New immunocytokines for the treatment of cancer

Abstract

The present invention relates to new immunocytokines which are useful for the treatment of cancer. These fusion proteins comprise (i) an antibody or antigen-binding fragment thereof fused to (ii) a cleavable peptide linker, and (iii) cytokine, or functional fragments thereof. Methods of treatment using these immunocytokines are also disclosed.

1 . A fusion protein comprising:
 (i) an antibody or antigen-binding fragment thereof fused to   (ii) a cleavable peptide linker, and   (iii) a cytokine, or functional fragments thereof.   
     
     
         2 . The fusion protein of  claim 1 , wherein the cytokine is IL-15, CXCL10, IL-36, or IFN-α. 
     
     
         3 . The fusion protein of  claim 1  or  2 , wherein the cleavable peptide linker comprises a protease cleavage site. 
     
     
         4 . The fusion protein of any one of  claims 1  to  3 , wherein the protease cleavage site is cleaved by a matrix metalloproteinase or by uPA. 
     
     
         5 . The fusion protein of  claim 4 , wherein the matrix metalloproteinase is MMP-2, MMP-9. 
     
     
         6 . The fusion protein of any one of  claims 1  to  5 , wherein the cleavable peptide linker has a sequence selected from the group consisting of: GPLGIAGQ, GPLGLWAQ, GPLGMLSQ, PLGLAG, PVGLIG, SGRS, SGRSA, and PSSRRRVN. 
     
     
         7 . The fusion protein of any one of  claims 1  to  6 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanised antibodies, scFv, single domain antibodies (e.g., shark and camelid antibodies), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv. 
     
     
         8 . The fusion protein of any one of  claims 1  to  7 , wherein the cytokine is a murine or human, preferably a human cytokine, or functional fragment thereof. 
     
     
         9 . The fusion protein of any one of  claims 1  to  8 , wherein:
 (i) the cytokine, or functional fragment thereof is fused to the cleavable peptide linker, and 
 (ii) the cleavable peptide linker is used N-terminally or C-terminally to the antibody or antigen-binding fragment thereof. 
 
     
     
         10 . The fusion protein of any one of  claims 1  to  9 , wherein:
 (i) the cytokine, or functional fragment thereof is fused to the cleavable peptide linker, and 
 (ii) the cleavable peptide linker is fused N-terminally or C-terminally to the heavy chain of the antibody or antigen-binding fragment thereof. 
 
     
     
         11 . The fusion protein of any one of  claims 1  to  10  for use in therapy. 
     
     
         12 . The fusion protein of any of  claims 1  to  10  for use in the treatment of cancer in a mammal, preferably in a human. 
     
     
         13 . The fusion protein for use according to  claim 12 , wherein said use comprises activation of immune cell, preferably T-cells or monocytes, of said mammal. 
     
     
         14 . A pharmaceutical composition comprising at least one fusion protein according to any one of  claims 1  to  9  and optionally a pharmaceutically acceptable excipient. 
     
     
         15 . A method of selecting a cytokine or a variant thereof, said method comprising:
 (i) providing a fusion protein as claimed in any one of  claims 1  to  10 , said fusion protein comprising the cytokine or variant thereof to be tested;   (ii) contacting said fusion protein with the relevant protease; and   (iii) detecting the activity of said cytokine.   
     
     
         16 . A method for identifying a cleavable peptide linker, said method comprising:
 (i) providing a fusion protein as claimed in any one of  claims 1  to  10 , said fusion protein comprising the peptide cleavable linker to be tested;   (ii) contacting said fusion protein with the relevant protease; and   (iii) detecting the cleavage of said fusion protein.   
     
     
         17 . The method of  claim 16 , wherein step (iii) of said method comprises measuring the activity of the cytokine of said fusion protein.