Conjugates of biologically active molecules to functionalized polymers
This document relates to conjugates of a biologically active molecule or a derivative thereof and functionalized (e.g., mono- or bi-functional) polymers (e.g., polyethylene glycol and related polymers) as well as methods and materials for making and using such conjugates.
1. A conjugate, or a pharmaceutically acceptable salt thereof, comprising a water-soluble, non-peptidic, and non-nucleotidic polymer backbone having at least one terminus covalently bonded to a structure of formula (9):
or a salt thereof,
wherein:
A is the point of covalent bonding to the terminus of the polymer backbone, wherein the polymer backbone is poly(ethylene glycol), wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da;
E is O;
K is selected from the group consisting of: alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene;
G is selected from the group consisting of: hydrogen, alkoxy, and a hydrophobic separation handle;
Z 1 and Z 2 are O;
L is selected from the group consisting of: a divalent radical of a nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
R 1 is absent or a hydrophobic separation handle, wherein only one of R 1 and G can be a hydrophobic separation handle;
L 2 is a covalent linking moiety between L on the polymer backbone and B; and
B is omalizumab or a derivative thereof.
2. The conjugate of claim 1 , wherein only one termini of the polymer backbone is covalently bonded to the structure of formula (9).
3. The conjugate of claim 1 , wherein the polymer backbone has two termini.
4. The conjugate of claim 3 , wherein only one termini of the polymer backbone is covalently bonded to the structure of formula (9).
5. The conjugate of claim 3 , wherein both termini of the polymer backbone are covalently bonded to a structure of formula (9).
6. The conjugate of claim 1 , wherein K is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol.
7. The method of claim 6 , wherein G is hydrogen.
8. The conjugate of claim 1 , wherein G is a substituted or unsubstituted trityloxy.
9. The conjugate of claim 1 , wherein L is a substituted or unsubstituted C 1 -C 12 alkylene.
10. A conjugate, or a pharmaceutically acceptable salt thereof, comprising a structure of formula (10):
or a salt form thereof,
wherein:
polymer is poly(ethylene glycol), wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da, wherein each linking group is bonded at a different terminus of said polymer;
E and E 1 are independently O;
K and K 1 are independently selected from the group consisting of: alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene;
G and G 1 are independently absent or are selected from the group consisting of: alkoxy and a hydrophobic separation handle;
each pair of Z 1 and Z 2 and Z 3 and Z 4 are O,
L and L 1 are independently selected from the group consisting of: a divalent radical of a nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
L 2 is a covalent linking moiety between L on the polymer backbone and B;
L 3 is a covalent linking moiety between L on the polymer backbone and B 1 ; and
B and B 1 are independently omalizumab, a derivative of omalizumab, a biologic other than omalizumab, a drug, a detectable group, a separation moiety, wherein at least one of B and B 1 is omalizumab or a derivative of omalizumab.
11. A conjugate, or a pharmaceutically acceptable salt thereof, comprising a compound of formula (11):
or a salt form thereof,
wherein:
polymer is poly(ethylene glycol wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da,
wherein L 4 and the phosphonate-derived functional group are bonded at a different terminus of said polymer;
E and E 1 are O;
K is selected from the group consisting of: alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene;
G is selected from the group consisting of: hydrogen, alkoxy, and a hydrophobic separation handle;
Z 1 and Z 2 are independently O;
L is selected from the group consisting of: a divalent radical of nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
L 2 is a covalent linking moiety between L on the polymer backbone and B;
L 4 is a covalent linking moiety between L on the polymer backbone and B 1 ; and
B and B 1 are independently omalizumab, a derivative of omalizumab, a biologic other than omalizumab, a drug, a detectable group, a separation moiety, wherein at least one of B and B 1 is omalizumab or a derivative of omalizumab.
12. A composition comprising the conjugate of claim 1 , and a pharmaceutically acceptable excipient.
13. The composition of claim 12 , wherein B is omalizumab.
14. A composition comprising the conjugate of claim 10 , and a pharmaceutically acceptable excipient.
15. The composition of claim 14 , wherein B is omalizumab.
16. The composition of claim 14 , wherein B 1 is omalizumab.
17. A composition comprising the conjugate of claim 11 , and a pharmaceutically acceptable excipient.
18. The composition of claim 17 , wherein B is omalizumab.
19. The composition of claim 17 , wherein B 1 is omalizumab.
20. A method of treating a patient diagnosed with asthma, said method comprising administering to said patient an effective amount of the conjugate of claim 1 .
21. The method of claim 20 , wherein B is omalizumab.
22. A method of treating a patient diagnosed with asthma, said method comprising administering to said patient an effective amount of the conjugate of claim 10 .
23. A method of treating a patient diagnosed with asthma, said method comprising administering to said patient an effective amount of the conjugate of claim 11 .