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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.

SUBMITTER: Kim JW

PROVIDER: S-EPMC7322068 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Kim Jun W JW Marquez Cesar P CP Sperberg R Andres Parra RAP Wu Jiaxiang J Bae Won G WG Huang Po-Ssu PS Sweet-Cordero E Alejandro EA Cochran Jennifer R JR

Proceedings of the National Academy of Sciences of the United States of America 20200610 25

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 bindi ...[more]

PMID: 32522868

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

Publications

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

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