Targeted human-interferon fusion proteins

Abstract

This disclosure relates to a modified α-helical bundle cytokine, with reduced activity via an α-helical bundle cytokine receptor, wherein the α-helical bundle cytokine is specifically delivered to target cells. Preferably, the α-helical bundle cytokine is a mutant, more preferably it is a mutant interferon, with low affinity to the interferon receptor, wherein the mutant interferon is specifically delivered to target cells. The targeting is realized by fusion of the modified α-helical bundle cytokine to a targeting moiety, preferably an antibody. This disclosure relates further to the use of such targeted modified α-helical bundle cytokine to treat diseases. A preferred embodiment is the use of a targeted mutant interferon, to treat diseases, preferably viral diseases and tumors.

1 . A targeting construct, comprising a modified α-helical bundle cytokine characterized by a reduced affinity for the α-helical bundle cytokine receptor, and a targeting moiety. 
     
     
         2 . The targeting construct, according to  claim 1 , wherein said modified α-helical bundle cytokine is a mutant α-helical bundle cytokine. 
     
     
         3 . The targeting construct according to  claim 1  or  2 , wherein said targeting moiety is targeting to a marker expressed on a α-helical bundle cytokine receptor expressing cell. 
     
     
         4 . The targeting construct, according to  claim 2 , wherein said mutant α-helical bundle cytokine is a mutant interferon. 
     
     
         5 . The targeting construct, according to  claim 4 , wherein said targeting moiety is targeting to a marker expressed on an interferon receptor expressing cell. 
     
     
         6 . The targeting construct according to  claim 5 , wherein said interferon receptor is IFNAR2. 
     
     
         7 . The targeting construct according to any of the preceding claims, wherein said targeting moiety is directed to a tissue specific marker 
     
     
         8 . The targeting construct according to any of the  claims 1 - 6 , wherein said targeting moiety is directed to a marker selected from the group consisting of Her2, DC-STAMP and CD20. 
     
     
         9 . The targeting construct according to any of the  claims 1 - 6 , wherein said targeting moiety is directed to a cell surface marker specific for viral infected cells 
     
     
         10 . The targeting construct according to any of the previous claims, wherein said targeting moiety is an antibody. 
     
     
         11 . The targeting construct according to  claim 10 , wherein said antibody is a nanobody. 
     
     
         12 . The targeting construct according to  claim 4 , wherein the mutant interferon is a mutant interferon alpha 2. 
     
     
         13 . The targeting construct according to  claim 12 , wherein said mutant interferon alpha 2 is mutated in one or more amino acids of the region 144-154. 
     
     
         14 . The targeting construct according to  claim 12 , wherein said mutant interferon alpha 2 is selected from the group consisting of IFNα2 L153A, IFNα2 R149A and IFNα2 M148A. 
     
     
         15 . A targeting construct according to any of the  claims 1 - 14  for use as a medicament. 
     
     
         16 . The targeting construct according to any of the  claims 1 - 14  for use in treatment of cancer. 
     
     
         17 . The targeting construct according to any of the  claims 1 - 14  for use in treatment of a viral disease. 
     
     
         18 . The targeting construct according to any of the  claims 1 - 14  for use in treatment of diseases involving bone degradation. 
     
     
         19 . A pharmaceutical composition, comprising a targeting construct according to any of the  claims 1 - 14 , and a suitable excipient.