Investigating the impact of dipeptidyl peptidase-1 inhibition in humans using multi-omics.

Abstract

Dipeptidyl peptidase-1 (DPP-1), also known as cathepsin C, processes and activates neutrophil serine proteases. Brensocatib (an oral, reversible, competitive DPP-1 inhibitor) is a novel therapy for bronchiectasis previously shown to reduce sputum protease activity and prevent exacerbations. Broader effects of DPP-1 inhibition on the immune response have not been investigated. We sought to profile effects of DPP-1 inhibition using a secondary analysis of the STOP-COVID19 trial. The STOP-COVID19 trial was a randomized placebo-controlled trial of brensocatib 25 mg in patients hospitalized for severe coronavirus disease 2019 (COVID-19) in the United Kingdom. In the primary analysis, brensocatib did not improve clinical outcomes at day 29. A prespecified substudy was performed at 2 UK hospitals to explore the effects of DPP-1 inhibition on the immune response. Blood samples were obtained at baseline and days 8, 15, and 29. Analyses included peripheral blood neutrophil mass spectrometry, neutrophil functional testing, serum cytokine analysis, whole blood mRNA sequencing, and measurement of circulating neutrophil-associated markers. Between June 2020 and January 2021, 161 patients were enrolled (brensocatib: n = 80; placebo: n = 81). Neutrophil proteomics showed significant alterations in 15 proteins (false discovery rate-adjusted P < .01) including reductions in cathepsin G and the pseudoenzyme azurocidin-1 (Azu-1) (false discovery rate-adjusted P < .0001) by day 29. In serum, Azu-1 levels, but not total elastase or proteinase 3, were significantly reduced (P < .0001). Neutrophil surface expression of protease-cleavable C5aR1/CD88 was significantly increased by day 29 (P < .05). There were no differences in neutrophil extracellular traps, phagocytosis, circulating immune cell proportions, or gene expression between treatment groups. Brensocatib treatment in COVID-19 altered multiple neutrophil proteins including profound effects on Azu-1, identifying this as a key DPP-1 target and potentially highly sensitive biomarker of treatment efficacy.