Mutated von Willebrand factor

1. A modified polypeptide which binds Factor VIII, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:5-12 and 17.

2. The modified polypeptide of claim 1 , wherein the modified polypeptide binds to Factor VIII with an off rate lower than a reference polypeptide comprising SEQ ID NO:3.

3. The modified polypeptide of claim 2 , wherein the modified polypeptide binds to Factor VIII with an off rate at least 5 fold lower than the reference polypeptide.

4. The modified polypeptide of claim 2 , wherein the modified polypeptide binds to Factor VIII with an off rate at least 10 fold lower than the reference polypeptide.

5. The modified polypeptide of claim 2 , wherein the modified polypeptide binds to Factor VIII with a dissociation constant (KD) at least 5 fold lower than the reference polypeptide.

6. The modified polypeptide of claim 5 , wherein the modified polypeptide binds to Factor VIII with an off rate at least 10 fold lower than the reference polypeptide.

7. The modified polypeptide of claim 1 , wherein the modified polypeptide is modified von Willebrand Factor.

8. The modified polypeptide of claim 1 , further comprising a half-life extending moiety.

9. The modified polypeptide of claim 8 , wherein the half-life extending moiety is a heterologous amino acid sequence fused to the modified polypeptide.

10. The modified polypeptide of claim 9 , wherein the heterologous amino acid sequence comprises a polypeptide selected from the group consisting of immunoglobulin constant regions and portions thereof, transferrin and fragments thereof, the C-terminal peptide of human chorionic gonadotropin, solvated random chains with large hydrodynamic volume known as XTEN, homo-amino acid repeats (HAP), proline-alanine-serine repeats (PAS), albumin, afamin, alpha-fetoprotein, Vitamin D binding protein, polypeptides capable of binding under physiological conditions to albumin or immunoglobulin constant regions, and combinations thereof.

11. The modified polypeptide of claim 9 , wherein the heterologous amino acid sequence comprises an Fc fragment.

12. The modified polypeptide of claim 9 , wherein the heterologous amino acid sequence comprises albumin.

13. The modified polypeptide of claim 12 , wherein the N-terminus of the albumin is fused to the C-terminus of the modified polypeptide, either directly or via a spacer.

14. The modified polypeptide of claim 13 , wherein 1 to 5 amino acids at the natural C-terminus of the modified polypeptide have been deleted.

15. The modified polypeptide of claim 8 , wherein the half-life extending moiety is conjugated to the modified polypeptide.

16. The modified polypeptide of claim 15 , wherein the half-life extending moiety is selected from the group consisting of hydroxyethyl starch (HES), polyethylene glycol (PEG), polysialic acids (PSAs), elastin-like polypeptides, heparosan polymers, hyaluronic acid, albumin binding ligands, and combinations thereof.

17. The modified polypeptide of claim 15 , wherein the half-life extending moiety is a fatty acid chain.

18. A complex comprising a Factor VIII molecule and the modified polypeptide of claim 1 .

19. A pharmaceutical composition comprising the modified polypeptide of claim 1 .

20. A method of treating a bleeding disorder, comprising administering to a patient in need thereof a pharmaceutically effective amount of the modified polypeptide of claim 1 .

21. The method of claim 20 , wherein the bleeding disorder is von Willebrand's disease (VWD) or hemophilia A.

22. A method of increasing the half-life of Factor VIII, comprising mixing a Factor VIII with the modified polypeptide of claim 1 .