Cytokine Activation by Antibody Fragments Targeted to Cytokine-Receptor Signaling Complexes
| Autor: | Bethany D. Harris, R. Mark L. Buller, Jeffrey A. Speir, Jill Schriewer, Shane Miersch, Sachdev S. Sidhu, Mark R. Walter, Ashlesha Deshpande, Srilalitha Kuruganti |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell signaling Protein Conformation medicine.medical_treatment Receptor Interferon alpha-beta Biology Antiviral Agents Biochemistry 03 medical and health sciences Interferon Cell surface receptor Cell Line Tumor medicine Humans Phosphorylation Receptors Cytokine Receptor Immunoglobulin Fragments Molecular Biology Cell Proliferation Binding Sites Cytokine Therapy Gene Expression Profiling Interferon-alpha Reproducibility of Results Cell Biology Cell biology Kinetics STAT1 Transcription Factor 030104 developmental biology Cytokine Gene Expression Regulation Mutation Immunology Cytokines Signal transduction Cytokine receptor Signal Transduction medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 291:447-461 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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