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 a TNF inhibitor 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 composition comprising the conjugate of claim 1 , and a pharmaceutically acceptable excipient.
11. The composition of claim 10 , wherein B is a TNF inhibitor.
12. A method of treating a patient diagnosed with an inflammatory disease, said method comprising administering to said patient an effective amount of the conjugate of claim 1 .
13. The method of claim 12 , wherein B is a TNF inhibitor.
14. The method of claim 12 , wherein the inflammatory disease is selected from rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), and ankylosing spondylitis (AS).
15. The method of claim 13 , wherein the TNF inhibitor is selected from etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab.
16. The conjugate of claim 1 , wherein the TNF inhibitor is selected from etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab.
17. The composition of claim 11 , wherein the TNF inhibitor is selected from etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab.