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 . A targeting construct, comprising a modified IL-1 family cytokine characterized by a reduced affinity for its receptor, and a targeting moiety. 
     
     
         2 . The targeting construct, according to  claim 1 , wherein said modified IL-1 family cytokine is a mutant IL-1 family cytokine. 
     
     
         3 . The targeting construct according to  claim 1  or  2 , wherein said targeting moiety is targeting to a marker expressed on a IL-1 family cytokine receptor expressing cell. 
     
     
         4 . The targeting construct, according to  claim 2 , wherein said mutant IL-1 family cytokine is a mutant IL-1β. 
     
     
         5 . The targeting construct, according to  claim 4 , wherein said targeting moiety is targeting to a marker expressed on an IL-1R1 and/or IL-1RacP expressing cell. 
     
     
         6 . The targeting construct according to any of the preceding claims, wherein said targeting moiety is directed to a tissue specific marker. 
     
     
         7 . The targeting construct according to any of the  claims 1 - 5 , wherein said targeting moiety is directed to Her2. 
     
     
         8 . The targeting construct according to any of the previous claims, wherein said targeting moiety is an antibody. 
     
     
         9 . The targeting construct according to  claim 8 , wherein said antibody is a nanobody. 
     
     
         10 . The targeting construct according to any of the preceding claims, wherein the modified IL-1 family cytokine is an IL-1β mutant, selected from the group consisting of A117G/P118G, R120GR120X, L122A, T125G/L126G, R127G, Q130X, Q131G, K132A, S137G/Q138Y, L145G, H146X, L145A/L147A, Q148X, Q148G/Q150G, Q150G/D151A, M152G, F162A, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K208E, K209A K209X, K209A/K210A, K219X, and E221KX, E221S/N224A, N224S/K225S, E244K and N245Q 
     
     
         11 . A targeting construct according to any of the  claims 1 - 10  for use as a medicament. 
     
     
         12 . The targeting construct according to any of the  claims 1 - 10  for use in stimulation of the immune response. 
     
     
         13 . The targeting construct according to any of the  claims 1 - 10  for use in treatment of cancer.