# US 2018/0023085 A1 · Immune regulatory oligonucleotide (iro) compounds to modulate toll-like receptor based immune response

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- Number: US 2018/0023085 A1
- Document ID: US20180023085A1
- Status: Published application
- Kind: A1
- Application number: 15/726,805
- Filed: 2017-10-06
- Published: 2018-01-25
- Earliest claimed: 2010-11-19
- Assignees: Idera Pharmaceuticals, Inc.
- Applicants: Idera Pharmaceuticals, Inc.
- Inventors: Ekambar R. Kandimalla; Daqing Wang; Ireneusz Nowak; Sudhir Agrawal
- Web page: https://patentgrep.com/patent/US20180023085A1

## CPC

- C12N 15/117: Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
- A61K 31/7115: Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 2310/17: Immunomodulatory nucleic acids
- C12N 2310/31: of the backbone
- C12N 2310/317: with an inverted bond, e.g. a cap structure
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/3341: 5-Methylcytosine
- C12N 2310/336: Modified G
- C12N 2310/3521: Methyl
- C12N 2310/51: in polymeric form, e.g. multimers, concatemers
- C12N 2310/52: branched
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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

### Claim 1

An antagonist of TLR7 and/or TLR9 having the structure
5-NpN3N2N1C*G1N1N2N3NzN4N5-3′,
wherein
C*G* is an oligonucleotide motif wherein C* is 5-Me-dC, and G1 is 7-deaza-dG;
N1-N2, at each occurrence, is independently a 2′-O-Me-ribonucleotide;
N3, at each occurrence, is independently a nucleotide;
N1-N3, 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′-O-Me-ribonucleotide;
p is 5; and
z is 3;
provided that the compound contains less than 3 consecutive guanosines.

### Claim 2 (depends on 1)

The antagonist according to claim 1 having the structure 5′-CTATCTGUC*G1TTCTCTGU-3′ or 5′-CTATCTGAC*G1TTCTCTGU-3′.

### Claim 3 (depends on 1, 2)

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

### Claim 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.

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 1, 2, 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 any one of claim 1, 2 or 4 or a composition thereof.

### Claim 7 (depends on 6)

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.

### Claim 8 (depends on 6)

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

### Claim 9 (depends on 6)

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.

### Claim 10 (depends on 1, 2, 4)

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.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 1, 2, 4)

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.

### Claim 13 (depends on 12)

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.

### Claim 14 (depends on 12)

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.

### Claim 15 (depends on 12)

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

### Claim 16 (depends on 1, 2, 4)

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.

### Claim 17 (depends on 16)

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.

### Claim 18 (depends on 16)

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.

### Claim 19 (depends on 16)

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

### Claim 20 (depends on 3)

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.

### Claim 21 (depends on 5)

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.