Rna viruses expressing il-12 for immunovirotherapy

Abstract

The present invention relates to a recombinant virus of the family Paramyxoviridae, comprising at least one expressible polynucleotide encoding an IL-12 polypeptide, wherein said IL-12 polypeptide is an IL-12 fusion polypeptide comprising a p35 subunit of an IL-12 and a p40 subunit of an IL-12; to a polynucleotide encoding the same, and to a kit comprising the same. Moreover, the present invention relates to a method for treating cancer in a subject afflicted with cancer, comprising contacting said subject with a recombinant virus of the family Paramyxoviridae of the invention, and thereby, treating cancer in a subject afflicted with cancer.

1 . A recombinant virus of the family Paramyxoviridae, comprising an expressible polynucleotide encoding an IL-12 polypeptide, wherein said IL-12 polypeptide is an IL-12 fusion polypeptide comprising a p35 subunit of an IL-12 and a p40 subunit of an IL-12. 
     
     
         2 . The recombinant virus of the family Paramyxoviridae of  claim 1 , wherein said p35 subunit and said p40 subunit of said IL-12 fusion polypeptide are from the same species. 
     
     
         3 . The recombinant virus of the family Paramyxoviridae of  claim 1 , wherein said IL-12 fusion polypeptide comprises the structure p35-linker-p40. 
     
     
         4 . The recombinant virus of the family Paramyxoviridae of  claim 1 , wherein said linker is -(glycine 4 -serine) n -, with n=1 to 10. 
     
     
         5 . The recombinant virus of the family Paramyxoviridae of  claim 1 , further comprising at least one expressible polynucleotide encoding a further activator of the immune response. 
     
     
         6 . The recombinant virus of the family Paramyxoviridae of  claim 5 , wherein said further activator of the immune response is a secreted immunoglobulin. 
     
     
         7 . The recombinant virus of the family Paramyxoviridae of  claim 5 , wherein said further activator of the immune response is an Fc domain of an antibody. 
     
     
         8 . The recombinant virus of the family Paramyxoviridae of  claim 5 , wherein said further activator of the immune response is a secreted soluble activator of the immune response. 
     
     
         9 . The recombinant virus of the family Paramyxoviridae of  claim 5 , wherein said further activator of the immune response is a secreted soluble anti-PD-L1 antibody. 
     
     
         10 . The recombinant virus of the family Paramyxoviridae of  claim 1 , wherein said recombinant virus is a recombinant Morbillivirus. 
     
     
         11 . The recombinant virus of the family Paramyxoviridae of  claim 1 , wherein said recombinant virus is derived from a measles virus strain Edmonston A or B. 
     
     
         12 . The recombinant virus of the family Paramyxoviridae of  claim 1 , wherein the at least one expressible polynucleotide encoding an IL-12 polypeptide is comprised in a polynucleotide encoding the recombinant virus of the family Paramyxoviridae. 
     
     
         13 . The recombinant virus of the family Paramyxoviridae of  claim 1 , wherein said polynucleotide encoding the recombinant virus of the family Paramyxoviridae comprises the nucleic acid sequence of any one of SEQ ID NOs:4 to 7, 14, and 15. 
     
     
         14 . A medicament comprising
 (a) (i) a recombinant virus of the family Paramyxoviridae comprising an expressible polynucleotide encoding an IL-12 and not comprising an expressible polynucleotide encoding a CTLA-4 antagonist, a PD-1 antagonist, a CD80 antagonist, a CD86 antagonist, or a PD-L1 antagonist;
 (ii) a recombinant virus of the family Paramyxoviridae according to  claim 1 , 
 (iii) a polynucleotide encoding the recombinant virus of the family Paramyxoviridae of (i) and/or (ii), 
 (iv) a host cell comprising the recombinant virus of the family Paramyxoviridae according to (i) or (ii) and/or a polynucleotide encoding the recombinant virus of the family Paramyxoviridae of (iii); or 
 (v) any combination of (i) to (iv); and 
   (b) at least one pharmacologically acceptable excipient.   
     
     
         15 . A method for treating cancer in a subject afflicted with cancer, comprising
 a) contacting said subject with
 (i) a recombinant virus of the family Paramyxoviridae comprising an expressible polynucleotide encoding an IL-12 and not comprising an expressible polynucleotide encoding a CTLA-4 antagonist, a PD-1 antagonist, a CD80 antagonist, a CD86 antagonist, or a PD-L1 antagonist; 
 (ii) a recombinant virus of the family Paramyxoviridae according of  claim 1 , 
 (iii) a polynucleotide encoding the recombinant virus of the family Paramyxoviridae of (i) and/or (ii), 
 (iv) a host cell comprising the recombinant virus of the family Paramyxoviridae according to (i) or (ii) and/or a polynucleotide encoding the recombinant virus of the family Paramyxoviridae of (iii); or 
 (v) any combination of (i) to (iv); and, thereby, 
   b) treating cancer in a subject afflicted with cancer.   
     
     
         16 . The method of  claim 15 , wherein said recombinant virus of the family Paramyxoviridae of (i) is a recombinant virus of the family Paramyxoviridae comprising an expressible polynucleotide encoding an IL-12 polypeptide and not comprising an expressible polynucleotide encoding a ligand for an immune checkpoint blockade protein. 
     
     
         17 . The method of  claim 15 , wherein said recombinant virus of the family Paramyxoviridae of (i) is a recombinant virus of the family Paramyxoviridae comprising an expressible polynucleotide encoding an IL-12 polypeptide as the only expressible polynucleotide encoding an activator of the immune response. 
     
     
         18 . The method of  claim 15 , wherein said cancer is a solid cancer, a metastasis, or a relapse thereof. 
     
     
         19 . The method of  claim 15 , wherein treating cancer is reducing tumor burden. 
     
     
         20 . The method of  claim 15 , wherein said cancer is malignant melanoma, head and neck cancer, hepatocellular carcinoma, pancreatic carcinoma, prostate cancer, renal cell carcinoma, gastric carcinoma, colorectal carcinoma, lymphomas or leukemias. 
     
     
         21 . The recombinant virus of the family Paramyxoviridae of  claim 1 , wherein said p35 subunit and said p40 subunit of said IL-12 fusion polypeptide are a mouse p35 subunit and a mouse p40 subunit or a variant thereof, or a human p35 subunit and a human p40 subunit or a variant thereof.