Cytokine Activation by Antibody Fragments Targeted to Cytokine-Receptor Signaling Complexes

J Biol Chem. 2016 Jan 1;291(1):447-61. doi: 10.1074/jbc.M115.665943. Epub 2015 Nov 6.


Exogenous cytokine therapy can induce systemic toxicity, which might be prevented by activating endogenously produced cytokines in local cell niches. Here we developed antibody-based activators of cytokine signaling (AcCS), which recognize cytokines only when they are bound to their cell surface receptors. AcCS were developed for type I interferons (IFNs), which induce cellular activities by binding to cell surface receptors IFNAR1 and IFNAR2. As a potential alternative to exogenous IFN therapy, AcCS were shown to potentiate the biological activities of natural IFNs by ∼100-fold. Biochemical and structural characterization demonstrates that the AcCS stabilize the IFN-IFNAR2 binary complex by recognizing an IFN-induced conformational change in IFNAR2. Using IFN mutants that disrupt IFNAR1 binding, AcCS were able to enhance IFN antiviral potency without activating antiproliferative responses. This suggests AcCS can be used to manipulate cytokine signaling for basic science and possibly for therapeutic applications.

Keywords: cell signaling; conformational change; cytokine; interferon; phage display; protein structure; receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / immunology*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Immunoglobulin Fragments / immunology*
  • Immunoglobulin Fragments / pharmacology
  • Interferon-alpha / pharmacology
  • Kinetics
  • Mutation / genetics
  • Phosphorylation
  • Protein Conformation
  • Receptor, Interferon alpha-beta / chemistry
  • Receptor, Interferon alpha-beta / metabolism
  • Receptors, Cytokine / immunology*
  • Reproducibility of Results
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction* / drug effects


  • Antiviral Agents
  • Cytokines
  • Immunoglobulin Fragments
  • Interferon-alpha
  • Receptors, Cytokine
  • STAT1 Transcription Factor
  • Receptor, Interferon alpha-beta