Antidotes for factor XA inhibitors and methods of using the same

Patent metadata

Field	Value
Publication number	US-9587233-B2
Application number	US-201514790305-A
Country	US
Kind code	B2
Filing date	Jul 2, 2015
Priority date	Sep 28, 2007
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

The present invention relates antidotes to anticoagulants targeting factor Xa. The antidotes are factor X and 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 reversing anticoagulation, stopping or preventing bleeding in a patient that is currently undergoing anticoagulant therapy with a factor Xa inhibitor.

First claim

The invention claimed is:

1. An isolated two-chain polypeptide comprising:
a first chain comprising amino acid residues 95-105 of SEQ ID NO: 20 or a first amino acid sequence having at least 95% sequence identity to amino acid residues 95-105 of SEQ ID NO: 20 and
a second chain comprising amino acid residues 112-346 of SEQ ID NO: 20 or a second amino acid sequence having at least 95% sequence identity to amino acid residues 112-346 of SEQ ID NO: 20,
wherein the polypeptide (a) has reduced catalytic activity as compared to the corresponding wild-type factor Xa protein, (b) is capable of binding to a factor Xa inhibitor and (c) cannot assemble into a prothrombinase complex, and
wherein (i) the first chain does not include amino acid residues 12-50 of SEQ ID NO: 20, (ii) the first chain does not include amino acid residues 51-94 of SEQ ID NO: 20, or (iii) the second chain does not include amino acid residues 347-365 of SEQ ID NO: 6.

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

3. The polypeptide of claim 2 , wherein the first chain comprises amino acid residues 95-105 of SEQ ID NO: 20 and the second chain comprises amino acid residues 112-346 of SEQ ID NO: 20.

4. The polypeptide of claim 2 , wherein the first chain comprises amino acid residues 51-105 of SEQ ID NO: 20 and the second chain comprises amino acid residues 112-346 of SEQ ID NO: 20.

5. The polypeptide of claim 2 , wherein the first chain comprises amino acid residues 12-105 of SEQ ID NO: 20 and the second chain comprises amino acid residues 112-346 of SEQ ID NO: 20.

6. The polypeptide of claim 1 , wherein the first amino acid sequence has at least 98% sequence identity to amino acid residues 95-105 of SEQ ID NO: 20, and the second amino acid sequence has at least 98% sequence identity to amino acid residues 112-346 of SEQ ID NO: 20.

7. The polypeptide of claim 1 , wherein the first amino acid sequence has at least 99% sequence identity to amino acid residues 95-105 of SEQ ID NO: 20, and the second amino acid sequence has at least 99% sequence identity to amino acid residues 112-346 of SEQ ID NO: 20.

Assignees

• Portola Pharm Inc

Inventors

• Sinha Uma
• Lu Genmin
• Conley Pamela B

Classifications

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61K38/4846

  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

• C12N9/6432 Primary

  Coagulation factor Xa (3.4.21.6) · CPC title

• A61K38/4853

  Kallikrein (3.4.21.34 or 3.4.21.35) · CPC title