Factor IX polypeptides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9670475-B2
Application number	US-201113809276-A
Country	US
Kind code	B2
Filing date	Jul 11, 2011
Priority date	Jul 9, 2010
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The present invention provides methods of administering Factor IX; methods of administering chimeric and hybrid polypeptides comprising Factor IX; chimeric and hybrid polypeptides comprising Factor IX; polynucleotides encoding such chimeric and hybrid polypeptides; cells comprising such polynucleotides; and methods of producing such chimeric and hybrid polypeptides using such cells.

First claim

What is claimed is:

1. A method of controlling a bleeding episode in a human subject in need thereof, comprising administering to the subject multiple doses of about 25 IU/kg to about 50 IU/kg of a chimeric Factor IX (“FIX”) polypeptide comprising FIX and an FcRn binding partner (“FcRn BP”) at a dosing interval of about 7 days between two doses, wherein the FcRn BP comprises Fc or albumin and wherein the subject exhibits the plasma FIX activity above 1 IU/dL during the dosing interval.

2. The method of claim 1 , wherein the plasma level of the chimeric FIX polypeptide in the subject reaches a trough of at least about 1 IU/dL after at least about 6 days after the administration.

3. The method of claim 1 , wherein the chimeric FIX polypeptide exhibits one or more characteristics selected from the group consisting of:
a. an incremental recovery (K-value) (activity; observed) of about 0.62-1.17 IU/dL per IU/kg;
b. a clearance (CL) (activity) of about 1.84-4.58 mL/hour/kg;
c. a mean residence time (MRT) (activity) of about 53.1-85.8 hours;
d. a t 1/2beta (activity) of about 40-67.4 hours;
e. a Vss (activity) of about 145-365 mL/kg;
f. an AUC/dose of about 21.80-54.30 IU*h/dL per IU/kg; and
g. any combination thereof.

4. The method of claim 1 , wherein each of the multiple doses is 25 IU/kg to 40 IU/kg.

5. The method of claim 1 , wherein each of the multiple doses is 25 IU/kg, 30 IU/kg, 35 IU/kg, 40 IU/kg, 45 IU/kg, or 50 IU/kg.

6. The method of claim 1 , wherein each of the multiple doses is 25 IU/kg.

7. The method of claim 1 , wherein each of the multiple doses is 30 IU/kg.

8. The method of claim 1 , wherein each of the multiple doses is 35 IU/kg.

9. The method of claim 1 , wherein each of the multiple doses is 40 IU/kg.

10. The method of claim 1 , wherein each of the multiple doses is 45 IU/kg.

11. The method of claim 1 , wherein each of the multiple doses is 50 IU/kg.

12. The method of claim 1 , wherein the dosing interval is 7 days.

13. The method of claim 4 , wherein the dosing interval is 7 days.

14. The method of claim 1 , wherein the subject has hemophilia B.

15. The method of claim 1 , wherein the subject is in need of control of bleeding in minor hemorrhage, hemarthroses, superficial muscle hemorrhage, soft tissue hemorrhage, moderate hemorrhage, intramuscle or soft tissue hemorrhage with dissection, mucous membrane hemorrhage, hematuria, major hemorrhage, hemorrhage of the pharynx, hemorrhage of the retropharynx, hemorrhage of the retroperitonium, hemorrhage of the central nervous system, bruises, cuts, scrapes, joint hemorrhage, nose bleed, mouth bleed, gum bleed, intracranial bleeding, intraperitoneal bleeding, minor spontaneous hemorrhage, bleeding after major trauma, moderate skin bruising, or spontaneous hemorrhage into joints, muscles, internal organs or the brain.

16. The method of claim 1 , wherein the subject is in need of treatment for hemarthrosis, muscle bleed, oral bleed, hemorrhage, hemorrhage into muscles, oral hemorrhage, trauma, trauma capitis, gastrointestinal bleeding, intracranial hemorrhage, intra-abdominal hemorrhage, intrathoracic hemorrhage, bone fracture, central nervous system bleeding, bleeding in the retropharyngeal space, bleeding in the retroperitoneal space, or bleeding in the illiopsoas sheath.

17. The method of claim 1 , wherein the FIX is at least 90% identical to amino acids 1 to 415 of SEQ ID NO:2.

18. The method of claim 1 , wherein the FIX is at least 95% identical to amino acids 1 to 415 of SEQ ID NO:2.

19. The method of claim 1 , wherein the FIX is identical to amino acids 1 to 415 of SEQ ID NO:2.

20. The method of claim 1 , wherein the FcRn BP comprises Fc.

21. The method of claim 1 , wherein the Fc is at least 90% identical to amino acids 1 to 227 of SEQ ID NO:4.

22. The method of claim 1 , wherein the Fc is at least 95% identical to amino acids 1 to 227 of SEQ ID NO:4.

23. The method of claim 1 , wherein the Fc is identical to amino acids 1 to 227 of SEQ ID NO:4.

24. The method of claim 1 , wherein the FcRn BP comprises albumin.

25. The method of claim 1 , wherein the chimeric FIX polypeptide further comprises a linker joining the FIX and the FcRn BP.

26. The method of claim 1 , wherein the chimeric FIX polypeptide exhibits an incremental recovery (K-Value) (activity; observed) of about 0.93 ±0.18 IU/dL per IU/kg.

27. The method of claim 1 , wherein the chimeric FIX polypeptide exhibits an incremental recovery (K-Value) (activity; observed) of about 1.2 IU/dL per IU/kg.

28. The method of claim 1 , wherein the chimeric FIX polypeptide exhibits a t 1/2beta (activity) of about 40 hours to about 67.4 hours.

29. The method of claim 1 , wherein the chimeric FIX polypeptide is administered intravenously.

30. The method of claim 4 , wherein a clearance (CL) (activity) of the chimeric FIX polypeptide is about 1.84 to about 4.58 mL/hour/kg.

31. The method of claim 4 , wherein a Vss (activity) of the chimeric FIX polypeptide is about 145 to about 365 mL/kg.

32. The method of claim 4 , wherein an AUC/dose of the chimeric FIX polypeptide is about 21.80 to about 54.30 IU*h/dL per IU/kg.

33. The method of claim 4 , wherein the FcRn BP comprises Fc.

34. The method of claim 4 , wherein the FcRn BP comprises albumin.

Assignees

• Pierce Glenn
• Truex Samantha
• Peters Robert T
• Jiang Haiyan
• Bioverativ Therapeutics Inc

Inventors

• Pierce Glenn
• Truex Samantha
• Peters Robert T
• Jiang Haiyan

Classifications

• C12N9/96 Primary

  Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates · CPC title

• C07K16/18

  against material from animals or humans · CPC title

• C12N9/644

  Coagulation factor IXa (3.4.21.22) · CPC title

• C12Y304/21022

  Coagulation factor IXa (3.4.21.22) · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title