Sting-dependent activators for treatment of disease

Abstract

The present disclosure relates, in general, to oligonucleotides that stimulate STING (STimulator of Interferon Genes) activity and increase activity of immune cells. The disclosed STING activators (STAVs) are useful in the treatment of cancer and other immune-mediated conditions.

What is claimed is: 
     
         1 . A composition for treating a human subject suffering from a cancer with a STAV (STing dependent ActiVator) comprising:
 the STAV comprising a dsDNA (double stranded DNA), where the dsDNA comprises:   a first strand, where the first strand comprises between seventy (70) nucleotides and ninety (90) nucleotides, where the first strand comprises eighty (80) percent or more of guanine nucleotides; and   a second strand where the second strand comprises between seventy (70) nucleotides and ninety (90) nucleotides, where the second strand comprises eighty (80) percent or more of cytosine nucleotides, where the STAV induces STING (STimulator of INterferon Genes) signaling, where one or both the first strand and the second strand further comprise at least one (1) modification.   
     
     
         2 . The composition of  claim 1 , where the modification is located at one or both a 3′ end and a 5′ end. 
     
     
         3 . The composition of  claim 2 , where the modification comprises one or more phosphorothioate linkages. 
     
     
         4 . The composition of  claim 1 , where the modification occurs at every third base. 
     
     
         5 . The composition of  claim 1 , where STING signaling is induced when the STAV is transfected into a cell. 
     
     
         6 . The composition of  claim 5 , where STING signaling is induced when the STAV remains cytosolic in the cell. 
     
     
         7 . The composition of  claim 1 , where one or more antigen presenting cells are induced by the STAV to infiltrate into a melanoma tumor associated with the cancer in the human subject. 
     
     
         8 . The composition of  claim 7 , where the one or more antigen presenting cells decrease a size of the melanoma tumor. 
     
     
         9 . The composition of  claim 7 , where the one or more antigen presenting cells are macrophages, dendritic cells, or other phagocytes. 
     
     
         10 . The composition of  claim 1 , where one or more antigen presenting cells are induced by the STAV to infiltrate into a malignant melanoma of head and neck associated with the cancer in the human subject. 
     
     
         11 . The composition of  claim 10 , where the one or more antigen presenting cells decrease a size of the malignant melanoma of head and neck. 
     
     
         12 . The composition of  claim 10 , where the one or more antigen presenting cells are macrophages, dendritic cells, or other phagocytes. 
     
     
         13 . A method of decreasing a size of a kidney tumor in a subject in need thereof comprising administering intratumorally a composition comprising a STAV (STing dependent ActiVator) comprising a double stranded DNA comprising:
 a first strand comprising:
 between seventy (70) nucleotides and ninety (90) nucleotides, where the first strand comprises eighty (80) percent or more of guanine nucleotides; and 
   a second strand comprising:
 between seventy (70) nucleotides and ninety (90) nucleotides, where the second strand comprises eighty (80) percent or more of cytosine nucleotides, where one or both the first strand and the second strand comprise at least one (1) modification, 
   where the STAV induces STING (STimulator of INterferon Genes) signaling,   where the size of the kidney tumor is decreased by between:
 a lower limit of 25%; and 
 an upper limit of 50%. 
   
     
     
         14 . The method of  claim 13 , where the modification is located at one or both a 3′ end and a 5′ end. 
     
     
         15 . The method of  claim 14 , where the modification comprises one or more phosphorothioate linkages. 
     
     
         16 . The method of  claim 13 , where the modification occurs at every third base. 
     
     
         17 . A method of decreasing a size of a kidney tumor in a subject in need thereof comprising administering intratumorally a composition comprising a STAV (STing dependent ActiVator) comprising a double stranded DNA comprising:
 a first strand comprising:
 between seventy (70) nucleotides and ninety (90) nucleotides, where the first strand comprises eighty (80) percent or more of alternating G and C oligonucleotide residues; and 
   a second strand comprising:
 between seventy (70) nucleotides and ninety (90) nucleotides, where the second strand comprises eighty (80) percent or more of alternating A and T oligonucleotide residues, where one or both the first strand and the second strand comprise at least one (1) modification, 
   where the STAV induces STING (STimulator of INterferon Genes) signaling,   where the size of the kidney tumor is decreased by between:
 a lower limit of 25%; and 
 an upper limit of 50%. 
   
     
     
         18 . The method of  claim 17 , where the modification is located at one or both a 3′ end and a 5′ end. 
     
     
         19 . The method of  claim 18 , where the modification comprises one or more phosphorothioate linkages. 
     
     
         20 . The method of  claim 17 , where the modification occurs at every third base.