# US 2018/0022792 A9 · Biological Materials and Uses Thereof

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- Number: US 2018/0022792 A9
- Document ID: US20180022792A9
- Status: Published application
- Kind: A9
- Application number: 14/806,068
- Filed: 2015-07-22
- Published: 2018-01-25
- Earliest claimed: 2009-03-15
- Assignees: Imperial Innovations Limited
- Applicants: Imperial Innovations Limited
- Inventors: Kim Suzanne Midwood; Brian Maurice John Foxwell
- Web page: https://patentgrep.com/patent/US20180022792A9

## CPC

- C07K 16/18: against material from animals or humans
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/17: from animals; from humans {(enzyme inhibitors A61K38/005)}
- A61K 38/39: Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 14/4702: {Regulators; Modulating activity}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 15/1138: {against receptors or cell surface proteins}
- C12Q 1/6883: for diseases caused by alterations of genetic material
- G01N 33/5038: {involving detection of metabolites per se}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/55: Fab or Fab'
- C07K 2317/569: Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2320/30: Special therapeutic applications
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/158: Expression markers
- G01N 2333/4703: Regulators; Modulating activity
- G01N 2333/525: Tumor necrosis factor [TNF]
- G01N 2333/5412: IL-6
- G01N 2333/5421: IL-8
- G01N 2500/02: Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
- G01N 2500/10: involving cells
- G01N 2800/7095: Inflammation
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

There is provided agents for modulation of a chronic inflammatory response wherein the agent modulates the biological activity of tenascin-C. There is also provided methods of identifying agents modulating tenascin-C and chronic inflammation. There are also provided uses of such agents.

## Claims

### Claim at position 1

1-91. (canceled)

### Claim 92

An agent for modulation of a chronic inflammatory response, wherein the agent modulates the biological activity of tenascin-C by altering the transcription, translation and/or binding properties of tenascin-C.

### Claim 93 (depends on 92)

An agent as claimed in claim 92, which is effective to inhibit tenascin C induced expression of at least one inflammatory cytokine.

### Claim 94 (depends on 92)

An agent as claimed in claim 92, wherein the agent is an antagonist of the TLR-4 receptor.

### Claim 95 (depends on 92)

An agent according to claim 92, selected from the group consisting of short interfering RNA (SiRNA) molecules, short hairpin RNA molecules (shRNA), antisense oligonucleotides, compounds with binding affinity for tenascin-C, antibodies (polyclonal or monoclonal) and antigen-binding fragments thereof, small inhibitor compounds, a domain of tenascin-C or variant thereof, polypeptides and proteins.

### Claim 96 (depends on 95)

An agent according to claim 95 wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of Fv fragments, scFv fragments, Fab, single variable domains and domain antibodies.

### Claim 97 (depends on 96)

An agent as claimed in claim 96, wherein the antibody or antigen-binding fragment thereof is humanized.

### Claim 98 (depends on 96)

An agent as claimed in claim 96, wherein the antibody or antigen-binding fragment thereof has specificity for Toll Like Receptor 4 (TLR4), tenascin-C or a domain thereof.

### Claim 99 (depends on 98)

An agent as claimed in claim 98 wherein the antibody or antigen-binding fragment thereof has specificity for the FBG domain of tenascin-C.

### Claim 100 (depends on 92)

An agent as claimed in claim 92, comprising at least one peptide fragment of the FBG domain of tenascin C or an antibody or antibody fragment immunologically specific therefore, said peptide being about 30 amino acids in length and said peptide fragment or antibody being effective to inhibit tenascin C induced expression of at least one inflammatory cytokine.

### Claim 101 (depends on 100)

The agent of claim 100, wherein said peptide is selected from the group consisting of peptide 3, peptide 8 and peptide 5.

### Claim 102 (depends on 101)

The agent of claim 101, wherein said peptide is peptide 5, and said cytokine is interleukin-8.

### Claim 103 (depends on 101)

The agent of claim 101, wherein said peptide is peptide 8 or peptide 3, said cytokines are tumor necrosis factor and interleukin-8.

