Conjugated blood coagulation factor VIIa
View Patent ↗The present invention provides a biocompatible polymer conjugated to FVIIa via one or more cysteine residues, suitably via a linker across a reduced disulphide bond in FVIIa, and pharmaceutical compositions comprising such conjugated forms of FVIIa.
1. A Factor VIIa-polyethylene glycol conjugate, wherein one or more polyethylene glycol groups are conjugated to FVIIa by a linker group bridging the sulphur atoms of two cysteine residues that formed a disulphide bond in FVIIa,
wherein each polyethylene glycol group conjugated to FVIIa by a linker group bridging the sulphur atoms of two cysteine residues that formed a disulphide bond in FVIIa:
wherein R 1 is a substituent which is a direct bond, an alkylene group, or an optionally-substituted aryl or heteroaryl group; wherein the aryl group is selected from the group consisting of phenyl, benzoyl and naphthyl; wherein a suitable heteroaryl group is selected from the group consisting of pyridine, pyrrole, furan, pyran, imidazole, pyrazole, oxazole, pyridazine, pyrimidine and purine; wherein linkage to the polymer is by a hydrolytically labile bond, or by a nonlabile bond.
2. The Factor VIIa-polyethylene glycol conjugate of claim 1 wherein the polyethylene glycol has a molecular weight of about 5-100 kDa.
3. The Factor VIIa-polyethylene glycol conjugate of claim 1 , wherein alkylene group is a C 1-10 alkylene group.
4. A pharmaceutical composition comprising the Factor VIIa-polyethylene glycol conjugate of claim 1 .
5. The pharmaceutical composition of claim 4 further comprising a pharmaceutically acceptable diluent, adjuvant or carrier.
6. The pharmaceutical composition of claim 4 further comprising another pharmaceutically active agent.
7. The pharmaceutical composition of claim 4 , wherein the composition is suitable for parenteral administration.
8. The pharmaceutical composition of claim 4 , wherein the composition is suitable for intradermal, subcutaneous, and intramuscular injections, and intravenous or intraosseous infusions.
9. The pharmaceutical composition of claim 4 wherein the composition is in the form of a solution, suspension or emulsion.
10. The pharmaceutical composition of claim 4 , wherein the FVIIa conjugate has a longer half-life as compared to unmodified FVIIa.
11. The pharmaceutical composition of claim 4 , wherein the FVIIa conjugate has a higher AUC as compared to unmodified FVIIa.
12. The pharmaceutical composition of claim 4 , wherein the FVIIa conjugate has a higher bioavailability as compared to unmodified FVIIa.
13. The pharmaceutical composition of claim 4 , wherein the FVIIa conjugate has a lower immunogenicity as compared to unmodified FVIIa.
14. A method of treatment of a blood clotting disease or trauma comprising administration of the pharmaceutical composition of claim 4 to a patient in need thereof.
15. The method of treatment as claimed in claim 14 wherein the blood clotting disease is haemophilia A or haemophilia B.
16. A method to reduce the risk of hemarthrosis, hemorrhage, gastrointestinal bleeding and menorrhagia in a patient with haemophilia A, haemophilia B or trauma, comprising administering to a patient in need thereof a pharmaceutical composition comprising the FVIIa conjugate of claim 4 .
17. The method of claim 16 , wherein the composition is administered subcutaneously.
18. The method of claim 16 , wherein the composition is administered intravenously.
19. The method of claim 16 , wherein the composition is administered once every one to fourteen days.
20. A method of treatment of a blood clotting disease or trauma comprising administration of the pharmaceutical composition of claim 4 to a mammal in need thereof.
21. The method of treatment as claimed in claim 20 wherein the blood clotting disease is haemophilia A or haemophilia B.
22. A method to reduce the risk of hemarthrosis, hemorrhage, gastrointestinal bleeding and menorrhagia in a mammal with haemophilia A, haemophilia B or trauma, comprising administering to a mammal in need thereof a pharmaceutical composition comprising the FVIIa conjugate of claim 4 .
23. The method of claim 22 , wherein the composition is administered subcutaneously.
24. The method of claim 22 , wherein the composition is administered intravenously.
25. The method of claim 22 , wherein the composition is administered once every one to fourteen days.