Discovery of a junctional epitope antibody that stabilizes IL-6 and gp80 protein:protein interaction and modulates its downstream signaling

Sci Rep. 2017 Jan 30;7:37716. doi: 10.1038/srep37716.


Protein:protein interactions are fundamental in living organism homeostasis. Here we introduce VHH6, a junctional epitope antibody capable of specifically recognizing a neo-epitope when two proteins interact, albeit transiently, to form a complex. Orthogonal biophysical techniques have been used to prove the "junctional epitope" nature of VHH6, a camelid single domain antibody recognizing the IL-6-gp80 complex but not the individual components alone. X-ray crystallography, HDX-MS and SPR analysis confirmed that the CDR regions of VHH6 interact simultaneously with IL-6 and gp80, locking the two proteins together. At the cellular level, VHH6 was able to alter the response of endothelial cells to exogenous IL-6, promoting a sustained STAT3 phosphorylation signal, an accumulation of IL-6 in vesicles and an overall pro-inflammatory phenotype supported further by transcriptomic analysis. Junctional epitope antibodies, like VHH6, not only offer new opportunities in screening and structure-aided drug discovery, but could also be exploited as therapeutics to modulate complex protein:protein interactions.

MeSH terms

  • Animals
  • Antibodies / chemistry*
  • Antibodies / immunology
  • CHO Cells
  • Camelus / immunology
  • Cricetulus
  • Epitope Mapping*
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Interleukin-6 / immunology*
  • Phosphorylation
  • Protein Structure, Tertiary
  • Receptors, Interleukin-6 / immunology*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction


  • Antibodies
  • Interleukin-6
  • Receptors, Interleukin-6
  • STAT3 Transcription Factor