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Long-acting anticoagulant fusion protein and use thereof

A fusion protein and anticoagulant technology, applied in the direction of fusion polypeptide, protease inhibitor, peptide/protein components, etc., can solve the problems of thrombocytopenia, bleeding, short plasma half-life, etc., and achieve the effect of preventing and treating thrombosis

Active Publication Date: 2019-01-15
BEIJING SH BIO TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the anticoagulant widely used clinically is mainly heparin, and its function is to inhibit the activity of thrombin (thrombin) by combining with antithrombin III (antithrombin III), which may cause the reduction of antithrombin III, and heparin An important disadvantage is the induction of thrombocytopenia (thrombocytopenia)
The low-molecular-weight heparin developed now can reduce the risk in the application of heparin, but it cannot fundamentally overcome its shortcomings
Hirudin is a new type of anticoagulant drug that has been marketed in Europe in recent years. It is a direct inhibitor of thrombin, but its strong inhibitory effect on thrombin can lead to a sharp increase in coagulation-related parameters, such as APTT and TT. Associated systemic or systemic bleeding risk
Compared with hirudin, Neorudin (EH) has good specific targeting and can reduce the side effects of systemic hemorrhage caused by hirudin non-specificity. However, EH is a short peptide with a molecular weight of only 7.3KD, which is very It is easily filtered by the glomerulus and excreted through urine, which makes the plasma half-life of EH in the body shorter, only 1-2h

Method used

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  • Long-acting anticoagulant fusion protein and use thereof
  • Long-acting anticoagulant fusion protein and use thereof
  • Long-acting anticoagulant fusion protein and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Embodiment 1: the preparation of fusion protein and in vitro anticoagulant activity assay

[0098] 1.1 Preparation of fusion protein

[0099] The nucleotide sequence encoding the fusion protein was constructed according to the construction method of each fusion protein shown in Table 2 by whole gene synthesis, wherein, the schematic diagram of the construct of EH-L-IgG1Fc, EH-L-IgG4Fc is as follows figure 1 As shown, the schematic diagram of the construct of EH-L-IgG4Fc-HV2 is shown in figure 2 As shown, the schematic diagram of the construct of IgG4Fc-L-EH is shown in image 3 As shown, the schematic diagram of the construct of IgG4Fc-EH is shown in Figure 4 shown. The nucleotide sequences encoding the above-mentioned fusion proteins were introduced into expression vectors by double enzyme digestion, and the obtained recombinant expression vectors were transfected into CHO cells by using liposomes, and the stably expressed expression vectors were obtained by pr...

Embodiment 2

[0124] Embodiment 2: the plasma half-life determination of fusion protein

[0125] 2.1 Experimental animals

[0126] Wistar rats, male, SPF grade, weighing 200-250g, were purchased from Beijing Weitong Lihua Company, and were raised in the experimental animal room of the Military Medical Research Institute. The experimental animals were given corresponding animal welfare and followed the 3R principles of animal experiments. start an experiment.

[0127] 2.2 Experimental method

[0128] The Wistar rats were randomly divided into 3 groups, 6 rats in each group, and IgG4Fc-EH (FcEH) was injected into the tail vein at low, medium and high doses (chemical doses were 4.5, 13.5, 27 mg / kg, respectively). Before administration and after administration 0.5h, 1h, 2h, 4h, 12h, 24h, 48h, 72h, 96h, 120h and 144h, blood was taken from the orbital venous plexus of rats, and 3.8% sodium citrate (Sinopharm Chemical Reagent Company) solution anticoagulant, separated plasma (3000r / min rota...

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Abstract

The invention relates to the fields of biotechnology and disease treatment, and in particular, relates to the field of thrombotic disease treatment. Specifically, the invention relates to a fusion protein comprising an anticoagulant protein and an immunoglobulin Fc structural domain, as well as a medical use of the fusion protein.

Description

technical field [0001] The invention relates to the fields of biotechnology and disease treatment, especially the field of thrombotic disease treatment. In particular, the present invention relates to fusion proteins comprising an anticoagulant protein and an immunoglobulin Fc domain, and the medical use of such fusion proteins. Background technique [0002] Cardiovascular disease is the number one killer that threatens human health and life in recent years. Thrombosis is an important cause of many cardiovascular diseases. Anticoagulants are important drugs for preventing and treating thrombosis. At present, the anticoagulant widely used clinically is mainly heparin, and its function is to inhibit the activity of thrombin (thrombin) by combining with antithrombin III (antithrombin III), which may cause the reduction of antithrombin III, and heparin An important disadvantage of is the induction of thrombocytopenia (thrombocytopenia). The low-molecular-weight heparin develop...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N15/62A61K38/58A61K47/42A61P7/02A61P11/00A61P9/10
CPCA61K38/00A61P7/02A61P9/10A61P11/00C07K14/815C07K2319/30
Inventor 吴祖泽于爱平李世崇庞玉红汪坤靳继德
Owner BEIJING SH BIO TECH
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