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

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2020-06, Vol.117 (25), p.14110-14118
Main Authors: Kim, Jun W., Marquez, Cesar P., Sperberg, R. Andres Parra, Wu, Jiaxiang, Bae, Won G., Huang, Po-Ssu, Sweet-Cordero, E. Alejandro, Cochran, Jennifer R.
Format: Article
Language:English
Subjects:
Animal models
Arteriosclerosis
Atherosclerosis
Binding
Biological Sciences
Biomedical materials
Cell culture
Ciliary neurotrophic factor
Cytokines
Glycoprotein gp130
Glycoproteins
Interleukin 6
Leukemia
Leukemia inhibitory factor
Ligands
Lung cancer
Mutation
Osteoporosis
Receptors
Signaling
Therapeutic applications
Xenografts
Xenotransplantation
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1922729117