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1. WO2012068470 - IMMUNE REGULATORY OLIGONUCLEOTIDE (IRO) COMPOUNDS TO MODULATE TOLL-LIKE RECEPTOR BASED IMMUNE RESPONSE

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[ EN ]

What is claimed is:

1. An antagonist of TLR7 and/or TLR9 having the structure

5-NpN3N2NiC*GlN1N2N3NzN4N5-3',

wherein

C*G* is an oligonucleotide motif wherein C* is 5-Me-dC, and Gl is 7-deaza-dG;

Ni-N2, at each occurrence, is independently a 2'-0-Me-ribonucleotide;

N , at each occurrence, is independently a nucleotide;

N 1 -N 3 , at each occurrence, is independently a nucleotide;

Nm and Nm, at each occurrence, is independently a nucleotide;

N4-N5, at each occurrence, is independently a 2'-0-Me-ribonucleotide;

p is 5; and

z is 3;

provided that the compound contains less than 3 consecutive guanosines.

2. The antagonist according to claim 1 having the structure 5'-CTATCTGUC*GlTTCTCTGU-3' or 5'-CTATCTGAC*GlTTCTCTGU-3'.

3. A pharmaceutical composition comprising an antagonist according to claim 1 or 2 and a pharmaceutically acceptable carrier.

4. An immune regulatory oligonucleotide (IRO) compound that is an antagonist of TLR7 and/or TLR9, selected from compound number 1 through compound number 67 and compound number 69 through compound number 111.

5. A pharmaceutical composition comprising an antagonist according to claim 4 and a pharmaceutically acceptable carrier.

6. A method for inhibiting a TLR7- and/or TLR9-mediated immune response in a mammal, the method comprising administering to the mammal an antagonist according to any one of claims 1, 2 or 4 or a composition thereof.

7. The method according to claim 6, 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.

8. The method according to claim 6, wherein the mammal is a human.

9. The method according to claim 6, wherein the antagonist 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, kinase inhibitors or co- stimulatory molecules.

10. A method for inhibiting the activity of a TLR7 and/or TLR9 agonist comprising administering an antagonist according to any one of claims 1, 2 or 4 or a composition thereof.

11. The method according to claim 10, comprising administering the antagonist prior to or at the same time as the TLR7 and/or TLR9 agonist.

12. A method for therapeutically treating a mammal having an autoimmune disease mediate by TLR7 and/or TLR9, wherein the autoimmune disease is selected from psoriasis, rheumatoid arthritis, alopecia universalis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Bullous pemphigoid, chagas disease, chronic obstructive pulmonary disease, coeliac disease, dermatomyositis, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus, pernicious anaemia, polymyositis, primary biliary cirrhosis, schizophrenia, Sjogren's syndrome, temporal arteritis, vasculitis, vitiligo, vulvodynia or

Wegener's granulomatosis, such method comprising administering to the mammal an antagonist according to any one of claims 1, 2 or 4 or a composition thereof.

13. The method according to claim 12, wherein the antagonist 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, kinase inhibitors or co-stimulatory molecules.

14. The method according to claim 12, 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.

15. The method according to claim 12, wherein the mammal is a human.

16. A method for preventing an autoimmune disease mediate by a TLR7 and/or TLR9, wherein the autoimmune disease is selected from psoriasis, rheumatoid arthritis, alopecia universalis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Bullous pemphigoid, chagas disease, chronic obstructive pulmonary disease, coeliac disease, dermatomyositis, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus, pernicious anaemia, polymyositis, primary biliary cirrhosis, schizophrenia, Sjogren's syndrome, temporal arteritis, vasculitis, vitiligo, vulvodynia or Wegener's granulomatosis , such method comprising administering to a mammal an antagonist according to any one of claims 1, 2 or 4 or a composition thereof.

17. The method according to claim 16, wherein the antagonist 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.

18. 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.

The method according to claim 16, wherein the mammal is a human.

20. The composition according to claim 3, further comprising 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.

21. The composition according to claim 5, further comprising 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.