Anti-adhesion therapies.
Cell adhesion molecules are key mediators of inflammatory processes and are attractive targets for discovery of novel therapeutics. There have been significant positive advances in both basic research and clinical development in this area. Basic research has yielded detailed insight into the structural basis of cell adhesion molecule function, especially the interaction of integrins with their ligands. Co-crystals of several integrin-ligand complexes have been published, including alpha v beta3 with ligand fragments, alpha IIb beta3 with multiple therapeutic ligands and alpha L beta2 (leukocyte function-associated antigen-1 [LFA-1]) with its cell-based ligand intercellular adhesion molecule-1. This has stimulated development of models of integrin function and also the mode of action of small-molecule inhibitors. The most exciting recent advances in the field of clinical development have come with the successful approval of two new anti-adhesion therapeutics: efalizumab (Raptiva) targeting LFA-1 for the treatment of chronic plaque psoriasis, and natalizumab (Tysabri/Antegren) targeting very late antigen-4 for the treatment of relapsing-remitting multiple sclerosis. However, the latter therapeutic ran into a surprising safety issue earlier this year and was withdrawn from the market, casting a shadow over what had seemed a promising new drug.
Simmons
David L
DL
Inflammation Discovery Research, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA02140, USA. dsimmons@wyeth.com
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D018845:CD11 Antigens / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology*; D006801:Humans; D039441:Integrin alpha4 / Q000276:immunology; D000069442:Natalizumab; D013678:Technology, Pharmaceutical / Q000379:methods / Q000639:trends
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018845:CD11 Antigens; D015815:Cell Adhesion Molecules; D000069442:Natalizumab; D039441:Integrin alpha4; C472181:efalizumab