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Cell Adhesion Antagonists

Therapeutic Potential in Asthma and Chronic Obstructive Pulmonary Disease

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Abstract

Chronic obstructive pulmonary disease (COPD) and asthma are inflammatory diseases of the lung where a hallmark feature is excessive leukocyte infiltration that leads to tissue injury. Cell adhesion molecules (e.g. selectins and integrins) play a key role in cell trafficking, and in the lung they regulate leukocyte extravasation, migration within the interstitium, cellular activation, and tissue retention. All selectin family members (including L-selectin, P-selectin, and E-selectin) and many of the β1 and β2 integrins appear to be important therapeutic targets, as numerous animal studies have demonstrated essential roles for these cell adhesion molecules in lung inflammation. Not surprisingly, these families of adhesion molecules have been under intense investigation by the pharmaceutical industry for the development of novel therapeutics. Integrins are validated drug targets, as drugs that antagonize integrin αIIbβ3 (e.g. abciximab), integrin αLβ2 (efalizumab), and integrin α4β1 (natalizumab) are currently US FDA-approved for acute coronary syndromes, psoriasis, and multiple sclerosis, respectively. However, none has been approved for indications related to asthma or COPD. Here, we provide an overview of roles played by selectins and integrins in lung inflammation. We also describe recent clinical results (both failures and successes) in developing adhesion molecule antagonists, with specific emphasis on those targets that may have potential benefit in asthma and COPD. Early clinical trials using selectin and integrin antagonists have met with limited success. However, recent positive phase II clinical trials with a small-molecule selectin antagonist (bimosiamose) and a small-molecule integrin α4β1 antagonist (valategrast [R411]), have generated enthusiastic anticipation that novel strategies to treat asthma and COPD may be forthcoming.

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Acknowledgments

The authors are employees of Encysive Pharmaceuticals, a company involved in the discovery and development of drugs for a number of cardiovascular and inflammatory diseases, including cell adhesion antagonists for the treatment of asthma. No other sources of funding were used to assist in the preparation of this review.

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  1. Department of Drug Discovery, Biological Sciences, Encysive Pharmaceuticals Inc., Houston, Texas, USA

    Darren G. Woodside & Peter Vanderslice

  2. Encysive Pharmaceuticals Inc., 7000 Fannin, Suite 1920, Houston, TX, 77030, USA

    Darren G. Woodside

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Woodside, D.G., Vanderslice, P. Cell Adhesion Antagonists. BioDrugs 22, 85–100 (2008). https://doi.org/10.2165/00063030-200822020-00002

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