4DTG

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

Summary for 4DTG

• Entry DOI: 10.2210/pdb4dtg/pdb
• Related: 1ADZ 1TFX
• Descriptor: Humanized recombinant FAB fragment, FAB 2021, of a murine antibody, light chain, Humanized recombinant FAB fragment, FAB 2021, of a murine antibody, heavy chain, Tissue factor pathway inhibitor, ... (7 entities in total)
• Functional Keywords: antibody, inhibitor, blood coagulation, blood clotting inhibitor-immune system complex, blood clotting inhibitor/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform Alpha: Secreted. Isoform Beta: Microsome membrane ; Lipid-anchor, GPI-anchor : P10646
• Total number of polymer chains: 3
• Total formula weight: 57098.52

Authors

Svensson, L.A.,Breinholt, J.,Krogh, B.O.,Hilden, I. (deposition date: 2012-02-21, release date: 2012-06-13, Last modification date: 2024-11-27)

Primary citation

Hilden, I.,Lauritzen, B.,Sorensen, B.B.,Clausen, J.T.,Jespersgaard, C.,Krogh, B.O.,Bowler, A.N.,Breinholt, J.,Gruhler, A.,Svensson, L.A.,Petersen, H.H.,Petersen, L.C.,Balling, K.W.,Hansen, L.,Hermit, M.B.,Egebjerg, T.,Friederichsen, B.,Ezban, M.,Bjorn, S.E.
Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model.
Blood, 119:5871-5878, 2012

PubMed 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.

PubMed: 22563084
DOI: 10.1182/blood-2012-01-401620

Experimental method

X-RAY DIFFRACTION (1.8 Å)