A high-affinity protein binder that blocks the IL-6/STAT3 signaling pathway effectively suppresses non-small cell lung cancer
- Authors
- Lee, Joong-Jae; Kim, Hyun Jung; Yang, Chul-Su; Kyeong, Hyun-Ho; Choi, Jung-Min; Hwang, Da-Eun; Yuk, Jae-Min; Park, Keunwan Department of Bio and Brai; Kim, Yu Jung; Lee, Seung-Goo; Kim, Dongsup; Jo, Eun-Kyeong; Cheong, Hae-Kap; Kim, Hak-Sung
- Issue Date
- Jul-2014
- Publisher
- Nature Publishing Group
- Citation
- Molecular Therapy, v.22, no.7, pp 1254 - 1265
- Pages
- 12
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- Molecular Therapy
- Volume
- 22
- Number
- 7
- Start Page
- 1254
- End Page
- 1265
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/25454
- DOI
- 10.1038/mt.2014.59
- ISSN
- 1525-0016
1525-0024
- 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. © The American Society of Gene & Cell Therapy.
- Files in This Item
-
Go to Link
- Appears in
Collections - COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY > ERICA 의약생명과학과 > 1. Journal Articles
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.