RT Journal Article
SR Electronic
T1 Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 723
OP 730
DO 10.1136/thoraxjnl-2017-210305
VO 73
IS 8
A1 Proudfoot, Alastair
A1 Bayliffe, Andrew
A1 O’Kane, Cecilia M
A1 Wright, Tracey
A1 Serone, Adrian
A1 Bareille, Philippe Jean
A1 Brown, Vanessa
A1 Hamid, Umar I
A1 Chen, Younan
A1 Wilson, Robert
A1 Cordy, Joanna
A1 Morley, Peter
A1 de Wildt, Ruud
A1 Elborn, Stuart
A1 Hind, Matthew
A1 Chilvers, Edwin R
A1 Griffiths, Mark
A1 Summers, Charlotte
A1 McAuley, Daniel Francis
YR 2018
UL http://thorax.bmj.com/content/73/8/723.abstract
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.Trial registration number ClinicalTrials.gov NCT01587807.