Truncated von Willebrand Factor polypeptides for treating hemophilia
The invention pertains to a polypeptide comprising a truncated von Willebrand Factor (VWF) and a half-life extending moiety, for use in the treatment of a blood coagulation disorder, said treatment comprising administering the polypeptide to a subject having a blood coagulation disorder and having endogenous Factor VIII (FVIII), wherein the activity level of endogenous FVIII in said subject before treatment with said polypeptide is reduced relative to the activity level of FVIII in normal human plasma (NHP) provided that the activity level of endogenous FVIII in said subject is at least 0.5% of the activity level of endogenous FVIII in normal human plasma (NHP), wherein the polypeptide is capable of binding to endogenous FVIII and wherein the endogenous FVIII level is increased following administration of said polypeptide.
1. A method of treating a blood coagulation disorder, comprising
administering an effective amount of a polypeptide comprising a truncated von Willebrand Factor (VWF) and a half-life extending moiety to a human subject having a blood coagulation disorder and having endogenous Factor VIII (FVIII), wherein the blood coagulation disorder is von-Willebrand disease,
wherein the truncated VWF comprises an amino acid sequence having a sequence identity of at least 90% to 764 to 1242 of SEQ ID NO:4,
wherein the activity level of endogenous FVIII in said human subject before treatment with said polypeptide is reduced relative to the activity level of FVIII in normal human plasma (NHP) provided that the activity level of endogenous FVIII in said human subject is from 0.5% to 40% of the activity level of endogenous FVIII in normal human plasma (NHP),
wherein the polypeptide is capable of binding to endogenous FVIII, and wherein the endogenous FVIII level is increased following administration of said polypeptide, wherein said polypeptide is administered for prophylactic treatment of said human subject,
wherein said treatment does not comprise co-administration of exogenous FVIII, and wherein the polypeptide is administered to the human subject in a molar ratio of the polypeptide to endogenous VWF in the human subject of at least 50.
2. The method of claim 1 , wherein, following administration of the polypeptide, the activity level of endogenous FVIII is increased to at least 1% of the activity level of endogenous FVIII in NHP.
3. The method of claim 1 , wherein the truncated von Willebrand Factor (VWF) is a human truncated von Willebrand Factor (VWF).
4. The method of claim 1 , wherein the activity level of endogenous FVIII in said human subject before treatment with said polypeptide is from 0.5% to 30% of the activity level of endogenous FVIII in NHP.
5. The method of claim 1 , wherein the activity level of endogenous FVIII in said human subject before treatment with said polypeptide is at least 1% of the activity level of endogenous FVIII in NHP.
6. The method of claim 1 , wherein the polypeptide is administered intravenously or extravascularly.
7. The method of claim 1 , wherein the polypeptide is a dimer.
8. The method of claim 7 , wherein the affinity of said dimer to FVIII is greater than the affinity of a monomeric polypeptide to said FVIII, wherein said monomeric polypeptide has the same amino acid sequence as a monomeric subunit of the dimer, and wherein the polypeptide binds to FVIII with a dissociation constant K D ranging from 0.1 pm to less than 1 nM.
9. The method of claim 1 , wherein the truncated VWF consists of (a) amino acids 764 to 1242 of SEQ ID NO:4, or (b) an amino acid sequence having a sequence identity of at least 90% to amino acids 764 to 1242 of SEQ ID NO:4.
10. The method of claim 1 , wherein the half-life extending moiety is a heterologous amino acid sequence that is fused to the truncated VWF.
11. The method of claim 10 , wherein said heterologous amino acid sequence is chosen from albumin or fragments thereof, transferrin or fragments thereof, the C-terminal peptide of human chorionic gonadotropin, an XTEN sequence, homo-amino acid repeats (HAP), proline-alanine-serine repeats (PAS), afamin, alpha-fetoprotein, Vitamin D binding protein, polypeptides capable of binding under physiological conditions to albumin or to immunoglobulin constant regions, and polypeptides capable of binding to the neonatal Fc receptor (FcRn).
12. The method of claim 1 , wherein the half-life extending moiety is conjugated to the truncated VWF of the polypeptide.
13. The method of claim 12 , wherein said half-life extending moiety is chosen from hydroxyethyl starch (HES), polyethylene glycol (PEG), polysialic acids (PSAs), elastin-like polypeptides, heparosan polymers, hyaluronic acid and albumin binding ligands, and combinations thereof.
14. The method of claim 1 , wherein the pharmacokinetic parameters of the endogenous FVIII are improved by the administration of the polypeptide, and wherein the mean residence time (MRT) of the endogenous FVIII is increased, the half-life of the endogenous FVIII is prolonged, and/or the clearance of the endogenous FVIII is reduced.
15. The method of claim 1 , wherein the plasma half-life of the polypeptide is higher than the plasma half-life of endogenous VWF and/or the plasma half-life of VWF of normal human plasma (NHP).
16. The method of claim 15 , wherein the plasma half-life of the polypeptide is at least 25% higher than the plasma half-life of endogenous VWF and/or the plasma half-life of VWF of normal human plasma (NHP).
17. The method of claim 1 , wherein following administration of the polypeptide, the human subject's endogenous FVIII activity level is increased up to the physiological FVIII level (100%=1 IU/mL) or not substantially increased above the physiological FVIII level in normal human plasma.
18. The method of claim 11 , wherein polypeptides capable of binding to the neonatal Fc receptor (FcRn) comprise immunoglobulin constant regions and portions thereof.
19. The method of claim 18 , wherein the immunoglobulin constant regions and portions thereof comprise the Fc portion of immunoglobulin, and combinations thereof.
20. The method of claim 4 , wherein the activity level of endogenous FVIII in said human subject before treatment with said polypeptide is less than 20% of the activity level of endogenous FVIII in NHP.
21. The method of claim 5 , wherein the activity level of endogenous FVIII in said human subject before treatment with said polypeptide is at least 2% of the activity level of endogenous FVIII in NHP.
22. The method of claim 8 , wherein the polypeptide binds to FVIII with a dissociation constant K D ranging from 0.1 pm to less than 500 pM.
23. The method of claim 8 , wherein the polypeptide binds to FVIII with a dissociation constant K D ranging from 0.1 pm to less than 200 pM.
24. The method of claim 8 , wherein the polypeptide binds to FVIII with a dissociation constant K D ranging from 0.1 pm to less than 100 pM.