TFPI inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-10201586-B2
Application number	US-201615373742-A
Country	US
Kind code	B2
Filing date	Dec 9, 2016
Priority date	Mar 19, 2010
Publication date	Feb 12, 2019
Grant date	Feb 12, 2019

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, an identify a TFPI-binding compound.

First claim

What is claimed:

1. A peptide comprising (a) an amino acid sequence having at least 80% identity to SYYKWH[CA-Moo-RDLKGTFTC]VWVKF (SEQ ID NO: 1334) or (b) a variant of SEQ ID NO: 1334, wherein the variant comprises one or two amino acid substitution(s), deletion(s) or insertion(s).

2. The peptide of claim 1 , further comprising N-terminal amino acid(s) and/or moieties 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.

3. The peptide of claim 1 , further comprising C-terminal amino acid(s) and/or moieties 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.

4. The peptide of claim 1 , wherein the IC50 of the peptide is less than 250 nM or less than 50 nM and wherein the peptide comprises a disulfide bond between two cysteine residues.

5. The peptide of claim 1 , wherein the peptide inhibits TFPI activity and binds to TFPI 1-alpha with a dissociation constant of less than 10 μM and wherein the peptide comprises a disulfide bond between two cysteine residues.

6. The peptide of claim 1 , operably linked to a moiety that enhances the half-life of the peptide.

7. The peptide of claim 1 , wherein the peptide is conjugated to a polyethylene glycol (PEG) moiety, human serum albumin (HSA), an antibody or fragment thereof, hydroxyethyl starch, a multimer comprising proline, alanine, serine, or a combination thereof (PASylation), or a C12-C18 fatty acid.

8. The peptide of claim 1 , wherein the peptide comprises 90% identity to SEQ ID NO: 1334.

9. The peptide of claim 8 , wherein the peptide comprises SEQ ID NO: 1334.

10. The peptide of claim 8 , wherein the peptide consists of SEQ ID NO: 1334.

11. A TFPI-binding peptide comprising a homo-dimer, homo-multimer, hetero-dimer, or hetero-multimer of one or more peptides of claim 1 .

12. A pharmaceutical composition for treating a subject suffering from a blood coagulation disorder or at risk of suffering from a blood coagulation disorder, comprising the peptide according to claim 1 .

13. A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable carrier.

14. A peptide complex comprising (i) the peptide of claim 1 and (ii) another peptide linked to the peptide of (i).

15. The peptide complex of claim 14 wherein peptide (i) is linked to peptide (ii) via a multimerization domain or chemical linkage.

16. The peptide complex of claim 14 , further comprising at least one moiety for improving peptide half life.

17. A pharmaceutical composition comprising the peptide complex of claim 14 for use in treating a subject suffering from a blood coagulation disorder or at risk of suffering from a blood coagulation disorder.

Assignees

• Baxalta GmbH
• Baxalta Inc

Inventors

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

Classifications

• A61P7/04

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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/00

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

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · CPC title

• G01N2333/8114

  Kunitz type inhibitors · CPC title