Inflammation & Allergy-Drug Targets (Discontinued) - Volume 12, Issue 2, 2013

Inhaled therapeutics are used routinely to treat a variety of pulmonary diseases including asthma, COPD and cystic fibrosis. In addition, biological therapies represent the fastest growing segment of approved pharmaceuticals. However, despite the increased availability of biological therapies, nearly all inhaled therapeutics are small molecule drugs with only a single inhaled protein therapeutic approved. There remains a significant unmet need for therapeutics in pulmonary diseases, and biological therapies with potential to alter disease progression represent a significant opportunity to treat these challenging diseases. This review provides a background into efforts to develop inhaled biological therapies and highlights some of the associated challenges. In addition, we speculate on the ideal properties of a biologic therapy for inhaled delivery.

Chronic respiratory diseases are a significant health problem requiring novel approaches to both complement existing therapies and provide breakthrough medicines. Recent clinical advances in understanding the behavior of inhaled oligonucleotides provide the impetus for application of this technology to microRNA therapeutics. MicroRNAs are evolutionarily conserved small regulatory RNA molecules involved in tuning gene networks controlling biological and pathological processes. Deletion or overexpression of microRNAs results in phenotypic changes in animal models of disease such as cancer, fibrosis, diabetes, and inflammation. Inhibition of microRNAs in preclinical models of asthma, cystic fibrosis, and idiopathic pulmonary fibrosis has shown therapeutic promise. In animals, inhibitors of microRNAs directly delivered to the airway at doses suitable for nebulizers or hand-held inhalers up-regulate expression of cohorts of genes containing complementary “seed” sequences for specific and directed microRNA binding within their mRNA untranslated regions. These observations suggest the opportunity to exploit intervention in microRNA biology to create new therapies for chronic pulmonary disorders.

Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) represent a significant health burden worldwide and are a major unmet medical need. Asthma affects over 300 million people and leads to 250,000 deaths per year, with an increasing prevalence particularly in developing countries. Although a large proportion of asthmatics are maintained on beta agonists and corticosteroids, there still remains a group of patients where these medicines fail to modulate symptoms and who may therefore benefit from monoclonal antibody based drugs that are aimed at controlling the disease. COPD is a cigarette smoke-driven chronic inflammatory airway disease with an increasing global prevalence. Given that current therapies fail to prevent disease progression or mortality, this patient population is also a focus for the development of monoclonal antibody therapies. At present anti-IgE (omalizumab, Xolair®) is the only monoclonal antibody based drug approved in the respiratory space for the treatment of asthma. However, an increasing number of antibodies targeting key mediators/pathways of disease are in clinical development for both asthma and COPD, including targeting the Th2 pathway for asthma (anti-IL-4/5/13) and the pro-inflammatory cytokine IL-1 for COPD. This review will examine the antibody engineering approaches used to develop the next generation of antibodies, with a focus on respiratory disease.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and usually fatal interstitial lung disease of unknown cause [1, 2]. The aetiology of IPF is unknown, although identified risk factors for IPF include cigarette smoking, environmental exposures, microbial agents, age, male gender and gastroesophageal reflux disease (GERD). Genetic factors may also play a role in the aetiology of IPF as familial cases of IPF are described in approximately 5% of patients with IPF [2]. Nothing has shown significant anti-fibrotic activity in IPF patients and due to this high unmet medical need, numerous therapeutics are currently under clinical investigation. In this review, we shall focus on recombinant protein based approaches for the treatment of IPF, with a particular focus on pathophysiology of lung fibrosis using the bleomycin mouse model.

Animal models are vital instruments of the drug discovery process. In addition to assessing the efficacy of candidate molecules, in vivo disease models also help validate the therapeutic potential of molecular targets. Over recent years, several molecules that have shown efficacy in preclinical models of respiratory diseases have failed to translate into new medicines for chronic respiratory conditions such as asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. As such, many scientists have argued that these systems are of limited value; however, we propose that a more careful and thorough approach to the characterization of these models and the interpretation of data generated using these systems would improve their translational utility. Herein, we describe two key elements of our strategy aiming to improve the predictive nature of these models: 1) Novel bioinformatics methods that can be used to identify animal models that best represent specific patient populations; and 2) Innovative physiological techniques that will improve our ability to discover drugs that can restore the functional capacity of lungs damaged during the course of the disease.

Intravenous immunoglobulin (IVIG) is a fractioned blood product consisting of IgG antibodies which was first used in antibody deficiency disorders. It is increasingly being used for several inflammatory and autoimmune conditions. IVIG can also be used in a wide range of dermatological diseases which are difficult to treat including autoimmune bullous skin diseases and toxic epidermal necrolysis. The use of IVIG in dermatological disorders is discussed in this article.

Background: The basophil activation test has been investigated for diagnosing hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs). This has not yet been done in relation to indomethacin. Objective: First seek to establish the viable concentrations of indomethacin and the diluent propylene glycol (PPG) in relation to basophils then test this in patients with hypersensitivity to NSAIDs. Materials & Methods: The ideal concentrations of PPG and indomethacin were assessed by incubating them with basophils from an atopic donor and evaluating the intensity of expression of CD63 molecules by means of flow cytometry. We also evaluated the cell viability directly using the trypan blue in seven controls. Then indomethacin was tested in ten patients with hypersensitivity to NSAIDs compared with eight persons in control group. Results: In relation to the toxicity of propylene glycol, concentrations less than or equal to 0.5% are safe. There was no cytotoxicity or nonspecific stimulation from using indomethacin at concentrations of 10 mcg/mL, 1 mcg/mL and 0.1 mcg/mL. Then indomethacin was tested at concentration of 10 mcg/mL diluted in 0.5% propylene glycol in both groups. There was no statistical difference in the intensity of activation of basophils comparing the group of patients with hypersensitivity to NSAIDs and the control group. Conclusions: As a diluent for indomethacin, PPG should be used at concentrations less than or equal to 0.5%. The indomethacin at concentration of 10 mcg/mL was not able to differentiate patients with and without hypersensitivity to NSAIDs.