Screening methods for superagonists, antagonists and superantagonists of human interleukin-6 based on receptor complex three-dimensional modeling

摘要

Ligands belonging to a group of cytokines similar to interleukin-6 (IL-6), namely oncostatin M (OSM), leukemia inhibitory factor (LIF), shape neurotrophic factor (CNTF), and interleukin 11 (IL-11) It is known that the membrane protein molecule gp130 induces the formation of a receptor complex that is part of it. The present invention relates to a process for preparing an amino acid sequence comprising:-comparing the amino acid sequence of bovine granulocyte colony stimulating factor (bG-CSF) with that of interleukin-6 hormone; And-based on the comparison, a three-dimensional model of the hormone capable of identifying residues forming sites (site 1) interacting with specific receptors and residues forming sites (site 2) interacting with gp130. A method for screening superagonists, antagonists, and superantagonists of human interleukin-6, which consists of forming processes.;The present invention identifies variants in human interleukin-6 and variants having greater affinity for specific receptors (superagonists and superantagonists) compared to wild type hormones, or variants having reduced or lost affinity for gp130. Enable isolation of antagonists and superantagonists. The figure is a schematic showing the method applied for identifying site 1 and site 2 in the case of human interleukin-6.;The present invention also describes the use of the superantagonists as low dose inhibitors for the acquisition of specific superagonists and superantagonists of interleukin-6 and for the growth of human myeloma cells dependent on wild type interleukin-6.