Conjugates of an EPO moiety and a polymer
View Patent ↗Conjugates of an EPO moiety and one or more non-peptidic water-soluble polymers are provided. Typically, the non-peptidic water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided are compositions comprising such conjugates, methods of making conjugates, and methods of administering compositions comprising such conjugates to a patient.
1. A conjugate of erythropoietin (EPO) having the structure:
wherein:
POLY is a polyalkylene oxide,
Q is an optional linking group having a length of from one to 10 atoms,
m is an integer ranging from 0 to 20,
Z is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl,
c is an integer from 1 to 5
EPO is a residue of erythropoietin, and
“—NH-EPO” represents an amino group of EPO, wherein said EPO corresponds to SEQ ID NO: 1 or SEQ ID NO: 2.
2. The conjugate of claim 1 , wherein POLY is a polyethylene glycol (PEG).
3. The conjugate of claim 2 , wherein Q has a length of from one to five atoms.
4. The conjugate of claim 1 , wherein Q is absent.
5. The conjugate of claim 1 , wherein m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
6. The conjugate of claim 5 , wherein m is 2 or 3.
7. The conjugate of claim 1 , wherein Z is lower alkyl or substituted lower alkyl.
8. The conjugate of claim 5 , wherein Z is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.
9. The conjugate of claim 8 , wherein Z is methyl.
10. The conjugate of claim 2 , wherein said PEG is linear or branched.
11. The conjugate of claim 2 , wherein said POLY possesses a weight average molecular weight from about 10,000 Daltons to about 60,000 Daltons.
12. The conjugate of claim 11 , wherein said POLY possesses a weight average molecular weight selected from the group consisting of about 20 kilodaltons, about 30 kilodaltons, about 40 kilodaltons, and about 50 kilodaltons.
13. The conjugate of claim 12 , wherein said POLY possesses a weight average molecular weight of about 30 kilodaltons.
14. The conjugate of claim 1 , comprising the structure:
wherein n ranges from about 200 to about 1400.
15. The conjugate of claim 14 , wherein said EPO corresponds to SEQ ID NO:1 or SEQ ID NO:2.
16. The conjugate of claim 14 , wherein said conjugate is a monoPEGylated EPO conjugate.
17. The conjugate of claim 14 , wherein said conjugate is a diPEGylated EPO conjugate.
18. A composition comprising the conjugate of claim 14 , wherein greater than about 85% of said PEG-EPO conjugates in the composition are monoPEGylated EPO.
19. The composition of claim 18 , wherein greater than about 90% of the PEG-EPO conjugates in said composition are monoPEGylated EPO.
20. A composition comprising the conjugate of claim 16 , wherein a minority of EPO conjugate species comprised in said composition have PEG covalently attached at lysine 52.
21. The composition of claim 16 , comprising a combination of monoPEGylated EPO and diPEGylated EPO.
22. The composition of claim 20 , comprising a minority of EPO conjugate species have PEG covalently attached at the N-terminus.
23. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable excipient.
24. A pharmaceutical composition comprising the conjugate of claim 14 and a pharmaceutically acceptable excipient.