# US 2016/0355584 A1 · Antibodies neutralizing gm-csf for use in the treatment of rheumatoid arthritis or as analgesics

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- Number: US 2016/0355584 A1
- Document ID: US20160355584A1
- Status: Published application
- Kind: A1
- Application number: 14/913,578
- Filed: 2014-09-01
- Published: 2016-12-08
- Earliest claimed: 2013-08-30
- Assignees: Takeda GmbH
- Applicants: Takeda GmbH
- Inventors: Thomas WAGNER; Malin CARLSSON; Margit STAUM KALTOFT
- Web page: https://patentgrep.com/patent/US20160355584A1

## CPC

- C07K 16/243: {Colony Stimulating Factors}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61K 2039/54: {characterised by the route of administration}
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to neutralizing antibodies of GM-CSF and compositions comprising the same for use in the treatment of inflammatory disorders such as rheumatoid arthritis according to specific dosing regimen. The invention relates also to neutralizing antibodies of GM-CSF and compositions comprising the same for use in the treatment of pain, e.g. pain experienced in inflammatory disorders such as rheumatoid arthritis, according to specific dosage regimen.

## Claims

### Claim at position 1

1-72. (canceled)

### Claim 73

A neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose within a period of 7-21 days after the first initial dose,
(iii) at least one further dose administered within a period of 21-35 days after said second dose,
(iv) optionally followed by further doses administered within intervals of 21-35 days.

### Claim 74 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease according to claim 73, wherein said disease is selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose after about 14 days after the first initial dose,
(iii) at least one further dose administered after about 28 days after said second dose,
(iv) optionally followed by further doses administered within intervals of about 28 days.

### Claim 75 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease according to claim 73, wherein said disease is selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose after about 14 days after the first initial dose,
(iii) at least one further dose administered after about 28 days after said second dose,
(iv) optionally followed by further doses administered within intervals of about 28 days, and wherein the patients receive at least one additional anti-inflammatory drug selected from the group comprising DMARDs, corticosteroids, NSAIDS, opioids, and biologic drugs.

### Claim 76 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease according to claim 73, wherein said disease is selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose after about 14 days after the first initial dose,
(iii) at least one further dose administered after about 28 days after said second dose,
(iv) optionally followed by further doses administered within intervals of about 28 days, and
wherein the at least one additional anti-inflammatory drug is selected from anti-folate compounds.

### Claim 77 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease according to claim 73, wherein said disease is selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose after about 14 days after the first initial dose,
(iii) at least one further dose administered after about 28 days after said second dose,
(iv) optionally followed by further doses administered within intervals of about 28 days, and wherein the anti-folate compound is methotrexate.

### Claim 78 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease according to claim 73, wherein said disease is selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose after about 14 days,
(iii) at least one further dose administered after about 28 days after said second dose,
(iv) optionally followed by further doses administered within intervals of about 28 days, and
wherein the methotrexate is administered once weekly.

### Claim 79 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease according to claim 73, wherein said disease is selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose after about 14 days after the first initial dose,
(iii) at least one further dose administered after about 28 days after said second dose,
(iv) optionally followed by further doses administered within intervals of about 28 days, and
wherein the at least one additional anti-inflammatory drug is methotrexate that is administered once a week at a dose per administration of 7.5 to 25 mg, e.g., 7.5 to 15 mg.

### Claim 80 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease according to claim 73, wherein said disease is selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis, wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose after about 14 days after the first initial dose,
(iii) at least one further dose administered after about 28 days after said second dose,
(iv) optionally followed by further doses administered within intervals of about 28 days, and
wherein the antibody or functional fragment thereof is formulated for subcutaneous administration.

### Claim 81

A neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and osteoarthritis,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose within a period of 7-21 days after the first initial dose,
(iii) at least one further dose administered within a period of 21-35 days after said second dose,
(iv) optionally followed by further doses administered within intervals of 21-35 days,
wherein the patients are selected from the following patient subgroups:
a-1) Patients not treated for an inflammatory disease selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, or osteoarthritis, or
a-2) Patients not treated for pain associated with a group of inflammatory diseases comprising rheumatoid arthritis, SLE, psoriatic arthritis, or osteoarthritis, or
a-3) Patients treated for an inflammatory condition.

