Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model
Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model
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DOI：
10.1182/blood-2012-01-401620
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发表时间：
2012-06-14
期刊：
影响因子：
20.3
通讯作者：
Bjorn, Soren Erik
中科院分区：
文献类型：
--
作者：
Hilden, Ida;Lauritzen, Brian;Bjorn, Soren Erik
血友病通过IV因子VIII（FVIII）或因子IX（FIX）替代治疗进行治疗，根据需要解决出血或作为预防。通过设计用于皮下和较低频率给药的药物可以提供改善的治疗，从而降低抑制物形成的风险。组织因子途径抑制剂（TFPI）通过抑制因子VIIa（FVIIa）/组织因子/因子Xa（FVIIa/TF/FXa）下调凝血的起始。在血友病环境中，TFPI抑制作用的阻断可促进凝血酶生成。研究了抗TFPI的高亲和力（K-D = 25 pM）mAb，mAb 2021。mAb 2021与TFPI的结合有效地防止了FVIIa/TF/FXa的抑制，并改善了血友病血液和血浆中的凝块形成。TFPI的Kunitz型蛋白酶抑制剂结构域2上的结合表位通过晶体学作图，并且显示出与FXa接触区域的广泛重叠，突出了其作用机制的结构基础。在兔血友病模型中，静脉或皮下给药显著减少了表皮出血。mAb 2021显示出与rFVIIa相当的效果。通过单次静脉注射mAb 2021，模型中的表皮出血减少至少7天。这项研究表明，通过mAb 2021中和TFPI可能构成血友病的新治疗选择。（血。2012; 119（24）：5871-5878）
Hemophilia is treated by IV replacement therapy with Factor VIII (FVIII) or Factor IX (FIX), either on demand to resolve bleeding, or as prophylaxis. Improved treatment may be provided by drugs designed for subcutaneous and less frequent administration with a reduced risk of inhibitor formation. Tissue factor pathway inhibitor (TFPI) down-regulates the initiation of coagulation by inhibition of Factor VIIa (FVIIa)/tissue factor/Factor Xa (FVIIa/TF/FXa). Blockage of TFPI inhibition may facilitate thrombin generation in a hemophilic setting. A high-affinity (K-D = 25pM) mAb, mAb 2021, against TFPI was investigated. Binding of mAb 2021 to TFPI effectively prevented inhibition of FVIIa/TF/FXa and improved clot formation in hemophilia blood and plasma. The binding epitope on the Kunitz-type protease inhibitor domain 2 of TFPI was mapped by crystallography, and showed an extensive overlap with the FXa contact region highlighting a structural basis for its mechanism of action. In a rabbit hemophilia model, an intravenous or subcutaneous dose significantly reduced cuticle bleeding. mAb 2021 showed an effect comparable with that of rFVIIa. Cuticle bleeding in the model was reduced for at least 7 days by a single intravenous dose of mAb 2021. This study suggests that neutralization of TFPI by mAb 2021 may constitute a novel treatment option in hemophilia. (Blood. 2012; 119(24):5871-5878)