COMPOSITIONS AND METHODS FOR TREATING OSTEOARTHRITIS

• US 20150203592A1
• Filed: 12/02/2014
• Published: 07/23/2015
• Est. Priority Date: 12/02/2013
• Status: Abandoned Application

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbvie Incorporated
• Inventors: Wang, Susanne X.
• Application Number:
  US14/558,602
• Publication Number:
  US 20150203592A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07K 16/245 IL-1
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention relates to the treatment of osteoarthritis in a human subject using anti-IL-1α and anti-IL-1β DVD-Ig proteins. In various embodiments, the osteoarthritis includes knee osteoarthritis or hand osteoarthritis.

Claims

1. A method for reducing one or more symptoms of osteoarthritis in an individual comprising administering to the individual

a binding protein that binds both IL-1α

and IL-1β

, wherein the binding protein is a dual variable domain immunoglobulin (DVD-Ig) binding protein including a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs;

46, 56, 66, 76, 86, 96, 106, 116, and 126, and including a variable light chain comprising an amino acid sequence selected from SEQ ID NOs;

51, 71, 81, 91, 101, 111, 121, and 131,

whereby one or more symptoms of osteoarthritis is reduced.

2. The method according to claim 1, wherein the osteoarthritis is moderate-to-severe knee osteoarthritis or moderate-to-severe erosive hand osteoarthritis.

5. The method according to claim 1, wherein administering to said individual is subcutaneous administration or intravenous administration.

6. The method according to claim 1, wherein the binding protein is administered at a dose of

from about 0.1 mg/kg to about 10 mg/kg;

from about 0.3 mg/kg to about 3 mg/kg;

from about 1 mg/kg to about 3 mg/kg;

or

about 3 mg/kg.

10. The method according to claim 1, wherein the binding protein is administered at a total dose of between about 1-25 mg, about 25-50 mg, about 50-75 mg, about 75-100 mg, about 100-200 mg, about 100-125 mg, about 125-150 mg, about 150-175 mg, about 175-200 mg, about 200-225 mg, about 225-250 mg, about 250-275 mg, about 275-300 mg, 300-325 mg, or about 325-350 mg of the binding protein.

12. The method according to claim 1, wherein the binding protein is administered:

in a single dose;

in multiple doses;

every week;

every other week;

every three weeks;

or

every four weeks.

16. The method according to claim 1, wherein reducing the one or more symptoms of osteoarthritis comprises a decrease in one or more biomarker levels selected from the group consisting of high-sensitivity C-reactive protein (hsCRP), MMP degradation product type I (C1M), MMP degradation product type III (C3M) and C-reactive protein (CRPM) is observed in the subject after receiving one or more doses of the DVD-Ig binding protein relative to the one or more biomarker levels in the subject prior to receiving the one or more doses of the DVD-Ig binding protein.

17. The method of claim 1, wherein reducing the one or more symptoms of osteoarthritis comprises a decrease in one or more parameter levels selected from the group consisting of systemic inflammation, chronic tissue inflammation, inflammation-mediated tissue destruction, inflammation-mediated joint destruction, and connective tissue turnover is observed in the subject after receiving one or more doses of the DVD-Ig binding protein relative to the one or more parameter levels in the subject prior to receiving the one or more doses of the DVD-Ig binding protein.

18. The method of claim 1, wherein reducing the one or more symptoms of osteoarthritis comprises a decrease in one or more characteristics selected from the group consisting of pain, joint swelling, joint stiffness, effusion, rate of bone lesion, rate of joint space narrowing, rate of bony deformity formation, rate of bone sclerosis, synovitis, synovial hypertrophy, synovial hyperplasia, angiogenesis, and the presence of osteophytes is observed in the subject after receiving one or more doses of the DVD-Ig binding protein relative to the one or more characteristics in the subject prior to receiving the one or more doses of the DVD-Ig binding protein.

