TFPI inhibitors and methods of use
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.
1. A method for treating a subject suffering from a blood coagulation disorder, the method comprising administering to the subject a peptide comprising (a) the 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 method 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-naphthyl sulfonyl, and 1-naphthyl sulfonyl.
3. The method 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 method of claim 1 , wherein the IC 50 of the peptide is less than 250 nM or less than 50 nM.
5. The method of claim 1 , wherein the peptide inhibits Tissue Factor Pathway Inhibitor (TFPI) activity and binds to TFPI 1-alpha with a dissociation constant of less than 10 μM.
6. The method of claim 1 , operably linked to a moiety that enhances the half-life of the peptide.
7. The method 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 C 12 -C 18 fatty acid.
8. The method of claim 1 , wherein the peptide comprises 90% identity to SEQ ID NO: 1334.
9. The method of claim 8 , wherein the peptide comprises SEQ ID NO: 1334.
10. The method of claim 8 , wherein the peptide consists of SEQ ID NO: 1334.
11. The method of claim 1 , wherein the peptide is part of a homo-dimer, homo-multimer, hetero-dimer, or hetero-multimer.
12. The method of claim 11 , wherein the peptide further comprises at least one moiety for improving peptide half life.
13. The method of claim 1 , wherein the peptide is linked to another peptide.
14. The method of claim 13 wherein the peptide is linked to another peptide via a multimerization domain or chemical linkage.
15. The method of claim 13 , wherein the peptide further comprises at least one moiety for improving peptide half life.
16. The method of claim 1 , wherein the peptide further comprises at least one moiety for improving peptide half life.
17. The method of claim 1 , wherein the blood coagulation disorder is caused by deficient blood coagulation factor activity and/or deficient platelet activity.
18. The method of claim 1 , wherein the blood coagulation disorder is hypoprothrombinemia; hemophilia A; hemophilia B; hemophilia C; thrombocytopenia; aplastic anemia; idiopathic thrombocytopenic purpura; thrombotic thrombocytopenia purpura; thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in cancer patients; posttransfusion purpura (PTP); Von Willebrand Disease; paraneoplastic platelet dysfunction; Glanzman's thrombasthenia; Bernard-Soulier disease; deficiency in FXI; deficiency in FXII; deficiency in prekallikrein; deficiency in HMWK; deficiency in vitamin K; afibrinogenemia; hypofibrinogenemia; dysfibrinogenemia; or deficiency in α2-antiplasmin.
19. The method of claim 18 , wherein the thrombocytopenia is idiopathic thrombocytopenia, immune thrombocytopenia; HIV-associated thrombocytopenia; metastatic tumor-associated thrombocytopenia; myelodysplastic syndrome-associated thrombocytopenia; acute profound thrombocytopenia following C7E3 Fab (Abciximab) therapy; alloimmune thrombocytopenia; maternal alloimmune thrombocytopenia; thrombocytopenia associated with antiphospholipid antibodies and thrombosis; autoimmune thrombocytopenia; drug-induced immune thrombocytopenia; carboplatin-induced thrombocytopenia; heparin-induced thrombocytopenia; fetal thrombocytopenia; gestational thrombocytopenia; lupoid thrombocytopenia; thrombocytopenia in patients with malignancies; Paris-Trousseau thrombocytopenia; neonatal alloimmune thrombocytopenia; or CMV-associated thrombocytopenia.
20. The method of claim 1 , wherein the blood coagulation disorder is hemophilia A.
21. The method of claim 1 , wherein the blood coagulation disorder is hemophilia B.
22. The method of claim 1 , wherein the blood coagulation disorder is hemophilia C.