Compositions comprising cyclic purine dinucleotides having defined stereochemistries and methods for their preparation and use
It is an object of the present invention to provide novel and highly active cyclic-di-nucleotide (CDN) immune stimulators that activates 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 that induce STING-dependent TBK1 activation, wherein the cyclic purine dinuclotides present in the composition are substantially pure Rp,Rp or Rp,Sp stereoisomers, and particularly substantially pure Rp,Rp, or RpSp CDN thiophosphate diastereomers.
1. A method of inducing an immune response to a cancer in an individual, or inducing an immune response to a pathogen in an individual, comprising:
parenterally administering to the individual in need thereof a composition comprising a cyclic dinucleotide or pharmaceutically acceptable salt thereof which induces STING-dependent TBK1 activation, wherein the cyclic dinucleotide is a substantially pure Rp,Rp thiophosphate cyclic dinucleotide, and wherein the cyclic dinucleotide comprises a 2′-F, 2′-amino or 2′-O-acyl substituent.
2. The method according to claim 1 , wherein the composition comprises an inactivated tumor cell or a mixture of different tumor cells type-matched to the individual's cancer.
3. The method according to claim 2 , wherein the tumor cell is selected from the group consisting of a colorectal cancer cell, a head and neck cancer, a lung cancer cell, a cervical cancer, a brain cancer cell, a liver cancer cell, a stomach cancer cell, a sarcoma cell, a leukemia cell, a lymphoma cell, a multiple myeloma cell, an ovarian cancer cell, a uterine cancer cell, a breast cancer cell, a melanoma cell, a prostate cancer cell, a pancreatic carcinoma cell, and a renal carcinoma cell.
4. The method according to claim 1 , wherein the cyclic dinucleotide is formulated with one or more lipids.
5. The method according to claim 4 , wherein the one or more lipids comprise digitonin.
6. The method according to claim 4 , wherein the one or more lipids form a liposome.
7. The method according to claim 1 , wherein the cyclic dinucleotide is formulated with one or more adjuvants.
8. The method according to claim 7 , wherein the one or more adjuvants comprise CpG and/or monophosphoryl lipid A.
9. The method according to claim 1 , further comprising administering one or more vaccines to the individual, wherein the vaccine(s) comprises one or more antigens selected to stimulate an immune response to a pathogen expressing one or more of the antigens.
10. The method according to claim 9 , wherein the vaccine(s) comprise inactivated or attenuated bacteria or viruses comprising the antigen of interest, purified antigens, live viral or bacterial delivery vectors recombinantly engineered to express and/or secrete the antigens, antigen presenting cell (APC) vectors comprising cells that are loaded with the antigens or transfected with a composition comprising a nucleic acid encoding the antigens, liposomal delivery vehicles comprising the antigens, or naked nucleic acid vectors encoding the antigens.
11. The method according to claim 1 , wherein the cyclic dinucleotide is formulated as a nanoparticle.
12. The method according to claim 1 , further comprising administering one or more of a CTLA-4 pathway antagonist or a PD-1 pathway antagonist to the individual.