Conjugates of tumor necrosis factor inhibitors to functionalized polymers
This document relates to conjugates of TNF inhibitors or derivatives 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 compound of formula (11):
or a salt form thereof, wherein:
polymer is a linear, water-soluble, non-peptidic, and non-nucleotidic polymer backbone, wherein M 2 and the phosphonate-derived functional group are bonded at a different terminus of said polymer;
E and E 1 are independently O or S;
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 selected from O and NH, wherein only one of Z 1 and Z 2 can be NH;
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 a TNF inhibitor, a derivative of a TNF inhibitor, a biologic other than a TNF inhibitor, a drug, a detectable group, a separation moiety, wherein at least one of B and B 1 is a TNF inhibitor or a derivative of a TNF inhibitor.
2. The conjugate of claim 1 , wherein the polymer has from 2 to 100 termini.
3. The conjugate of claim 1 , wherein the polymer backbone has two termini.
4. The conjugate of claim 1 , wherein one of Z 1 and Z 2 is NH and the other is O.
5. The conjugate of claim 4 , wherein Z 1 is O and Z 2 is NH.
6. The conjugate of claim 4 , wherein Z 1 is NH and Z 2 is O.
7. The conjugate of claim 1 , wherein both Z 1 and Z 2 are O.
8. 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.
9. The conjugate of claim 1 , wherein G is a substituted or unsubstituted trityloxy.
10. The conjugate of claim 1 , wherein L is a substituted or unsubstituted C 1 -C 12 alkylene.
11. The conjugate of claim 1 , wherein E is O.
12. The conjugate of claim 1 , wherein E is S.
13. The conjugate of claim 1 , wherein said polymer backbone is selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(α-hydroxy acid), poly(vinyl alcohol), polyoxazoline, and copolymers.
14. The conjugate of claim 1 , wherein said polymer backbone is poly(ethylene glycol).
15. The conjugate of claim 14 , wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da.
16. The conjugate of claim 1 , wherein said TNF inhibitor is selected from the group consisting of a fusion protein, a monoclonal antibody, and an antibody fragment.
17. The conjugate of claim 1 , wherein said TNF inhibitor is selected from the group consisting of etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab.
18. A composition comprising the conjugate of claim 1 , and a pharmaceutically acceptable excipient.
19. 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 .
20. The method of claim 19 , wherein the inflammatory disease is selected from rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), and ankylosing spondylitis (AS).