Dataset Information

MG1113, a specific anti-tissue factor pathway inhibitor antibody, rebalances the coagulation system and promotes hemostasis in hemophilia.

ABSTRACT:

Background

Replacement therapy is the most common treatment for reduction of bleeding and control of episodic bleeding in individuals with hemophilia. Despite the proven effectiveness of factor replacement therapy, repeated intravenous administration is a heavy burden to individuals with hemophilia.

Objectives

To reduce the burden, therapeutic agents that can be subcutaneously administered need to be developed, and an anti-tissue factor pathway inhibitor (TFPI) antibody may be a suitable candidate for this purpose.

Methods

MG1113 is an IgG4 monoclonal antibody that binds to Kunitz-2 domain (KD2) of TFPI. To confirm the coagulation potential of MG1113, several tests were conducted using factor VIII (FVIII)- or IX (FIX)-deficient plasma. For the ex vivo spiking test, platelet-poor plasma samples from 14 individuals with hemophilia were spiked with MG1113. The in vivo efficacy was determined using blood loss tests, modified prothrombin time (mPT), and free TFPI quantification after intravenous or subcutaneous administration of MG1113 into hemophilia A (HA)-induced rabbits.

Results

Radiographic crystallography demonstrated the specific binding site between MG1113 and KD2. In FVIII-deficient plasma and the plasma of individuals with hemophilia, peak thrombin and endogenous thrombin levels were increased by MG1113 in a concentration-dependent manner. Rotational thromboelastometry assay revealed that clotting time, clot formation time, and maximum clot firmness were normalized in MG1113-treated blood of patients. Intravenous or subcutaneous injection of MG1113 into HA-induced rabbits resulted in rebalancing of blood loss, mPT, and free TFPI levels.

Conclusions

These results indicate that subcutaneous administration of MG1113 neutralizes the function of TFPI and regulates bleeding in individuals with hemophilia.

SUBMITTER: Kwak H

PROVIDER: S-EPMC7695563 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

MG1113, a specific anti-tissue factor pathway inhibitor antibody, rebalances the coagulation system and promotes hemostasis in hemophilia.

Kwak Heechun H Lee Sumin S Jo Seunghyun S Kwon Young Eun YE Kang Hyunju H Choi Gahee G Jung Myung Eun ME Kwak Mi-Jeong MJ Kim Seonghoon S Oh Byung-Ha BH Kim Dong-Sik DS Hwang Sung Ho SH

Research and practice in thrombosis and haemostasis 20201022 8

<h4>Background</h4>Replacement therapy is the most common treatment for reduction of bleeding and control of episodic bleeding in individuals with hemophilia. Despite the proven effectiveness of factor replacement therapy, repeated intravenous administration is a heavy burden to individuals with hemophilia.<h4>Objectives</h4>To reduce the burden, therapeutic agents that can be subcutaneously administered need to be developed, and an anti-tissue factor pathway inhibitor (TFPI) antibody may be a s ...[more]

PMID: 33313469

Similar Datasets

Project description:Development of inhibitory antibodies to coagulation factor VIII (fVIII) is the primary obstacle to the treatment of hemophilia A in the developed world. This adverse reaction occurs in 20-30% of persons with severe hemophilia A treated with fVIII-replacement products and is characterized by the development of a humoral and neutralizing immune response to fVIII. Patients with inhibitory anti-fVIII antibodies are treated with bypassing agents including recombinant factor VIIa (rfVIIa). However, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Recently, we demonstrated that fVIII inhibitors display widely variable kinetics of inhibition that correlate with their respective target epitopes. Thus, it was hypothesized that for antibodies that display slow rates of inhibition, supplementation of rfVIIa with fVIII would result in improved thrombin generation and be predictive of clinical responses to this novel treatment regimen. In order to test this hypothesis, 10 murine monoclonal antibodies (MAbs) with non-overlapping epitopes spanning fVIII, differential inhibition titers, and inhibition kinetics were studied using a thrombin generation assay. Of the 3 MAbs with high inhibitory titers, only the one with fast and complete (classically defined as "type I") kinetics displayed significant inhibition of thrombin generation with no improvement upon supplementation of rfVIIa with fVIII. The other two MAbs that displayed incomplete (classically defined as "type II") inhibition did not suppress the potentiation of thrombin generation by fVIII. All antibodies that did not completely inhibit fVIII activity demonstrated potentiation of thrombin generation by the addition of fVIII as compared to rfVIIa alone. In conclusion, fVIII alone or in combination with rfVIIa corrects the thrombin generation defect produced by the majority of anti-fVIII MAbs better than single agent rfVIIa. Therefore, combined fVIII/rfVIIa therapy may provide better hemostatic control than current therapy in some patients with anti-fVIII inhibitors.

Dataset Information

MG1113, a specific anti-tissue factor pathway inhibitor antibody, rebalances the coagulation system and promotes hemostasis in hemophilia.

Background

Objectives

Methods

Results

Conclusions

Publications

MG1113, a specific anti-tissue factor pathway inhibitor antibody, rebalances the coagulation system and promotes hemostasis in hemophilia.

Similar Datasets

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