19. The method according to claim 1, wherein reducing the one or more symptoms of osteoarthritis comprises an improvement in one or more metrics selected from the group consisting of Western Ontario and McMaster Universities Arthritis Index (WOMAC), Whole-Organ Magnetic Imaging Score (WORMS), Intermittent and Constant Osteoarthritis Pain (ICOAP) score;

11-point Numeric Rating Score (NRS) score, Physician Global Assessment of Disease Activity, Patient Reported Outcome, a Health Assessment Questionnaire (HAQ-DI), a patient global assessment of disease activity (VAS), measurement or presence of an anti-drug antibody (ADA), tender joint count (TJC), swollen joint count (SJC), patient'"'"'s assessment of pain, Work Instability Scale for Rheumatoid Arthritis, Short Form Health Survey (SF-36), American College of Rheumatology (ACR);

proportion of subjects achieving Low Disease Activity (LDA);

Disease Activity Score 28 (DAS28);

Clinical Disease Activity Index (CDAI), simple disease activity index (SDAI), Clinical Remission criteria, and the individual'"'"'s assessment is observed in the subject after receiving one or more doses of the DVD-Ig binding protein relative to the one or more metrics in the subject prior to receiving the one or more doses.

20. The method according to claim 1, wherein the binding prevents degradation or loss of cartilage.

3. A method for reducing pain associated with osteoarthritis in an individual, comprising administering to the individual

a binding protein that binds both IL-1α

and IL-1β

, wherein the binding protein is a DVD-Ig binding protein including a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs;

46, 56, 66, 76, 86, 96, 106, 116, and 126, and including a variable light chain comprising an amino acid sequence selected from SEQ ID NOs;

51, 71, 81, 91, 101, 111, 121, and 131,

whereby the pain is reduced.

4. The method for reducing pain according to claim 3, wherein the individual suffers from a pain condition selected from the group consisting of allodynia, hyperalgesia, and a combination of allodynia and hyperalgesia.

7-9. -9. (canceled)

11. (canceled)

13-15. -15. (canceled)

21. A method of reducing one or both of osteoarthritis and pain associated with osteoarthritis in a human subject, the method comprising

administering to the human subject a binding protein that binds both IL-1α

and IL-1β

,

wherein administering the binding protein is performed using a dose of between about 1 to about 3 mg/kg of weight of the binding protein to weight of the individual, or

wherein administering the binding protein is performed using a dose of between about 100 mg and about 200 mg of the binding protein, and

wherein a decrease in one or more biomarker levels selected from the group consisting of hsCRP, C1M, C3M and C-reactive protein CRPM is observed in the subject after receiving one or more doses of the binding protein that binds both IL-1α and

IL-1β

relative to the one or more biomarker levels in the subject prior to receiving the one or more doses of the binding protein that binds both IL-1α and

IL-1β

, to reduce one or both of the osteoarthritis and the pain associated with osteoarthritis.

22. The method of claim 21, wherein the binding protein comprises a DVD-Ig binding protein binding protein including a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs:

46, 56, 66, 76, 86, 96, 106, 116, and 126, and including a variable light chain comprising an amino acid sequence selected from SEQ ID NOs;

51, 71, 81, 91, 101, 111, 121, and 131.

23. The method according to claim 21, wherein the osteoarthritis is moderate-to-severe knee osteoarthritis or moderate-to-severe erosive hand osteoarthritis.

24. The method according to claim 21, wherein administering to said individual is by subcutaneous administration or intravenous administration.

25. The method according to claim 21, wherein the binding protein is administered:

at a dose of between about 1 and about 3 mg/kg;

at a dose of about 3 mg/kg;

or

at a total dose of between about 100 mg and about 200 mg.

28. The method according to claim 21, wherein the binding protein is administered:

in a single dose;

every other week;

or

every four weeks.