### Claim 82 (depends on 81)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease according to claim 81,
wherein the neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF is used according to the following dosing scheme:
(i) a first initial dose,
(ii) followed by administration of a second dose after about 14 days after the first initial dose,
(iii) at least one further dose administered after 28 days after said second dose,
(iv) optionally followed by further doses administered within intervals of about 28 days, and
wherein the patients are selected from the following subgroups:
a-1) Patients not treated for an inflammatory condition or for pain, further selected from
individuals with RA that have not previously been treated for RA, or
individuals that have not previously been treated for RA who were diagnosed as RA patients at least 6 months prior to the first initial dose, at least 1 year prior to the first initial dose, 2 years prior to the first initial dose, 3 years prior to the first initial dose, 4 years prior to the first initial dose, or more than 5 years prior to the first initial dose, or
a-2) Patients treated for RA who have not received medication for pain in addition to the treatment for RA,
a-3) Patients treated for an inflammatory condition, selected from the group comprising rheumatoid arthritis, SLE, psoriatic arthritis, or osteoarthritis selected from the following subgroups:
patients receiving a non-biologic DMARD treatment, but who have previously not been treated with biologics (biologics treatment naïve),
patients receiving a treatment with anti-folate compounds, e.g., methotrexate, or other DMARS and/or glucocorticoids,
patients receiving a treatment with anti-folate compounds, e.g., methotrexate who do not suffer from neutropenia,
patients that are treated with methotrexate for at least 3 months, wherein said patients further receiving folinic acid or folic acid on the days after methotrexate administration, but not on the day when methotrexate is administered,
patients that are treated with methotrexate but not co-treated with adenosine receptor antagonists selected from a group comprising theophylline and caffeine,
patients that are treated with methotrexate without any signs of marrow suppression, said signs comprising neutropenia, for at least 12 weeks after initial administration of weekly doses of 7.5-25 mg per week, e.g., after initial administration of weekly doses of 7.5-15 mg per week,
Patients that are treated with methotrexate, which having a genetic polymorphism in at least one thymidylate synthase gene, the AICAR transformylase gene, or the RFC1 gene;
patients without polymorphism at C677T in the MTHFR (methylene tetrahydrofolate reductase gene),
patients with insufficiently controlled RA treated with methotrexate for at least 3 months with moderate, moderate to severe, or severe disease activity,
patients with insufficiently controlled RA treated with DMARDs selected from sulfasalazine, leflunomide or hydroxychloroquine for at least 3 months with moderate, moderate to severe, or severe disease activity,
patients with moderate, moderate to severe, or severe disease activity insufficiently controlled RA treated with methotrexate for at least 3 months in combination with another non-biologic DMARD, an anti-folate compound, methotrexate,
patients selected from the group of individuals receiving non-biologic DMARD treatment, treatment with an anti-folate compound, treatment with methotrexate, plus biologic treatment, wherein the biologic treatment is selected from the group of compounds comprising
anti-cytokine antagonists selected from a group chemical antagonists and antibodies or derivatives thereof,
cytokine receptor antagonists selected from a group comprising chemical antagonists and antibodies or derivatives thereof,
TNF-alpha neutralising agents selected from a group comprising chemical neutralising agents and antibodies or derivatives thereof,
IL-1 neutralising agents selected from a group comprising chemical neutralising agents and antibodies or derivatives thereof,
IL-6 neutralising agents selected from a group comprising chemical neutralising agents and antibodies or derivatives thereof,
IL-6R neutralising agents selected from a group comprising chemical neutralising agents and antibodies or derivatives thereof,
IL-17 neutralising agents selected from a group comprising chemical neutralising agents and antibodies or derivatives thereof, and
CD20 neutralising agents selected from a group comprising chemical neutralising agents and antibodies or derivatives thereof,
patients with insufficiently controlled RA treated with methotrexate for at least 3 months in combination with a biologic DMARD with moderate, moderate to severe, or severe disease activity,
a-4) Patients treated for inflammatory pain comprising individuals selected from the follow subgroups of patients:
patients treated for pain associated with a disease other than rheumatoid arthritis, wherein said disease is selected from autoimmune diseases, neuropathies, or inflammatory diseases,
patients treated with methotrexate for at least 3 months in combination with a biologic DMARD with moderate/moderate to severe/severe disease activity, wherein the inflammatory pain is insufficiently controlled by the treatment
patients with a non-biologic DMARD treatment and reduction of RA signs and symptoms and inhibition of progression of structural damage, wherein the pain persists or remits,
patients with no signs of ongoing inflammation, where pain in the joints is still present,
patients insufficiently controlled on methotrexate
patients who were insufficiently controlled on methotrexate plus TNF alpha inhibitor treatment;
patients with insufficiently controlled RA treated with DMARDs selected from sulfasalazine, leflunomide or hydroxychloroquine for at least 3 months with moderate, moderate to severe, or severe disease activity,
patients that do not suffer from neutropenia; or
patients that have not been treated with GM-CSF prior to the first initial dose;
patients that have previously not been treated to correct chemotherapy induced cytopenias and to counteract cytopenia-related predisposition to infections and hemorrhages, patients that do not suffer from respiratory tract problems, particularly lung problems associated with infections.

### Claim 83 (depends on 73)

A neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease as defined in claim 73, wherein the administration of the second dose is omitted, thereby having the doses after the first initial dose administered in intervals of 21 to 35 days, specifically after 28 days.

### Claim 84 (depends on 73)

The neutralizing antibody or functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease as defined in claim 73, wherein the patient suffers from moderate, moderate to severe or severe rheumatoid arthritis.

### Claim 85 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease as defined in claim 73, wherein the antibody is formulated for subcutaneous administration.

### Claim 86 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease as defined in claim 73, wherein the first initial dose of said neutralizing antibody or functional fragment thereof as well as the second dose, the third dose and optionally further doses administered within intervals of about 28 days comprises a quantity of 10 to 50 mg, or of 25 to 100 mg, or of 50 to 300 mg.

### Claim 87 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease as defined in claim 73, wherein the first initial dose of said neutralizing antibody or functional fragment thereof as well as the second dose, the third dose and optionally further doses administered within intervals of about 28 days comprises a quantity of 20 mg, or of 80 mg, or of 150 mg.

### Claim 88 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease as defined in claim 73, wherein said antibody comprises a light chain variable region comprising an amino acid sequence as set out in SEQ ID NOs: 19, 34, 54 or 55, and a heavy chain variable region comprising an amino acid sequence chosen from the group consisting of those set out in any of the SEQ ID NOs: 20-33, 35-48, 52 or 53.

### Claim 89 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease as defined in claim 73, wherein said neutralizing antibody or functional fragment thereof comprises in its light chain variable region a CDR1 comprising an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 having an amino acid sequence as set out in SEQ ID NO: 17 and a CDR3 having an amino acid sequence as set out in SEQ ID NO: 18; and comprising in its heavy chain variable region a CDR1 region comprising an amino acid sequence as set out in SEQ ID NO: 14, a CDR2 region having an amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 having an amino acid sequence as set out in SEQ ID NOs: 1-13 or 56.

### Claim 90 (depends on 73)

The neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF for use in the treatment of an inflammatory disease as defined in claim 73, comprising a light chain amino acid sequence as set out in SEQ ID NO: 34 and a heavy chain amino acid sequence as set out in SEQ ID NO: 35.

### Claim 91 (depends on 73)

A method of treatment of a disease selected from a group comprising rheumatoid arthritis, SLE, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, or osteoarthritis in a patient comprising administering a neutralizing antibody or a functional fragment thereof specifically binding primate GM-CSF as defined in claim 73.

### Claim 92 (depends on 91)

The method according to claim 91, wherein the subject has moderate, moderate to severe, or severe rheumatoid arthritis that is insufficiently controlled by either methotrexate alone, or by methotrexate in combination with at least one other chemical DMARD(s) and/or at least one TNF-inhibitor and/or at least one inhibitor of a cytokine different from TNF, e.g. an IL-6R inhibitor.

### Claim 93 (depends on 91)

The method according to claim 91, wherein the neutralizing antibody or functional fragment thereof is administered subcutaneously.

### Claim 94 (depends on 91)

The method according to claim 91, wherein the neutralizing antibody or functional fragment thereof as defined in any of the preceding claims is administered subcutaneously in at least 3, at least 5, or at least 7 doses over a at least 21 weeks.

### Claim 95 (depends on 91)

The method according to claim 91, wherein structural joint damages does not advance for at least 1 year subsequent to the start of treatment.

### Claim 96 (depends on 91)

The method according to claim 91, wherein the disease activity (DAS28CRP) after at least 12 weeks subsequent to the start of treatment, e.g., at least 24 weeks subsequent to the start of treatment is reduced to a DAS score of <3.2.

### Claim 97 (depends on 73)

The neutralizing antibody or functional fragment thereof or a method according to claim 73, wherein the first dose is optionally a loading dose with said neutralizing antibody or functional fragment thereof, comprising two times the amount of the neutralizing antibody or functional fragment thereof administered as the first dose, as defined in the preceding claims, preferably 40 mg, 80 mg, 160 mg or 300 mg of said neutralizing antibody or functional fragment thereof.

### Claim 98 (depends on 73)

The neutralizing antibody or functional fragment, or the method according to claim 73, wherein a loading dose of about 250 to 400 mg, preferably 300 mg is administered about 7 to 21 days, 10 to 18, or 14 days before the first dose.