IMMUNE REGULATORY OLIGONUCLEOTIDE (IRO) COMPOUNDS TO MODULATE TOLL-LIKE RECEPTOR BASED IMMUNE RESPONSE

• US 20160138022A1
• Filed: 12/01/2015
• Published: 05/19/2016
• Est. Priority Date: 10/12/2005
• Status: Active Grant

• Current Assignee: Idera Pharmaceuticals, Inc. (Aceragen Incorporated)
• Original Assignee: Idera Pharmaceuticals, Inc. (Aceragen Incorporated)
• Inventors: Kandimalla, Ekambar R., Wang, Daqing, Li, Yukui, Yu, Dong, Zhu, FuGang, Bhagat, Lakshmi, Agrawal, Sudhir
• Granted Patent: US 9,453,228 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C12N 15/117 Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
• CPC Class Codes: C12N 2310/17 Immunomodulatory nucleic acids
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/33 of the base
• CPC Class Codes: C12N 2310/335 : Modified T or U
• CPC Class Codes: C12N 2320/31 : Combination therapy

Abstract

The invention provides novel immune regulatory oligonucleotides (IRO) as antagonist of TLRs and methods of use thereof. These IROs have unique sequences that inhibit or suppress TLR-mediated signaling in response to a TLR ligand or TLR agonist. The methods may have use in the prevention and treatment of cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, skin disorders, allergy, asthma or a disease caused by a pathogen.

Claims

1. :

An immune regulatory oligonucleotide (IRO) compound comprising the sequence 5′

-CTATCTGUYZTTCTCTGT-3′

, wherein G is 2′

-OMe-G and U is 2′

-OMe-U and wherein YZ is an oligonucleotide motif that is CpG, C*pG, C*pG* or CpG* wherein C is deoxycytosine, C* is 2′

-deoxythymidine, 1-(2′

-deoxy-B-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, 2′

-dideoxy-5-halocytosine, 2′

-dideoxy-5-nitrocytosine, arabinocytidine, 2′

-deoxy-5-hydroxycytidine, 2′

-deoxy-N4-alkyl-cytidine, 2′

-deoxy-4-thiouridine, or other pyrimidine nucleoside analogs;

G is deoxyguanosine, and G* is 2′

-deoxy-7-deazaguanosine, 2′

-deoxy-6-thioguanosine, arabinoguanosine, 2′

-deoxyinosine, or other purine nucleoside analogs.

2. :

The compound according to claim 1, wherein the compound comprises the sequence 5′

-CTATCTGUCG₁TTCTCTGT-3′

, 5′

-CTATCTGUCG₄TTCTCTGT-3′

, 5′

-CTATCTGUC₄GTTCTCTGT-3′

, 5′

-CTATCTGUC₅GTTCTCTGT-3′

, 5′

-CTATCTGUC₆GTTCTCTGT-3′

, 5′

-CTATCTGUCG₅TTCTCTGT-3′

, or 5′

-CTATCTGUC₇GTTCTCTGT-3′

, wherein G₁ is 7-deaza-dG, G₄ is araG, C₄ is araC, C₅ is 5-OH-dC, C₆ is 1-(2′

-deoxy-β

-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, G₅ is N1-Me-dG, and C₇ is N3-Me-dC.

3. :

The compound according to claim 1 wherein the compound further comprises a 2′

-substituted ribonucleoside, 2′

-O-substituted ribonucleoside, 2′

-substituted arabinoside, or 2′

-O-substituted arabinoside.

4. :

The compound according to claim 3, wherein the 2′

-O-substituted ribonucleoside is a 2′

-OMe-ribonucleoside.

16. :

A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

19. :

The compound according to claim 2, wherein the compound further comprises a 2′

-substituted ribonucleoside, 2′

-O-substituted ribonucleoside, 2′

-substituted arabinoside, or 2′

-O-substituted arabinoside.

20. :

The compound according to claim 19, wherein the 2′

-O-substituted ribonucleoside is a 2′

-OMe-ribonucleoside.

5. :

A method for inhibiting a TLR7-, TLR8- and/or TLR9-mediated immune response in a vertebrate comprising administering to the vertebrate an immune regulatory oligonucleotide (IRO) compound comprising the sequence 5′

-CTATCTGUYZTTCTCTGT-3′

, wherein G is 2′

-OMe-G and U is 2′

-OMe-U and wherein YZ is an oligonucleotide motif that is C*pG, C*pG* or CpG* wherein C is deoxycytosine, C* is 2′

-deoxythymidine, 1-(2′

-deoxy-B-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, 2′

-dideoxy-5-halocytosine, 2′

-dideoxy-5-nitrocytosine, arabinocytidine, 2′

-deoxy-5-hydroxycytidine, 2′

-deoxy-N4-alkyl-cytidine, 2′

-deoxy-4-thiouridine, or other pyrimidine nucleoside analogs;

G is deoxyguanosine, and G* is 2′

-deoxy-7-deazaguanosine, 2′

-deoxy-6-thioguanosine, arabinoguanosine, 2′

-deoxyinosine, or other purine nucleoside analogs.

