# US 2008/0187544 A1 · Treating and evaluating inflammatory disorders

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- Number: US 2008/0187544 A1
- Document ID: US20080187544A1
- Status: Published application
- Kind: A1
- Application number: 11/937,687
- Filed: 2007-11-09
- Published: 2008-08-07
- Earliest claimed: 2005-05-10
- Inventors: Linda C. Burkly; Timothy Zheng
- Web page: https://patentgrep.com/patent/US20080187544A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 38/1793: {for cytokines; for lymphokines; for interferons}
- A61K 39/39541: {against normal tissues, cells}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- 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
- C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- G01N 2800/102: Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
- 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
- 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)
- 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

Methods of treating inflammatory disorders, such as rheumatoid arthritis, by modulating TWEAK and TNF-α are disclosed, as are other methods.

## Claims

### Claim 1

A method comprising:
administering, to a human subject who has rheumatoid arthritis, a TWEAK blocking agent in combination with a TNF-α blocking agent, in amounts and for a time to provide a therapeutic effect.

### Claim 2 (depends on 1)

The method of claim 1 wherein the TWEAK blocking agent and the TNF-α blocking agent are administered in an amount effective to inhibit TWEAK and TNF-α in synoviocytes, chondrocytes, osteoclasts, or osteoblasts.

### Claim 3 (depends on 1)

The method of claim 1 wherein the TWEAK blocking agent and the TNF-α blocking agent are administered in an amount effective to reduce transcription of a set of genes induced by TWEAK and TNF-α cellular programs in synoviocytes, chondrocytes, osteoclasts, or osteoblasts.

### Claim 4 (depends on 1)

The method of claim 1 wherein the TWEAK blocking agent and the TNF-α blocking agent are administered in an amount effective to reduce transcription of one or more genes list in Table 1 in synoviocytes, chondrocytes, osteoclasts, or osteoblasts.

### Claim 5 (depends on 1)

The method of claim 1 wherein the TWEAK blocking agent is administered in an amount that is at least 20% less than standard dosages for TWEAK blocking agent monotherapy for treating an adult subject for rheumatoid arthritis.

### Claim 6 (depends on 1, 5)

The method of claim 1 or 5 wherein the TNF-α blocking agent is administered in an amount that is at least 20% less than standard dosages for TNF-α blocking agent monotherapy for treating an adult subject for rheumatoid arthritis.

### Claim 7 (depends on 1)

The method of claim 1 wherein the subject is not receiving methotrexate.

### Claim 8 (depends on 1)

The method of claim 1 wherein the subject is not receiving any other disease modifying anti-rheumatic drug (DMARD).

### Claim 9 (depends on 1)

The method of claim 1 wherein the amounts result in a statistically significant reduction in joint damage as measured by the Sharp erosion score.

### Claim 10 (depends on 1)

The method of claim 1 wherein the TWEAK blocking agent reduces the ability of TWEAK to bind to a TWEAK receptor.

### Claim 11 (depends on 1)

The method of claim 1 wherein the TWEAK blocking agent is an antibody that binds to TWEAK.

### Claim 12 (depends on 1)

The method of claim 1 wherein the TWEAK blocking agent comprises an antibody that binds to a TWEAK receptor.

### Claim 13 (depends on 1)

The method of claim 1 wherein the TWEAK blocking agent comprises a soluble form of a TWEAK receptor.

### Claim 14 (depends on 1)

The method of claim 1 wherein the TWEAK blocking soluble form of the TWEAK receptor is fused with an antibody Fc region.

### Claim 15 (depends on 1)

The method of claim 1 wherein the TNF-α blocking agent reduces the ability of TNF-α to bind to a TNF-α receptor.

### Claim 16 (depends on 1)

The method of claim 1 wherein the TNF-α blocking agent comprises an antibody that binds to TNF-α, TNFR-I, or TNFR-II.

### Claim 17 (depends on 16)

The method of claim 16 wherein the TNF-α blocking agent is infliximab or adalimumab.

### Claim 18 (depends on 1)

The method of claim 1 wherein the TNF-α blocking agent comprises a soluble form of a TNF-α receptor.

### Claim 19 (depends on 1)

The method of claim 1 wherein the TNF-α blocking agent is etanercept.

### Claim 20 (depends on 1)

The method of claim 1 further comprising: evaluating the subject using a total Sharp score (TSS), Sharp erosion score, HAQ disability index, or radiologic method.

### Claim 21

A method comprising:
administering, to a human subject who has rheumatoid arthritis, a TWEAK blocking agent in combination with another biologic DMARD, in amounts and for a time to provide a therapeutic effect.

### Claim 22

A kit that comprises a TWEAK blocking agent and a TNF-α blocking agent, wherein the agents are provided as separate pharmaceutical compositions or a single pharmaceutical composition.

### Claim 23 (depends on 22)

The kit of claim 22 further comprising instructions for administration to treat rheumatoid arthritis.

