VLA-4 antagonists: potent inhibitors of lymphocyte migration

Circulating lymphocytes normally migrate through extravascular spaces in relatively low numbers as important members of the immunosurveillance process. That is until signals are received by endothelial cells that there is an underlying infection or inflammatory condition. These vascular surface cells in turn overexpress and present ligands to circulating lymphocyte adhesion molecules. Upon encountering this higher density of ligands, lymphocytes, which had been leisurely rolling along the vascular surface, now become more firmly attached, change shape, and migrate through tight junctions to the sites of infection or inflammation. If the initiating events are not resolved and the condition becomes chronic, there can be a sustained extravasation of lymphocytes that can exacerbate the inflammatory condition, which in turn will continue to recruit more inflammatory cells resulting in unwanted tissue destruction. It is for the attenuation of this cycle of sustained inflammatory cell recruitment that very late activating antigen-4 (VLA-4) antagonists are being developed. Most lymphocytes, except neutrophils, express VLA-4 on their surface and they interact with endothelial vascular cell adhesion molecule-1 (VCAM-1). It is this interaction that VLA-4 antagonists are intended to disrupt, thus, putting an end to the cycle of chronic inflammation, which is the hallmark of many diseases. This review will provide an update of VLA-4 antagonists that have appeared since early 2001 and will discuss some of the issues, both positive and negative, that may be encountered in their development.