Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
Commun Biol. 2021 Apr 12;4(1):452. doi: 10.1038/s42003-021-01928-2.
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.
白血病抑制因子 (LIF) 是一种由基质肌纤维母细胞和肿瘤细胞分泌的细胞因子，最近被强调通过 KRAS 驱动的细胞信号促进胰腺和其他癌症的肿瘤进展。我们设计了一种高亲和力的可溶性人 LIF 受体 (LIFR) 诱饵，它可以隔离人 LIF 并抑制其信号作为一种治疗策略。这种工程化的“配体陷阱”与抗体 Fc 结构域融合，与野生型 LIFR-Fc 相比，亲和力提高了约 50 倍（~20 pM），并且对 LIF 的抑制作用得到改善，能够有效地阻断 LIF 介导的胰腺癌细胞效应，并减缓胰腺癌细胞异种移植瘤的生长。这些结果以及在动物模型中观察到的明显毒性缺乏，进一步强调了配体陷阱作为癌症治疗的一种有前途的治疗策略。
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