title: 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.affiliation: Biopharmaceuticals Research Unit, Novo Nordisk, Maaloev, Denmark. IDAH@novonordisk.com
authors.forename: Ida
authors.initials: I
authors.lastname: Hilden
authors.forename: Brian
authors.initials: B
authors.lastname: Lauritzen
authors.forename: Brit Binow
authors.initials: BB
authors.lastname: Sørensen
authors.forename: Jes Thorn
authors.initials: JT
authors.lastname: Clausen
authors.forename: Christina
authors.initials: C
authors.lastname: Jespersgaard
authors.forename: Berit Olsen
authors.initials: BO
authors.lastname: Krogh
authors.forename: Andrew Neil
authors.initials: AN
authors.lastname: Bowler
authors.forename: Jens
authors.initials: J
authors.lastname: Breinholt
authors.forename: Albrecht
authors.initials: A
authors.lastname: Gruhler
authors.forename: L Anders
authors.initials: LA
authors.lastname: Svensson
authors.forename: Helle Heibroch
authors.initials: HH
authors.lastname: Petersen
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Petersen
authors.forename: Kristoffer W
authors.initials: KW
authors.lastname: Balling
authors.forename: Lene
authors.initials: L
authors.lastname: Hansen
authors.forename: Mette Brunsgaard
authors.initials: MB
authors.lastname: Hermit
authors.forename: Thomas
authors.initials: T
authors.lastname: Egebjerg
authors.forename: Birgitte
authors.initials: B
authors.lastname: Friederichsen
authors.forename: Mirella
authors.initials: M
authors.lastname: Ezban
authors.forename: Søren Erik
authors.initials: SE
authors.lastname: Bjørn
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D003429:Cross Reactions / Q000187:drug effects; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005169:Factor VIII / Q000494:pharmacology; D015951:Factor Xa / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D057809:HEK293 Cells; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008958:Models, Molecular; D009500:Neutralization Tests; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011817:Rabbits; D013045:Species Specificity; D013925:Thromboplastin / Q000494:pharmacology
chemical_list: D019138:Antibodies, Blocking; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000939:Epitopes; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; C574488:concizumab; D005169:Factor VIII; D005337:Fibrin; D013925:Thromboplastin; D015951:Factor Xa