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

Abstract

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.

• Authors: Ida Hilden, Brian Lauritzen, Brit Binow Sørensen, Jes Thorn Clausen, Christina Jespersgaard, Berit Olsen Krogh, Andrew Neil Bowler, Jens Breinholt, Albrecht Gruhler, L Anders Svensson, Helle Heibroch Petersen, Lars Christian Petersen, Kristoffer W Balling, Lene Hansen, Mette Brunsgaard Hermit, Thomas Egebjerg, Birgitte Friederichsen, Mirella Ezban, Søren Erik Bjørn
• Journal: Blood (Blood) Vol. 119 Issue 24 Pg. 5871-8 (Jun 14 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22563084 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Blocking
• Antibodies, Monoclonal, Humanized
• Antibodies, Neutralizing
• Epitopes
• Lipoproteins
• lipoprotein-associated coagulation inhibitor
• concizumab
• Factor VIII
• Fibrin
• Thromboplastin
• Factor Xa

Topics

• Animals
• Antibodies, Blocking (administration & dosage, pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacology, therapeutic use)
• Antibodies, Neutralizing (pharmacology)
• Bleeding Time
• Blood Coagulation (drug effects)
• Cross Reactions (drug effects)
• Disease Models, Animal
• Epitopes (immunology)
• Factor VIII (pharmacology)
• Factor Xa (immunology, metabolism)
• Female
• Fibrin (metabolism)
• HEK293 Cells
• Hemophilia A (blood, drug therapy)
• Hemostasis (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• Lipoproteins (metabolism)
• Models, Molecular
• Neutralization Tests
• Protein Binding (drug effects)
• Protein Structure, Tertiary
• Rabbits
• Species Specificity
• Thromboplastin (pharmacology)