Delving into the Latest Updates on Depelestat with Synapse

Overview

Basic Info

Drug Type

Recombinant protein

Synonyms

Depelestat (USAN/INN), Reltran

+ [4]

Target

ELA2

Mechanism

ELA2 inhibitors(Leukocyte elastase inhibitors)

Therapeutic Areas

Congenital DisordersDigestive System DisordersRespiratory Diseases+ [1]

Active Indication-

Inactive Indication

Acute Lung InjuryCystic FibrosisFibrosis+ [6]

Originator Organization

Dyax Corp.

Active Organization-

Inactive Organization

Debiopharm International SA

Dyax Corp.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Gene Sequence

Sequence Code 13852631

Source: *****

BACKGROUNDNeutrophil elastase (NE)-mediated inflammation contributes to lung damage in cystic fibrosis (CF). We investigated if DX-890, a small-protein NE inhibitor, could reduce neutrophil trans-epithelial migration and reduce activity released from neutrophils and NE-induced cytokine expression in airway epithelial cells.METHODSActivated blood neutrophils (CF and healthy) treated ±DX-890 were assayed for NE activity. Transmigration of calcein-labeled neutrophils was studied using a 16HBE14o(-) epithelial monolayer. IL-8 release from primary nasal epithelial monolayers (CF and healthy) was measured after treatment ±DX-890 and NE or CF sputum.RESULTSDX-890 reduced NE activity from neutrophils (CF and healthy) and reduced neutrophil transmigration. DX-890 pre-treatment reduced IL-8 release from epithelial cells of healthy or CF subjects after stimulation with NE and CF sputum sol. All improvements with DX-890 were statistically significant (p<0.05).CONCLUSIONSDX-890 reduces NE-mediated transmigration and inflammation. NE inhibition could be useful in managing neutrophilic airway inflammation in CF.

01 Dec 2010·Respiratory ResearchQ2 · MEDICINE

Effect of neutrophil elastase and its inhibitor EPI-hNE4 on transepithelial sodium transport across normal and cystic fibrosis human nasal epithelial cells

Q2 · MEDICINE

ArticleOA

Author: Grégoire Vuagniaux ; Estelle Escudier ; Virginie Prulière-Escabasse ; Christine Clerici ; Carole Planès ; Andre Coste

BACKGROUNDHyperactivity of the epithelial sodium (Na+) channel (ENaC) and increased Na+ absorption by airway epithelial cells leading to airway surface liquid dehydration and impaired mucociliary clearance are thought to play an important role in the pathogenesis of cystic fibrosis (CF) pulmonary disease. In airway epithelial cells, ENaC is constitutively activated by endogenous trypsin-like serine proteases such as Channel-Activating Proteases (CAPs). It was recently reported that ENaC activity could also be stimulated by apical treatment with human neutrophil elastase (hNE) in a human airway epithelial cell line, suggesting that hNE inhibition could represent a novel therapeutic approach for CF lung disease. However, whether hNE can also activate Na+ reabsorption in primary human nasal epithelial cells (HNEC) from control or CF patients is currently unknown.METHODSWe evaluated by short-circuit current (Isc) measurements the effects of hNE and EPI-hNE4, a specific hNE inhibitor, on ENaC activity in primary cultures of HNEC obtained from control (9) and CF (4) patients.RESULTSNeither hNE nor EPI-hNE4 treatments did modify Isc in control and CF HNEC. Incubation with aprotinin, a Kunitz-type serine protease inhibitor that blocks the activity of endogenous CAPs, decreased Isc by 27.6% and 54% in control and CF HNEC, respectively. In control and CF HNEC pretreated with aprotinin, hNE did significantly stimulate Isc, an effect which was blocked by EPI-hNE4.CONCLUSIONSThese results indicate that hNE does activate ENaC and transepithelial Na+ transport in both normal and CF HNEC, on condition that the activity of endogenous CAPs is first inhibited. The potent inhibitory effect of EPI-hNE4 on hNE-mediated ENaC activation observed in our experiments highlights that the use of EPI-hNE4 could be of interest to reduce ENaC hyperactivity in CF airways.

01 Mar 2007·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

Validation of an ELISA for determination of antibodies induced in monkeys against Epi-hNE4, a recombinant protein inhibitor of human neutrophil elastase

Q3 · MEDICINE

Article

Author: Valérie Delaunay ; Mathieu Dubois ; Eric Ezan ; Laurent Delestre

The engineered protein inhibitor of human neutrophil elastase, Epi-hNE4, is being developed for the treatment of cystic fibrosis. Like many recombinant proteins, Epi-hNE4 may induce antibodies in pre-clinical species and in humans. The aim of this report was to validate an ELISA to assess its immunogenicity in monkeys. We have designed and optimized a classical ELISA in which Epi-hNE4 was coated directly on microtitre plates and the antibodies were detected using a secondary antibody labelled with peroxidase. We report implementation of the recent recommendations proposed for the validation of immunogenicity assessment. The cut-off point was determined by means of statistical analysis of negative samples. Linearity, reproducibility, stability and specificity were estimated using quality control samples obtained from a pool of positive samples. The method was applied to monkeys given Epi-hNE4 by inhalation. A confirmation test and a neutralization assay were developed in order to further assess positive samples. In conclusion, we present here one of the first examples of validation in application of recent recommendations [A.R. Mire-Sluis, Y.C. Barrett, V. Devanarayan, E. Koren, H. Liu, M. Maia, T. Parish, G. Scott, G. Shankar, E. Shores, S.J. Swanson, G. Taniguchi, D. Wierda, L.A. Zuckerman, J. Immunol. Methods 289 (2004) 1-16].

100 Deals associated with Depelestat

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External Link

KEGG	Wiki	ATC	Drug Bank
D03686	-	-	-

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Respiratory Distress Syndrome, Acute	Phase 2	ES	Debiopharm International SA	01 Jul 2006
Acute Lung Injury	Phase 2	-	Dyax Corp.	-
Acute Lung Injury	Phase 2	-	Debiopharm International SA	-
Cystic Fibrosis	Phase 2	-	Dyax Corp.	-
Cystic Fibrosis	Phase 2	US	Debiopharm International SA	-
Cystic Fibrosis	Phase 2	EU	Debiopharm International SA	-
Pulmonary Disease, Chronic Obstructive	Phase 2	-	Debiopharm International SA	-
Pulmonary Disease, Chronic Obstructive	Phase 2	-	Dyax Corp.	-
Respiratory Distress Syndrome, Newborn	Phase 2	-	Debiopharm International SA	-
Respiratory Distress Syndrome, Newborn	Phase 2	-	Dyax Corp.	-