Antidotes for factor Xa inhibitors and methods of using the same

Patent metadata

Field	Value
Publication number	US-11839646-B2
Application number	US-202016869117-A
Country	US
Kind code	B2
Filing date	May 7, 2020
Priority date	Sep 28, 2007
Publication date	Dec 12, 2023
Grant date	Dec 12, 2023

Abstract

The present invention relates antidotes to anticoagulants targeting factor Xa. The antidotes are factor Xa protein derivatives that bind to the factor Xa inhibitors thereby substantially neutralizing them but do not assemble into the prothrombinase complex. The derivatives describe herein lack or have reduced intrinsic coagulant activity. Disclosed herein are methods of stopping or preventing bleeding in a patient that is currently undergoing anticoagulant therapy with a factor Xa inhibitor.

First claim

What is claimed:

1. A polypeptide comprising SEQ ID NO:12 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:12, wherein the amino acid sequence, upon cleavage at the -RKRRKR- (SEQ ID NO:17) linker within the sequence in a cell, produces a two-chain polypeptide comprising a first chain and a second chain, and wherein the two-chain polypeptide (a) has reduced catalytic activity as compared to the wild-type factor Xa protein, (b) is capable of binding to a factor Xa inhibitor and (c) cannot assemble into a prothrombinase complex.

2. The polypeptide of claim 1 , wherein the amino acid sequence has at least 95% sequence identity to SEQ ID NO:12.

3. The polypeptide of claim 1 , wherein the amino acid sequence has at least 98% sequence identity to SEQ ID NO:12.

4. The polypeptide of claim 1 , wherein the first chain does not include amino acid residues 6-39 as shown in SEQ ID NO: 3.

5. The polypeptide of claim 1 , wherein the first chain does not include the Gla domain of factor Xa.

6. The polypeptide of claim 1 , wherein the second chain comprises at least an amino acid addition, deletion or substitution at the catalytic domain as compared to wild-type factor Xa such that the two-chain polypeptide has reduced catalytic activity as compared to wild-type factor Xa and retains the ability to bind a small molecule factor Xa inhibitor.

7. The polypeptide of claim 6 , wherein the amino acid addition, deletion or substitution is at one or more of Arg306, Glu310, Arg347, Lys351, Lys414, or Arg424, wherein numbering of the amino acid residues is according to SEQ ID NO. 3.

8. The polypeptide of claim 6 , wherein the amino acid addition, deletion or substitution is at one or more of Glu216, Glu218, Arg332, Arg347, Lys351, or Ser379, wherein numbering of the amino acid residues is according to SEQ ID NO. 3.

9. The polypeptide of claim 6 , wherein the amino acid addition, deletion or substitution is at Ser379, wherein numbering of the amino acid residues is according to SEQ ID NO. 3.

10. The polypeptide of claim 1 , wherein the two-chain polypeptide further comprises a disulfide bond between a first Cysteine residue at position 132 (Cys132) of the first chain and a second Cysteine residue at position 302 (Cys302) of the second chain, and wherein numbering of the amino acid residues is according to SEQ ID NO. 3.

11. A recombinant polynucleotide that encodes the polypeptide of claim 1 .

12. A cell transfected with the recombinant polynucleotide of claim 11 .

Assignees

• Alexion Pharma Inc

Inventors

• Lu Genmin
• Phillips David R
• Andre Patrick
• Sinha Uma

Classifications

• A61K39/00

  Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53) · CPC title

• A61K38/4846 Primary

  Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38) · CPC title

• A61K38/4826

  Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1) · CPC title

• A61K38/4833

  Thrombin (3.4.21.5) · CPC title

• A61K38/4853

  Kallikrein (3.4.21.34 or 3.4.21.35) · CPC title