Engineering activated protein C to maximize therapeutic efficacy

Quinn, Louise M.; Drakeford, Clive; O’Donnell, James S.; Preston, Roger J. S.

doi:10.1042/bst20140312

Cited by 11 publications

(8 citation statements)

References 43 publications

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“…Eli Lilly and Company announced a worldwide voluntary market withdrawal of Xigris [Drotrecogin alfa (activated)] in 2011 following the PROWESS-SHOCK study which failed to show a survival benefit for patients with severe sepsis and septic shock (41). We have demonstrated that patients who undergo a sepsis evaluation in PICU have homogenous immune responses to endotoxin despite their heterogeneous diagnoses.…”

Section: Discussionmentioning

confidence: 99%

Pediatric Intensive Care: Immunomodulation With Activated Protein C ex vivo

et al. 2019

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Objective: Sepsis is major cause of morbidity and mortality in the Pediatric Intensive Care Unit (PICU). PICU patients may develop transient immune deficiency during sepsis. Activated Protein C (APC) has significant anti-inflammatory and cytoprotective effects. Clinical trials of APC in adult sepsis initially showed improved outcome but recent trials showed no benefit in adults or children. We aimed to assess the effects of APC treatment on innate immune responses in children.Design and Subjects: We compared neutrophil and monocyte responses to lipopolysaccharide (LPS) with and without APC treatment in PICU patients at the time of evaluation for sepsis compared with healthy adults and age-matched pediatric controls. We used flow cytometry to examine cell activation (CD11b expression), function [intracellular reactive oxygen intermediate (ROI) release] and LPS recognition [Toll like Receptor 4 (TLR4) expression].Results: PICU patients had significantly decreased protein c levels and LPS responses compared with adult and pediatric controls for all parameters. APC reduced LPS-induced neutrophil PICU TLR4 and adult ROI (p < 0.05). PICU non-survivors had increased LPS induced neutrophil and monocyte ROI production vs. survivors which was significantly reduced by APC.Conclusion: PICU patients demonstrate significantly reduced endotoxin reactivity which may predispose them to sepsis and alter effective antibacterial responses. APC reduces LPS-induced ROI production in adults and may have a role in treating severely compromised PICU patients especially given that newer APC forms are associated with decreased bleeding risk and enhanced anti-inflammatory effects.

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Section: Discussionmentioning

confidence: 99%

Pediatric Intensive Care: Immunomodulation With Activated Protein C ex vivo

et al. 2019

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“…PAR1-mediated cytoprotective can be stimulated in many cell types, including neurons, dendritic cells, astrocytes, epithelial cells, fibroblasts, and others. Cellular signaling responses to APC are complex and PAR1 is not the only relevant substrate mediating its cytoprotection (for reviews see [22,23]). However, knockdown or inhibition of PAR1 blocks cytoprotective effects in many preclinical disease models [22].…”

Section: Par1 Mechanism Of Actionmentioning

confidence: 99%

Targeting PAR1: Now What?

Flaumenhaft

Ceunynck

2017

Trends in Pharmacological Sciences

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Protease-activated receptors (PARs) are a ubiquitously expressed class of GPCRs that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. This review will critically evaluate prospects for the next generation of PAR1-targeted therapeutics.

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“…101 Alternatively, signaling-selective engineered APC analogs with diminished anticoagulant properties may offer a safer approach. 102 An alternative potential therapeutic strategy is to use the high affinity of EPCR for PfEMP1 CIDRa1 domains to create recombinant sEPCR analogs that could prevent IE cytoadherence to the vessel wall. To this end, a bioengineered sEPCR analog containing an amino acid substitution (E86A) that has previously been demonstrated to ablate protein C binding was developed.…”

Section: Attenuation Of Anticoagulation Pathwaysmentioning

confidence: 99%

Emerging roles for hemostatic dysfunction in malaria pathogenesis

O’Sullivan

Preston

O’Regan

et al. 2016

Blood

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Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum–infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance.

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Engineering activated protein C to maximize therapeutic efficacy

Cited by 11 publications

References 43 publications

Pediatric Intensive Care: Immunomodulation With Activated Protein C ex vivo

Pediatric Intensive Care: Immunomodulation With Activated Protein C ex vivo

Targeting PAR1: Now What?

Emerging roles for hemostatic dysfunction in malaria pathogenesis

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