Glycopegylated factor IX

• US 8,791,070 B2
• Filed: 10/11/2013
• Issued: 07/29/2014
• Est. Priority Date: 04/09/2003
• Status: Expired due to Term

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: DeFrees, Shawn, Bayer, Robert J., Bowe, Caryn, Paneerselvam, Krishnasamy
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US14/052,442
• Publication Number:
  US 20140112903A1
• Time in Patent Office: 291 Days
• US Class Current: 514/13.5
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C12N 9/644 Coagulation factor IXa (3.4.21.22)
• CPC Class Codes: C12Y 304/21022 Coagulation factor IXa (3.4.21.22)

Abstract

Conjugates between Factor IX and PEG moieties. are disclosed in the present application. The conjugates are linked via a glycosyl linking group interposed between and covalently attached to the peptide and the modifying group. Conjugates are formed from glycosylated peptides by the action of a glycosyltransferase. The glycosyltransferase ligates a modified sugar moiety onto a glycosyl residue on the peptide. Also provided are methods for preparing the conjugates, methods for treating various disease conditions with the conjugates, and pharmaceutical formulations including the conjugates.

Claims

1. A PEGylated Factor IX protein comprising SEQ ID NO:

1 and a poly(ethylene glycol) moiety, wherein the poly(ethylene glycol) moiety is conjugated to an amino acid selected from Asn 157 and Asn 167 of SEQ ID NO;

1 via a glycosyl linking group of a glycosyl residue, and having a composition according to the formula;

2. A pharmaceutical formulation comprising the Factor IX conjugate of claim 1 and a pharmaceutically acceptable carrier.

3. A method of stimulating blood coagulation in a mammal, said method comprising administering to said mammal the PEGylated Factor IX conjugate of claim 1.

4. A method of treating hemophilia in a subject, said method comprising administering to said subject said Factor IX conjugate of claim 1.

5. The method of treating hemophilia of claim 4, wherein hemophilia is hemophilia B.

6. A Factor IX conjugate comprising a Factor IX protein comprising SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) moiety, wherein the PEG moiety is conjugated to an amino acid of SEQ ID NO;

1 via a glycosyl linking group of a glycosyl residue, and having a composition according to the formula;

7. The Factor IX conjugate of claim 6, wherein the PEG moiety is conjugated to an amino acid of SEQ ID NO:

1 selected from the group consisting of Asn157 and Asn167 1 via a glycosyl linking group of a glycosyl residue.

8. The Factor IX conjugate of claim 7, wherein the PEG moiety is conjugated to amino acids Asn 157 and Asn167 of SEQ ID NO:

11 via a glycosyl linking group of a glycosyl residue.

9. The Factor IX conjugate of claim 6, wherein the branched PEG moiety has a molecular weight of about 40 kD.

10. A pharmaceutical formulation comprising the Factor IX conjugate of claim 6 and a pharmaceutically acceptable carrier.

11. A method of stimulating blood coagulation in a mammal, said method comprising administering to said mammal the Factor IX conjugate of claim 6.

12. A method of treating hemophilia in a subject, said method comprising administering to said subject said Factor IX conjugate of claim 6.

13. The method of treating hemophilia of claim 12, wherein hemophilia is hemophilia B.

14. A Factor IX conjugate comprising a Factor IX protein comprising SEQ ID NO:

1 and a poly(ethylene glycol) (PEG) moiety, wherein the PEG moiety is conjugated to an amino acid selected from Asn 157 and Asn 167 of SEQ ID NO;

1 via a glycosyl linking group of a glycosyl residue, and having a composition according to the formula;

15. The Factor IX conjugate of claim 14, wherein the PEG moiety has a molecular weight of about 40 kD.

16. A pharmaceutical formulation comprising the Factor IX conjugate of claim 14 and a pharmaceutically acceptable carrier.

17. A method of stimulating blood coagulation in a mammal, said method comprising administering to said mammal said Factor IX conjugate of claim 14.

18. A method of treating hemophilia in a subject, said method comprising administering to said subject said Factor IX conjugate of claim 14.

19. A Factor IX conjugate comprises a glycosyl residue having the formula:

20. A Factor IX conjugate of claim 19, wherein j, k, l, and m are 1, and e, f, g, and h are 3 or less.