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De-immunized factor viii molecule and pharmaceutical compositions comprising the same

A factor, recombinant factor technology, applied in the field of therapeutic proteins, can solve the problems of unsuccessful ITI

Pending Publication Date: 2020-12-22
BIOTEST SERUM INST GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, in a significant proportion of patients, ITI is not successful

Method used

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  • De-immunized factor viii molecule and pharmaceutical compositions comprising the same
  • De-immunized factor viii molecule and pharmaceutical compositions comprising the same
  • De-immunized factor viii molecule and pharmaceutical compositions comprising the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0242] Using EpiMatrix tools (Epivax, Providence, RI, USA) and the ClustiMer algorithm to conduct a preliminary computer analysis of peptides that bind to MHC class II (T cell epitopes) in human FVIII, EpiMatrix tools can predict eight common class II supertypes, etc. Binding potential of alleles (DRB1*0101, DRB1*0301, DRB1*0401, DRB1*0701, DRB1*0801, DRB1*1110, DRB1*1301, DRB1*1501), which cover most of the population (>90%) , the ClustiMer algorithm identifies clusters of putative T-cell epitopes (assigned immunogenic clusters). The FVIII sequence (FVIII-6rs) shown in SEQ ID NO: 2 was analyzed, which contained 1514 amino acids, excluding the signal sequence of 19 amino acids and the B domain of 818 amino acids. Amino acids of the excluded B domain do not interfere with the furin or thrombin cleavage sites. The computer tool revealed a total of 52 clusters of immunogenic peptides, with cluster scores ranging from 4 to 34, indicating high affinity at high values ​​and lower a...

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Abstract

The present invention relates to the field of therapeutic proteins, in particular, to recombinant coagulation factors. It provides a recombinant Factor VIII (FVIII) protein comprising specific point mutations at defined positions, which serve to reduce the immunogenicity of said FVIII protein, wherein the Factor VIII protein substantially retains its coagulant activity. The invention further provides nucleic acids encoding said de-immunized protein, cell lines and methods of recombinant preparation as well as pharmaceutical compositions comprising the recombinant FVIII of the invention, whichare advantageous for use in treatment of patients with Hemophilia A, particularly those who have not yet been treated with a FVIII product. Additionally, it can be a safe alternative for previously treated patients and even for patients who have developed an immune-response to FVIII, e.g., for immune-tolerance-induction therapy (ITI / ITT) or rescue ITI. The invention also provides an assay for determining immunogenicity of a protein.

Description

Background technique [0001] The invention relates to the field of therapeutic proteins, in particular to recombinant coagulation factors. It provides a recombinant Factor VIII (FVIII) protein comprising specific point mutations at defined positions for reducing the immunogenicity of the FVIII protein, wherein the Factor VIII protein substantially retains its coagulation activity. It also provides nucleic acid encoding the deimmunized protein, cell lines and recombinant production methods as well as pharmaceutical compositions comprising the recombinant FVIII of the present invention, which are useful for treating patients with hemophilia A (especially those who have not yet used FVIII patients who have been treated with the product) are beneficial. In addition, it is a safe option for previously treated patients, even for patients who have developed an immune response to FVIII (eg, for immune tolerance induction therapy (ITI / ITT) or rescue ITI). The invention also provides a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/64
CPCC07K14/755C07K2319/00A61K38/00A61K31/573A61K31/675A61K38/37A61K39/39541C07K16/2887G01N33/5047G01N33/505
Inventor K·温特林S·基斯特纳J·道芬巴赫A·德格鲁特W·马丁C·昂格雷尔
Owner BIOTEST SERUM INST GMBH
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