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Use of protease nexin II\KPI protein mutant

A mutant and fusion protein technology, applied in the field of hemorrhagic disease treatment, can solve the problems of different bleeding severity and improve the bleeding severity of hemophiliac patients, and achieve the effects of promoting blood coagulation, good therapeutic application prospects, and low immunity

Inactive Publication Date: 2019-07-26
宁波百施宁生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Bleeding manifestations in hemophilia correlate with FVIII or FIX activity in plasma, however, bleeding severity remains variable in patients with similar levels of clotting factor activity
Coexistence of prothrombotic genetic risk factors with hemophilia may improve bleeding severity in hemophilia patients, findings suggest

Method used

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  • Use of protease nexin II\KPI protein mutant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Inhibition of protein C by protease nexin II\KPI mutant (R15K / M17K)

[0026]In the purified protein system, different concentrations of protease nexin II\KPI mutants (R15K / M17K) were reacted with activated protein C, and the protease nexin II\KPI mutants (R15K / M17K ) inhibited the activity of residual aPC, the results showed that with the increase of the concentration of protease nexin II\KPI mutant (R15K / M17K), the activity of aPC gradually decreased, and the effect of protease nexin II\KPI mutant (R15K / M17K) on aPC has moderate inhibitory activity (IC50~1uM)( figure 1 ).

Embodiment 2

[0028] The protease nexin II\KPI mutant (R15K / M17K) corrects the defect of thrombin generation in the plasma of hemophilia A and B patients and the plasma of hemophilia A patients with inhibitors

[0029] Thrombin generation test (TGT): It can be used to evaluate the thrombin generation ability in plasma. It is an overall coagulation function test that simulates coagulation conditions in vivo, reflecting the total effect of coagulation and anticoagulation systems. Plasma coagulation reaction is started after adding activators (including tissue factor and phospholipids), thrombin generation is detected by specific fluorescent substrate, and the change of fluorescence intensity is dynamically monitored by FLUOROSKAN fluorescence reader, and specific thrombin generation experiment software is used The fluorescent signal is converted into a digital signal, and the thrombin generation curve is drawn. The ability to generate thrombin can be evaluated from several parameters of the g...

Embodiment 3

[0032] Protease nexin II\KPI mutant (R15K / M17K) improves tail-docked bleeding phenotype in hemophilic mice

[0033] The protease nexin II\KPI mutant (R15K / M17K) was injected into the mouse model of hemophilia at 4-8 weeks through the tail vein to make the peak concentration of protease nexin II\KPI mutant (R15K / M17K) in plasma up to 30uM. Simultaneous injection of physiological saline was used as a negative control, and blood coagulation factor VIII (peak concentration was 100% of normal) was used as a positive control. After the mouse was anesthetized, the tail was docked at a place with a diameter of 2 mm at the end of the mouse, and the tail was suspended in PBS buffer at room temperature. Timed for 10 minutes, the concentration of hemoglobin in the test tube was detected, and the bleeding volume of the docked tail was calculated according to the hemoglobin measurement. The amount of hemorrhage in saline-treated hemophilic mice was that of the control (100%) ( image 3 )....

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Abstract

The invention relates to use of a protease nexin II\KPI protein mutant and a derivative, an analogue or a constituent fragment thereof for the preparation of a hemophilia-related disease or symptoms for the treatment of diseases or symptoms related to acquired hemophilia and hemophilia generating an inhibitor. The protease nexin II\KPI protein mutant can be applied to the preparation of medicinesfor treating hemorrhagic diseases and particularly relevant medicines for treating hemophilia having an inhibitor and has a good application prospect.

Description

technical field [0001] The invention belongs to the field of hemorrhagic disease treatment, and particularly relates to the application of a protease nexin II\KPI protein mutant and its derivatives, analogs or constituent fragments. Background technique [0002] Hemophilia A and B are hereditary bleeding disorders caused by deficiencies in coagulation factor VIII (FVIII) or IX (FIX), with an incidence rate of 1 / 5000 and 1 / 2000 in the male population, and patients clinically present with coagulation dysfunction , There may be spontaneous muscle hematoma and joint cavity hemorrhage. FVIII / FIX replacement therapy is currently the only effective treatment. With the development of biotechnology, genetically recombined FVIII / FIX has gradually replaced plasma or plasma-derived FVIII / FIX as the main preparation for replacement therapy. The in vivo half-life of FVIII is less than 12 hours, and FIX is only about 24 hours. In order to maintain sufficient plasma concentration to preve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/55A61K47/55A61K47/64A61P7/04
CPCA61K38/55A61K47/55A61K47/64A61P7/04
Inventor 许晓倩
Owner 宁波百施宁生物医药科技有限公司
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