26-27. -27. (canceled)

29. (canceled)

30. A method of decreasing one or more biomarker levels associated with osteoarthritis in a subject comprising

administering to the subject a DVD-Ig binding protein binding protein including a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs:

46, 56, 66, 76, 86, 96, 106, 116, and 126, and including a variable light chain comprising an amino acid sequence selected from SEQ ID NOs;

51, 71, 81, 91, 101, 111, 121, and 131,

wherein administering the binding protein is performed using a dose of between about 1 to about 3 mg/kg of weight of the binding protein to weight of the individual, or

wherein administering the binding protein is performed using a dose of between about 100 mg and about 200 mg of the binding protein, and

wherein a decrease in one or more biomarker levels selected from the group consisting of hsCRP, C1M, C3M and C-reactive protein CRPM is observed in the subject after administration of the DVD-Ig binding protein relative to the one or more biomarker levels in the subject prior to administration of the DVD-Ig binding protein, to decrease one or more biomarker levels associated with osteoarthritis.

31. The method according to claim 30, wherein the osteoarthritis is moderate-to-severe knee osteoarthritis or moderate-to-severe erosive hand osteoarthritis.

32. The method according claim 30, wherein administering to said individual is by subcutaneous administration or intravenous administration.

33. The method according to claim 30, wherein the binding protein is administered:

at a dose of between about 1 and about 3 mg/kg;

at a dose of about 3 mg/kg;

or

at a total dose of between about 100 mg and about 200 mg;

in a single dose;

every other week;

or

every four weeks.

34-37. -37. (canceled)

38. A method for treating osteoarthritis in a human subject comprising the step of administering to the human subject a binding protein that binds both IL-1α

and IL-1β

, wherein the binding protein is a DVD-Ig binding protein including a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs;

46, 56, 66, 76, 86, 96, 106, 116, and 126, and including a variable light chain comprising an amino acid sequence selected from SEQ ID NOs;

51, 71, 81, 91, 101, 111, 121, and 131, in a dose to achieve;

(a) an area under the curve (AUC) of between about 5 and about 300 μ

g×

day/mL;

(b) a serum or plasma half-life (T½

) of at least about 8 days;

(c) a time point to maximum observed serum concentration (Tmax) of between about 2 days and about 8 days; and

/or

(d) a maximum observed serum concentration (Cmax) of between about 0.5 and about 25 μ

g/mL,

following administration of the DVD-Ig binding protein to the human subject.

39. The method of claim 38, wherein the AUC is between about 12 and about 280 μ

g×

day/mL, the T½

is at least about 10 days, the Tmax is between about 2.5 days and about 7 days, and/or the Cmax is between about 0.1 and about 23 μ

g/mL.

40. The method of claim 38, wherein the AUC is at least about 30 μ

g×

day/mL, the T½

is at least about 10 days, the Tmax is less than about 7 days, and/or the Cmax is at least about 2.5 μ

g/mL.

41. A method for treating pain associated with osteoarthritis in a human subject, wherein the pain is associated with osteoarthritis, the method comprising the step of administering to the human subject a binding protein that binds both IL-1α

and IL-1β

, wherein the binding protein is a DVD-Ig binding protein including a variable heavy chain comprising an amino acid sequence selected from SEQ ID NOs;

46, 56, 66, 76, 86, 96, 106, 116, and 126, and including a variable light chain comprising an amino acid sequence selected from SEQ ID NOs;

51, 71, 81, 91, 101, 111, 121, and 131, in a dose to achieve;

(a) an AUC of between about 5 and about 300 μ

g×

day/mL;

(b) a T½

of at least about 8 days;

(c) a Tmax of between about 2 days and about 8 days; and

/or

(d) a Cmax of between about 0.5 and about 25 μ

g/mL,

following administration of the DVD-Ig binding protein to the human subject.

42. The method of claim 41, wherein the AUC is between about 12 and about 280 μ

g×

day/mL, the T½

is at least about 10 days, the Tmax is between about 2.5 days and about 7 days, and/or the Cmax is between about 0.1 and about 23 μ

g/mL.

43. The method of claim 41, wherein the AUC is at least about 30 μ

g×

day/mL, the T½

is at least about 10 days, the Tmax is less than about 7 days, and/or the Cmax is at least about 2.5 μ

g/mL.