Coagulation factor VII derivatives
The present invention relates to novel human coagulation Factor VII polypeptides, Factor VII derivatives as well as polynucleotide constructs encoding such polypeptides, vectors and host cells comprising and expressing the polynucleotide, pharmaceutical compositions, uses and methods of treatment.
1. A human Factor VII variant polypeptide, said polypeptide comprising the amino acid sequence of SEQ ID NO: 1 in which at least one amino acid has been substituted with a different amino acid or inserted, wherein said variant comprises a substitution or insertion selected from the group consisting of: Q250C; P406C; and 407C.
2. The polypeptide as defined in claim 1 , wherein the different substituted or inserted amino acid is conjugated with a chemical group that increases the actual molecular weight of the conjugated polypeptide relative to the molecular weight of the variant polypeptide when unconjugated from about 300 daltons to about 100,000 daltons and wherein said conjugated polypeptide has substantially the same activity or increased activity compared to recombinant wild type human Factor VIIa.
3. The polypeptide as defined in claim 2 , wherein said chemical group is substantially neutral.
4. The polypeptide as defined in claim 2 , wherein said increase in molecular weight is from about 1,000 daltons to about 80,000 daltons.
5. The polypeptide as defined in claim 4 , wherein said increase in molecular weight is from about 5,000 daltons to about 60,000 daltons.
6. The polypeptide as defined in claim 5 , wherein said increase in molecular weight is from about 10,000 daltons to about 40,000 daltons.
7. The polypeptide as defined in claim 2 , wherein said chemical group is polyethylene glycol.
8. A pharmaceutical composition comprising the Factor VII variant polypeptide as defined in claim 1 and, optionally, a pharmaceutically acceptable carrier.
9. A method for the treatment of bleeding episodes or bleeding disorders in a subject or for the enhancement of the normal haemostatic system, said method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the Factor VII variant polypeptide as defined in claim 2 .