TOLL LIKE RECEPTOR MODULATORS

• US 20090053148A1
• Filed: 08/15/2008
• Published: 02/26/2009
• Est. Priority Date: 08/15/2007
• Status: Active Grant

• Current Assignee: Idera Pharmaceuticals, Inc. (Aceragen Incorporated)
• Original Assignee: Idera Pharmaceuticals, Inc. (Aceragen Incorporated)
• Inventors: Bhagat, Lakshmi, Kandimalla, Ekambar, Wang, Daqing, Putta, Mallikarjuna, Agrawal, Sudhir
• Granted Patent: US 8,853,375 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 31/711 Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• 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: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to TLR9 antagonist compounds and their therapeutic or prophylactic use. The invention provides novel immune regulatory oligonucleotides and immunomers as antagonist of TLRs and methods of use thereof. These immune regulatory oligonucleotides have unique sequences that suppress, without completely ablating, TLR-mediated signaling in response to a TLR ligand or TLR signaling agonist. The methods may have use in the prevention and treatment of autoimmunity, inflammation, inflammatory bowel disease, lupus, allergy, asthma, infection, sepsis, cancer and immunodeficiency.

Claims

1. A TLR9 antagonist compound comprising an oligonucleotide-based compound having the structure 5′

-N_m—

N₁N₂C₁G₁-N_p—

N₃N₄C₂G₂-N_m-3′

, wherein C₁ and C₂ are independently cytosine or a cytosine derivative, and G₁ and G₂ are independently guanosine or a guanosine derivative, wherein at least one of C₁ and G₁ is a modified nucleoside;

N₁ and N₂, at each occurrence, are independently a nucleotide, 2′

-substituted (e.g. 2′

-O-methyl) nucleotide or nucleotide derivative or other blocking moiety that inhibits the TLR stimulatory activity of C₁G₁ provided that at least one N₁ or N₂ is a blocking moiety that inhibits the TLR stimulatory activity of C₁G₁;

N₃ and N₄, at each occurrence, is independently a nucleotide or nucleotide derivative that does not inhibit the TLR stimulatory activity of C₂G₂;

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

N_p, at each occurrence, is independently a nucleotide or nucleotide derivative, provided that the compound contains less than 3 consecutive guanosine nucleotides, wherein m is a number from 0 to about 20, wherein p is a number from 0 to about 20; and

wherein the oligonucleotide would be immune stimulatory but for the 2′

-O-substituted nucleotide, nucleotide derivative or other modification that inhibits the TLR stimulatory activity of C₁G₁.

2. The TLR9 antagonist compound according to claim 1, wherein the compound comprises at least two oligonucleotides linked through 2′

, 3′

or 5′

attachments, or functionalized nucleobase attachments, or combinations thereof.

3. The TLR9 antagonist compound according to claim 2, wherein the oligonucleotides are linked directly to each other at their 2′

ends, 3′

ends or 5′

ends, or functionalized nucleobases.

4. The TLR9 antagonist compound according to claim 2, wherein the 2′

ends, 3′

ends or 5′

ends, or functionalized nucleobases of the oligonucleotides are linked to a non-nucleotidic linker.

5. The TLR9 antagonist compound according to claim 4, wherein the non-nucleotidic linker is an alkyl linker or amino linker, wherein the alkyl or amino linker may be optionally branched or unbranched, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated, chiral, achiral or racemic mixture.

6. The TLR9 antagonist compound according to claim 5, wherein the alkyl linker has from about 2 to about 18 carbon atoms.

