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

• Published in: Thorax Vol. 73; no. 8; pp. 723 - 730
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.08.2018; BMJ Publishing Group
• Series: Original article
• Subjects: Acute Lung Injury - drug therapy; Acute Lung Injury - immunology; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacology; Biomarkers, Pharmacological; Bronchoalveolar Lavage Fluid - cytology; Critical Care; Cytokines; Dose-Response Relationship, Drug; Edema; Endothelial Cells - drug effects; Flow Cytometry; Humans; Immunoglobulins; Inflammation; Inflammation - drug therapy; Laboratory animals; Lungs; Macaca fascicularis; Molecular Targeted Therapy; Monkeys & apes; Nebulizers and Vaporizers; Necrosis; Neutrophils; Pharmacology, Clinical; Receptors, Tumor Necrosis Factor, Type I - antagonists & inhibitors; Receptors, Tumor Necrosis Factor, Type I - metabolism; Respiratory distress syndrome; Sepsis; Signal Transduction; Studies; TNF inhibitors; Translational Research, Biomedical; Tumor necrosis factor-TNF; Ventilation; Ventilators; neutrophil biology; ARDS
• ISSN: 0040-6376; 1468-3296; 1468-3296
• DOI: 10.1136/thoraxjnl-2017-210305

BackgroundTumour 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.MethodsWe 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.ResultsSelective 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.ConclusionThese 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 numberClinicalTrials.gov NCT01587807.