Compositions and methods for activating "stimulator of interferon gene"-dependent signalling

Abstract

The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce STING-dependent type I interferon production, wherein the cyclic purine dinuclotides present in the composition are substantially pure 2′,5′,2′,5′ and 2′,5′,3′,5′ CDNs, and prefereably Rp,Rp stereosiomers thereof.

1 . A method of treating cancer in a subject in need thereof, comprising:
 administering to the subject one or both of a CTLA-4 pathway antagonist and a PD-1 pathway antagonist; and   co-administering to the subject a cyclic dinucleotide that induces Stimulator of Interferon Genes (“STING”)-dependent type I interferon production.   
     
     
         2 . The method of  claim 1 , wherein the cyclic dinucleotide has the formula: 
       
         
           
           
               
               
           
         
         where R 1  and R 2  are each H, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The method of  claim 1 , wherein the cyclic dinucleotide and one or both of a CTLA-4 pathway antagonist and a PD-1 pathway antagonist are administered as separate administrations. 
     
     
         4 . The method of  claim 1 , wherein the cyclic dinucleotide and one or both of a CTLA-4 pathway antagonist and a PD-1 pathway antagonist are administered at different times. 
     
     
         5 . The method of  claim 1 , wherein the cyclic dinucleotide and one or both of a CTLA-4 pathway antagonist and a PD-1 pathway antagonist are administered by different routes of administration. 
     
     
         6 . The method of  claim 1 , wherein the cancer is selected from the group consisting of a colorectal cancer, an aero-digestive squamous cancer, a lung cancer, a brain cancer, a liver cancer, a stomach cancer, a sarcoma, a leukemia, a lymphoma, a multiple myeloma, an ovarian cancer, a uterine cancer, a breast cancer, a melanoma, a prostate cancer, a pancreatic carcinoma, and a renal carcinoma.