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A High-Affinity Protein Binder that Blocks the IL-6/STAT3 Signaling Pathway Effectively Suppresses Non-Small Cell Lung Cancer.
- Source :
-
Molecular Therapy . Jul2014, Vol. 22 Issue 7, p1254-1265. 12p. - 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15250016
- Volume :
- 22
- Issue :
- 7
- Database :
- Academic Search Index
- Journal :
- Molecular Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 96868603
- Full Text :
- https://doi.org/10.1038/mt.2014.59