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

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Title
A high-affinity protein binder that blocks the IL-6/STAT3 signaling pathway effectively suppresses non?small cell lung cancer
Author(s)
J J Lee; H J Kim; C S Yang; H H Kyeong; J M Choi; D E Hwang; J M Yuk; K Park; Yu Jung Kim; Seung Goo Lee; D Kim; E K Jo; H K Cheong; H S Kim
Bibliographic Citation
Molecular Therapy, vol. 22, no. 7, pp. 1254-1265
Publication Year
2014
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.
ISSN
1525-0016
Publisher
Elsevier-Cell Press
DOI
http://dx.doi.org/10.1038/mt.2014.59
Type
Article
Appears in Collections:
Synthetic Biology and Bioengineering Research Institute > 1. Journal Articles
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