TFPI inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-9018167-B2
Application number	US-201313846359-A
Country	US
Kind code	B2
Filing date	Mar 18, 2013
Priority date	Mar 19, 2010
Publication date	Apr 28, 2015
Grant date	Apr 28, 2015

Abstract

The invention provides peptides that bind Tissue Factor Pathway Inhibitor (TFPI), including TFPI-inhibitory peptides, and compositions thereof. The peptides may be used to inhibit a TFPI, enhance thrombin formation in a clotting factor-deficient subject, increase blood clot formation in a subject, treat a blood coagulation disorder in a subject, purify TFPI, and identify a TFPI-binding compound.

First claim

What is claimed is:

1. A method for inhibiting human TFPI, the method comprising contacting human TFPI with a peptide comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NOs: 4133, 4137, 4153-4155, or 4158.

2. A method for treating a subject suffering from a blood coagulation disorder or at risk of suffering from a blood coagulation disorder, the method comprising administering to the subject a peptide comprising an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NOs: 4133, 4137, 4153-4155, or 4158.

3. The method of claim 1 , wherein the peptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NOs: 4133, 4137, 4153-4155, or 4158.

4. The method of claim 3 , wherein the peptide comprises the amino acid sequence of SEQ ID NOs: 4133, 4137, 4153-4155, or 4158.

5. The method according to claim 1 , wherein the peptide comprises an N-terminal amino acid and/or moiety selected from the group consisting of FAM-Ttds, PE, Palm, 2-phenyl acetyl, 3-phenyl propionyl, 2-(naphtha 2-yl)acetyl, hexanoyl, 2-methyl propionyl, 3-methyl butanoyl, 2-naphthylsulfonyl, and 1-naphthylsulfonyl.

6. The method according to claim 1 , wherein the peptide comprises an C-terminal amino acid and/or moiety selected from the group consisting of C, c, C(NEM), K(Ttds-maleimidopropionyl(EtSH)), FA19205, FA19204, FA19203, FA03202, K(Tdts-maleimide), K(AOA), and Cea.

7. The method according to claim 2 , wherein the peptide is conjugated to a polyethylene glycol (PEG) moiety.

8. The method according to claim 2 , wherein the peptide is conjugated to human serum albumin (HSA), an antibody or fragment thereof, hydroxyethyl starch, a proline-alanine-serine multimer (PASylation), a C12-C18 fatty acid, or polysialic acid.

9. The method according to claim 1 , wherein the peptide is conjugated to a polyethylene glycol (PEG) moiety.

10. The method according to claim 1 , wherein the peptide is conjugated to human serum albumin (HSA), an antibody or fragment thereof, hydroxyethyl starch, a proline-alanine-serine multimer (PASylation), a C12-C18 fatty acid, or polysialic acid.

11. The method of claim 2 , wherein the peptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NOs: 4133, 4137, 4153-4155, or 4158.

12. The method of claim 2 , wherein the peptide comprises the amino acid sequence of SEQ ID NOs: 4133, 4137, 4153-4155, or 4158.

13. The method according to claim 2 , wherein the peptide comprises an N-terminal amino acid and/or moiety selected from the group consisting of FAM-Ttds, PE, Palm, 2-phenyl acetyl, 3-phenyl propionyl, 2-(naphtha-2-yl)acetyl, hexanoyl, 2-methyl propionyl, 3-methyl butanoyl, 2-naphthylsulfonyl, and 1-naphthylsulfonyl.

14. The method according to claim 2 , wherein the peptide comprises an C-terminal amino acid and/or moiety selected from the group consisting of C, c, C(NEM), K(Ttds-maleimidopropionyl(EtSH)), FA19205, FA19204, FA19203, FA03202, K(Tdts-maleimide), K(AOA), and Cea.

15. The method of claim 2 , wherein the blood coagulation disorder is hemophilia.

16. The method of claim 15 , wherein the subject has hemophilia.

Assignees

• Baxter Int
• Baxter Healthcare Sa

Inventors

• Dockal Michael
• Hartmann Rudolf
• Fries Markus
• Scheiflinger Friedrich
• Ehrlich Hartmut
• Reineke Ulrich
• Osterkamp Frank
• Polakowski Thomas

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• G01N2333/96444

  Factor X (3.4.21.6) · CPC title

• G01N2333/745

  Assays involving non-enzymic blood coagulation factors · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title