Anti-Inflammatory Approaches that Target the Chemokine Network
John R. McDonald, Barbara K. Finck, Laura M. McIntosh and Susan E. Wilson
Affiliation: Osprey Pharmaceuticals Inc., 409 Illinois Street, San Francisco CA 94158, USA.
Chemokine-ligand/receptor axes play pivotal roles in a myriad of inflammatory, allergic and autoimmune diseases, as well as in the promotion of tumor growth and metastasis. Upon insult, tissue resident cells (and cancer cells in general) release a defined set of inflammatory chemokines that are responsible for the recruitment of activated pathological leukocytes. Recruited leukocytes synthesize and release a host of inflammatory mediators such as chemokines, cytokines, reactive oxygen and nitrogen species, and proteinases. These agents are responsible for the maintenance and amplification of inflammatory responses, and are directly responsible for secondary tissue damage, promotion of autoimmunity, fibrosis and tissue remodelling. Many cancers are associated with the expression of chemokine ligands that co-opt leukocytes such as tumor associated macrophages which in turn provide mediators including growth factors, chemokines and proteinases that promote angiogenesis, tumor growth, and cancer metastasis. Here, we discuss the relevant patents, development and the mechanism of action of a range of therapeutic and potential therapeutic agents that specifically target the chemokine ligand and receptor network. The main approaches that will be highlighted here are antagonism, cell depletion and the relatively unexplored fields of anti-sense, gene and stem cell therapies.
Keywords: Antagonists, antibodies, antisense, chemokine, gene therapy, glycosaminoglycans, receptor, stem cells, reactive oxygen, proteinases, autoimmunity, fibrosis, growth factors, hematopoiesis, neovascularization, cysteine, CXCR1-7, CCL1-10, CCL, CAMs, GPCR, MIG, neutrophils, COPD, rheumatoid arthritis, GAG, hERG, Pfizer, GlaxoSmithKline, Genzyme, CCL5, DOP, FDA, Maraviroc, haematopoietic stem cells, Crohn's disease, EAE, BCSIS, BINDARIT, SPIEGELMERS, KW-0761, Shigella dysenteria, OV-HM, UUO, VEGF, RNAi, ERNBC, Evasins
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