Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases

Guarino, Carla; Hamon, Yveline; Croix, Cécile; Lamort, Anne Sophie; Dallet‐Choisy, Sandrine; Marchand-Adam, S.; Lesner, Adam; Baranek, Thomas; Viaud-Massuard, Marie Claude; Lauritzen, Conni; Pedersen, John; Heuzé-Vourc’h, Nathalie; Si‐Tahar, Mustapha; Fıratlı, Erhan; Jenne, Dieter E.; Gauthier, Francis; Horwitz, Marshall S.; Borregaard, Niels; Korkmaz, Brice

doi:10.1016/j.bcp.2017.02.009

Cited by 33 publications

(57 citation statements)

References 48 publications

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“…AZD7986 was generally well tolerated, with no signs of increased infections, consistent with the hypothesis that DPP1 inhibition does not affect the overall function or recruitment of neutrophils . However, five subjects experienced nonserious skin events possibly related to treatment.…”

Section: Discussionsupporting

confidence: 75%

“…Furthermore, in vivo inhibition of NSP activity has been confirmed in rat blood, both with AZD7986 and structurally similar compounds . Importantly, both the onset of inhibition and recovery of NSP activity in rat blood is delayed compared to initiation and cessation of dosing, consistent with the hypothesis that NSP activation is limited to a relatively short timeframe during early neutrophil maturation in the bone marrow . In rat blood, steady‐state inhibition of NSP activity was reached within 8 days of dosing.…”

supporting

confidence: 57%

“…A possible explanation for the shallower shape of the cellular and in vivo concentration–responses could be continuous accumulation of NSP zymogens inside the cells when activation by DPP1 is inhibited. Although NSP zymogens are believed to be efficiently degraded if not activated during neutrophil maturation, a certain degree of intracellular zymogen accumulation may still occur during the early stages when the zymogens are produced. Since the inhibition of NSP activation by AZD7986 is dependent on the concentration of competing substrate, accumulating zymogens could create a complex relationship between AZD7986 and overall activation of NSPs, where the concentration–response becomes shallow at high concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Palmer

Mäenpää

Jauhiainen

et al. 2018

Clin Pharma and Therapeutics

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Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo‐controlled, first‐in‐human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure‐dependent, indirect manner—consistent with in vitro and preclinical predictions. Several dose‐dependent, possibly DPP1‐related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.

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Section: Discussionsupporting

confidence: 75%

supporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Palmer

Mäenpää

Jauhiainen

et al. 2018

Clin Pharma and Therapeutics

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“…There are few examples where both CTSC activity and NSP activity were determined in cases of CTSC loss of activity <90%. Recent studies continue to suggest high levels of inhibition (>75%) are required, although the absolute levels are not completely consistent across studies . We do not understand why the levels of NSP inhibition in this study are so low, as 80% inhibition of CTSC was achieved.…”

Section: Discussioncontrasting

confidence: 60%

Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660)

Miller¹,

Mayer²,

Goyal³

et al. 2017

Brit J Clinical Pharma

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“…Serine proteases, which are stored in granules in their active forms until they are released after neutrophil exposure to activating stimuli, exhibit broad biological effects including intracellular microbial killing and modulation of the recruitment of inflammatory cells (Pham, 2006). Cathepsin C is involved in the activation of elastase and cathepsin G in neutrophils and chymase and tryptase in mast cells (Pham and Ley, 1999; Pham, 2006; Guarino et al, 2017). Peripheral blood neutrophils upregulate their granzyme B expression and secretion when they are infected with Mycobacterium tuberculosis (Mattila et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Salivary Tick Cystatin OmC2 Targets Lysosomal Cathepsins S and C in Human Dendritic Cells

Zavašnik–Bergant

Vidmar

Sekirnik

et al. 2017

Front. Cell. Infect. Microbiol.

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To ensure successful feeding tick saliva contains a number of inhibitory proteins that interfere with the host immune response and help to create a permissive environment for pathogen transmission. Among the potential targets of the salivary cystatins are two host cysteine proteases, cathepsin S, which is essential for antigen- and invariant chain-processing, and cathepsin C (dipeptidyl peptidase 1, DPP1), which plays a critical role in processing and activation of the granule serine proteases. Here, the effect of salivary cystatin OmC2 from Ornithodoros moubata was studied using differentiated MUTZ-3 cells as a model of immature dendritic cells of the host skin. Following internalization, cystatin OmC2 was initially found to inhibit the activity of several cysteine cathepsins, as indicated by the decreased rates of degradation of fluorogenic peptide substrates. To identify targets, affinity chromatography was used to isolate His-tagged cystatin OmC2 together with the bound proteins from MUTZ-3 cells. Cathepsins S and C were identified in these complexes by mass spectrometry and confirmed by immunoblotting. Furthermore, reduced increase in the surface expression of MHC II and CD86, which are associated with the maturation of dendritic cells, was observed. In contrast, human inhibitor cystatin C, which is normally expressed and secreted by dendritic cells, did not affect the expression of CD86. It is proposed that internalization of salivary cystatin OmC2 by the host dendritic cells targets cathepsins S and C, thereby affecting their maturation.

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Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases

Cited by 33 publications

References 48 publications

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660)

Salivary Tick Cystatin OmC2 Targets Lysosomal Cathepsins S and C in Human Dendritic Cells

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