Factor VIII fusion protein
The present invention relates to modified coagulation factors. In particular, the present invention relates to conjugated Factor VIII molecules fused to a polypeptide such as e.g. an antibody binding protein or a Fc domain.
1. A fusion protein comprising a Factor VIII (FVIII) molecule and a fusion partner, wherein: (1) the FVIII molecule comprises a heavy chain and a light chain; and (2) the fusion partner is an Fcγ receptor or an immunoglobulin-binding fragment thereof fused to the N-terminus end of the light chain.
2. The fusion protein according to claim 1 , wherein said Fcγ receptor is FcγRI comprising the amino acid sequence of SEQ ID NO:9.
3. The fusion protein of claim 1 , wherein the FVIII molecule contains an amino acid substitution selected from the group consisting of Y1680F, Y1680R, Y1680N, E1682T and Y1680C numbered relative to SEQ ID NO: 1.
4. A pharmaceutical composition comprising a fusion protein according to claim 1 .
5. A fusion protein comprising a B-domain truncated Factor VIII (FVIII) molecule and a fusion partner, wherein: (1) the FVIII molecule comprises a heavy chain and a light chain; (2) the fusion partner is an Fcγ receptor or an immunoglobulin-binding fragment thereof fused to the N-terminus end of the light chain; and (3) wherein residues 1649-1689 of the FVIII molecule numbered relative to SEQ ID NO:1 are fully or partially deleted.
6. A fusion protein comprising a B-domain truncated Factor VIII (FVIII) molecule and a fusion partner, wherein: (1) the FVIII molecule comprises a heavy chain and a light chain; (2) the fusion partner is an Fcγ receptor or an immunoglobulin-binding fragment thereof fused to the N-terminus end of the light chain; and (3) wherein residues 1647-1687 of the FVIII molecule numbered relative to SEQ ID NO:1 are fully or partially deleted.
7. A fusion protein comprising a B-domain truncated Factor VIII (FVIII) molecule and a fusion partner, wherein: (1) the FVIII molecule comprises a heavy chain and a light chain; (2) the fusion partner is an Fcγ receptor or an immunoglobulin-binding fragment thereof fused to the N-terminus end of the light chain; and (3) the heavy chain of the FVIII molecule comprises a truncated B-domain having the amino acid sequence of SEQ ID NO:2.
8. The fusion protein of claim 7 , wherein the truncated B-domain has an O-linked glycan attached to Serine at residue 750 numbered relative to SEQ ID NO:1.
9. The fusion protein of claim 8 , wherein a side group is attached to the O-linked glycan via a sialic acid.
10. The fusion protein of claim 9 , wherein the side group is polyethylene glycol (PEG).
11. The fusion protein according to claim 7 , wherein said Fcγ receptor is FcγRI comprising the amino acid sequence of SEQ ID NO:9.
12. The fusion protein of claim 7 , wherein the FVIII molecule contains an amino acid substitution selected from the group consisting of Y1680F, Y1680R, Y1680N, E1682T and Y1680C numbered relative to SEQ ID NO:1.
13. A pharmaceutical composition comprising a fusion protein according to claim 7 .
14. A fusion protein comprising a Factor VIII (FVIII) molecule and a fusion partner, wherein the Factor VIII molecule comprises a heavy chain and a light chain; the fusion partner is an Fcγ receptor or an immunoglobulin-binding fragment thereof fused to C-terminus end of the light chain.
15. A fusion protein comprising a B-domain truncated Factor VIII (FVIII) molecule and a fusion partner, wherein the Factor VIII molecule comprises a heavy chain and a light chain; the fusion partner is an Fcγ receptor or an immunoglobulin-binding fragment thereof fused to C-terminus end of the light chain.
16. The fusion protein of claim 15 , wherein the truncated B-domain has an O-linked glycan attached to Serine at residue 750 numbered relative to SEQ ID NO:1.
17. The fusion protein of claim 16 , wherein a side group is attached to the O-linked glycan via a sialic acid.
18. The fusion protein of claim 17 , wherein the side group is polyethylene glycol (PEG).
19. A method for treating haemophilia comprising administering an effective amount of the molecule of claim 1 to a subject in need thereof.