Excessive infiltration of lymphocytes has been implicated in the pathogenesis of several inflammatory conditions, including inflammatory bowel disease (IBD). The mucosal vascular addressin, MAdCAM-1 is a tissue specific endothelial adhesion receptor selectively expressed in mucosal lymphoid tissues including Peyer's patches and in the lamina propria. Cell adhesion assays and in vivo homing experiments have shown that the alpha 4 beta 7 integrin, expressed on both B and T cell subsets, defines a mucosal homing receptor which preferentially interacts with MAdCAM-1. We have now demonstrated effective inhibition of recruitment of alpha 4 beta 7 positive lymphocytes to inflammatory sites in murine models of IBD and attenuation of symptoms by treatment with an anti-alpha 4 beta 7 monoclonal antibody in a primate model of colitis. As a major step in developing a first generation drug for IBD, we will humanize and test this antibody for affinity and specificity. In addition, a high throughput drug screen was developed and employed to identify small molecule inhibitors of alpha 4 beta 7 binding to MAdCAM-1. We will continue to develop the best leads into specific, orally active, high affinity inhibitors that will be tested in our murine IBD models. This proposal will therefore lay the foundation for a new class of anti-inflammatory drugs.
Humanization of an efficacious monoclonal antibody and development of small molecule inhibitors of alpha 4 beta 7 binding to MAdCAM-1 will be a major step in the evolution of a new class of drugs to treat inflammatory bowel disease.
