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• W2593291278 abstract "Abstract Extrinsic coagulation pathway is an initial phase of clotting when tissue damage occurs. Activation of extrinsic pathway by tissue factor (TF) triggers the coagulation cascade through factor VII (FVII), and factor X (FX). Tissue factor pathway inhibitor (TFPI), an endogenous inhibitor of the extrinsic coagulation pathway, blocks the coagulation signal. TFPI is a single-chain polypeptide which can reversibly inhibit Factor Xa (FXa). While FXa is inhibited, the FXa-TFPI complex can also inhibit the FVIIa-TF complex. TFPI consists of three tandem linked Kunitz domains (KD). Among the three kunitz domains, KD1 is well known for binding to FVII directly and KD2 is for FXa or FX. MG1113 is a human IgG4 type antibody targeting KD2 of human TFPI. Inhibiting TFPI can trigger extrinsic pathway and lead to coagulation independent of intrinsic pathway. To verify the coagulation efficacy of MG1113, we performed several in vitro and ex vivo assays. Through FXase activity assay, we measured the recovery of FX activity by blocking TFPI. Since TFPI can bind and inhibit TF/FVIIa/FX complex, we also measured how much FX is activated through the TF/FVII/FX complex in the presence of MG1113. MG1113 targets the KD2 of TFPI. To confirm blocking KD2 can activate the FVII, we checked FVII activity in the presence of MG1113. Modified prothrombin time (PT) assay under a diluted condition was conducted to measure the efficacy of MG1113. Additionally, thrombin is a key factor of coagulation and therefore, thrombin generation was also determined. Most of all, ex vivo whole blood coagulation test is one of the best ways to experimentally confirm the clotting efficacy. We recruited healthy subjects and hemophilia patients and collected their blood samples. Healthy donor-derived blood was pretreated with FVIII-neutralizing antibody to make it to hemophilia condition. This condition is similar to that of hemophilia patients with inhibitors. After spiking MG1113 to their blood, clotting time is measured by ROTEM. In FXase assay, FXa was generated with increasing concentrations of MG1113. FXa was also increased by MG1113 treatment through the formation of TF/FVIIa/FX complex. Next, FVIIa activity was measured in the presence of MG1113 or anti-TFPI KD1 antibody. Although FVII directly binds to KD1 of TFPI, blocking KD2 by MG1113 was much more efficient to recover FVIIa activity compared with blocking KD1 by anti-TFPI KD1 antibody. Furthermore, prothrombin time was significantly shortened by increasing concentrations of MG1113 under the modified PT assay condition. The results reached normal prothrombin time when 2.5 nM of MG1113 was treated. Thrombin also increased meaningfully to the normal level at increasing concentrations of MG1113. Finally, MG1113 shortened clotting time in a dose-dependent manner in the hemophilia mimicking condition produced by the pretreatment of FVIII-neutralizing antibody in healthy blood. MG1113 also shortened significantly the clotting time for both types of hemophilia, A and B. In conclusion, treatment of MG1113 increased coagulation efficacy in all of the assays used. Moreover, hemophilia patients' blood efficiently clotted by the spiking of MG1113. Our results suggest the potential of anti-TFPI antibody as one of the alternative therapeutics for hemophilia patients. Disclosures Choi: Greencross: Research Funding. Lee:Greencross: Research Funding. Kwak:Greencross: Research Funding. Hwang:Greencross: Research Funding." @default.
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• W2593291278 date "2016-12-02" @default.
• W2593291278 modified "2023-10-18" @default.
• W2593291278 title "MG1113, Anti-TFPI Antibody, Efficiently Recovers Coagulation Efficacy through Blocking the Kunitz 2 Domain of Human TFPI" @default.
• W2593291278 doi "https://doi.org/10.1182/blood.v128.22.1406.1406" @default.
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