Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 양철수 | - |
dc.date.accessioned | 2018-03-29T01:32:23Z | - |
dc.date.available | 2018-03-29T01:32:23Z | - |
dc.date.issued | 2014-07 | - |
dc.identifier.citation | Molecular Therapy, 2014, 22(7), P.1254-1265 | en_US |
dc.identifier.issn | 1525-0016 | - |
dc.identifier.uri | http://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(16)30717-1 | - |
dc.identifier.uri | http://hdl.handle.net/20.500.11754/53545 | - |
dc.description.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. | en_US |
dc.description.sponsorship | This research was supported by the Pioneer Research Center Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT, and Future Planning (2008-2000217), BrainKorea 21 of Ministry of Education, and KBSI grant (C.H.K). We thank Kyung Mok Sohn (Chungnam National University) for kindly providing a humanized anti-IL-6R monoclonal antibody (IgG1 class), tocilizumab.We thank Sang Jick Kim (KRIBB) for helpful technical support for a phage display. The authors declare no competing financial interests. | en_US |
dc.language.iso | en | en_US |
dc.publisher | Elsevier Science B.V., Amsterdam | en_US |
dc.subject | VARIABLE LYMPHOCYTE RECEPTORS | en_US |
dc.subject | RHEUMATOID-ARTHRITIS | en_US |
dc.subject | ANTIBODY THERAPY | en_US |
dc.subject | TARGETED THERAPY | en_US |
dc.subject | INTERLEUKIN-6 | en_US |
dc.subject | IL-6 | en_US |
dc.subject | STAT3 | en_US |
dc.subject | INFLAMMATION | en_US |
dc.subject | COMPLEXES | en_US |
dc.subject | DESIGN | en_US |
dc.title | A High-Affinity Protein Binder that Blocks the IL-6/STAT3 Signaling Pathway Effectively Suppresses Non-Small Cell Lung Cancer | en_US |
dc.title.alternative | STAT3 Signaling Pathway Effectively Suppresses Non-Small Cell Lung Cancer | en_US |
dc.type | Article | en_US |
dc.relation.no | 7 | - |
dc.relation.volume | 22 | - |
dc.identifier.doi | 10.1038/mt.2014.59 | - |
dc.relation.page | 1254-1265 | - |
dc.relation.journal | MOLECULAR THERAPY | - |
dc.contributor.googleauthor | Lee, JoongJae | - |
dc.contributor.googleauthor | Kim, HyunJung | - |
dc.contributor.googleauthor | Yang, ChulSu | - |
dc.contributor.googleauthor | Kyeong, HyunHo | - |
dc.contributor.googleauthor | Choi, JungMin | - |
dc.contributor.googleauthor | Hwang, DaEun | - |
dc.contributor.googleauthor | Yuk, JaeMin | - |
dc.contributor.googleauthor | Park, Keunwan | - |
dc.contributor.googleauthor | Kim, YuJung | - |
dc.contributor.googleauthor | Lee, SeungGoo | - |
dc.relation.code | 2014036259 | - |
dc.sector.campus | S | - |
dc.sector.daehak | GRADUATE SCHOOL[S] | - |
dc.sector.department | DEPARTMENT OF BIONANOTECHNOLOGY | - |
dc.identifier.pid | chulsuyang | - |
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