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

초록

Interleukin-6 (IL -6) family cytokines signal through multimeric re- ceptor 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, osteopo- rosis, and atherosclerosis. Once bound to ciliary neurotrophic fac- tor 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 bind- ing 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 engineer- ing cytokine activity through a small number of mutations.

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