Introduction
Chronic obstructive pulmonary disease (COPD) is defined by airflow obstruction that is not fully reversible and is usually progressive. Cigarette smoking is the main causative agent, although other exposures like air pollution, occupation, and biomass fuel are increasingly being recognized as important causative agents.
COPD is characterized by persistent symptoms punctuated by episodes of worsening symptoms beyond day-to-day variability, known as exacerbations. It is one of the most common causes of morbidity and mortality worldwide. Current therapies alleviate symptoms and reduce exacerbations but have little or no effect on disease progression. They follow a one-size-fits-all approach to the disease. However, a 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 the selection of a patient group in which the intervention will be both safe and effective, and the therapy will be affordable.
What Happens in COPD?
The pathophysiology of COPD comprises the following events:
- Airway Inflammation - Smoking, together with other pollutants, pathogens, and in some cases, allergens, insult the lung, promoting airway inflammation and damage in a susceptible host.
The inflammatory profile in COPD is typically associated with increased CD8-positive T cells (mediators of adaptive immunity and are cytotoxic in nature) and neutrophils. In a few COPD patients, the inflammation is caused due to eosinophils. The cause of eosinophilic inflammation is unknown, but eosinophils have been found in the sputum, broncho-alveolar lavage, and during exacerbations.
- Airway Re-modelling - 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 (filaments that remove the microbes and debris out of the airways), squamous metaplasia of the respiratory epithelium (benign changes in the squamous epithelium), goblet cell hyperplasia (increase in the number of goblet cells), mucous gland enlargement, bronchiolar smooth muscle hyperplasia and hypertrophy (increase in the number and size of bronchiolar smooth muscles, which secrete inflammatory mediators), airway wall fibrosis, and inflammatory cell infiltration.
Small airways are the major site of airway obstruction in COPD. Airway obstruction in COPD is due to a combination of remodeling and the accumulation of inflammatory exudates within the airway lumen.
Epithelial changes observed in COPD include small airway squamous metaplasia, which increases with increasing COPD severity. These squamous cells express increased interleukin (IL-1ꞵ), which induces fibrotic response along with activation of the transforming growth factor (TGF- β). TGF- β is a potent fibrogenic factor, and its activation correlates with disease severity and small airway thickening in COPD.
- Lung Damage - The inflammatory infiltrates, along with the fibrosis and airway thickening, leads to emphysema, which in turn leads to the activation of neutrophils. These neutrophils release neutrophil elastase, a proteinase that can destroy elastin (an essential part of the extracellular matrix of the lung).
Apart from this, macrophages and neutrophils are also found in abundance in the COPD airways, and they release elastolytic proteinases, which, when activated, will lead to the degradation of the extracellular matrix.
What Are the Biologics in COPD?
The two standard drugs used in the management of COPD are bronchodilators and anti-inflammatories. However, the recent advancement in molecular biology has furthered the understanding of inflammatory pathways in the pathogenesis of COPD and led to the development of targeted therapies in the form of biologics.
According to the World Health Organization (WHO), biologics are a heterogeneous group of drugs that include growth factors, vaccines, antibodies, immunomodulators, human plasma, and blood, all of which target specific genotypes of protein receptors. The various biologics used in the management of COPD are:
- Omalizumab - Omalizumab is the first monoclonal antibody cleared for the management of COPD and asthma. Monoclonal antibodies are artificially created proteins that act like human antibodies in the immune system. Omalizumab targets IgE (immunoglobulin E) - an antibody responsible for causing hypersensitivity reactions.
In COPD, the inhaled allergens stimulate the production of IgE by B-lymphocytes (a type of white blood cell). The binding of the IgE to the allergen induces the release of inflammatory mediators, such as histamine or leukotrienes, leading to the bronchoconstriction seen in COPD exacerbations.
Omalizumab binds to the IgE, which inhibits the binding of the IgE to the allergen, thereby limiting the degree of release of the inflammatory mediators.
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Mepolizumab - Mepolizumab is a monoclonal antibody designed to target IL-5, which is a cytokine that regulates the proliferation, maturation, migration, and effector functions of eosinophils. Several studies have shown that Mepolizumab can significantly reduce eosinophil-induced exacerbations compared to a placebo. Other biologics that also target IL-5 are Reslizumab and Benralizumab.
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Dupilumab - It is a monoclonal antibody that targets IL-4, which plays an important role in regulating antibody production and the development of effector T-cell (a type of white blood cell) responses.
Dupilimab inhibits the receptors of IL-4, prevents exacerbations, and improves lung function in patients receiving long-acting beta-agonists (for COPD and asthma) and inhaled steroids.
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Lebrikizumab And Tralokinumab - Both are monoclonal antibodies that target IL-3 - a protein that functionally activates neutrophils, macrophages, and other immune cells, all of which promote inflammation. These drugs have initially yielded benefits with respect to airway function but are still being studied further in regard to their application in COPD.
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Tezepelumab (AMG-157) - It targets thymic stromal lipoprotein, which is a relatively novel target for COPD. It is an epithelial-derived cytokine that drives allergic inflammatory responses by activating dendritic cells (a specialized immune cell that presents antigens to other immune cells) and mast cells (a white blood cell rich in histamine and heparin).
Tezepelumab lowers the rates of exacerbation by binding to the thymic stromal lipoprotein.
- Brodalumab - It is a human monoclonal antibody that binds to IL-17- a cytokine that plays an important role in the immunologic responses seen in COPD and asthma. IL-17 receptor activation leads to the secretion of inflammatory mediators like tumor necrosis factor-alpha (TNF-ɑ) and granulocyte-macrophage colony-stimulating factor, both of which ultimately lead to neutrophil recruitment.
Brodalumab binds to the IL-17 receptor and inhibits the activation of inflammatory mediators.
Apart from the biologics mentioned above, a couple of biologics that are still being researched are Navarixin and Imatinib.
Conclusion
Biologics in the treatment of COPD have mixed responses, mainly because most of them target neutrophil-mediated inflammation. This is not effective in patients in whom the inflammation is mediated by eosinophils. However, new drugs are emerging that target this pathway. A combination that targets both pathways will improve the outcome.
