Immune regulatory oligonucleotide (IRO) compounds to modulate toll-like receptor based immune response

• US 20090060898A1
• Filed: 10/12/2006
• Published: 03/05/2009
• Est. Priority Date: 10/12/2005
• Status: Active Grant

• Current Assignee: Idera Pharmaceuticals, Inc. (Aceragen Incorporated)
• Original Assignee: Idera Pharmaceuticals, Inc. (Aceragen Incorporated)
• Inventors: Li, Yukui, Bhagat, Lakshmi, Yu, Dong, Wang, Daqing, Agrawal, Sudhir, Kandimalla, Ekambar R., Zhu, FuGang
• Granted Patent: US 8,357,665 B2
• Time in Patent Office: Days
• US Class Current: 424/130.100
• 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. A TLR antagonist comprising an immune regulatory oligonucleotide (IRO) compound.

2. The antagonist according to claim 1, having one or more chemical modifications in the sequence flanking the immune stimulatory motif.

3. The antagonist according to claim 1, having one or more chemical modifications in an oligonucleotide motif that would be immune stimulatory but for the modification.

4. The antagonist according to claim 1, having one or more chemical modifications in an oligonucleotide motif that would be immune stimulatory but for the modification in the sequence flanking the oligonucleotide motif.

6. A pharmaceutical composition comprising an antagonist according to claim 1 and a pharmaceutically acceptable carrier.

8. A method for inhibiting a TLR-mediated immune response in a vertebrate, the method comprising administering to the vertebrate an IRO compound according to claim 1 in a pharmaceutically effective amount.

9. The method according to claim 8, 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.

16. A method for therapeutically treating a vertebrate having a disease mediated by a TLR, such method comprising administering to the vertebrate an IRO compound according to claim 1 in a pharmaceutically effective amount

17. The method according to claim 16 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.

18. The method according to claim 16, wherein the IRO compound is administered in combination with one or more vaccines, antigens, antibodies, cytotoxic agents, allergens, antibiotics, antisense oligonucleotides, TLR agonists, TLR antagonists, peptides, proteins, gene therapy vectors, DNA vaccines, adjuvants or co-stimulatory molecules.

19. The method according to claim 16, 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.

20. A method for preventing cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, skin disorders, allergy, asthma or a disease caused by a pathogen in a vertebrate, such method comprising administering to the vertebrate an IRO compound according to claim 1 in a pharmaceutically effective amount.

21. The method according to claim 20, wherein the IRO compound is administered in combination with one or more vaccines, antigens, antibodies, cytotoxic agents, allergens, antibiotics, antisense oligonucleotides, TLR agonists, TLR antagonists, peptides, proteins, gene therapy vectors, DNA vaccines, adjuvants or co-stimulatory molecules.

22. The method according to claim 20 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.

5. An IRO compound having the structure

5-N_m—

N₃N₂N₁CGN¹N²N³—

N^m-3′

;

wherein;

CG is an oligonucleotide motif and C is cytosine or a pyrimidine nucleotide derivative or non-nucleotide linkage, and G is guanosine a purine nucleotide derivative or non-nucleotide linkage;

N1-N3, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage;

Nm, at each occurrence, is independently a nucleotide, nucleotide derivative or non-nucleotide linkage;

provided that at least one N1 to N3 and/or C and/or G is a nucleotide derivative or non-nucleotide linkage;

and further provided that compound contains less than 4 consecutive guanosine nucleotides

wherein the oligonucleotide motif would be immune stimulatory but for the nucleotide derivative or non-nucleotide linkage;

and wherein m is a number from 0 to about 30.

7. A method for modifying a TLR-stimulating oligonucleotide comprising an immune stimulatory oligonucleotide motif comprising incorporating chemical modifications into the immune stimulatory oligonucleotide motif and/or to the sequence flanking the immune stimulatory oligonucleotide motif, wherein the immune stimulatory activity of the immune stimulatory oligonucleotide motif is suppressed by the chemical modifications.

10. A method for inhibiting TLR stimulation comprising administering an IRO compound.

11. The method of claim 10, wherein the TLR is selected from TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9.

12. A method for inhibiting the activity of a TLR agonist comprising administering an IRO compound.

13. The method according to claim 12, comprising administering the IRO at the same time as the TLR agonist.

14. The method according to claim 12, comprising administering the IRO prior to the TLR agonist.

15. The method of claim 14, wherein the TLR agonist is selected from an agonist of TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9.