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

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

Author information

1
From the Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
2
Banting and Best Department of Medical Science, Donnelly Centre, University of Toronto, Toronto, Ontario M5G 1L6, Canada.
3
National Resource for Automated Molecular Microscopy, Department of Integrative Structural and, Computational Biology, The Scripps Research Institute, La Jolla, California 92037, and.
4
Department of Microbiology and Immunology, Saint Louis University Health Sciences Center, St. Louis, Missouri 63104.
5
From the Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, walter@uab.edu.

Abstract

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

PMID:
26546677
PMCID:
PMC4697184
DOI:
10.1074/jbc.M115.665943
[Indexed for MEDLINE]
Free PMC Article

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