PMID- 24682171
OWN - NLM
STAT- MEDLINE
DCOM- 20150219
LR  - 20211021
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 22
IP  - 7
DP  - 2014 Jul
TI  - A high-affinity protein binder that blocks the IL-6/STAT3 signaling pathway 
      effectively suppresses non-small cell lung cancer.
PG  - 1254-1265
LID - S1525-0016(16)30717-1 [pii]
LID - 10.1038/mt.2014.59 [doi]
AB  - 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-6Ralpha 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.
FAU - Lee, Joong-Jae
AU  - Lee JJ
AD  - Department of Biological Sciences, Korea Advanced Institute of Science and 
      Technology, Daejeon, Korea.
FAU - Kim, Hyun Jung
AU  - Kim HJ
AD  - Division of Magnetic Resonance Research, Korea Basic Science Institute, 
      Cheongwon, Chungbuk, Korea.
FAU - Yang, Chul-Su
AU  - Yang CS
AD  - 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.
FAU - Kyeong, Hyun-Ho
AU  - Kyeong HH
AD  - Department of Biological Sciences, Korea Advanced Institute of Science and 
      Technology, Daejeon, Korea.
FAU - Choi, Jung-Min
AU  - Choi JM
AD  - Department of Biological Sciences, Korea Advanced Institute of Science and 
      Technology, Daejeon, Korea.
FAU - Hwang, Da-Eun
AU  - Hwang DE
AD  - Department of Biological Sciences, Korea Advanced Institute of Science and 
      Technology, Daejeon, Korea.
FAU - Yuk, Jae-Min
AU  - Yuk JM
AD  - Department of Microbiology, Chungnam National University College of Medicine, 
      Daejeon, Korea.
FAU - Park, Keunwan
AU  - Park K
AD  - Department of Bio and Brain Engineering, Korea Advanced Institute of Science and 
      Technology, Daejeon, Korea.
FAU - Kim, Yu Jung
AU  - Kim YJ
AD  - Industrial Biotechnology and Bioenergy Research Center, Korea Research Institute 
      of Bioscience and Biotechnology, Daejeon, Korea.
FAU - Lee, Seung-Goo
AU  - Lee SG
AD  - Industrial Biotechnology and Bioenergy Research Center, Korea Research Institute 
      of Bioscience and Biotechnology, Daejeon, Korea.
FAU - Kim, Dongsup
AU  - Kim D
AD  - Department of Bio and Brain Engineering, Korea Advanced Institute of Science and 
      Technology, Daejeon, Korea.
FAU - Jo, Eun-Kyeong
AU  - Jo EK
AD  - Department of Microbiology, Chungnam National University College of Medicine, 
      Daejeon, Korea. Electronic address: hayoungj@cnu.ac.kr.
FAU - Cheong, Hae-Kap
AU  - Cheong HK
AD  - Division of Magnetic Resonance Research, Korea Basic Science Institute, 
      Cheongwon, Chungbuk, Korea. Electronic address: haekap@kbsi.re.kr.
FAU - Kim, Hak-Sung
AU  - Kim HS
AD  - Department of Biological Sciences, Korea Advanced Institute of Science and 
      Technology, Daejeon, Korea. Electronic address: hskim76@kaist.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140331
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Interleukin-6)
RN  - 0 (STAT3 Transcription Factor)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/therapeutic use
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism
MH  - Female
MH  - Humans
MH  - Interleukin-6/*metabolism
MH  - Mice
MH  - Mice, Nude
MH  - STAT3 Transcription Factor/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC4089000
EDAT- 2014/04/01 06:00
MHDA- 2015/02/20 06:00
PMCR- 2015/07/01
CRDT- 2014/04/01 06:00
PHST- 2014/01/27 00:00 [received]
PHST- 2014/03/20 00:00 [accepted]
PHST- 2014/04/01 06:00 [entrez]
PHST- 2014/04/01 06:00 [pubmed]
PHST- 2015/02/20 06:00 [medline]
PHST- 2015/07/01 00:00 [pmc-release]
AID - S1525-0016(16)30717-1 [pii]
AID - 10.1038/mt.2014.59 [doi]
PST - ppublish
SO  - Mol Ther. 2014 Jul;22(7):1254-1265. doi: 10.1038/mt.2014.59. Epub 2014 Mar 31.