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:
 (1) a mutated human IL-1β cytokine characterized by a reduced activity as compared to wild type human IL-1β cytokine, wherein the mutation is one or more mutations selected from R120G, Q131G, L145A, H146A, L147A, Q148G, F162A, Q164E, and K208E, and the numbering is based on the human IL-1β sequence, and   (2) a targeting moiety directed against human CD8,   
       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 CD8 expressed on human IL-1β cytokine receptor expressing cell. 
     
     
         16 . The composition of  claim 14 , wherein the targeting moiety is directed to CD8 expressed on an IL-1R1 and/or IL-1RacP expressing cell. 
     
     
         17 . The composition of  claim 14 , wherein the mutated human IL-1β further comprises at least one mutation from mutations comprising A117G/P118G, L122A, T125G/L126G, R127G, K132A, S137G/Q138Y, Q148G/Q150G, Q150G/D151A, M152G, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K209A, K209A/K210A, E221K, E221S/N224A, N224S/K225S, E244K, or N245Q. 
     
     
         18 . The composition of  claim 14 , wherein the mutated human IL-1β comprises Q131G and Q148G. 
     
     
         19 . The composition of  claim 14 , wherein the mutated human IL-1β comprises Q148G and K208E. 
     
     
         20 . The composition of  claim 14 , wherein the mutated human IL-1β comprises R120G and Q131G. 
     
     
         21 . The composition of  claim 14 , wherein the mutated human IL-1β comprises R120G and H146A. 
     
     
         22 . The composition of  claim 14 , wherein the mutated human IL-1β comprises R120G and K208E. 
     
     
         23 . The composition of  claim 14 , wherein the mutated human IL-1β comprises R120G, F162A, and Q164E. 
     
     
         24 . A method of stimulating an immune response in a cell, comprising contacting the cell with the composition of  claim 14 .