Abstract
Leukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling. We engineered a high affinity soluble human LIF receptor (LIFR) decoy that sequesters human LIF and inhibits its signaling as a therapeutic strategy. This engineered ‘ligand trap’, fused to an antibody Fc-domain, has ~50-fold increased affinity (~20 pM) and improved LIF inhibition compared to wild-type LIFR-Fc, potently blocks LIF-mediated effects in pancreatic cancer cells, and slows the growth of pancreatic cancer xenograft tumors. These results, and the lack of apparent toxicity observed in animal models, further highlights ligand traps as a promising therapeutic strategy for cancer treatment.
Highlights
Leukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling
To assess whether a ligand trap was a viable therapeutic approach, we first showed that soluble mouse LIFR (mLIFR)-fragment crystallizable (Fc) inhibited mouse LIF (mLIF) induced phospho-signal transducer and activator of transcription 3 (STAT3) in a Pancreatic ductal adenocarcinoma (PDAC) cell line derived from the pancreas of a KPf/fCL mouse (Fig. 1b, Supplementary Fig. 1b)
We identified eight mutations (I217V, L218P, H240R, I257V, I260V, V262A, T273I, and N277D) (Fig. 2e) that collectively increase the affinity of soluble eLIFR-Fc or hLIFR-Fc were serially diluted (eLIFR)-Fc over human LIFR (hLIFR)-Fc by ~50-fold (Fig. 3d)
Summary
Leukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling. We engineered a high affinity soluble human LIF receptor (LIFR) decoy that sequesters human LIF and inhibits its signaling as a therapeutic strategy This engineered ‘ligand trap’, fused to an antibody Fc-domain, has ~50-fold increased affinity (~20 pM) and improved LIF inhibition compared to wild-type LIFR-Fc, potently blocks LIF-mediated effects in pancreatic cancer cells, and slows the growth of pancreatic cancer xenograft tumors. We fused the highest affinity variant to an antibody Fc domain to create a construct that binds LIF with 50-fold higher apparent affinity (Kd ~ 20 pM) as compared to wild-type (WT) LIFR and competes directly with LIFR for binding This engineered protein potently inhibits LIFderived signaling and sphere formation in PDAC cells and slows tumor progression in a mouse model of disease
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