oa Editorial [Hot Topic: Targeting Cell Migration - The Next Generation Blockbusters (Guest Editors: Amanda E.I. Proudfoot, Marie Kosco-Vilbois and Zoe Johnson)]

Disease modifying, anti-inflammatory strategies often target pathogenic cells once they are localized within the site of inflammation. The prototypes of biologic drugs such as anti-TNFα or anti-p40 (IL-12 and IL-23) therapies act on cytokines produced by tissue macrophages for example in the synovium in Rheumatoid Arthritis (RA) or in the intestinal mucosa in Intestinal Bowel Disease (IBD). Furthermore, immunosuppressant drugs such as cyclosporin, steroids, cyclophosphamide and mycophenolate mofetil (MMF) similarly act on intracellular targets in cells already localized in the target organ. A similar phenomenon applies to cancer, where chemotherapies address the cells locally in the tumour, such as anti-epidermal growth factor receptor and all commonly used cytotoxic agents. However while effective for a certain subpopulation of patients, a significant unmet medical need exists for most diseases where dysregulation of the immune system is the fundamental cause. An attractive alternative strategy is to prevent aberrantly activated cells from accessing the site of inflammation in the first place, in other words targeting the capacity of cells to migrate through the endothelium. Cell migration is a well orchestrated and tightly coordinated succession of steps depicted below. The first event is the activation of the endothelium by proinflammatory cytokines. This results in the upregulation of selectins, molecules which mediate rolling of leukocytes on the endothelial surface. Therefore, prevention of the release of soluble TNF from its tethered transmembrane form by the inhibition of the enzyme catalyzing this shedding, would be a relevant target. This is covered in Chapter 1. Chapters 2 and 3 address the second stage of the cell recruitment process, the activation of integrins on the leukocyte mediated by the activation of chemokine receptors by their respective ligand. The chemokine family is a large family of small proteins, whose major, but not only, function is the control of cellular migration. Chemokine receptors belong to the class of sevenmembrane spanning G protein-coupled receptors, which have proved highly tractable targets for many pharmaceutical drugs. Therefore, the identification of the chemokine family over a quarter of a century ago gave great promise to the pharmaceutical industry as potentially tractable anti-inflammatory targets. We have decided not to include a chapter on the small molecular weight inhibitors of chemokine receptors, as this subject has been addressed extensively by a number of recent reviews, and the reader is referred to these [1-11]. However, overall the success of this approach has been disappointing, and again the reader is referred to recent opinion articles discussing several hypotheses addressing why success has been so difficult [12, 13]. But we do not exclude the future success of this approach, as the first anti-inflammatory program to meet its endpoints in Phase II, inhibition of CCR9 for Crohn's disease, is currently in Phase III, and if successful, will dispel the reputation of chemokine receptors being “undruggable”....