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

BACKGROUND: Tumor necrosis factor alpha (TNF-) 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-, while sparing or potentiating the protective effects of TNFR2 signaling. 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 (HMVEC-L) cells 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, and also significantly attenuated inflammation and signs of lung injury in non-human primates. In a randomized, placebo-controlled trial of nebulised GSK1995057 in healthy humans challenged with a low-dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release and signs of endothelial injury in bronchoalveolar lavage and serum samples.

CONCLUSION: Pulmonary delivery of a selective TNFR1 dAb antagonist may offer a novel therapeutic approach to the prevention or treatment of acute respiratory distress syndrome (ARDS).