Interleukin-6 receptor agonists

Details Interleukin-6 receptor agonists Interleukin-6 receptor agonists

1998-01-16

1999-06-22

Mertz, Prema

Drug, bio-affecting and body treating compositions

Lymphokine

Interleukin

514 2, 514 12, 435 6952, 4352523, 435325, 4353201, 530351, 930141, C07K 1454, A61K 3820, C12N 1524, C12N 1563

Patent

active

059141069

ABSTRACT:
It is known that the ligands of the group of cytokines similar to Interleuk 6 (IL-6), that is Oncostatin M (OSM), Leukemia Inhibitory Factor (LIF), Ciliary Neurotrophic Factor (CNTF) and Interleukin 11 (IL-11), induce the formation of a receptor complex of which the membrane molecule gp 130 is a part. The present invention refers to a methodology for selecting superagonists, antagonists and superantagonists of human interleukin-6 comprising the following operations: comparing the amino acid sequence of bovine granulocyte colony stimulating factor (bG-CSF) with the sequence of said hormone; and on the basis of the above comparison, formulating a three dimensional model of said hormone, which allows the identification of residues that form the site of interaction with the specific receptor (Site 1) and those that constitute the site of interaction with gp 130 (Site 2) respectively. The invention allows the identification of these sites in human interleukin-6 and the isolation of variants having, with respect to the wild type hormone, a greater affinity for the specific receptor (superagonists and superantagonists) or affinity for gp 130 reduced or abolished (antagonists and superantagonists). A scheme illustrating the methodology applied to identify site 1 and site 2 in the case of human interleukin-6 is disclosed. The invention also describes the obtaining of specific superagonists and superantagonists of interleukin-6 and the use of superantagonists as low dose inhibitors of the growth of human myeloma cells dependent on wild type interleukin-6.

REFERENCES:
Ehlers et al, "Identification of Two Novel Regions of Human IL-6 Responsi for Receptor Binding and Signal Transduction", J. Immunol., 153(4):1744-1753 (1994).
Savino et al, "Saturation mutagenesis of the human interleukin 6 receptor-bidning site: Implications for its three-dimensional structure", PNAS, USA, 90:4067-4071 (1993).
Savino et al, "Generation of interleukin-6 receptor antagonists by molecular-modeling guided mutagenesis of residues important for gp130 activation", The EMBO Journal, 13(6):1357-1367 (1994).

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