6. :

The method according to claim 5, wherein the compound comprises the sequence 5′

-CTATCTGUCGiTTCTCTGT-3′

, 5′

-CTATCTGUCG₄TTCTCTGT-3′

, 5′

-CTATCTGUC₄GTTCTCTGT-3′

, 5′

-CTATCTGUC₅GTTCTCTGT-3′

, 5′

-CTATCTGUC₆GTTCTCTGT-3′

, 5′

-CTATCTGUCG₅TTCTCTGT-3′

, or 5′

-CTATCTGUC₇GTTCTCTGT-3′

, wherein G₁ is 7-deaza-dG, G₄ is araG, C₄ is araC, C₅ is 5-OH-dC, C₆ is 1-(2′

-deoxy-β

-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, Gs is N1-Me-dG, and C₇ is N3-Me-dC.

7. :

The method according to claim 5, wherein the compound further comprises a 2′

-substituted ribonucleoside, 2′

-O-substituted ribonucleoside, 2′

-substituted arabinoside, or 2′

-O-substituted arabinoside.

8. :

The method according to claim 7, wherein the 2′

-O-substituted ribonucleoside is a 2′

-OMe-ribonucleoside.

14. :

The method according to claim 5, wherein the compound is administered in combination with one or more vaccines, antigens, antibodies, cytotoxic agents, allergens, antibiotics, antisense oligonucleotides, TLR antagonists, peptides, proteins, gene therapy vectors, DNA vaccines, adjuvants, chemotherapeutic agents, or kinase inhibitors.

15. :

The method according to claim 5, wherein the route of administration is parenteral, mucosal delivery, oral, sublingual, transdermal, topical, inhalation, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, by gene gun, dermal patch or in eye drop or mouthwash form.

21. :

The method according to claim 6, wherein the compound further comprises a 2′

-substituted ribonucleoside, 2′

-O-substituted ribonucleoside, 2′

-substituted arabinoside, or 2′

-O-substituted arabinoside.

22. :

The method according to claim 21, wherein the 2′

-O-substituted ribonucleoside is a 2′

-OMe-ribonucleoside.

9. :

A method for treating a vertebrate having a disease comprising administering to the vertebrate an immune regulatory oligonucleotide (IRO) compound comprising the sequence 5′

-CTATCTGUYZTTCTCTGT-3′

, wherein G is 2′

-OMe-G and U is 2′

-OMe-U and wherein YZ is an oligonucleotide motif that is C*pG, C*pG* or CpG* wherein C is deoxycytosine, C* is 2′

-deoxythymidine, 1-(2′

-deoxy-B-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, 2′

-dideoxy-5-halocytosine, 2′

-dideoxy-5-nitrocytosine, arabinocytidine, 2′

-deoxy-5-hydroxycytidine, 2′

-deoxy-N4-alkyl-cytidine, 2′

-deoxy-4-thiouridine, or other pyrimidine nucleoside analogs;

G is deoxyguanosine, and G* is 2′

-deoxy-7-deazaguanosine, 2′

-deoxy-6-thioguanosine, arabinoguanosine, 2′

-deoxyinosine, or other purine nucleoside analogs.

10. :

The method according to claim 9, wherein the compound comprises the sequence 5′

-CTATCTGUCGiTTCTCTGT-3′

, 5′

-CTATCTGUCG4TTCTCTGT-3′

, 5′

-CTATCTGUC₄GTTCTCTGT-3′

, 5′

-CTATCTGUC₅GTTCTCTGT-3′

, 5′

-CTATCTGUC₆GTTCTCTGT-3′

, 5′

-CTATCTGUCG₅TTCTCTGT-3′

, or 5′

-CTATCTGUC₇GTTCTCTGT-3′

, wherein G₁ is 7-deaza-dG, G₄ is araG, C₄ is araC, C₅ is 5-OH-dC, C₆ is 1-(2′

-deoxy-β

-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, G₅ is N1-Me-dG, and C₇ is N3-Me-dC.

11. :

The method according to claim 9 wherein the disease is cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, skin disorders, allergy, asthma or a disease caused by a pathogen.

12. :

The method according to claim 9, wherein the compound further comprises a 2′

-substituted ribonucleoside, 2′

-O-substituted ribonucleoside, 2′

-substituted arabinoside, or 2′

-O-substituted arabinoside.

13. :

The method according to claim 12, wherein the 2′

-O-substituted ribonucleoside is a 2′

-OMe-ribonucleoside.

17. :

The method according to claim 9, wherein the compound is administered in combination with one or more vaccines, antigens, antibodies, cytotoxic agents, allergens, antibiotics, antisense oligonucleotides, TLR antagonists, peptides, proteins, gene therapy vectors, DNA vaccines, adjuvants, chemotherapeutic agents, or kinase inhibitors.

18. :

The method according to claim 9, wherein the route of administration is parenteral, mucosal delivery, oral, sublingual, transdermal, topical, inhalation, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, by gene gun, dermal patch or in eye drop or mouthwash form.

23. :

The method according to claim 10, wherein the compound further comprises a 2′

-substituted ribonucleoside, 2′

-O-substituted ribonucleoside, 2′

-substituted arabinoside, or 2′

-O-substituted arabinoside.

24. :

The method according to claim 23, wherein the 2′

-O-substituted ribonucleoside is a 2′

-OMe-ribonucleoside.