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

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.

What is claimed is: 
     
         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′ or 5′-CTATCT GA C*G1TTCTCT GU -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  claim 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  claim 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-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, 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, such method comprising administering to the mammal an antagonist according to any one of  claim 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-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, 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, such method comprising administering to a mammal an antagonist according to any one of  claim 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. 
     
     
         19 . 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.