Immune regulatory oligonucleotide (IRO) compounds to modulate toll-like receptor based immune response
View Patent ↗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.
1. An antagonist of TLR7 and/or TLR9 having the structure
5-N p N 3 N 2 N 1 C*G1N 1 N 2 N 3 N z N 4 N 5 -3′,
wherein
C*G* is an oligonucleotide motif wherein C* is 5-Me-dC, and G1 is 7-deaza-dG;
N 1 -N 2 , at each occurrence, is independently a 2′-O-Me-ribonucleotide;
N 3 , at each occurrence, is independently a nucleotide;
N 1 -N 3 , at each occurrence, is independently a nucleotide;
N m and N m , at each occurrence, is independently a nucleotide;
N 4 -N 5 , at each occurrence, is independently a 2′-O-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′-CTATCT GU C*G1TTCTCT GU -3′ (SEQ ID NO: 42) or 5′-CTATCT GA C*G1TTCTCT GU -3′ (SEQ ID NO: 68), wherein G , A , or U =2-O-Me-ribonucleotide, C*=5-Me-dC, and G1=7-deaza-dG.
3. A pharmaceutical composition comprising an antagonist according to claim 1 or 2 and a pharmaceutically acceptable carrier.
4. 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 claims 1 or 2 or a composition thereof.
5. The method according to claim 4 , 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.
6. The method according to claim 4 , wherein the mammal is a human.
7. The method according to claim 4 , wherein the antagonist 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.
8. A method for inhibiting the immune stimulation caused by a TLR7 and/or TLR9 agonist comprising administering an antagonist according to claims 1 or 2 or a composition thereof.
9. The method according to claim 8 , comprising administering the antagonist prior to or at the same time as the TLR7 and/or TLR9 agonist.
10. A method for therapeutically treating a mammal having an autoimmune disease mediated by TLR7 and/or TLR9, such method comprising administering to the mammal an antagonist according to claims 1 or 2 or a composition thereof.
11. The method according to claim 10 , wherein the antagonist 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.
12. The method according to claim 10 , 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.
13. The method according to claim 10 , wherein the mammal is a human.
14. The composition according to claim 3 , further comprising one or more vaccines, antigens, antibodies, cytotoxic agents, allergens, antibiotics, antisense oligonucleotides, TLR antagonists, peptides, proteins, gene therapy vectors, DNA vaccines, chemotherapeutic agents, kinase inhibitors or adjuvants.
15. The method according to claim 10 , wherein the autoimmune disease is selected from psoriasis, rheumatoid arthritis, multiple sclerosis, type I diabetes mellitus, irritable bowel syndrome, Chron's disease, septic shock, 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-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus, pernicious anaemia, polymyositis, primary biliary cirrhosis, schizophrenia, Sjögren's syndrome, temporal arteritis, vasculitis, vitiligo, vulvodynia or Wegener's granulomatosis.
16. The method according to claim 8 , wherein the antagonist 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.