe COPD and Chronic bronchitis (frOntier 4and safety of tezepelumab in Patients With moderate to very severe COPD

Table 1 .
Clinical trials that have evaluated biologics in the management of COPD.

Table 2 .
Clinical trials that are evaluating biologics in the management of COPD.