### Claim 24

A pharmaceutical composition that includes:
a TWEAK blocking agent; and
a TNF-α blocking agent.

### Claim 25

A method comprising:
identifying a subject who has TWEAK and TNF-α mediated inflammation; and
administering to the subject: (i) a TWEAK blocking agent; (ii) a TNF-α blocking agent; or (iii) a combination of (i) and (ii).

### Claim 26 (depends on 25)

The method of claim 25 wherein the subject is identified by evaluating expression of one or more genes in synoviocytes from the subject.

### Claim 27 (depends on 26)

The method of claim 26 wherein the evaluated one or more genes include one or more genes selected from Table 1.

### Claim 28 (depends on 26)

The method of claim 26 wherein the evaluating comprises obtaining a sample of cells or tissue from the subject.

### Claim 29 (depends on 25)

The method of claim 25 wherein the identifying further comprises detecting symptoms of rheumatoid arthritis in the subject.

### Claim 30

A method comprising:
administering, to a human subject who has rheumatoid arthritis, and who is being or has been withdrawn from a TNF-α blocking agent, a TWEAK blocking agent in an amount and for a time effective to provide a therapeutic effect.

### Claim 31 (depends on 30)

The method of claim 30 wherein the TNF-α blocking agent causes toxicity, induces an immune-compromised state, or lacks efficacy.

### Claim 32 (depends on 30)

The method of claim 30 wherein the subject is refractory to therapy with the TNF-α blocking agent.

### Claim 33 (depends on 30)

The method of claim 30 wherein the subject has tuberculosis, an opportunistic infection, or a pathogenic bacterial infection.

### Claim 34 (depends on 30)

The method of claim 30 wherein the subject has glomerulonephritis.

### Claim 35 (depends on 30)

The method of claim 30 wherein the subject has a demyelinating syndrome.

### Claim 36 (depends on 30)

The method of claim 30 wherein the subject has a lupus-like reaction.

### Claim 37

A method comprising:
detecting an adverse event in a human subject who has rheumatoid arthritis, wherein the subject is being treated with a TNF-α blocking agent, but not a TWEAK blocking agent; and
administering, to the subject, a TWEAK blocking agent in an amount and for a time effective to provide an overall therapeutic effect.

### Claim 38 (depends on 37)

The method of claim 37 further comprising withdrawing the TNF-α blocking agent.

### Claim 39 (depends on 37)

The method of claim 37 wherein the adverse event comprises a lupus-like reaction.

### Claim 40 (depends on 37)

The method of claim 37 wherein the adverse event comprises a bacterial or opportunistic infection.

### Claim 41 (depends on 37)

The method of claim 37 wherein the adverse event comprises tuberculosis.

### Claim 42

A method comprising:
administering, to a human subject who has rheumatoid arthritis, and who is being or has been withdrawn from a DMARD other than a TWEAK blocking agent, a TWEAK blocking agent in an amount and for a time to provide a therapeutic effect.

### Claim 43 (depends on 42)

The method of claim 42 wherein the DMARD is methotrexate, parenteral gold, sulphasalazine, or hydroxychloroquinone.

### Claim 44 (depends on 42)

The method of claim 42 wherein the DMARD is other than a TNF-α blocking agent.

### Claim 45 (depends on 42)

The method of claim 42 wherein the DMARD is withdrawn due to toxicity or to lack of efficacy.

### Claim 46

A method comprising:
administering, to a human subject who has an inflammatory disorder, a TWEAK blocking agent in combination with a TNF-α blocking agent, in amounts and for a time to provide a therapeutic effect, wherein the inflammatory disorder is one that a TNF-α blocking agent does not exacerbate.

### Claim 47 (depends on 46)

The method of claim 46 wherein the inflammatory disorder is psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, or inflammatory myositis.

### Claim 48 (depends on 46)

The method of claim 46 wherein the subject is less than 17 years of age, and the disorder is juvenile rheumatoid arthritis or pediatric psoriasis.

### Claim 49

A method of reducing joint inflammation, the method comprising identifying a subject having joint inflammation, and administering to the subject a TWEAK blocking agent in combination with a TNF-α blocking agent.

### Claim 50 (depends on 49)

The method of claim 49 wherein the subject has rheumatoid arthritis.

### Claim 51 (depends on 49)

The method of claim 49 wherein the TWEAK blocking agent is an antibody that binds to TWEAK.

### Claim 52 (depends on 49)

The method of claim 49 wherein the TWEAK blocking agent comprises an antibody that binds to a TWEAK receptor.

### Claim 53 (depends on 49)

The method of claim 49 wherein the TWEAK blocking agent comprises a soluble form of a TWEAK receptor.

### Claim 54 (depends on 53)

The method of claim 53 wherein the soluble form of the TWEAK receptor is fused with an antibody Fc region.