SB‐656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone‐induced airway inflammation in humans

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation.• It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans. WHAT THIS STUDY ADDS• SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects. AIMSTo determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects. METHODSFlow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the doseresponse for ozone-induced airway inflammation, as measured by sputum biomarkers. RESULTSOral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70%) relative to placebo was observed following administration of SB-656933 400 mg (95% CI 60%, 77%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55% (95% CI 20%, 75%) and 74% (95% CI 55%, 85%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8% (95% CI 9.2, 50.3) and 50.5% (95% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses. CONCLUSIONSSB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophilpredominant diseases.

Antibiotic and Anti-Inflammatory Therapies for Cystic Fibrosis

“…CXCR2 is an important receptor in neutrophil chemotaxis. Clinical and preclinical studies have evaluated the effects of CXCR2 antagonists in many lung diseases including COPD, asthma, and ozone-induced airway inflammation (Lazaar et al 2011). A clinical trial in CF of SB-656933, a CXCR2 antagonist, was recently completed and shows some promise in modulating airway inflammation (Moss et al 2012).…”

Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist

“…These are in different stages of drug development and have been shown to have an effect on neutrophil recruitment to the lung in clinical studies (Holz et al, 2010;Lazaar et al, 2011;Virtala et al, 2012;Pavord et al, 2013). In addition, the effect of inhibiting neutrophil recruitment has been shown for clinical biomarkers and endpoints indicative of disease efficacy as investigated in cystic fibrosis, severe asthma, and COPD (Nair et al, 2012;Moss et al, 2013;Rennard et al, 2015).…”

The mercurial nature of neutrophils: still an enigma in ARDS?

“…It will therefore be important to consider the appropriateness of targeting CXCR2, or indeed the neutrophilic innate immune response, in certain patient groups with an underlying infection. Despite these species differences, and the potential for microbial outgrowth, a number of promising CXCR2 antagonists are being developed for use in humans to treat neutrophilic lung disease (28,78,92,102).…”