7. The TLR9 antagonist compound according to claim 5, wherein the alkyl linker has from about 3 to about 9 carbon atoms.

8. The TLR9 antagonist compound according to claim 5, wherein the alkyl linker is selected from 1,2,3-Propanetriol, 1,2,4-Butanetriol, 2-Hydroxymethyl-1,3-proanediol, 1,1,1-Tris(hydroxymethyl)ethane, 2-Amino-2-(hydroxymethyl)1,3-proanediol, tris(hydroxymethyl)nitromethane, 1,1,1-Tri(hydroxymethyl)propane, 1,2,6-Hexanetriol, 1,3,5-Hexanetriol, 1,3,5-Pentanetriol, 3-Methyl-1,3,5-pentanetriol, 1,2,3-Heptanetriol, 2-(Hydroxymethyl)1,4-butanediol, 1,3-Di(hydroxymethyl)phenol, 1,3,5-Tri(hydroxymethyl)benzene, 1,3-Di(hydroxyethoxy)-2-hydroxy-propane, 1,3-Di(hydroxypropoxy)-2-hydroxy-propane, D-Galactal, 1,3,5-Tris(2-hydroxyethyl)cyanuric acid, 1,3,5-Tris(4-hydroxyphenyl)benzene, 1,3-Propanediol, 1,2-Propanediol, 1,4-Butanediol, 1,3-Butanediol, 2,3-Butanediol, 1,4-Butanediol, 1,5-Pentanediol, 2,4-Pentanediol, 1,6-Hexanediol, 1,2-Hexanediol, 1,5-Hexanediol, 2,5-Hexanediol, 1,7-Heptanediol, 1,8-Octanediol, 1,2-Octanediol, 1,9-Nonanediol, 1,12-Dodecanediol or 2-(1-Aminopropyl)-1,3-propanediol.

9. A pharmaceutical composition comprising a TLR9 antagonist compound according to claim 1 and a pharmaceutically acceptable carrier.

10. A method for reducing a TLR9-mediated immune response in a vertebrate, the method comprising administering to the vertebrate a compound according to claim 1 in an amount that reduces, but does not abolish the TLR9-mediated immune response.

11. A method for therapeutically treating a vertebrate having a disease or disorder where reducing a TLR9-mediated immune response is beneficial, such method comprising administering to the vertebrate having such a disorder or disease a compound according to claim 1 in a pharmaceutically effective amount.

12. The method according to claim 11, wherein the disease or disorder is selected from cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, malaria, Lyme disease, ocular infections, skin disorders, psoriasis, scleroderma, cardiovascular disease, atherosclerosis, chronic fatigue syndrome, sarcoidosis, allergy, asthma or a disease caused by a pathogen.

13. The method according to claim 12, wherein the autoimmune disorder is selected from lupus erythematosus, multiple sclerosis, type I diabetes mellitus, irritable bowel syndrome, Chron'"'"'s disease, rheumatoid arthritis, 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, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus, pernicious anaemia, polymyositis, primary biliary cirrhosis, schizophrenia, Sjö

gren'"'"'s syndrome, temporal arteritis (“

giant cell arteritis”

), vasculitis, vitiligo, vulvodynia and Wegener'"'"'s granulomatosis.

14. The method according to claim 12, wherein the inflammatory disorder is selected from airway inflammation, asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, Behç

et'"'"'s disease, hypersensitivities, inflammatory bowel disease, reperfusion injury, rheumatoid arthritis, transplant rejection, ulcerative colitis, uveitis, conjunctivitis and vasculitis.

15. A method for preventing a disease or disorder in a vertebrate where reducing a TLR9-mediated immune response is beneficial, such method comprising administering to a vertebrate that is susceptible to such a disorder or disease a compound according to claim 1 in a pharmaceutically effective amount.

16. The method according to claim 15, wherein the disease or disorder is selected from cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, malaria, Lyme disease, ocular infections, conjunctivitis, skin disorders, psoriasis, scleroderma, cardiovascular disease, atherosclerosis, chronic fatigue syndrome, sarcoidosis, transplant rejection, allergy, asthma or a disease caused by a pathogen.

17. The method according to claim 16, wherein the autoimmune disorder is selected from lupus erythematosus, multiple sclerosis, type I diabetes mellitus, irritable bowel syndrome, Chron'"'"'s disease, rheumatoid arthritis, 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, morphea, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus, pernicious anemia, polymyositis, primary biliary cirrhosis, schizophrenia, Sjö

gren'"'"'s syndrome, temporal arteritis (“

giant cell arteritis”

), vasculitis, vitiligo, vulvodynia and Wegener'"'"'s granulomatosis.

18. The method according to claim 16, wherein the inflammatory disorder is selected from airway inflammation, asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, Behç

et'"'"'s disease, hypersensitivities, inflammatory bowel disease, reperfusion injury, rheumatoid arthritis, transplant rejection, ulcerative colitis, uveitis, conjunctivitis and vasculitis.

19. The method according the 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.

20. The method according to claim 10, comprising further administering one or more vaccines, antigens, antibodies, cytotoxic agents, allergens, antibiotics, antisense oligonucleotides, TLR agonist, TLR antagonist, siRNA, miRNA, proteins, gene therapy vectors, DNA vaccines, adjuvants, co-stimulatory molecules or combinations thereof.