The therapeutic potential of interleukin-6 hyperagonists and antagonists

Interleukin-6 (IL-6) is a 4-helical protein that binds to a specific IL-6 receptor on target cells and to two molecules of the promiscuous signal transducing protein, glycoprotein 130 (gp130). Structure-function analysis has led to the definition of molecular contacts between IL-6 and its receptor subunits. This knowledge has led to the design of competitive antagonistic proteins that retain their receptor binding capability, but fail to stimulate one or both gp130 proteins; the properties of such recombinant antagonistic proteins are compared with traditional neutralising monoclonal antibodies targeted at IL-6 or receptor subunits. Furthermore, several strategies have been employed to construct molecules with increased bioactivity. Possible therapeutic applications in putative IL-6 dependent haematologic disorders, e.g., Castleman's disease (CD), POEMS syndrome, multiple myeloma, and bone diseases, e.g., Paget's disease, osteoporosis, are outlined. IL-6 antagonists could also, in theory, suppress inflammatory activity in rheumatic and autoimmune diseases and could prevent secondary amyloidosis. This principle may prove advantageous in myocardial infarction (MI) and unstable angina pectoris. More generally, IL-6 antagonists could improve the wasting and microcytic anaemia of chronic diseases. IL-6 antagonists might slow down development of mesangio-proliferative glomerulonephritis (MPGN). Hyperagonistic variants of IL-6 have a potential use in the ex vivo expansion of haematopoietic progenitor cells and as thrombopoietic agents. They might well be the first drugs to aid liver regeneration in vivo.