Von willebrand factor- and factor VIII-polymer conjugates having a releasable linkage

Patent metadata

Field	Value
Publication number	US-9493544-B2
Application number	US-201213620285-A
Country	US
Kind code	B2
Filing date	Sep 14, 2012
Priority date	Dec 27, 2006
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present invention provides von Willebrand Factor-polymer conjugates and Factor VIII-polymer conjugates, each having a releasable linkage. Methods of making conjugates, methods for administering conjugates, are also provided.

First claim

The invention claimed is:

1. A method of treating a bleeding disorder in a subject, said method comprising administering a therapeutically effective amount of a modified protein having an extended in-vivo half life over the unmodified parent protein, wherein the unmodified parent protein is either a von Willebrand Factor moiety or a Factor VIII moiety and the modified protein is a conjugate having a formula:

wherein:
POLY 1 is a first water-soluble polymer;
POLY 2 is a second water-soluble polymer;
X 1 is a first spacer moiety;
X 2 is a second spacer moiety;
H α is an ionizable hydrogen atom;
R 1 is H or an organic radical;
R 2 is H or an organic radical;
(a) is either zero or one;
(b) is either zero or one;
R e1 , when present, is a first electron altering group;
R e2 , when present, is a second electron altering group;
Y 1 is O or S; and
Y 2 is O or S, such that

from the formula is a releasable linkage that is selected from a carbamate linkage, a thiocarbamate linkage, and a dithiocarbamate linkage; and
(vWF/F8) is a residue of an amine-containing biologically active agent that is either a von Willebrand Factor moiety or a Factor VIII moiety.

2. The method of claim 1 , wherein

from the formula is a releasable linkage that is either a carbamate linkage or a thiocarbamate linkage.

3. The method of claim 2 , wherein the releasable linkage is a carbamate linkage, and the compound possesses the structure:

4. The method of claim 1 , wherein the first water-soluble polymer is a poly(alkylene oxide) and the second water-soluble polymer is a poly(alkylene oxide).

5. The method of claim 4 , wherein the first water-soluble polymer has a weight-average molecular weight of between 10,000 Daltons to 85,000 Daltons and the second water-soluble polymer has a weight-average molecular weight of between 10,000 Daltons to 85,000 Daltons.

6. The method of claim 1 , wherein the amine-containing biologically active agent is a von Willebrand Factor moiety.

7. The method of claim 6 , wherein the von Willebrand Factor moiety is human recombinant von Willebrand Factor.

8. The method of claim 1 , wherein the amine-containing biologically active agent is a Factor VIII moiety.

9. The method of claim 8 , wherein the Factor VIII moiety is human recombinant B-domain deleted Factor VIII.

10. The method of claim 8 , wherein the Factor VIII moiety is human recombinant full length Factor VIII.

11. The method of claim 1 , wherein the conjugate is comprised in a composition together with one or more pharmaceutically acceptable excipients.

12. The method of claim 11 , wherein said administering is by injection.

13. The method of claim 12 , wherein the composition is in a form selected from the group consisting of a powder that can be reconstituted, a suspension, and a solution.

14. The method of claim 12 , wherein the composition is in a unit dosage form.

15. The method of claim 1 , wherein the modified protein has a structure selected from the group consisting of:

wherein, for each structure and in each instance, (n) is independently an integer from 4 to 1500.

16. The method of claim 15 , wherein the amine-containing biologically active agent is a von Willebrand Factor moiety.

17. The method of claim 16 , wherein the von Willebrand Factor moiety is human recombinant von Willebrand Factor.

18. The method of claim 15 , wherein the amine-containing biologically active agent is a Factor VIII moiety.

19. The method of claim 17 , wherein the Factor VIII moiety is human recombinant B-domain deleted Factor VIII.

20. The method of claim 15 , wherein the Factor VIII moiety is human recombinant full length Factor VIII.

Assignees

• Bossard Mary J
• Stephenson Gayle
• Fang Zhihao
• Zappe Harold
• Mitchell Stacy
• Zhang Ping
• Scheiflinger Friedrich
• Turecek Peter
• Siekmann Juergen
• Varadi Katalin
• Gritsch Herbert
• Nektar Therapeutics
• Baxalta Inc
• Baxalta GmbH

Inventors

• Bossard Mary J
• Stephenson Gayle
• Fang Zhihao
• Zappe Harold
• Mitchell Stacy
• Zhang Ping
• Scheiflinger Friedrich
• Turecek Peter
• Siekmann Juergen
• Varadi Katalin
• Gritsch Herbert

Classifications

• C07K14/755 Primary

  Factors VIII {, e.g. factor VIII C (AHF), factor VIII Ag (VWF)} · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/50

  the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• C08G61/12

  Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule · CPC title