Selectin - its role as a target for airway disorders

The incidence of asthma has dramatically increased over recent years and although currently available treatments are generally effective, patient compliance is currently poor, especially with respect to inhaled treatment. Furthermore 5% of patients are unresponsive to these treatments and it is this cohort that accounts for a large segment of asthma related healthcare cost.

The lack of effective candidate oral therapies means that inhalation will remain the primary mode of delivery in the medium term. In our recent feature “Asthma and COPD - Combinations breathe life into the asthma and COPD markets” it is predicted that the market for airway inflammatory diseases will increase by 35% to over $18 billion by 2011, largely driven by the success of combined steroid/beta agonist formulations, rather than novel drug launches (click here for this report). More distant advances are however likely to focus on novel anti-inflammatory targets.

The selectin family is one group of potential anti-inflammatory targets. Selectins mediate the tethering and rolling of circulating leucocytes over endothelial cells, the first steps for leucocyte transvascular migration. Cell adhesion is mediated by binding to glycoproteins and glycolipids on the surface of leucocytes and endothelial cells. L selectin is expressed on the surface of leucocytes, E selectin on activated endothelial cells and P selectin on activated platelets and endothelial cells.

Due to their key role in the inflammatory process the selectins represent much investigated therapeutic targets in the context of various inflammatory diseases including rheumatoid arthritis and asthma. See the following reports for details:

In asthmatic subjects, serum concentrations and lung endothelial expression of E selectin and selectin ligands increase during asthma attacks, probably as a result of increased endothelial expression. Animal and clinical studies suggest that selectins are involved in the recruitment of inflammatory cells into the airway after allergen challenge. Knockout mice deficient in P or L selectin have decreased airway hyper-reactivity, and attenuated influx of eosinophils and/or lymphocytes in a model of asthma providing proof of concept for the development of selectin antagonists.

Recently, small non-oligosaccharide molecules such as Texas Biotech’s (now Encysive) TBC1269 have been designed to inhibit the interaction between selectins and sialyl-Lewis(x) tetrasaccharide (sLe(x)). Because sLe(x) is a natural ligand for all 3 selectins, these compounds are potential antagonists for all selectins. TBC1269 reduces early and late airway responses, prevents allergen induced airway hyper-reactivity and reduces allergen-induced airway neutrophilia during the late airway response in an animal model of asthma.

Despite its promise, Avila et al report in their recent Clinical & Experimental Allergy journal article that TBC1269 (30mg/kg) administered intravenously to asthmatic patients 15 min before inhalation allergen challenge did not attenuate the early or late asthmatic response, nor it did inhibit influx of eosinophils or neutrophils into the airway to a great extent.

Several reasons could explain the discrepancy between the successful effects of TBC1269 in animal and in vitro studies with human leucocytes and these results. Methodologically, using the sheep to predict therapeutically active doses in humans may be unreliable or alternatively inhaled TBC1269 may be more effective than systemic delivery. Such possibilities require further study.

More fundamentally, selectins may play a relatively minor role in human in asthma patients. For example blocking the activation of resident eosinophils as well as their infiltration may be important to disease limitation; selectins may not play a key role in the airway influx of inflammatory cells in human asthma; or selectin inhibitors may be of greater utility in diseases associated with neutrophilia. This last possibility is of particular interest. Asthma is predominantly associated with eosinophilia contrasting with COPD for example, which is primarily associated with neutrophil infiltration. In preclinical studies TBC1269 was shown to be particularly active in models involving neutrophils and in this respect the evaluation of TBC1269 in patients with COPD may be warranted.

There is a pressing need to develop new treatments for COPD. World-wide, 600 million people suffer from COPD, with some three million dying from the disease each year. A global market of US$2.8 billion parallels this serious healthcare problem and efficacy of TBC1269 in this disease state would be particularly welcome.

Entry date Wednesday, April 14, 2004

Adapted from Avila et al, Clin Exp Allergy. 2004 Jan; 34(1): 77-84.