Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand.

Abstract

Interleukin-6 (IL-6) family cytokines signal through multimeric receptor complexes, providing unique opportunities to create novel ligand-based therapeutics. The cardiotrophin-like cytokine factor 1 (CLCF1) ligand has been shown to play a role in cancer, osteoporosis, and atherosclerosis. Once bound to ciliary neurotrophic factor receptor (CNTFR), CLCF1 mediates interactions to coreceptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). By increasing CNTFR-mediated binding to these coreceptors we generated a receptor superagonist which surpassed the potency of natural CNTFR ligands in neuronal signaling. Through additional mutations, we generated a receptor antagonist with increased binding to CNTFR but lack of binding to the coreceptors that inhibited tumor progression in murine xenograft models of nonsmall cell lung cancer. These studies further validate the CLCF1-CNTFR signaling axis as a therapeutic target and highlight an approach of engineering cytokine activity through a small number of mutations.

• Authors: Jun W Kim, Cesar P Marquez, R Andres Parra Sperberg, Jiaxiang Wu, Won G Bae, Po-Ssu Huang, E Alejandro Sweet-Cordero, Jennifer R Cochran
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 25 Pg. 14110-14118 (06 23 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32522868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CLCF1 protein, human
• CNTFR protein, human
• Ciliary Neurotrophic Factor Receptor alpha Subunit
• Cytokines
• LIFR protein, human
• Leukemia Inhibitory Factor Receptor alpha Subunit
• Ligands
• Cytokine Receptor gp130

Topics

• Animals
• Binding Sites
• Cell Line, Tumor
• Cells, Cultured
• Ciliary Neurotrophic Factor Receptor alpha Subunit (agonists, antagonists & inhibitors, metabolism)
• Cytokine Receptor gp130 (metabolism)
• Cytokines (chemistry, genetics, metabolism)
• Humans
• Leukemia Inhibitory Factor Receptor alpha Subunit (metabolism)
• Ligands
• Neurons (metabolism)
• Protein Binding
• Protein Engineering (methods)
• Rats
• Signal Transduction