Mechanisms and Development of Chemokine Network Targeting Agents for the Treatment of Allergic, Autoimmune and Inflammatory Diseases and Cancers pp. 1-46
Authors: John R. McDonald, Barbara K. Finck, Laura M. McIntosh, Susan E. Wilson, Osprey Pharmaceuticals USA Inc., San Francisco, California, and others
Abstract: It is well established that specific chemokine ligand/receptor axes play dominant roles in a plethora 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. Predominant leukocyte subpopulations exhibiting defined profiles of upregulated inflammatory chemokine receptors are associated with certain diseases. For example, activated monocytes and macrophages expressing CCR2 are the predominant pathological leukocytes active in human glomerulonephritides and nephropathies. Recruited leukocytes synthesize and release a host of inflammatory mediators such as cytokines, reactive oxygen and nitrogen species, proteinases and autoantibodies. These agents are responsible for the maintenance and amplification of inflammatory responses, 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 inflammatory mediators including growth factors, chemokines and proteinases that promote tumor growth, neovascularization and cancer metastasis. Tumor growth and metastasis are facilitated by the expression of several autocrine growth factors and chemokine receptors by tumor cells. Here we discuss the development of a range of agents with different mechanisms of action that specifically target the chemokine ligand and receptor network in order to not only dissect the biology of the network but also to explore their therapeutic potentials. These agents can be divided into two main groups: those which target the chemokine ligands and others that target chemokine receptors. Categories in the former group include neutralizing antibodies, modified chemokine ligand and peptide antagonists, RNA oligonucleotide antagonists, soluble chemokine receptors, and peptides that disrupt ligand functional interactions. Categories of the latter group include receptor blocking antibodies, a variety of small compound antagonists, modified ligand antagonists, cell depleting antibodies, fusion proteins, and bispecific constructs (vaccines). Other approaches include targeting the interactions of chemokine ligands with their low affinity glycosaminoglycan ligand receptors, gene targeting therapies (e.g., RNA interference) and various stem cell therapy strategies.