Development of an IL-6 inhibitor based on the functional analysis of murine IL-6Ralpha(1).
Dysregulated cytokine production contributes to inflammatory and proliferative diseases. Therefore, inhibition of proinflammatory mediators such as TNF, IL-1, and IL-6 is of great clinical relevance. Actual strategies are aimed at preventing receptor activation through sequestration of the ligand. Here we describe the development of an inhibitor of murine IL-6 based on fused receptor fragments. Molecular modeling-guided analysis of the murine IL-6Ralpha revealed that mutations in the Ig-like domain D1 severely affect protein function, although D1 is not directly involved in the ligand-binding interface. The resulting single chain IL-6 inhibitor (mIL-6-RFP) consisting of domains D1-D3 of mgp130, a flexible linker, and domains D1-D3 of mIL-6Ralpha is a highly potent and specific IL-6 inhibitor. mIL-6-RFP will permit further characterization of the role of IL-6 in various disease models and could ultimately lead to anti-IL-6 therapy.
Wiesinger
Monique Y
MY
Institut für Biochemie, Universitätsklinikum RWTH Aachen, Aachen 52074, Germany.
Haan
Serge
S
Wüller
Stefan
S
Kauffmann
Maria-Elisabeth
ME
Recker
Tobias
T
Küster
Andrea
A
Heinrich
Peter C
PC
Müller-Newen
Gerhard
G
D000818:Animals; D015195:Drug Design; D007249:Inflammation / Q000188:drug therapy; D008024:Ligands; D051379:Mice; D009154:Mutation; D015202:Protein Engineering / Q000379:methods*; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D000093242:Interleukin-6 Inhibitors
D008024:Ligands; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors