# US 2010/0166756 A1 · Method for treating an autoimmune disease using a soluble ctla4 molecule and a dmard or nsaid

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2010/0166756 A1
- Document ID: US20100166756A1
- Status: Published application
- Kind: A1
- Application number: 12/720,064
- Filed: 2010-03-09
- Published: 2010-07-01
- Earliest claimed: 2000-07-03
- Assignees: Bristol-Myers Squibb Company
- Inventors: ROBERT COHEN; SUZETTE CARR; DAVID HAGERTY; ROBERT JAMES PEACH; JEAN-CLAUDE BECKER
- Web page: https://patentgrep.com/patent/US20100166756A1

## CPC

- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- A61K 39/0008: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 47/6811: {the drug being a protein or peptide, e.g. transferrin or bleomycin}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- C07K 14/70521: {CD28, CD152}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2319/00: Fusion polypeptide
- 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)

## Abstract

The present invention relates to compositions and methods for treating immune system diseases such as rheumatic disease, by administering to a subject soluble CTLA4 molecules that block endogenous B7 molecules from binding their ligands, alone, or in conjunction with other agents including Disease Modifying Anti-Rheumatic Drugs (DMARDs).

## Claims

### Claim 1

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a first agent and a second agent, wherein
a) the first agent is CTLA4Ig beginning with methionine at position +1 or with alanine at position −1 and ending with lysine at position +357 as shown in FIG. 24 (SEQ ID NO: 19), and
b) the second agent is selected from a group consisting of immunosuppressive agents, corticosteroids, nonsteroidal
anti-inflammatory drugs, prednisone, azathioprine, methotrexate, TNF (blockers or antagonists, infliximab, any biological agent targeting an inflammatory cytokine, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, anakinra, cyclophosphamide, leflunomide, collagen, dnaJ, a molecule that blocks TNF receptors, pegsunercept, a molecule that blocks cytokine function, AMG719, a molecule that blocks LFA-1 function, efalizumab, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, codeine phosphate, propoxyphene napsylate, oxycodone hydrochloride, oxycodone bitartrate and tramadol.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier is selected from the group consisting of ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, phosphate buffered saline solution, water, emulsions, salts or electrolytes, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sterile solutions, tablets, excipients, sucrose, glucose, maltose, flavor and color additives, lipid compositions and polymeric compositions.

### Claim 3

A kit for treating rheumatoid arthritis in a subject in need thereof comprising an effective amount of a first agent and a label and/or instructions, wherein
a) the first agent is CTLA4Ig beginning with methionine at position +1 or with alanine at position −1 and ending with lysine at position +357 as shown in FIG. 24 (SEQ ID NO: 19); and
b) the label and/or instructions indicate that an effective amount of the first agent is administered to a subject having active rheumatoid arthritis with an inadequate response to methotrexate.

### Claim 4 (depends on 3)

The kit of claim 3 wherein the label and/or instructions teaches the use of said first agent to reduce symptoms of rheumatoid arthritis, improve physical function, or induce major clinical response.

### Claim 5

A method for treating rheumatoid arthritis in a subject having active rheumatoid arthritis with an inadequate response to a TNF blocking agent comprising administering to the subject an effective amount of CTLA4Ig beginning with methionine at position +1 or with alanine at position −1 and ending with lysine at position +357 as shown in FIG. 24 (SEQ ID NO: 19).

### Claim 6 (depends on 5)

The method of claim 5 wherein the effective amount of the CTLA4Ig is 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

### Claim 7 (depends on 6)

The method of claim 6 wherein the effective amount of the CTLA4Ig molecule is administered at 2 and 4 weeks after the first infusion.

### Claim 8 (depends on 5)

The method of claim 5, wherein ACR 20, 50 and/or 70 response rates are improved.

### Claim 9 (depends on 5)

The method of claim 5 wherein the active rheumatoid arthritis comprises one or more symptom selected from the group consisting of joint swelling, joint tenderness, inflammation, morning stiffness, and pain leading to physical disability.

### Claim 10 (depends on 5)

The method of claim 5 wherein treating rheumatoid arthritis comprises improving physical function.

### Claim 11 (depends on 5)

The method of claim 5 wherein treating rheumatoid arthritis comprises inducing a major clinical response.

### Claim 12 (depends on 5)

The method of claim 5 wherein treating rheumatoid arthritis comprises inhibiting progression of structural damage.

### Claim 13

A method for treating rheumatoid arthritis in a subject having active rheumatoid arthritis with an inadequate response to a TNF blocking agent, etanercept or infliximab comprising administering to the subject an effective amount of CTLA4Ig beginning with methionine at position +1 or with alanine at position −1 and ending with lysine at position +357 as shown in FIG. 24 (SEQ ID NO: 19); wherein the effective amount of the CTLA4Ig is 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg; wherein the effective amount of the CTLA4Ig molecule is administered at 2 and 4 weeks after the first infusion, then once a month thereafter; and wherein the effective amount of the CTLA4Ig is infused intravenously over 30 minutes.

