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Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury

BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenua...

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Autores principales: Proudfoot, Alastair, Bayliffe, Andrew, O’Kane, Cecilia M, Wright, Tracey, Serone, Adrian, Bareille, Philippe Jean, Brown, Vanessa, Hamid, Umar I, Chen, Younan, Wilson, Robert, Cordy, Joanna, Morley, Peter, de Wildt, Ruud, Elborn, Stuart, Hind, Matthew, Chilvers, Edwin R, Griffiths, Mark, Summers, Charlotte, McAuley, Daniel Francis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204954/
https://www.ncbi.nlm.nih.gov/pubmed/29382797
http://dx.doi.org/10.1136/thoraxjnl-2017-210305
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author Proudfoot, Alastair
Bayliffe, Andrew
O’Kane, Cecilia M
Wright, Tracey
Serone, Adrian
Bareille, Philippe Jean
Brown, Vanessa
Hamid, Umar I
Chen, Younan
Wilson, Robert
Cordy, Joanna
Morley, Peter
de Wildt, Ruud
Elborn, Stuart
Hind, Matthew
Chilvers, Edwin R
Griffiths, Mark
Summers, Charlotte
McAuley, Daniel Francis
author_facet Proudfoot, Alastair
Bayliffe, Andrew
O’Kane, Cecilia M
Wright, Tracey
Serone, Adrian
Bareille, Philippe Jean
Brown, Vanessa
Hamid, Umar I
Chen, Younan
Wilson, Robert
Cordy, Joanna
Morley, Peter
de Wildt, Ruud
Elborn, Stuart
Hind, Matthew
Chilvers, Edwin R
Griffiths, Mark
Summers, Charlotte
McAuley, Daniel Francis
author_sort Proudfoot, Alastair
collection PubMed
description BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01587807.
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spelling pubmed-62049542018-11-08 Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury Proudfoot, Alastair Bayliffe, Andrew O’Kane, Cecilia M Wright, Tracey Serone, Adrian Bareille, Philippe Jean Brown, Vanessa Hamid, Umar I Chen, Younan Wilson, Robert Cordy, Joanna Morley, Peter de Wildt, Ruud Elborn, Stuart Hind, Matthew Chilvers, Edwin R Griffiths, Mark Summers, Charlotte McAuley, Daniel Francis Thorax Critical Care BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01587807. BMJ Publishing Group 2018-08 2018-01-29 /pmc/articles/PMC6204954/ /pubmed/29382797 http://dx.doi.org/10.1136/thoraxjnl-2017-210305 Text en © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
spellingShingle Critical Care
Proudfoot, Alastair
Bayliffe, Andrew
O’Kane, Cecilia M
Wright, Tracey
Serone, Adrian
Bareille, Philippe Jean
Brown, Vanessa
Hamid, Umar I
Chen, Younan
Wilson, Robert
Cordy, Joanna
Morley, Peter
de Wildt, Ruud
Elborn, Stuart
Hind, Matthew
Chilvers, Edwin R
Griffiths, Mark
Summers, Charlotte
McAuley, Daniel Francis
Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
title Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
title_full Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
title_fullStr Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
title_full_unstemmed Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
title_short Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
title_sort novel anti-tumour necrosis factor receptor-1 (tnfr1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
topic Critical Care
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204954/
https://www.ncbi.nlm.nih.gov/pubmed/29382797
http://dx.doi.org/10.1136/thoraxjnl-2017-210305
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