BJTJ-1837, a novel FXI activation-blocking antibody.
blood coagulation factors
factor XI
factor XII
monoclonal antibody
thrombosis
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:
Feb 2023
Feb 2023
Historique:
received:
14
08
2022
revised:
22
12
2022
accepted:
02
01
2023
entrez:
20
3
2023
pubmed:
21
3
2023
medline:
21
3
2023
Statut:
epublish
Résumé
Factor (F)XI contributes to thrombosis development while it plays a limited role in normal hemostasis. FXI targeting has the potential for preventing and treating thrombosis with little bleeding risk. The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. Mouse hybridoma technology was applied to screen for anti-FXI antibodies. Surface plasma resonance, enzyme inhibition, activated partial thromboplastin time, and prothrombin time assays were conducted to characterize the binding affinity and activity of antibodies. A cynomolgus monkey arterial venous shunt model was applied to validate the antithrombotic activities. A humanized antibody, BJTJ-1837, reported here bound to the protease domain of FXI and activated FXI with high affinity. BJTJ-1837 fully inhibited the activation of FXI by activated FXII and thrombin. BJTJ-1837 also demonstrated strong anticoagulant activity in human and cynomolgus monkey plasma as measured by activated partial thromboplastin time. Moreover, BJTJ-1837 showed favorable antithrombotic activity with a dose-dependent protection in an arterial venous shunt thrombosis model in cynomolgus monkeys without the bleeding adverse effect. Furthermore, BJTJ-1837 displayed favorable pharmacokinetic and pharmacodynamic properties and good developability. As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.
Sections du résumé
Background
UNASSIGNED
Factor (F)XI contributes to thrombosis development while it plays a limited role in normal hemostasis. FXI targeting has the potential for preventing and treating thrombosis with little bleeding risk.
Objectives
UNASSIGNED
The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases.
Methods
UNASSIGNED
Mouse hybridoma technology was applied to screen for anti-FXI antibodies. Surface plasma resonance, enzyme inhibition, activated partial thromboplastin time, and prothrombin time assays were conducted to characterize the binding affinity and activity of antibodies. A cynomolgus monkey arterial venous shunt model was applied to validate the antithrombotic activities.
Results
UNASSIGNED
A humanized antibody, BJTJ-1837, reported here bound to the protease domain of FXI and activated FXI with high affinity. BJTJ-1837 fully inhibited the activation of FXI by activated FXII and thrombin. BJTJ-1837 also demonstrated strong anticoagulant activity in human and cynomolgus monkey plasma as measured by activated partial thromboplastin time. Moreover, BJTJ-1837 showed favorable antithrombotic activity with a dose-dependent protection in an arterial venous shunt thrombosis model in cynomolgus monkeys without the bleeding adverse effect. Furthermore, BJTJ-1837 displayed favorable pharmacokinetic and pharmacodynamic properties and good developability.
Conclusion
UNASSIGNED
As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.
Identifiants
pubmed: 36936858
doi: 10.1016/j.rpth.2023.100067
pii: S2475-0379(23)00033-X
pmc: PMC10017418
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100067Informations de copyright
© 2023 Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.
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