### Claim 14

A method for treating rheumatoid arthritis in a subject having active rheumatoid arthritis with an inadequate response to methotrexate comprising administering to the subject an effective amount of CTLA4Ig beginning with methionine at position +1 or with alanine at position −1 and ending with lysine at position +357 as shown in FIG. 24 (SEQ ID NO: 19).

### Claim 15 (depends on 14)

The method of claim 14 wherein the effective amount of the CTLA4Ig is 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

### Claim 16 (depends on 15)

The method of claim 15 wherein the effective amount of the CTLA4Ig molecule is administered at 2 and 4 weeks after the first infusion.

### Claim 17 (depends on 14)

The method of claim 14, wherein ACR 20, 50 and/or 70 response rates are improved.

### Claim 18 (depends on 14)

The method of claim 14 wherein the active rheumatoid arthritis comprises one or more symptom selected from the group consisting of joint swelling, joint tenderness, inflammation, morning stiffness, and pain leading to physical disability.

### Claim 19 (depends on 14)

The method of claim 14 wherein treating rheumatoid arthritis comprises improving physical function.

### Claim 20 (depends on 14)

The method of claim 14 wherein treating rheumatoid arthritis comprises inducing a major clinical response.

### Claim 21 (depends on 14)

The method of claim 14 wherein treating rheumatoid arthritis comprises inhibiting progression of structural damage.

### Claim 22 (depends on 14)

The method of claim 14 wherein the effective amount of the CTLA4Ig is 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg; wherein the effective amount of the CTLA4Ig molecule is administered at 2 and 4 weeks after the first infusion, then once a month thereafter; and wherein the effective amount of the CTLA4Ig is infused intravenously over 30 minutes.

### Claim 23

A method for improving physical function in a subject having a rheumatic disease comprising administering an effective amount of a soluble CTLA4 fusion molecule comprising an extracellular domain of a CTLA4 molecule, wherein the extracellular domain of the CTLA4 molecule comprises the amino acids shown in SEQ ID NO: 17 beginning with methionine at position +27 or with alanine at position +26 and ending with aspartic acid at position +150.

### Claim 24

A method for inducing a major clinical response in a subject having a rheumatic disease comprising administering an effective amount of a soluble CTLA4 fusion molecule comprising an extracellular domain of a CTLA4 molecule, wherein the extracellular domain of the CTLA4 molecule comprises the amino acids shown in SEQ ID NO: 17 beginning with methionine at position +27 or with alanine at position +26 and ending with aspartic acid at position +150.

### Claim 25 (depends on 23, 24)

The method of claim 23 or 24 herein the rheumatic disease is rheumatoid arthritis.

### Claim 26 (depends on 23, 24)

The method of claim 23 or 24, wherein the effective amount of soluble CTLA4 fusion molecule is about 0.5 mg/kg weight of the subject, 2 mg/kg weight of the subject, 10 mg/kg weight of the subject, 0.5 to 100 mg/kg weight of the subject, 0.5 to 10 mg/kg weight of a subject, 0.1 to 20 mg/kg weight of a subject, 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

### Claim 27 (depends on 23, 24)

The method of claim 23 or 24, wherein the soluble CTLA4 fusion molecule is CTLA4Ig shown in SEQ ID NO: 19 beginning with methionine at position +27 or with alanine at position +26 and ending with lysine at position +383.

### Claim 28 (depends on 27)

The method of claim 27 wherein the effective amount of the CTLA4Ig is administered at 2 and 4 weeks after the first infusion, then once a month thereafter.

### Claim 29 (depends on 27)

The method of claim 27 wherein the effective amount of the CTLA4Ig molecule is administered at 2 and 4 weeks after the first infusion, then once a month thereafter; and wherein the effective amount of the CTLA4Ig is infused intravenously over 30 minutes.

### Claim 30 (depends on 27)

The method of claim 27 wherein the effective amount of the CTLA4Ig is 500 mg for a subject weighing less than 60 kg, 750 mg for a subject weighing between 60-100 kg or 1000 mg for a subject weighing more than 100 kg.

### Claim 31 (depends on 23, 24)

The method of claim 23 or 24 wherein the soluble CTLA4 fusion molecule is encoded by a nucleic acid molecule designated ATCC No. 68629.

### Claim 32 (depends on 23, 24)

The method of claim 23 or 24 wherein the soluble CTLA4 fusion molecule has the amino acid sequence of a CTLA4Ig fusion protein expressed by the cell deposited as ATCC CRL-10762.

### Claim 33 (depends on 23, 24)

The method of claim 23 or 24, wherein the extracellular domain of the CTLA4 molecule is joined to a non-CTLA4 molecule.

### Claim 34 (depends on 33)

The method of claims 33, wherein the non-CTLA4 molecule comprises an amino acid sequence which alters the solubility or affinity of the soluble CTLA4 fusion molecule.

### Claim 35 (depends on 34)

The method of claim 34, wherein the amino acid sequence which alters the solubility or affinity comprises an immunoglobulin moiety.

### Claim 36 (depends on 35)

The method of claim 35, wherein the immunoglobulin moiety is an immunoglobulin constant region or portion thereof.

### Claim 37 (depends on 36)

The method of claim 36, wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function.

### Claim 38 (depends on 37)

The method of claim 37, wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule.