Preventative and therapeutic effects of a novel humanized anti-glycoprotein Ibα fragment of antigen-binding region in a murine model of thrombotic thrombocytopenic purpura.
Liang Zheng, Reheman Adili, Zhijian Wu, Quan Zhang, Guangheng Zhu, Xi Lei, Zhenze Liu, Miguel A D Neves, Wenjing Ma, Sladjana Slavkovic, Xiaohong Ruby Xu, Heyu Ni, X Long Zheng
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引用次数: 0
Abstract
Background: Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal blood disorder resulting from severe deficiency of plasma ADAMTS-13 activity. Current treatment for immune-mediated TTP includes daily therapeutic plasma exchange plus caplacizumab and immunosuppressives. For hereditary TTP resulting from mutations of ADAMTS-13, plasma infusion or recombinant ADAMTS-13 is the treatment of choice. However, there are still unmet needs for an effective alternative therapy for TTP.
Objectives: The present study aimed to evaluate the therapeutic efficacy of a novel humanized antibody fragment of antigen binding against platelet glycoprotein Ibα (CA1001) in a murine model of TTP.
Methods: Platelet agglutination profiles, microfluidic shear-based assay, intravital microscopy thrombosis model, and lysine histone-induced murine "TTP-like" model were employed.
Results: CA1001 exhibited potent inhibition of botrocetin-induced murine platelet agglutination in a dose- and time-dependent manner. CA1001 also significantly inhibited shear-dependent adhesion and aggregation of murine platelets to endothelial von Willebrand factor (VWF) released from calcium ionophore-activated cremaster venules in Adamts-13 null mice and blocked the formation of platelet-VWF rich thrombosis. More importantly, CA1001 appeared to be efficacious in preventing and treating a histone-induced "TTP-like" syndrome in Adamts-13 null mice, demonstrated by the alleviation of thrombocytopenia, prerenal injury, and formation of microvascular thrombosis in major organ tissues.
Conclusion: CA1001 can effectively inhibit VWF-platelet interaction and thrombus formation under various (patho)physiological conditions. Thus, CA1001 may be a potential candidate for further development as a novel therapeutic for immune-mediated and hereditary TTP and perhaps for other inflammatory thrombotic disorders such as ischemic stroke.
期刊介绍：
The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community.
Types of Publications:
The journal publishes a variety of content, including:
Original research reports
State-of-the-art reviews
Brief reports
Case reports
Invited commentaries on publications in the Journal
Forum articles
Correspondence
Announcements
Scope of Contributions:
Editors invite contributions from both fundamental and clinical domains. These include:
Basic manuscripts on blood coagulation and fibrinolysis
Studies on proteins and reactions related to thrombosis and haemostasis
Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms
Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases
Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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