Truncated von willebrand factor polypeptides for treating hemophilia

A technology for factors and uses, applied in the field of improving the treatment of coagulation disorders, can solve the problem of not prolonging the survival of FVIII, and achieve the effect of reducing the frequency of administration

Pending Publication Date: 2019-06-21
CSL BEHRING LENGNAU AG
View PDF36 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, while the VWF D'D3-Fc fusion protein exhibited significantly prolonged survival when infused into FVIII-deficient mice, the VWF D'D3-Fc fusion protein did not prolong the survival of co-infused FVIII

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Truncated von willebrand factor polypeptides for treating hemophilia
  • Truncated von willebrand factor polypeptides for treating hemophilia
  • Truncated von willebrand factor polypeptides for treating hemophilia

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0234] 【Preparation of polypeptide】

[0235] Nucleic acids encoding polypeptides of the present invention can be prepared according to methods known in the art. Based on the cDNA sequence of VWF (SEQ ID NO: 3), recombinant DNA encoding the above-mentioned truncated VWF construct or polypeptide of the present invention can be designed and produced.

[0236] Even if the polypeptide secreted by the host cell does not comprise amino acids 1 to 763 of VWF, it is preferable that the nucleic acid (eg, DNA) encoding the intracellular precursor of the polypeptide comprises a nucleotide sequence encoding the amino acid sequence. Has at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to amino acids 23-763 or preferably to amino acids 1-763 of SEQ ID NO:4. Most preferably, the nucleic acid (eg DNA) encoding the intracellular precursor of the polypeptide comprises a nucleotide sequence encoding amino acids 23-763 of SEQ ID NO:4 or amino acids 1-763 of...

Embodiment 1

[0311] [Example 1: Analysis of FVIII levels in plasma after administration of rD'D3-FP]

[0312] Our aim was to characterize the effect of rD'D3-FP on endogenous FVIII levels, thereby generally supporting the treatment of mild to moderate or severe hemophilia A patients with low levels of VWF and functional endogenous FVIII or certain Types of von Willebrand disease. We studied this effect in different ways:

[0313] Models with normal endogenous FVIII and VWF levels, namely rats (Example 1.1), rabbits (Example 1.2) and monkeys (Example 1.3), were administered intravenously to study intravenous (iv ) Potential further increase of endogenous FVIII after administration of rD'D3-FP.

[0314] Models with low FVIII levels due to VWF deficiency, namely VWF ko rats (Example 1.4) and VWF ko mice (Example 1.5), were administered intravenously to study intravenous administration of rD'D3 in diseased subjects - Increased size of endogenous FVIII after FP.

[0315] VWF ko rats, a mode...

Embodiment 11

[0355] [Example 1.1: Effect of intravenous treatment with rD'D3-FP on physiological endogenous FVIII levels in rats]

[0356] 【animal】

[0357] Female Crl:CD (Sprague Dawley) rats weighing in the range of 200-294 g were bred at Charles River Laboratories (Sulzfeld, Germany). Indoors, animals were maintained under standard cage conditions, ie, 12-24°C, 12h / 12h light-dark cycle. with standard mouse and rat diet (Ssniff Soest, Germany) fed the animals ad libitum. Free supply of tap water. Animal husbandry and research procedures complied with German animal welfare law and EU regulations.

[0358] For the 1 mg / kg group, the group size was n=9, divided into 3 groups except for the control (n=3 animals only). The group size of the 1 mg / kg group was n=6, divided into 2 groups. Therefore, n=3 animals per time point were always used.

[0359] 【Experiment Details】

[0360] Test articles were administered intravenously by a single injection into the lateral tail vein of rats (n=...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
elongationaaaaaaaaaa
elongationaaaaaaaaaa
elongationaaaaaaaaaa
Login to view more

Abstract

The invention pertains to a polypeptide comprising a truncated von Willebrand Factor (VWF) and a half-life extending moiety, for use in the treatment of a blood coagulation disorder, said treatment comprising administering the polypeptide to a subject having a blood coagulation disorder and having endogenous Factor VIII (FVIII), wherein the activity level of endogenous FVIII in said subject beforetreatment with said polypeptide is reduced relative to the activity level of FVIII in normal human plasma (NHP) provided that the activity level of endogenous FVIII in said subject is at least 0.5% of the activity level of endogenous FVIII in normal human plasma (NHP), wherein the polypeptide is capable of binding to endogenous FVIII and wherein the endogenous FVIII level is increased following administration of said polypeptide.

Description

[0001] 【Field of Invention】 [0002] The present invention relates to products and methods for improving the treatment of coagulation disorders. [0003] 【Background technique】 [0004] Various bleeding disorders are caused by deficiencies in clotting factors. The most common diseases are hemophilia A and B, caused by deficiencies of clotting factors VIII (FVIII) and IX, respectively. Another known bleeding disorder is von Willebrand's disease (VWD). [0005] In plasma, FVIII exists mainly as a non-covalent complex with von Willebrand factor (VWF), and its coagulation function is to accelerate the factor IXa-dependent conversion of factor X to Xa. [0006] Classic hemophilia, or hemophilia A, is an inherited bleeding disorder. It is caused by a deficiency of the chromosome X-linked blood clotting FVIII and affects almost exclusively males, with an incidence of one to two per 10,000. The X chromosome defect is transmitted by female carriers who are not themselves carriers of...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/36A61K38/37C07K14/755A61P7/04
CPCA61K38/36A61K38/37A61K2300/00A61P7/04A61K47/6811A61K47/643A61K47/61A61K47/60C07K14/745C07K14/755C07K19/00C07K2319/00A61K9/0019C07K14/765C07K2319/30C07K2319/31
Inventor S·舒尔特T·韦默S·佩斯特尔H·梅茨纳S·都韦尔
Owner CSL BEHRING LENGNAU AG
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap