Mutant single-chain human blood coagulation factor VIII fusion protein and its preparation method and application

A technology of human blood coagulation factor and fusion protein, which is applied to the fusion protein of mutant human blood coagulation factor VIII and its preparation to treat a variety of coagulation-related diseases, and can solve the instability of FVIII derivatives heterologous number, structure and thrombin activation To achieve good in vitro stability, prolong half-life, and eliminate ADCC and CDC effects

Active Publication Date: 2021-06-18
AMPSOURCE BIOPHARMA (SHANGHAI) INC +1
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Problems solved by technology

[0009] In summary, although many studies have provided effective recombinant FVIII protein preparation solutions, compared with full-length FVIII, the heterologous number, structure and instability of thrombin activation of FVIII derivatives are still a serious problem.
Furthermore, since many B-domain-deleted FVIIIs are expressed as fusion proteins, new immunogenicity may emerge after administration of non-native amino acid sequences

Method used

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  • Mutant single-chain human blood coagulation factor VIII fusion protein and its preparation method and application
  • Mutant single-chain human blood coagulation factor VIII fusion protein and its preparation method and application
  • Mutant single-chain human blood coagulation factor VIII fusion protein and its preparation method and application

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Embodiment Construction

[0062] hCG-β carboxy-terminal peptide (CTP)

[0063] CTP is a short peptide derived from the carboxy-terminus of the β-subunit of human chorionic gonadotropin (hCG). The four reproductive-related polypeptide hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyrotropin (TSH) and chorionic gonadotropin (hCG) contain the same α-subunit and each specific β -subunit. Compared with the other three hormones, the half-life of hCG in vivo is significantly prolonged, which is mainly derived from the unique carboxy-terminal peptide (CTP) on its β-subunit (Fares FA et al., Proc NatlAcad Sci USA, 1992,89 (10): 4304 -4308). Native CTP contains 37 amino acid residues with 4 O-glycosylation sites terminated by sialic acid residues. Negatively charged, highly sialylated CTP can resist its clearance by the kidneys, thereby prolonging the half-life in vivo (Fares FA et al., Proc Natl Acad Sci USA, 1992, 89(10): 4304-4308). However, the present invention creatively links...

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Abstract

The invention discloses a mutant recombinant single-chain human blood coagulation factor VIII (FVIII) fusion protein, its preparation method and application. The fusion protein sequentially comprises mutant single-chain human FVIII missing part of the B-domain, a flexible peptide linker, at least one rigid unit of human chorionic gonadotropin β subunit carboxy-terminal peptide, and a half-life extension part ( Human IgG Fc variants are preferred). The fusion protein has biological activity similar to recombinant FVIII, extended half-life in vivo, and better stability in vitro and in vivo, thereby improving the pharmacokinetics and efficacy of the fusion protein.

Description

technical field [0001] The present invention relates to the field of fusion proteins, more specifically, to a fusion protein of mutant human blood coagulation factor VIII (FVIII) and its preparation method and application, especially the application for treating various blood coagulation-related diseases. Background technique [0002] Coagulation factor VIII (FVIII), also known as antihemophilic factor, plays a very important role in the endogenous coagulation system. Numerous studies in the molecular genetics of FVIII have shown that a lack of FVIII in the sex chromosome X-linked gene causes hemophilia A. According to statistics, the prevalence of hemophilia A in the male population is 1 / 5000, accounting for more than 80% of the total number of hemophilias. The current commonly used treatment for hemophilia A is replacement therapy, which is to supplement the FVIII that is lacking in hemophilia patients. [0003] Mature FVIII consists of a light chain with an approximate ...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N15/62A61K38/37A61K47/68A61P7/04
CPCC07K14/755A61P7/04A61K38/00C07K2319/30C07K2319/31A61K38/37A61P7/00C07K14/59C07K2319/91
Inventor 高永娟贾世香郑云程金莹莹王著董炤陈思孙乃超李强
Owner AMPSOURCE BIOPHARMA (SHANGHAI) INC
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