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

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 rec...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2016-01, Vol.291 (1), p.447-461
Main Authors: Kuruganti, Srilalitha, Miersch, Shane, Deshpande, Ashlesha, Speir, Jeffrey A., Harris, Bethany D., Schriewer, Jill M., Buller, R. Mark L., Sidhu, Sachdev S., Walter, Mark R.
Format: Article
Language:English
Subjects:
Antiviral Agents - chemistry
Binding Sites
Cell Line, Tumor
Cell Proliferation
cell signaling
conformational change
cytokine
Cytokines - immunology
Gene Expression Profiling
Gene Expression Regulation
Humans
Immunoglobulin Fragments - immunology
Immunoglobulin Fragments - pharmacology
interferon
Interferon-alpha - pharmacology
Kinetics
Mutation - genetics
phage display
Phosphorylation
Protein Conformation
protein structure
receptor
Receptor, Interferon alpha-beta - chemistry
Receptor, Interferon alpha-beta - metabolism
Receptors, Cytokine - immunology
Reproducibility of Results
Signal Transduction
Signal Transduction - drug effects
STAT1 Transcription Factor - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Cytokines are administered to patients to eliminate viral infections and cancer yet often have side effects. Antibody fragments have been designed that recognize cytokine-receptor complexes and change cytokine biological activity profiles. Designed proteins enhance interferon antiviral activity without inducing antiproliferative signaling pathways. Antibody fragments targeted to cytokine-receptor complexes provide new tools for manipulating cytokine signaling.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M115.665943