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A high-affinity protein binder that blocks the IL-6/STAT3 signaling pathway
effectively suppresses non-small cell lung cancer
#MMPMID24682171
Lee JJ
; Kim HJ
; Yang CS
; Kyeong HH
; Choi JM
; Hwang DE
; Yuk JM
; Park K
; Kim YJ
; Lee SG
; Kim D
; Jo EK
; Cheong HK
; Kim HS
Mol Ther
2014[Jul]; 22
(7
): 1254-1265
PMID24682171
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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-6R? 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.
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