DNA aptamers specific to CD200R1 and their therapeutic uses
Disclosed are short DNA aptamers that selectively recognize CD200R1, a protein expressed on the surface of myeloid and lymphoid cells that delivers immune inhibitory signals to modulate inflammation when engaged with its ligand, CD200. Also disclosed is the use of said aptamers as therapeutic agents, for the purpose of decreasing inflammatory response; treatment of spinal cord injury; treatment of an immune related disease such as arthritis, allergy, infection; as a course of treatment during or after transplantation; or for treatment of an autoimmune disorders such as systemic lupus erythematosus, Parkinson's Disease, or multiple sclerosis.
1. An aptamer or oligonucleotide that binds to a CD200R1 target, wherein the aptamer or oligonucleotide is selected from the group consisting of M49 (SEQ ID NO:1), M52 (SEQ ID NO:2), CCS8 (SEQ ID NO.: 16), TrM49 (SEQ ID NO.: 12), TrM52 (SEQ ID NO.: 13), TM49 (SEQ ID NO.: 4), TM52 (SEQ ID NO.: 5), TCCS8 (SEQ ID NO.: 15) and TCCS13 (SEQ ID NO.: 6).
2. An aptamer or oligonucleotide according to claim 1 , wherein the aptamer or oligonucleotide comprises at least one chemical modification.
3. The aptamer of claim 2 , wherein the modification is selected from the group consisting of: incorporation of a modified nucleotide; 3′ and 5′ capping; conjugation to a high molecular weight, non-immunogenic compound, and conjugation to a lipophilic compound or conjugation to another oligonucleotide such as siRNAs, antisense oligonucleotides, ribozymes and DNA/RNA chimeras.
4. The aptamer of claim 3 wherein the modification is pegylation.
5. The aptamer of claim 4 wherein the pegylation is a monovalent pegylation.
6. The aptamer or oligonucleotide of claim 1 , where said aptamer or oligonucleotide is conjugated or otherwise associated with a cytotoxic agent.
7. The aptamer or oligonucleotide of claim 1 , where said aptamer or oligonucleotide is an aptamer-drug conjugate comprising the aptamer or oligonucleotide and a cytotoxic drug.
8. The aptamer or oligonucleotide of claim 1 , where said aptamer or oligonucleotide is an aptamer-protein conjugate comprising the aptamer or oligonucleotide and a therapeutic protein.
9. The aptamer or oligonucleotide of claim 1 , where said aptamer or oligonucleotide is an aptamer-radionuclide conjugate comprising the aptamer or oligonucleotide and a radionuclide.
10. The aptamer or oligonucleotide of claim 1 , where said aptamer or oligonucleotide is an aptamer-metal chelator conjugate comprising the aptamer or oligonucleotide and a metal chelator.
11. The aptamer or oligonucleotide of claim 1 , where said aptamer or oligonucleotide is an aptamer-nanostructure conjugate comprising the aptamer or oligonucleotide and a nanostructure.
12. The aptamer or oligonucleotide of claim 1 , wherein the CD200R1 target is a human CD200R1.
13. The aptamer or oligonucleotide of claim 1 , wherein the CD200R1 target is a murine CD200R1.
14. The aptamer or oligonucleotide of claim 1 , having CD200R1 agonist activity.
15. A pharmaceutical composition comprising an aptamer or oligonucleotide of claim 1 and a therapeutically acceptable carrier.
16. A method of delivering a cytotoxic drug to a CD200R1-overexpressing cell, comprising contacting the cell with the cytotoxic drug and an aptamer or oligonucleotide selected from the group consisting of:
an aptamer that binds to a CD200R1 target, wherein the aptamer is selected from the group consisting of M49 (SEQ ID NO:1), M52 (SEQ ID NO:2), CCS13 (SEQ ID NO:3), CCS8 (SEQ ID NO.: 16), TrM49 (SEQ ID NO.: 12), TrM52 (SEQ ID NO.: 13), TM49 (SEQ ID NO.: 4), TM52 (SEQ ID NO.: 5), TCCS8 (SEQ ID NO.: 15), and TCCS13 (SEQ ID NO.: 6); and
an oligonucleotide that binds to a CD200R1 target, comprising a sequence selected from the group consisting of M49 (SEQ ID NO:1), M52 (SEQ ID NO:2), CCS13 (SEQ ID NO:3), CCS8 (SEQ ID NO.: 16), TrM49 (SEQ ID NO.: 12), TrM52 (SEQ ID NO.: 13), TM49 (SEQ ID NO.: 4), TM52 (SEQ ID NO.: 5), TCCS8 (SEQ ID NO.: 16) and TCCS13 (SEQ ID NO.: 6).
17. The method of claim 16 , wherein the cell is contacted by administering the cytotoxic drug and aptamer or oligonucleotide to a patient in need of treatment for: decreasing an inflammatory response, arthritis, or in need of treatment during or after transplantation.
18. A method of decreasing an inflammatory response in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of claim 15 .
19. A method of treating arthritis in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 15 to the patient.
20. A method of improving transplantation outcomes in a patient undergoing a transplant, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 15 to the patient before, during, and/or after said transplant.