In vitro characterization of CT-001-a short-acting factor VIIa with enhanced prohemostatic activity.
blood coagulation
factor VIIa
hemorrhage
hemostasis
protein engineering
Journal
Research and practice in thrombosis and haemostasis
ISSN: 2475-0379
Titre abrégé: Res Pract Thromb Haemost
Pays: United States
ID NLM: 101703775
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
received:
24
03
2021
accepted:
12
04
2021
entrez:
15
7
2021
pubmed:
16
7
2021
medline:
16
7
2021
Statut:
epublish
Résumé
Traumatic injury and the associated acute bleeding are leading causes of death in people aged 1 to 44 years. Acute bleeding in pathological and surgical settings also represents a significant burden to the society. Yet there are no approved hemostatic drugs currently available. While clinically proven as an effective pro-coagulant, activated factor VII (FVIIa) use in acute bleeding has been hampered by unwanted thromboembolic events. Enhancing the ability of FVIIa to quickly stop a bleed and clear rapidly from circulation may yield an ideal molecule suitable for use in patients with acute bleeding. To address this need and the current liability of FVIIa, we produced a novel FVIIa molecule (CT-001) with enhanced potency and shortened plasma residence time by cell line engineering and FVIIa protein engineering for superior efficacy for acute bleeding and safety. To address safety, CT-001, a FVIIa protein with 4 desialylated N-glycans was generated to promote active recognition and clearance via the asialoglycoprotein receptor. To enhance potency, the gamma-carboxylated domain was modified with P10Q and K32E, which enhanced membrane binding. Together, these changes significantly enhanced potency and clearance while retaining the ability to interact with the key hemostatic checkpoint proteins antithrombin and tissue factor pathway inhibitor. These results demonstrate that a FVIIa molecule engineered to combine supra-physiological activity and shorter duration of action has the potential to overcome the current limitations of recombinant FVIIa to be a safe and effective approach to the treatment of acute bleeding.
Sections du résumé
BACKGROUND
BACKGROUND
Traumatic injury and the associated acute bleeding are leading causes of death in people aged 1 to 44 years. Acute bleeding in pathological and surgical settings also represents a significant burden to the society. Yet there are no approved hemostatic drugs currently available. While clinically proven as an effective pro-coagulant, activated factor VII (FVIIa) use in acute bleeding has been hampered by unwanted thromboembolic events. Enhancing the ability of FVIIa to quickly stop a bleed and clear rapidly from circulation may yield an ideal molecule suitable for use in patients with acute bleeding.
OBJECTIVES
OBJECTIVE
To address this need and the current liability of FVIIa, we produced a novel FVIIa molecule (CT-001) with enhanced potency and shortened plasma residence time by cell line engineering and FVIIa protein engineering for superior efficacy for acute bleeding and safety.
METHODS
METHODS
To address safety, CT-001, a FVIIa protein with 4 desialylated N-glycans was generated to promote active recognition and clearance via the asialoglycoprotein receptor. To enhance potency, the gamma-carboxylated domain was modified with P10Q and K32E, which enhanced membrane binding.
RESULTS
RESULTS
Together, these changes significantly enhanced potency and clearance while retaining the ability to interact with the key hemostatic checkpoint proteins antithrombin and tissue factor pathway inhibitor.
CONCLUSIONS
CONCLUSIONS
These results demonstrate that a FVIIa molecule engineered to combine supra-physiological activity and shorter duration of action has the potential to overcome the current limitations of recombinant FVIIa to be a safe and effective approach to the treatment of acute bleeding.
Identifiants
pubmed: 34263099
doi: 10.1002/rth2.12530
pii: S2475-0379(22)01402-9
pmc: PMC8265787
doi:
Types de publication
Journal Article
Langues
eng
Pagination
e12530Informations de copyright
© 2021 Coagulant Therapeutics. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).
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