Abstract

Chronic inflammatory diseases of the lung are some of the leading causes of mortality and significant morbidity worldwide. Despite the tremendous burden these conditions put on global healthcare, treatment options for most of these diseases remain scarce. Inhaled corticosteroids and beta-adrenergic agonists, while effective for symptom control and widely available, are linked to severe and progressive side effects, affecting long-term patient compliance. Biologic drugs, in particular peptide inhibitors and monoclonal antibodies show promise as therapeutics for chronic pulmonary diseases. Peptide inhibitor-based treatments have already been proposed for a range of diseases, including infectious disease, cancers and even Alzheimer disease, while monoclonal antibodies have already been implemented as therapeutics for a range of conditions. Several biologic agents are currently being developed for the treatment of asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and pulmonary sarcoidosis. This article is a review of the biologics already employed in the treatment of chronic inflammatory pulmonary diseases and recent progress in the development of the most promising of those treatments, with particular focus on randomised clinical trial outcomes.

Keywords: biologic drugs, monoclonal antibodies, asthma, COPD, IPF, pulmonary sarcoidosis

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1. Introduction

The classical definition of inflammation is “a response which arises in vascularised tissue upon exposure to infections and damaging stimuli, which recruits host defence cells to the site of exposure to eliminate the harmful agents”. The role of correctly functioning inflammation is that of an immediate response to the presence of pathogens at the site of a lesion. Inflammation constitutes a part of the innate immune response, the first line of the immune defence system . Normally, inflammation is an acute event which ultimately supports wound healing. Leukocytes migrate to the site of inflammation, remove the pathogens and support the process of tissue repair. However, in the event of dysregulation, inflammation can become chronic. Chronic inflammation is a detrimental process involving persistent, abnormal inflammation which ultimately leads to tissue damage and transformation . Chronic inflammation is the pathophysiological basis of a plethora of disease units, with several of the most prevalent and severe conditions affecting the respiratory system. Pulmonary chronic inflammation is one of the leading causes of mortality and significant morbidity worldwide. In 2019, 262 million active cases of asthma were estimated, causing 455 thousand deaths worldwide . Chronic obstructive pulmonary disease (COPD) is responsible for the third highest number of deaths worldwide, surpassed only by ischemic heart disease and malignant neoplasms. In 2015, COPD was estimated to affect around 174 million people worldwide, leading to approximately 3.2 million fatalities .

Common therapeutics for chronic inflammatory lung disease symptoms such as inhaled corticosteroids and beta-adrenergic agonists are effective and widely utilised. However, sustained long-term usage of these drugs is linked to increasingly severe side effects. To ensure continuing patient compliance required to properly manage these conditions, new pharmacological targets related to the pathophysiology of inflammation have to be considered and understood. An assortment of cell signalling pathways, related to a network of receptors and ligands have been linked to inflammation. Targeted inhibition of select elements within these pathways may serve as a superior approach to anti-inflammatory drug design.

Inhibiting specific pathways to manage chronic inflammation has many advantages over classical approaches to treatment, as the drugs target underlying pathophysiology of a given disease directly, instead of managing symptoms. Two main categories of therapeutic inhibitors are currently used to treat patients - small molecule drugs and biologic drugs. Two relatively recent subclasses of biologic drugs - peptide inhibitors and monoclonal antibodies show promise as therapeutics. Peptide inhibitor-based treatments have already been proposed for a range of diseases, including infectious disease, cancers  and even Alzheimer disease , while monoclonal antibodies have already been implemented as therapeutics for a range of conditions. This review describes a selection of biologic inhibitors which are currently undergoing research and clinical trials as potential treatments for chronic inflammatory lung diseases.

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2. Small molecule and biologic agents

Biological medications are a category which includes products such as vaccines, blood components, recombinant proteins or even somatic cells. The composition of biologics may include any combination of proteins, nucleic acids and sugars. Biologics can be derived from a variety of sources, such as animals, microorganisms or humans. The production of biologics frequently utilises cutting-edge biotechnological methods, and novel types of biological therapeutics such as cellular or genetic biologics constitute the frontiers of biomedical research. Unlike traditional drugs produced by chemical synthesis, with strictly defined structures, many biologics are heterogeneous mixtures of substances which may not be precisely defined. Biologics are highly specific and exhibit very low levels of toxicity, compared to small molecule drugs. However, biologics may display immunogenicity in some patients, unlike most small molecule drugs . The primary factor hindering the use of biologics is their enormous cost. Unlike small molecules, the structure of proteins is rife with complexities such as folding patterns or surface glycosylation. Thus, the manufacturing process of most biologics is highly complex. With currently available technologies, scaling up production and maintaining consistency between batches of biologics is challenging. Problems with heterogeneous post-translational modifications or discrepancies in protein conformation are common issues. Biologics tend to be sensitive to heat and microbial contamination, unlike chemically synthesised drugs. Finally, some patients may develop immune responses to biologics, causing a gradual loss of effectiveness and increase in immunogenicity, at unpredictable rates .

Small molecule drugs (SMs) are defined as low molecular weight (0.1 to 1 kDA) compounds capable of modulating biochemical processes in vivo, which can be used in disease diagnosis and management. Examples of SMs include diphenhydramine and aspirin. This category of drugs remains a useful and attractive option despite advances in the field of biologics for several reasons. The relatively simple chemical structure and low molecular weight of most SMs lead to pharmacokinetics and pharmacodynamics more calculable than those of biological drugs, and ultimately - less complicated administration protocols. The development, characterising and manufacturing of SMs also tend to be simpler than those of biologics. Due to the lower cost of raw materials and relative simplicity of the synthesis process, production costs of SMs may be a fraction of the cost of producing biologics. Lastly, SMs are usually highly stable molecules and can be administered orally, enhancing patient compliance, unlike antibodies and proteins, the current formulations of which must be administered intravenously. Due to all these factors, SMs are in most cases a more affordable option than biologics. What is more, SMs can pass through the cellular membrane and affect intracellular receptors, intranuclear targets and the nervous system. Outside of lysosomes and endosomes, delivering proteins to intracellular targets is difficult. Gene therapy may offer a solution to this limitation of biologics, but currently SMs remain the best choice for targeting most intracellular targets. However, as most SMs function by imitating effector molecules or through allosteric regulation of enzymes, not all biological processes are viable targets for SM-based regulation. What is more, several microbes and cancers exhibit resistance to SMs due to modifications in enzyme structure and chemistry, presence of efflux pumps or mutations rendering drug targets unrecognisable .