Imperial College London
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DrMatthewHind

Faculty of Medicine, National Heart & Lung Institute

Honorary Research Officer
 
 
 
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Contact

 

m.hind

 
 
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Location

 

Royal BromptonRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Proudfoot:2018:10.1136/thoraxjnl-2017-210305,
author = {Proudfoot, A and Bayliffe, A and O'Kane, CM and Wright, T and Serone, A and Bareille, PJ and Brown, V and Hamid, UI and Chen, Y and Wilson, R and Cordy, J and Morley, P and de, Wildt R and Elborn, S and Hind, M and Chilvers, ER and Griffiths, M and Summers, C and McAuley, DF},
doi = {10.1136/thoraxjnl-2017-210305},
journal = {Thorax},
pages = {723--730},
title = {Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury},
url = {http://dx.doi.org/10.1136/thoraxjnl-2017-210305},
volume = {73},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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. TRI
AU  - Proudfoot,A
AU  - Bayliffe,A
AU  - O'Kane,CM
AU  - Wright,T
AU  - Serone,A
AU  - Bareille,PJ
AU  - Brown,V
AU  - Hamid,UI
AU  - Chen,Y
AU  - Wilson,R
AU  - Cordy,J
AU  - Morley,P
AU  - de,Wildt R
AU  - Elborn,S
AU  - Hind,M
AU  - Chilvers,ER
AU  - Griffiths,M
AU  - Summers,C
AU  - McAuley,DF
DO  - 10.1136/thoraxjnl-2017-210305
EP  - 730
PY  - 2018///
SN  - 1468-3296
SP  - 723
TI  - Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
T2  - Thorax
UR  - http://dx.doi.org/10.1136/thoraxjnl-2017-210305
UR  - http://hdl.handle.net/10044/1/56778
VL  - 73
ER  -
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