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Edited by Joseph Schlessinger, Yale University, New Haven, CT, and approved May 5, 2020 (received for review December 26, 2019)
Significance
The interleukin-6 family of cytokines play an increasingly recognized role in inflammation, metabolism, and tissue regeneration. Cytokine binding to CNTFR triggers JAK-STAT, MAPK, and other associated pathways. From limited studies reported to date, CLCF1 has been implicated in lung cancer, osteoporosis, and atherosclerosis, identifying the CLCF1–CNTFR signaling axis as a therapeutic target for a number of diseases. To modulate multireceptor engagement to drive cell signaling, we used rational and combinatorial protein engineering methods to create two unique CLCF1 variants: one that promotes enhanced cell signaling in neuronal regeneration and one that blocks cell signaling to inhibit tumor progression. These studies highlight an approach of engineering cytokine activity to target the CLCF1–CNTFR signaling axis.
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: alejandro.sweet-cordero{at}ucsf.edu or jennifer.cochran{at}stanford.edu.
Author contributions: J.W.K., C.P.M., W.G.B., E.A.S.-C., and J.R.C. designed research; J.W.K., C.P.M., R.A.P.S., J.W., and P.-S.H. performed research; J.W.K., C.P.M., W.G.B., and E.A.S.-C. contributed new reagents/analytic tools; J.W.K., C.P.M., R.A.P.S., J.W., P.-S.H., E.A.S.-C., and J.R.C. analyzed data; and J.W.K., C.P.M., E.A.S.-C., and J.R.C. wrote the paper.
Competing interest statement: J.W.K., C.P.M., E.A.S.-C., and J.R.C. are included as inventors on university-owned intellectual property related to the work described in this paper.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1922729117/-/DCSupplemental.
Published under the PNAS license.
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Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand
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