CTLA-4 aptamer conjugates
Provided herein are, inter alia, nucleic acid compounds useful for targeting CTLA-4-expressing cells and modulating cell activity of the CTLA-4-expressing cells. The compositions provided herein may be part of pharmaceutical compositions and may be used for treatment of cancer, inflammatory diseases, infectious diseases or metabolic diseases.
1. A method of stimulating the immune system of a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of a CTLA-4 aptamer nucleic acid conjugated to a cell activity modulating nucleic acid, wherein said cell activity modulating nucleic acid is a FoxP3 antisense nucleic acid, an anti-tyrosine kinase antisense nucleic acid, or a Signal Transducer and Activator of Transcription (STAT) antisense nucleic acid, thereby stimulating the immune system of said subject.
2. The method of claim 1 , wherein stimulating the immune system comprises maturation, differentiation, or proliferation of natural killer cells, T cells, monocytes, or macrophages.
3. The method of claim 1 , wherein stimulating the immune system comprises an increase in a T H 1-type immune response.
4. The method of claim 1 , wherein stimulating the immune system comprises stimulating a plasmacytoid dendritic cell, myeloid dendritic cell, myeloid-derived suppressor cell, macrophage, B cell, activated NK cell, or activated neutrophil.
5. The method of claim 1 , wherein stimulating the immune system comprises increasing the activity of a cytotoxic T cell.
6. The method of claim 5 , wherein the cytotoxic T cell is a tumor-specific cytotoxic T cell.
7. The method of claim 1 , wherein said CTLA-4 aptamer nucleic acid is conjugated to said cell activity modulating nucleic acid through a linker.
8. The method of claim 7 , wherein said linker comprises a non-nucleic acid spacer.
9. The method of claim 8 , wherein said non-nucleic acid spacer connects said cell activity modulating nucleic acid to the 3′ terminal end of said linker nucleic acid sequence.
10. The method of claim 7 , wherein said linker connects said cell activity modulating nucleic acid to the 3′ terminal end of said CTLA-4 aptamer nucleic acid.
11. The method of claim 1 , wherein said antisense nucleic acid is a siRNA.
12. The method of claim 1 , wherein said cell activity modulating nucleic acid is a FoxP3 antisense nucleic acid.
13. The method of claim 1 , wherein said cell activity modulating nucleic acid is an anti-tyrosine kinase antisense nucleic acid.
14. The method of claim 1 , wherein said cell activity modulating nucleic acid is a Signal Transducer and Activator of Transcription (STAT) antisense nucleic acid.