title: Cytokine Activation by Antibody Fragments Targeted to Cytokine-Receptor Signaling Complexes.
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.
authors.affiliation: From the Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Srilalitha
authors.initials: S
authors.lastname: Kuruganti
authors.affiliation: Banting and Best Department of Medical Science, Donnelly Centre, University of Toronto, Toronto, Ontario M5G 1L6, Canada.
authors.forename: Shane
authors.initials: S
authors.lastname: Miersch
authors.affiliation: From the Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Ashlesha
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: National Resource for Automated Molecular Microscopy, Department of Integrative Structural and, Computational Biology, The Scripps Research Institute, La Jolla, California 92037, and.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Speir
authors.affiliation: From the Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Bethany D
authors.initials: BD
authors.lastname: Harris
authors.affiliation: Department of Microbiology and Immunology, Saint Louis University Health Sciences Center, St. Louis, Missouri 63104.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Schriewer
authors.affiliation: Department of Microbiology and Immunology, Saint Louis University Health Sciences Center, St. Louis, Missouri 63104.
authors.forename: R Mark L
authors.initials: RM
authors.lastname: Buller
authors.affiliation: Banting and Best Department of Medical Science, Donnelly Centre, University of Toronto, Toronto, Ontario M5G 1L6, Canada.
authors.forename: Sachdev S
authors.initials: SS
authors.lastname: Sidhu
authors.affiliation: From the Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, walter@uab.edu.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Walter
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology* / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D007700:Kinetics; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011487:Protein Conformation; D053633:Receptor, Interferon alpha-beta / Q000737:chemistry / Q000378:metabolism; D018121:Receptors, Cytokine / Q000276:immunology*; D015203:Reproducibility of Results; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D007128:Immunoglobulin Fragments; D016898:Interferon-alpha; D018121:Receptors, Cytokine; D050794:STAT1 Transcription Factor; D053633:Receptor, Interferon alpha-beta
keywords: cell signaling; conformational change; cytokine; interferon; phage display; protein structure; receptor