Patent · US10201586B2 · B2 · US

TFPI inhibitors and methods of use

(11) Publication number

US10201586B2

(21) Application number

15/373,742

(22) Filing date

2016-12-09

(30) Priority date

2010-03-19

(43) Publication date

2019-02-12

(45) Date of grant

2019-02-12

(51) IPC

A61K 38/10; C07K 1/14; C07K 7/08; G16B 15/00; G16B 20/30; G16B 20/50; A61K 38/57; C07K 14/00; C07K 14/745; C07K 14/81; G01N 33/68

(52) CPC

A61K Preparations for medical, dental or toiletry purposes: 38/10, 2121/00, 38/00
A61P Specific therapeutic activity of chemical compounds or medicinal preparations: 7/00, 7/02, 7/04
C07K Peptides: 1/14, 14/00, 14/8114, 7/08
G01N Investigating or analysing materials by determining their chemical or physical properties: 2333/745, 2333/8114, 2333/96444, 2333/96447, 2500/02, 2500/04, 2500/20, 33/68
G06F Electric digital data processing: 19/16, 19/18
G16B Bioinformatics, i.e. information and communication technology [ICT] specially adapted for genetic or protein-related data processing in computational molecular biology: 15/00, 20/00, 20/30, 20/50

(73) Assignee

Baxalta GmbH; Baxalta Inc

(72) Inventors

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

(54) Title

TFPI inhibitors and methods of use

(57) 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.

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Claims (17)

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).
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.
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.
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.
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.
The peptide of claim 1, operably linked to a moiety that enhances the half-life of the peptide.
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.
The peptide of claim 1, wherein the peptide comprises 90% identity to SEQ ID NO: 1334.
The peptide of claim 8, wherein the peptide comprises SEQ ID NO: 1334.
The peptide of claim 8, wherein the peptide consists of SEQ ID NO: 1334.
A TFPI-binding peptide comprising a homo-dimer, homo-multimer, hetero-dimer, or hetero-multimer of one or more peptides of claim 1.
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.
A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable carrier.
A peptide complex comprising (i) the peptide of claim 1 and (ii) another peptide linked to the peptide of (i).
The peptide complex of claim 14 wherein peptide (i) is linked to peptide (ii) via a multimerization domain or chemical linkage.
The peptide complex of claim 14, further comprising at least one moiety for improving peptide half life.
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.

Description

The invention generally relates to peptides that bind Tissue Factor Pathway Inhibitor (TFPI) and uses thereof.

Hemostasis relies on the complex coagulation cascade, wherein a series of events mediated by blood clotting factors leads to conversion of prothrombin to thrombin. Factor X (FX) activation is the central event of both the intrinsic and extrinsic pathways of the coagulation cascade. The extrinsic pathway has been proposed as the primary activator of the coagulation cascade (Mackman et al., Arterioscler. Thromb. Casc. Biol., 27, 1687-1693 (2007)). Circulating Tissue Factor (TF) and activated Factor VII (FVIIa) interact to form the “extrinsic complex,” which mediates activation of FX. The coagulation cascade is amplified by the intrinsic pathway, during which successive activation of factors XII, XI, IX, and VIII results in formation of the “intrinsic” FIXa-FVIIIa complex that also mediates FX activation. Activated FX promotes thrombin formation, which is required for the body to create fibrin and effectively curb bleeding.

Severe bleeding disorders, such as hemophilia, result from disruption of the blood coagulation cascade. Hemophilia A, the most common type of hemophilia, stems from a deficiency in factor VIII, while hemophilia B is associated with deficiencies in Factor IX (FIX). Hemophilia C is caused by a deficiency in Factor XI (FXI) (Cawthem et al., Blood, 91(12), 4581-4592 (1998)). There is currently no cure for hemophilia and other clotting diseases. Factor replacement therapy is the most common treatment for blood coagulation disorders.

Citations (152)

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Record as JSON

{
  "publication_number": "US10201586B2",
  "country": "US",
  "kind": "B2",
  "title": "TFPI inhibitors and methods of use",
  "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.",
  "claims": [
    "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."
  ],
  "description_excerpt": "The invention generally relates to peptides that bind Tissue Factor Pathway Inhibitor (TFPI) and uses thereof.\n\nHemostasis relies on the complex coagulation cascade, wherein a series of events mediated by blood clotting factors leads to conversion of prothrombin to thrombin. Factor X (FX) activation is the central event of both the intrinsic and extrinsic pathways of the coagulation cascade. The extrinsic pathway has been proposed as the primary activator of the coagulation cascade (Mackman et al., Arterioscler. Thromb. Casc. Biol., 27, 1687-1693 (2007)). Circulating Tissue Factor (TF) and activated Factor VII (FVIIa) interact to form the “extrinsic complex,” which mediates activation of FX. The coagulation cascade is amplified by the intrinsic pathway, during which successive activation of factors XII, XI, IX, and VIII results in formation of the “intrinsic” FIXa-FVIIIa complex that also mediates FX activation. Activated FX promotes thrombin formation, which is required for the body to create fibrin and effectively curb bleeding.\n\nSevere bleeding disorders, such as hemophilia, result from disruption of the blood coagulation cascade. Hemophilia A, the most common type of hemophilia, stems from a deficiency in factor VIII, while hemophilia B is associated with deficiencies in Factor IX (FIX). Hemophilia C is caused by a deficiency in Factor XI (FXI) (Cawthem et al., Blood, 91(12), 4581-4592 (1998)). There is currently no cure for hemophilia and other clotting diseases. Factor replacement therapy is the most common treatment for blood coagulation disorders.",
  "cpc": [
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  "assignees": [
    "Baxalta GmbH",
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  "inventors": [
    "Michael Dockal",
    "Rudolf Hartmann",
    "Markus Fries",
    "Friedrich Scheiflinger",
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  ],
  "filing_date": "2016-12-09",
  "publication_date": "2019-02-12",
  "grant_date": "2019-02-12",
  "priority_date": "2010-03-19",
  "application_number": "US-201615373742-A",
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