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 method of making a TNF inhibitor conjugate, said method comprising reacting a TNF inhibitor with a preparation comprising a compound of formula (3):
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 each bonded at a different terminus of said polymer;
E and E′ are each O;
K is selected from: alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene;
G is selected from: hydrogen, alkoxy, and a hydrophobic separation handle;
Z 1 and Z 2 are each O;
L is selected from: a divalent radical of nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene;
M is selected from a protected group that when deprotected is reactive with the TNF inhibitor or a group reactive with the TNF inhibitor;
M 2 is O; and
R is absent, a protecting group, a hydrophobic separation handle, or an activating group;
R 2 is hydrogen or a protecting group;
wherein when M is a protected group that when deprotected is reactive with the TNF inhibitor, then R is a protecting group or a hydrophobic separation handle; and
wherein when M is a group reactive with a TNF inhibitor, R is absent, hydrogen, or an activating group.
2. The method of claim 1 , wherein said polymer is selected from poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(α-hydroxy acid), poly(vinyl alcohol), polyoxazoline, and copolymers.
3. The method of claim 1 , wherein said polymer is poly(ethylene glycol).
4. The method of claim 3 , wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da.
5. The method of claim 1 , wherein K is a linear or branched alkylene.
6. The method of claim 5 , wherein K is methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene.
7. The method of claim 1 , wherein K is an alkyleneoxyalkylene or an oligomeric alkyleneoxyalkylene.
8. The method of claim 7 , wherein K is a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol.
9. The method of claim 1 , wherein G is a hydrophobic separation handle.
10. The method of claim 9 , wherein G is a substituted or unsubstituted trityloxy group.
11. The method of claim 10 , wherein G is selected from monoalkoxy substituted trityloxy group and dialkoxy substituted trityloxy group.
12. The method of claim 1 , wherein L is alkylene.
13. The method of claim 12 , wherein L is selected from: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene.
14. The method of claim 1 , wherein L is selected from alkyleneoxyalkylene and oligomeric alkyleneoxyalkylene.
15. The method of claim 14 , wherein L is a residue from diethylene glycol, triethylene glycol, tetraethylene glycol, or hexaethylene glycol.
16. The method of claim 1 , wherein L is a divalent radical of a nucleoside.
17. The method of claim 16 , wherein L is a divalent radical of adenosine, deoxyadenosine, guanosine, deoxyguanosine, 5-methyluridine, thymidine, uridine, deoxyuridine, cytidine, or deoxycytidine.
18. The method of claim 1 , wherein M is a group reactive with the TNF inhibitor and the group is selected from: hydroxyl, amine, thiol, carboxyl, aldehyde, glyoxal, dione, alkenyl, alkynyl, alkedienyl, azide, acrylamide, vinyl sulfone, hydrazide, aminoxy, maleimide, dithiopyridine, and iodoacetamide.
19. The method of claim 1 , wherein said TNF inhibitor is selected from the group consisting of a fusion protein, a monoclonal antibody, and an antibody fragment.
20. The method of claim 19 , wherein said TNF inhibitor is selected from the group consisting of etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab.