Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model

被引：130

作者：

Hilden, Ida ^{[1
]}

Lauritzen, Brian ^{[1
]}

Sorensen, Brit Binow ^{[1
]}

Clausen, Jes Thorn ^{[1
]}

Jespersgaard, Christina ^{[2
]}

Krogh, Berit Olsen ^{[1
]}

Bowler, Andrew Neil ^{[1
]}

Breinholt, Jens ^{[1
]}

Gruhler, Albrecht ^{[1
]}

Svensson, L. Anders ^{[1
]}

Petersen, Helle Heibroch ^{[1
]}

Petersen, Lars Christian ^{[1
]}

Balling, Kristoffer W. ^{[1
]}

Hansen, Lene ^{[1
]}

Hermit, Mette Brunsgaard ^{[1
]}

Egebjerg, Thomas ^{[1
]}

Friederichsen, Birgitte ^{[1
]}

Ezban, Mirella ^{[1
]}

Bjorn, Soren Erik ^{[1
]}

机构：

[1] Novo Nordisk AS, Biopharmaceut Res Unit, Malov, Denmark

[2] Novo Nordisk AS, CMC Supply, Malov, Denmark

来源：

BLOOD | 2012年 / 119卷 / 24期

关键词：

FACTOR PATHWAY INHIBITOR; TISSUE FACTOR; COAGULATION INHIBITOR; ENDOTHELIAL-CELLS; FACTOR XA; PLASMA; EXPRESSION; PLATELETS; SHORTENS; TIME;

D O I：

10.1182/blood-2012-01-401620

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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)

引用

页码：5871 / 5878

页数：8

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