### Claim 104 (depends on 92)

A composition comprising the agent of claim 92 in a pharmaceutically acceptable carrier.

### Claim 105 (depends on 104)

The composition of claim 104, further comprising at least one additional agent.

### Claim 106 (depends on 105)

The composition of claim 105, wherein said at least one additional agent is selected from the group consisting of an anti-inflammatory agent, a statin, a biological agent, an immunosuppressive agent, a salicylate and a microbicidal agent.

### Claim 107 (depends on 106)

A composition as claimed in claim 106, wherein the anti-inflammatory agent is selected from the group consisting non-steroidal anti-inflammatories (NSAIDs), corticosteroids, disease-modifying antirheumatic drugs (DMARDs) or immunosuppressants.

### Claim 108

An agent for modulation of a chronic inflammatory response comprising at least one nucleic acid effective to inhibit expression of tenascin-C in a target cell, said nucleic acid hybridizing to a tenascin-C encoding nucleic acid thereby inhibiting expression thereof, said inhibition of tenascin-C expression reducing expression of at least one inflammatory cytokine.

### Claim 109 (depends on 108)

The agent of claim 108, which is an antisense oligonucleotide or a siRNA.

### Claim 110 (depends on 108)

A composition comprising the agent of claim 108 in a pharmaceutically acceptable carrier.

### Claim 111 (depends on 110)

The composition of claim 110, further comprising at least one additional agent.

### Claim 112

A method of identifying an agent that modulates the activity of tenascin-C activity in a cell comprising:
(i) incubating at least one cell and tenascin C in the presence and absence of at least one candidate agent;
(ii) determining whether said candidate agent modulates the effect of tenascin-C on said at least one cell relative to cells as compared to cells incubated in the absence of said agent.

### Claim 113 (depends on 112)

The method of claim 112, wherein said candidate agent modulates a tenascin C activity selected from the group consisting of altered transcription of tenascin-C, inhibition of translation of tenascin-C and inhibition of the binding properties of tenascin C.

### Claim 114 (depends on 112)

The method of claim 112, wherein said agent is an antagonist of the TLR-4 receptor.

### Claim 115 (depends on 112)

The method as claimed in claim 112 wherein said at least cell expresses toll-like receptor 4 (TLR4).

### Claim 116 (depends on 112)

The method as claimed in claim 112 where said at least one cell is selected from the group consisting of inflammatory cells, fibroblasts, fibroblast like cells (including RA synovial fibroblasts, also known as synoviocytes), mouse embryonic fibroblasts, human embryonic kidney cells.

### Claim 117 (depends on 116)

The method as claimed in claim 116 wherein the inflammatory cells are selected from the group consisting of macrophages, dendritic cells, monocytes, lymphocytes, monocyte like cells and macrophage like cells.

### Claim 118 (depends on 112)

The method of claim 112, wherein said candidate agent modulates a chronic inflammatory response.

### Claim 119 (depends on 118)

A method as claimed in claim 118 wherein the chronic inflammatory response is associated with a condition characterized by inappropriate inflammation.

### Claim 120 (depends on 118)

A method as claimed in claim 118 wherein the chronic inflammatory response is associated with rheumatoid arthritis (RA), autoimmune conditions, inflammatory bowel diseases, non-healing wounds, multiple sclerosis, cancer, atherosclerosis, sjogrens disease, diabetes, lupus erythrematosus (including systemic lupus erythrematosus), asthma, fibrotic diseases (including liver cirrhosis), pulmonary fibrosis, UV damage and psoriasis.

### Claim 121 (depends on 120)

A method as claimed in claim 120 wherein the chronic inflammation is associated with rheumatoid arthritis (RA).

### Claim 122 (depends on 92)

An agent identified according to the method as claimed in claim 92.

### Claim 123 (depends on 92)

A method of treating a chronic inflammatory condition comprising administering to a subject an effective amount of an agent identified by the method of claim 92.

### Claim 124 (depends on 112)

A kit for practicing the method of claim 112.