von Willebrand factor- and factor VIII-polymer conjugates having a releasable linkage
View Patent ↗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.
1. A compound having the following structure:
wherein:
POLY' 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;
Y 2 is O or S; and
(vWF/F8) is a residue of an amine-containing biologically active agent selected from the group consisting of a von Willebrand Factor moiety and a Factor VIII moiety, wherein the amine-containing biologically active agent is liberated from the compound in its native form under physiological conditions and is bioactive.
2. The compound of claim 1 , wherein the amine-containing biologically active agent is a von Willebrand Factor moiety.
3. The compound of claim 2 , wherein the von Willebrand Factor moiety is human recombinant von Willebrand Factor.
4. A construct comprising a compound of claim 2 bound to at least one Factor VIII moiety.
5. The construct of claim 4 , having an in vivo half-life that is increased as compared to the in vivo half-life of a VWF molecule.
6. The construct of claim 4 , having an in vivo half-life that is increased as compared to the in vivo half-life of a Factor VIII moiety not bound to said construct.
7. The compound of claim 2 , having an in vivo half-life that is increased as compared to the in vivo half-life of a VWF molecule.
8. The compound of claim 7 , wherein the in vivo half-life is increased by a factor of at least 1.5 as compared to the in vivo half-life of a VWF molecule.
9. The compound of claim 7 , wherein the in vivo half-life is increased by a factor of at least 2 as compared to the in vivo half-life of a VWF molecule.
10. The compound of claim 1 , wherein the amine-containing biologically active agent is a Factor VIII moiety.
11. The compound of claim 10 , wherein the Factor VIII moiety is human recombinant B-domain deleted Factor VIII.
12. The compound of claim 11 , wherein the Factor VIII moiety is human recombinant full length Factor VIII.
13. The compound of claim 10 , having an in vivo half-life that is increased as compared to the in vivo half-life of a FVIII molecule.
14. The compound of claim 13 , wherein the in vivo half-life is increased by a factor of at least 1.5 as compared to the in vivo half-life of a FVIII molecule.
15. The compound of claim 13 , wherein the in vivo half-life is increased by a factor of at least 2 as compared to the in vivo half-life of a FVIII molecule.
16. The compound 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).
17. The compound of claim 1 , 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.
18. The compound of claim 1 , having 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, and (vWF/F8) is a residue of an amine-containing biologically active agent selected from the group consisting of a von Willebrand Factor moiety and a Factor VIII moiety.
19. The compound of claim 1 , having the following structure:
wherein, vWF is a residue of an amine-containing, recombinant human von Willebrand Factor and (n), in each instance, is independently from 4 to 1500.
20. The compound of claim 1 , having the following structure:
wherein, vWF is a residue of an amine-containing, recombinant human von Willebrand Factor and (n), in each instance, is independently from 4 to 1500.
21. The compound of claim 1 , having the structure
wherein, F8 is an amine-containing residue of a Factor VIII moiety and (n), in each instance, is independently from 4 to 1500.
22. The compound of claim 21 , wherein the Factor VIII moiety is recombinant B-domain deleted Factor VIII.
23. The compound of claim 21 , wherein the Factor VIII moiety is human recombinant full length Factor VIII.
24. The compound of claim 1 , having the following structure:
wherein, F8 is a residue of an amine-containing Factor VIII moiety and (n), in each instance, is independently from 4 to 1500.
25. The compound of claim 24 , wherein the Factor VIII moiety is recombinant B-domain deleted Factor VIII.
26. The compound of claim 24 , wherein the Factor VIII moiety is human recombinant full length Factor VIII.
27. A composition comprising a compound of any one of claims 1 through 26 and a pharmaceutically acceptable excipient.