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Open AccessArticle

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

1
Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Valdeolmos, 28130 Madrid, Spain
2
Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid), Cantoblanco, 28049 Madrid, Spain
3
Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 Dublin 2, Ireland
*
Author to whom correspondence should be addressed.
Present adress: Centro de Investigación en Sanidad Animal; Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Valdeolmos, 28130 Madrid, Spain.
Present address: Cancer, University College Cork, Cork T12YT20, Ireland.
J. Clin. Med. 2020, 9(1), 25; https://doi.org/10.3390/jcm9010025
Received: 28 November 2019 / Revised: 16 December 2019 / Accepted: 18 December 2019 / Published: 20 December 2019
The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein. A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model. View Full-Text
Keywords: tumor necrosis factor; chemokine; receptor; inflammation; immune evasion; virus tumor necrosis factor; chemokine; receptor; inflammation; immune evasion; virus
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MDPI and ACS Style

Alejo, A.; Sánchez, C.; Amu, S.; Fallon, P.G.; Alcamí, A. Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor. J. Clin. Med. 2020, 9, 25.

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