DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lee, Joong Jae | ko |
dc.contributor.author | Kim, Hyun Jung | ko |
dc.contributor.author | Yang, Chul-Su | ko |
dc.contributor.author | Kyeong, Hyunho | ko |
dc.contributor.author | Choi, Jung-Min | ko |
dc.contributor.author | Hwang, Da Eun | ko |
dc.contributor.author | Yuk, Jae-Min | ko |
dc.contributor.author | Park, Keunwan | ko |
dc.contributor.author | Kim, Yu Jung | ko |
dc.contributor.author | Lee, Seung-Goo | ko |
dc.contributor.author | Kim, Dongsup | ko |
dc.contributor.author | Jo, Eun-Kyeong | ko |
dc.contributor.author | Cheong, Hae-Kap | ko |
dc.contributor.author | Kim, Hak-Sung | ko |
dc.date.accessioned | 2014-09-04T08:25:01Z | - |
dc.date.available | 2014-09-04T08:25:01Z | - |
dc.date.created | 2014-07-04 | - |
dc.date.created | 2014-07-04 | - |
dc.date.issued | 2014-07 | - |
dc.identifier.citation | MOLECULAR THERAPY, v.22, no.7, pp.1254 - 1265 | - |
dc.identifier.issn | 1525-0016 | - |
dc.identifier.uri | http://hdl.handle.net/10203/189975 | - |
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-6Ra 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. | - |
dc.language | English | - |
dc.publisher | NATURE PUBLISHING GROUP | - |
dc.subject | VARIABLE LYMPHOCYTE RECEPTORS | - |
dc.subject | RHEUMATOID-ARTHRITIS | - |
dc.subject | ANTIBODY THERAPY | - |
dc.subject | TARGETED THERAPY | - |
dc.subject | INTERLEUKIN-6 | - |
dc.subject | IL-6 | - |
dc.subject | STAT3 | - |
dc.subject | INFLAMMATION | - |
dc.subject | COMPLEXES | - |
dc.subject | DESIGN | - |
dc.title | A High-Affinity Protein Binder that Blocks the IL-6/STAT3 Signaling Pathway Effectively Suppresses Non-Small Cell Lung Cancer | - |
dc.type | Article | - |
dc.identifier.wosid | 000338189800006 | - |
dc.identifier.scopusid | 2-s2.0-84903763186 | - |
dc.type.rims | ART | - |
dc.citation.volume | 22 | - |
dc.citation.issue | 7 | - |
dc.citation.beginningpage | 1254 | - |
dc.citation.endingpage | 1265 | - |
dc.citation.publicationname | MOLECULAR THERAPY | - |
dc.identifier.doi | 10.1038/mt.2014.59 | - |
dc.contributor.localauthor | Kim, Dongsup | - |
dc.contributor.localauthor | Kim, Hak-Sung | - |
dc.contributor.nonIdAuthor | Kim, Hyun Jung | - |
dc.contributor.nonIdAuthor | Yang, Chul-Su | - |
dc.contributor.nonIdAuthor | Choi, Jung-Min | - |
dc.contributor.nonIdAuthor | Yuk, Jae-Min | - |
dc.contributor.nonIdAuthor | Kim, Yu Jung | - |
dc.contributor.nonIdAuthor | Lee, Seung-Goo | - |
dc.contributor.nonIdAuthor | Jo, Eun-Kyeong | - |
dc.contributor.nonIdAuthor | Cheong, Hae-Kap | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordPlus | VARIABLE LYMPHOCYTE RECEPTORS | - |
dc.subject.keywordPlus | RHEUMATOID-ARTHRITIS | - |
dc.subject.keywordPlus | ANTIBODY THERAPY | - |
dc.subject.keywordPlus | TARGETED THERAPY | - |
dc.subject.keywordPlus | INTERLEUKIN-6 | - |
dc.subject.keywordPlus | IL-6 | - |
dc.subject.keywordPlus | STAT3 | - |
dc.subject.keywordPlus | INFLAMMATION | - |
dc.subject.keywordPlus | COMPLEXES | - |
dc.subject.keywordPlus | DESIGN | - |
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