Item request has been placed!
×
Item request cannot be made.
×
Processing Request
Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model.
Item request has been placed!
×
Item request cannot be made.
×
Processing Request
- Additional Information
- Source:
Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
- Publication Information:
Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]
- Subject Terms:
Models, Molecular*;
Antibodies, Blocking/
*pharmacology ;
Antibodies, Monoclonal, Humanized/
*pharmacology ;
Antibodies, Monoclonal, Humanized/
*therapeutic use ;
Factor Xa/
*metabolism ;
Hemophilia A/
*drug therapy ;
Hemostasis/
*drug effects ;
Lipoproteins/
*metabolism;
Animals ;
Antibodies, Blocking/
administration & dosage ;
Antibodies, Blocking/
therapeutic use ;
Antibodies, Monoclonal, Humanized/
administration & dosage ;
Antibodies, Neutralizing/
pharmacology ;
Bleeding Time ;
Blood Coagulation/
drug effects ;
Cross Reactions/
drug effects ;
Disease Models, Animal ;
Epitopes/
immunology ;
Factor VIII/
pharmacology ;
Factor Xa/
immunology ;
Female ;
Fibrin/
metabolism ;
HEK293 Cells ;
Hemophilia A/
blood ;
Human Umbilical Vein Endothelial Cells ;
Humans ;
Neutralization Tests ;
Protein Binding/
drug effects ;
Protein Structure, Tertiary ;
Rabbits ;
Species Specificity ;
Thromboplastin/
pharmacology - 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.
- Accession Number:
0 (Antibodies, Blocking)
0 (Antibodies, Monoclonal, Humanized)
0 (Antibodies, Neutralizing)
0 (Epitopes)
0 (Lipoproteins)
0 (lipoprotein-associated coagulation inhibitor)
68603V9EAF (concizumab)
9001-27-8 (Factor VIII)
9001-31-4 (Fibrin)
9035-58-9 (Thromboplastin)
EC 3.4.21.6 (Factor Xa)
- Publication Date:
Date Created: 20120508 Date Completed: 20120824 Latest Revision: 20220317
- Publication Date:
20231215
- Accession Number:
10.1182/blood-2012-01-401620
- Accession Number:
22563084
No Comments.