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  3. A high-affinity protein binder that blocks the IL-6/STAT3 signaling pathway effectively suppresses non-small cell lung cancer

A high-affinity protein binder that blocks the IL-6/STAT3 signaling pathway effectively suppresses non-small cell lung cancer

  • Mol Ther. 2014 Jul;22(7):1254-1265. doi: 10.1038/mt.2014.59.
Joong-Jae Lee 1,  Hyun Jung Kim 2,  Chul-Su Yang 3,  Hyun-Ho Kyeong 1,  Jung-Min Choi 1,  Da-Eun Hwang 1,  Jae-Min Yuk 4,  Keunwan Park 5,  Yu Jung Kim 6,  Seung-Goo Lee 6,  Dongsup Kim 5,  Eun-Kyeong Jo 7,  Hae-Kap Cheong 8,  Hak-Sung Kim 9
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
  • 2 Division of Magnetic Resonance Research, Korea Basic Science Institute, Cheongwon, Chungbuk, Korea.
  • 3 Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Korea; Current address: Department of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan, Korea.
  • 4 Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Korea.
  • 5 Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
  • 6 Industrial Biotechnology and Bioenergy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
  • 7 Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Korea. Electronic address: hayoungj@cnu.ac.kr.
  • 8 Division of Magnetic Resonance Research, Korea Basic Science Institute, Cheongwon, Chungbuk, Korea. Electronic address: haekap@kbsi.re.kr.
  • 9 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea. Electronic address: hskim76@kaist.ac.kr.
PMID: 24682171 DOI: 10.1038/mt.2014.59
Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates immune responses for host defense and tumorigenic process. Upregulation of IL-6 is known to constitutively phosphorylate signal transducer and activator of transcription 3 (STAT3), leading to activation of multiple oncogene pathways and inflammatory cascade. Here, we present the development of a high-affinity protein binder, termed repebody, which effectively suppresses non-small cell lung Cancer in vivo by blocking the IL-6/STAT3 signaling. We selected a repebody that prevents human IL-6 (hIL-6) from binding to its receptor by a competitive immunoassay, and modulated its binding affinity for hIL-6 up to a picomolar range by a modular approach that mimics the combinatorial assembly of diverse modules to form antigen-specific receptors in nature. The resulting repebody was highly specific for hIL-6, effectively inhibiting the STAT3 phosphorylation in a dose- and binding affinity-response manner in vitro. The repebody was shown to have a remarkable suppression effect on the growth of tumors and STAT3 phosphorylation in xenograft mice with non-small cell lung Cancer by blocking the hIL-6/STAT3 signaling. Structural analysis of the repebody and IL-6 complex revealed that the repebody binds the site 2a of hIL-6, overlapping a number of epitope residues at site 2a with gp130, and consequently causes a steric hindrance to the formation of IL-6/IL-6Rα complex. Our results suggest that high-affinity repebody targeting the IL-6/STAT3 pathway can be developed as therapeutics for non-small cell lung Cancer.

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