Journal of thrombosis and haemostasis : JTH · 2025
Preventative and therapeutic effects of a novel humanized anti-glycoprotein Ibα fragment of antigen-binding region in a murine model of thrombotic thrombocytopenic purpura.
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Zheng Liang, Adili Reheman, Wu Zhijian, Zhang Quan, Zhu Guangheng, Lei Xi, Liu Zhenze, Neves Miguel A D, Ma Wenjing, Slavkovic Sladjana, Xu Xiaohong Ruby, Ni Heyu, Zheng X Long
Аннотация
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.
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.