Alpha4-integrin antagonism--an effective approach for the treatment of inflammatory diseases?
Inhibition of leucocyte trafficking by antagonism of the alpha4 (alpha4)-integrin has now been validated as a therapeutic approach for the treatment of inflammatory diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). This validation has been overshadowed by three incidences of progressive multifocal leucoencaphalopathy (PML) in patients receiving natalizumab (Tysabri), a therapeutic monoclonal IgG antibody directed against alpha4-integrins. This led to the initial removal of natalizumab from the market. Following a safety review, it was reintroduced for the treatment of relapsing-remitting MS patients (with restrictions). This has led to a refocus on alpha4-integrins as a therapeutic target across the pharmaceutical industry. Recent advances in small molecule development are worth reviewing. New understanding of pharmacokinetics and selectivity will potentially contribute to the development of alpha4 antagonist with greater clinical efficacy and safety.
Davenport
Richard J
RJ
Global Chemistry, UCB-Group, Granta Park, Great Abington, Cambridge CB16GS, UK. richard.davenport@ucb-group.com
Munday
James R
JR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology; D039441:Integrin alpha4 / Q000276:immunology / Q000502:physiology*; D016023:Integrins / Q000037:antagonists & inhibitors; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D000069442:Natalizumab; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014508:Urea / Q000031:analogs & derivatives / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016023:Integrins; D000069442:Natalizumab; C071777:integrin alpha4beta7; D039441:Integrin alpha4; D010649:Phenylalanine; D014508:Urea