Slow-release cytokine conjugates

1 . A hydrogel of the formula

wherein:

M is a macromolecular carrier;

q is an integer from 1 to 10 when M is a soluble macromolecular carrier or q is a multiple number in a suitable ratio to M when M is an insoluble macromolecular carrier;

Z* is a connecting group comprising an amide, oxime, triazole, thioether, thiosuccinimide, or ether;

n is an integer from 0 to 6;

R 1 is-CN, —NO 2 , —COR 5 , —SOR 5 , or —SO 2 R 5 , wherein R 5 is C 1 -C 6 alkyl, aryl, heteroaryl, or NR 6 2 , wherein each R 6 is independently C 1 -C 6 alkyl, aryl, or heteroaryl, and wherein R 5 and R 6 are independently optionally substituted;

R 2 is H or alkyl;

each R 4 is independently H or C 1 -C 3 alkyl or the two R 4 are taken together with the carbon atom to which they attach to form a 3-6 membered ring;

S is absent or (CH 2 CH 2 O) h (CH 2 ) g CONH wherein g=1-6 and h=0-1000;

Y is NH (CH 2 CH 2 O) p (CH 2 ) m wherein m=2-6 and p=0-1000; and

D is an interleukin-15 (IL-15) or a fusion protein of interleukin-15 with an interleukin-15 Rα sushi domain (IL-15·IL-15RαSu).

2 . The hydrogel of claim 1 , wherein Z* is a triazole moiety.

3 . The hydrogel of claim 1 , wherein R 1 is —CN or —SO 2 R 5 , wherein R 5 is C 1 -C 6 alkyl, aryl, heteroaryl, or NR 6 2 , wherein each R 6 is independently C 1 -C 6 alkyl, aryl, or heteroaryl, and R 2 is H.

4 . The hydrogel of claim 3 , wherein R 1 is —CN, —SO 2 N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 Ph, —SO 2 PhCl, SO 2 CH(CH 3 ) 2 , —SO 2 N(CH 3 )(CH 2 CH 3 ), —SO 2 N(CH 2 CH 2 OCH 3 ) 2 , or

5 . The hydrogel of claim 1 , wherein R 2 is H.

6 . The hydrogel of claim 1 , wherein n is 4, each R 4 is H, R 1 is —SO 2 R 5 wherein R 5 is methyl, R 2 is H, S is (CH 2 CH 2 O) h (CH 2 ) g CONH wherein g=2 and h=4, and Y is NH (CH 2 CH 2 O) p (CH 2 ) m wherein m=3 and p=0.

7 . The hydrogel of claim 1 , wherein M comprises polymers having multi-armed chains.

8 . The hydrogel of claim 7 , wherein M comprises r-armed polymers, wherein r is an integer from 2 to 8.

9 . The hydrogel of claim 8 , wherein r is 4.

10 . The hydrogel of claim 8 , wherein the r-armed polymers are pegylated polymers.

11 . The hydrogel of claim 10 , wherein r is 4.

12 . The hydrogel of claim 8 , wherein the r-armed polymers are linked through a cleavable linker.

13 . A hydrogel comprising repeating units of the formula:

wherein:

P 1 and P 2 are independently r-armed polymers wherein r is an integer from 2 to 8;

A* is a connecting group comprising carboxamide, oxime, ether, thioether or triazole;

C* is a connecting group comprising carboxamide, oxime, ether, thioether or triazole;

each n is independently an integer from 0 to 6;

x, y, and z are independently an integer from 0 to 6;

R 11 is-CN, —NO 2 , —COR 5 , —SOR 5 , or —SO 2 R 5 , wherein R 5 is C 1 -C 6 alkyl, aryl, heteroaryl, or NR 6 2 , wherein each R 6 is independently C 1 -C 6 alkyl, aryl, or heteroaryl;

R 12 is H or alkyl;

each R 14 is independently C 1 -C 3 alkyl or the two R 14 are taken together with the carbon atom to which they attach to form a 3-6 membered ring;

Z* is a connecting group comprising a carboxamide, amide, oxime, triazole, thioether, thiosuccinimide, or ether;

S is absent or (CH 2 CH 2 O) h (CH 2 ) g CONH wherein g=1-6 and h=0-1000;

Y is NH (CH 2 CH 2 O) p (CH 2 ) m wherein m=2-6 and p=0-100;

R 1 is —CN, —NO 2 , —COR 5 , —SOR 5 , or —SO 2 R 5 , wherein R 5 is C 1 -C 6 alkyl, aryl, heteroaryl, or NR 6 2 , wherein each R 6 is independently C 1 -C 6 alkyl, aryl, or heteroaryl;

R 2 is H or alkyl;

each R 4 is independently H or C 1 -C 3 alkyl or the two R 4 are taken together with the carbon atom to which they attach to form a 3-6 membered ring; and

D is an IL-15 or an IL-15·IL-15RπSu fusion protein.

14 . The hydrogel of claim 13 , wherein P 1 and P 2 are pegylated polymers.

15 . The hydrogel of claim 13 , wherein r is 4.

16 . The hydrogel of claim 13 , wherein A* and C* are independently carboxamide, oxime, ether, thioether or triazole.

17 . The hydrogel of claim 13 , wherein both R 14 groups are methyl.

18 . The hydrogel of claim 13 of the formula: