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Modified factor IX polypeptides and uses thereof

A factor and amino acid technology, applied in the field of modified factor IX polypeptide, can solve problems such as defect coagulation

Inactive Publication Date: 2011-06-01
BAYER HEALTHCARE LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Insufficient levels of FIX lead to defective coagulation and symptoms from uncontrolled bleeding

Method used

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  • Modified factor IX polypeptides and uses thereof
  • Modified factor IX polypeptides and uses thereof
  • Modified factor IX polypeptides and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] Example 1: Computer analysis

[0177] Implementation of solvent accessibility, known secondary structure, the location of known hemophilia B mutations, proximity to the predicted site of interaction with both FVIII and FX, and the prediction of the stability of the FIX protein for a given mutation Computer analysis of the FIX sequence on the impact to identify potential sites for the addition of a consensus sequence of new N-glycosylation sites.

[0178] Based on this analysis, 5 sites were identified within the catalytic domain to create new N-linked glycosylation sites. Table 2 shows the selected site design and the changed amino acid sequence.

[0179] Table 2

[0180]

Embodiment 2

[0181] Example 2: Sequence alignment of activation peptides

[0182] Identify the conserved and non-conserved residues in the activation peptide by multi-species sequence alignment, such as figure 1 Shown in.

[0183] The consensus sequence for the N-linked glycosylation site is Asn-X-Ser / Thr (where X is any amino acid except proline or aspartic acid (which may also not be advantageous)). In order to design new N-linked glycosylation sites in the FIX activation peptide, avoid the consensus sequence of amino acids that are conserved among species in the activation peptide and the consensus sequence of other N-linked sites and the consensus sequence of tyrosine sulfation. These post-translational modifications are not disrupted, as these can be important for the pharmacokinetics of FIX. Using these criteria, three sites for adding new N-linked glycosylation sites within the activation peptide were identified, as shown in Table 3.

[0184] table 3

[0185] name

[0186] HG2

Embodiment 3

[0187] Example 3: Insertion of amino acids to create N-linked glycosylation sites

[0188] Multiple sequence alignment ( figure 1 ) Also revealed that mice, rats, and guinea pigs have additional amino acids between residues A161 and E162 relative to human, macaque, pig, dog, and rabbit FIX. These extra amino acids vary in size from 7 to 10 across the three species, and contain an overrepresentation of Asp and to some extent Ile residues. This observation indicates that 7-10 additional residues are tolerated at this site in rats, mice, and guinea pigs, and have no significant effect on FIX activity. According to the criteria used to perform multiple sequence alignments among FIXs from 8 species, the apparent sites for finding extra amino acids in rats, mice, and guinea pigs can vary so that the sites can be Between E160 and A161, between A161 and E162, between E162 and T163, or between T163 and I164 of human FIX.

[0189] In the activation peptide, 9 additional amino acids with th...

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PUM

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Abstract

The present invention relates to modified Factor IX polypeptides such as Factor IX polypeptides with one or more introduced glycosylation sites. The modified Factor IX polypeptides may exhibit increased in vitro or in vivo stability such as a longer plasma half-life. The invention also relates to methods of making modified Factor IX polypeptides, and methods of using modified Factor IX polypeptides, for example, to treat patients afflicted with hemophilia B.

Description

[0001] This application requires the rights and interests of the U.S. Provisional Application Serial No. 61 / 124,567 filed on April 16, 2008 and the U.S. Provisional Application Serial No. 61 / 045,961 filed on April 17, 2008, the contents of which are included in this article in their entirety by reference. Invention field [0002] The present invention relates to modified Factor IX polypeptides, such as Factor IX polypeptides having one or more introduced glycosylation sites. Modified Factor IX polypeptides can exhibit increased in vitro or in vivo stability such as longer plasma half-life. The present invention also relates to methods of producing modified Factor IX polypeptides, and methods of using the modified Factor IX polypeptides, for example, to treat patients suffering from hemophilia B. Background of the invention [0003] Hemophilia B affects one in 34,500 men and is caused by multiple genetic defects in the gene encoding factor IX (FIX) that cause low or undetectable FI...

Claims

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Application Information

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IPC IPC(8): C07K14/745
CPCA61K38/00C12Y304/21022C12N9/644A61P7/04
Inventor 艾伦·布鲁克斯约翰·E·墨菲马里安·塞托蒋晓乔钱德拉·帕特尔尤维·格里赞科尼利亚·柯克纳乌尔里克·豪普茨
Owner BAYER HEALTHCARE LLC
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