Targeted modified il-1 family members

Abstract

The present disclosure relates to a modified Interleukin-1 (IL-1) family member cytokine, with reduced activity via its cytokine receptor, wherein said interleukin-1 family member cytokine is specifically delivered to target cells. Preferably, the IL-1 family member cytokine is a mutant, more preferably it is a mutant IL-1 with low affinity to the IL-1 receptor, wherein said mutant IL-1 is specifically delivered to target cells. The targeting is preferably realized by fusion of the modified IL-1 family member cytokine to a targeting moiety, preferably an antibody or antibody-like molecule. The disclosure relates further to the use of such targeted modified IL-1 family member cytokine to treat diseases.

1 .- 13 . (canceled) 
     
     
         14 . A composition comprising a construct comprising:
 (a) a mutated human IL-1β cytokine characterized by a reduced activity as compared to wild type human IL-1β cytokine, wherein the mutation is Q148G, and the numbering is based on the human IL-1β sequence, and   (b) a targeting moiety, the targeting moiety being an antibody or antibody-like molecule and wherein the targeting moiety restores activity of the mutated human IL-1β cytokine on target cells.   
     
     
         15 . The composition of  claim 14 , wherein the targeting moiety is directed to a marker expressed on human IL-1β cytokine receptor expressing cell. 
     
     
         16 . The composition of  claim 15 , wherein the targeting moiety is directed to a marker expressed on an IL-1R1 expressing cell. 
     
     
         17 . The composition of  claim 15 , wherein the targeting moiety is directed to a marker expressed on an IL-1RacP expressing cell. 
     
     
         18 . The composition of  claim 14 , wherein the targeting moiety is directed to a tissue specific marker. 
     
     
         19 . The composition of  claim 14 , wherein the targeting moiety is directed to HER2. 
     
     
         20 . The composition of  claim 14 , wherein the targeting moiety is directed to CD8. 
     
     
         21 . The composition of  claim 14 , wherein the mutated human IL-1β further comprises one or two mutations selected from: A117G/P118G, R120G, L122A, T125G/L126G, R127G, Q131G, K132A, S137G/Q138Y, Q150G, Q150G/D151A, M152G, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K208E, K209A, K209A/K210A, E221K, E221 S/N224A, N224S/K225 S, E244K, and N245Q. 
     
     
         22 . The composition according to  claim 21 , wherein the mutated human IL-1β comprises Q131G and Q148G. 
     
     
         23 . The composition according to  claim 22 , wherein the targeting moiety is directed to HER2. 
     
     
         24 . The composition according to  claim 22 , wherein the targeting moiety is directed to CD8. 
     
     
         25 . The composition according to  claim 21 , wherein the mutated human IL-1β comprises Q148G and K208E. 
     
     
         26 . The composition according to  claim 25 , wherein the targeting moiety is directed to HER2. 
     
     
         27 . The composition according to  claim 25 , wherein the targeting moiety is directed to CD8.