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BJTJ-1837, a novel FXI activation-blocking antibody

BACKGROUND: 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: The aim of this study was to develop novel antibody therapeutics against FX...

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Autores principales: He, Xugang, Zhang, Jin, Du, Yanping, Liu, Xiao, Hu, Dongmei, Cao, Baohua, Gao, Hong, Wu, Yongguang, Zhou, Tianlin, Wu, Qimei, Huang, Qi, Yang, Changyong, Liao, Cheng, Zhang, Lianshan, Shen, Chenxi, Wang, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10017418/
https://www.ncbi.nlm.nih.gov/pubmed/36936858
http://dx.doi.org/10.1016/j.rpth.2023.100067
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author He, Xugang
Zhang, Jin
Du, Yanping
Liu, Xiao
Hu, Dongmei
Cao, Baohua
Gao, Hong
Wu, Yongguang
Zhou, Tianlin
Wu, Qimei
Huang, Qi
Yang, Changyong
Liao, Cheng
Zhang, Lianshan
Shen, Chenxi
Wang, Lei
author_facet He, Xugang
Zhang, Jin
Du, Yanping
Liu, Xiao
Hu, Dongmei
Cao, Baohua
Gao, Hong
Wu, Yongguang
Zhou, Tianlin
Wu, Qimei
Huang, Qi
Yang, Changyong
Liao, Cheng
Zhang, Lianshan
Shen, Chenxi
Wang, Lei
author_sort He, Xugang
collection PubMed
description BACKGROUND: 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: The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. METHODS: 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: 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: As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate.
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spelling pubmed-100174182023-03-17 BJTJ-1837, a novel FXI activation-blocking antibody He, Xugang Zhang, Jin Du, Yanping Liu, Xiao Hu, Dongmei Cao, Baohua Gao, Hong Wu, Yongguang Zhou, Tianlin Wu, Qimei Huang, Qi Yang, Changyong Liao, Cheng Zhang, Lianshan Shen, Chenxi Wang, Lei Res Pract Thromb Haemost Original Article BACKGROUND: 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: The aim of this study was to develop novel antibody therapeutics against FXI for the treatment of thrombosis-related diseases. METHODS: 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: 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: As a potential antithrombotic therapeutic agent with a safe profile, BJTJ-1837 is a very promising FXI activation-blocking antibody candidate. Elsevier 2023-02-07 /pmc/articles/PMC10017418/ /pubmed/36936858 http://dx.doi.org/10.1016/j.rpth.2023.100067 Text en © 2023 Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
He, Xugang
Zhang, Jin
Du, Yanping
Liu, Xiao
Hu, Dongmei
Cao, Baohua
Gao, Hong
Wu, Yongguang
Zhou, Tianlin
Wu, Qimei
Huang, Qi
Yang, Changyong
Liao, Cheng
Zhang, Lianshan
Shen, Chenxi
Wang, Lei
BJTJ-1837, a novel FXI activation-blocking antibody
title BJTJ-1837, a novel FXI activation-blocking antibody
title_full BJTJ-1837, a novel FXI activation-blocking antibody
title_fullStr BJTJ-1837, a novel FXI activation-blocking antibody
title_full_unstemmed BJTJ-1837, a novel FXI activation-blocking antibody
title_short BJTJ-1837, a novel FXI activation-blocking antibody
title_sort bjtj-1837, a novel fxi activation-blocking antibody
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10017418/
https://www.ncbi.nlm.nih.gov/pubmed/36936858
http://dx.doi.org/10.1016/j.rpth.2023.100067
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