Use of human TNFα antibodies for treatment of erosive polyarthritis

• US 8,715,664 B2
• Filed: 05/16/2006
• Issued: 05/06/2014
• Est. Priority Date: 05/16/2005
• Status: Active Grant

• Current Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Original Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Inventors: Hoffman, Rebecca S., Weinberg, Mark
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US11/435,844
• Publication Number:
  US 20070071747A1
• Time in Patent Office: 2,912 Days
• Field of Search: None
• US Class Current: 424/142.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/70 Multivalent vaccine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention describes methods of treating erosive polyarthritis comprising administering a TNFα antibody, or antigen-binding portion thereof. The invention also describes a method for testing the efficacy of a TNFα antibody, or antigen-binding portion thereof, for the treatment of erosive polyarthritis.

Claims

1. A method for inhibiting radiographic disease progression in a human subject having erosive polyarthritis associated with a disorder in which TNFα

activity is detrimental, comprising administering to the subject having erosive polyarthritis an isolated human anti-TNFα

antibody, or antigen-binding portion thereof, such that radiographic disease progression is inhibited in the subject, wherein a Total Sharp Score (TSS) of the subject is either maintained or decreased following administration of the human anti-TNFα

antibody, or antigen-binding portion thereof, wherein the human anti-TNFα

antibody, or an antigen-binding portion thereof, dissociates from human TNFα

with a K_d of 1×

10<sup>−

8</sup> M or less and a K_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less, both determined by surface plasmon resonance, and neutralizes human TNFα

cytotoxicity in a standard in vitro L929 assay with an IC₅₀ of 1×

10<sup>−

7</sup> M or less.

2. The method of claim 1, wherein the human anti-TNFα

antibody is golimumab, or an antigen-binding portion thereof.

3. The method of claim 1, wherein the human anti-TNFα

antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO;

2.

4. The method of claim 1, wherein the human anti-TNFα

antibody is adalimumab, or an antigen-binding portion thereof.

5. The method of claim 1, wherein the human anti-TNFα

antibody, or antigen-binding portion thereof, is administered to the subject on a biweekly dosing regimen.

6. The method of claim 1, further comprising administering an additional therapeutic agent to the subject.

7. The method of claim 6, wherein the additional therapeutic agent is methotrexate.

15. The method of claim 1, wherein the disorder in which TNFα

is detrimental is an autoimmune disease or a spondyloarthropathy.

16. The method of claim 15, wherein the autoimmune disease is rheumatoid arthritis, or juvenile rheumatoid arthritis.

17. The method of claim 15, wherein the spondyloarthropathy is ankylosing spondylitis or psoriatic arthritis.

30. The method of claim 1, wherein the human anti-TNFα

antibody, or antigen-binding portion thereof, comprises;

a light chain variable region (LCVR) comprising a CDR3 domain set forth in the amino acid sequence of SEQ ID NO;

3, or modified from SEQ ID NO;

3 by a single alanine substitution at position 1, 4, 5, 7, and/or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9, a CDR2 domain set forth in the amino acid sequence of SEQ ID NO;

5, and a CDR1 domain set forth in the amino acid sequence of SEQ ID NO;

7;

and a heavy chain variable region (HCVR) comprising a CDR3 domain set forth in the amino acid sequence of SEQ ID NO;

4, or modified from SEQ ID NO;

4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12, a CDR2 domain set forth in the amino acid sequence of SEQ ID NO;

6, and a CDR1 domain set forth in the amino acid sequence of SEQ ID NO;

8.

8. A method for treating erosive polyarthritis comprising administering to a subject having erosive polyarthritis associated with a disorder in which TNFα

activity is detrimental, an amount of a isolated human anti-TNFα

antibody, or an antigen-binding portion thereof, such that erosive polyarthritis is treated, wherein the amount of the human TNFα

antibody, or antigen-binding portion thereof, results in a statistically significant reduction or inhibition in joint damage as measured by a Total Sharp Score (TSS), wherein the human anti-TNFα

antibody, or an antigen-binding portion thereof, dissociates from human TNFα

with a K_d of 1×

10<sup>−

8</sup> M or less and a K_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less, both determined by surface plasmon resonance, and neutralizes human TNFα

cytotoxicity in a standard in vitro L929 assay with an IC₅₀ of 1×

10<sup>−

7</sup> M or less.

9. The method of claim 8, wherein the disorder in which TNFα

is detrimental is an autoimmune disease or a spondyloarthropathy.

10. The method of claim 9, wherein the autoimmune disorder is rheumatoid arthritis or juvenile rheumatoid arthritis.

11. The method of claim 9, wherein the spondyloarthropathy is ankylosing spondylitis or psoriatic arthritis.

12. The method of claim 8, further comprising administering an additional therapeutic agent to the subject.

13. The method of claim 8, wherein the additional therapeutic agent is methotrexate.

18. The method of claim 8, wherein the human anti-TNFα

antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO;

2.

19. The method of claim 8, wherein the human anti-TNFα

antibody is adalimumab, or an antigen-binding portion thereof.

20. The method of claim 8, wherein the human anti-TNFα

antibody, or antigen-binding portion thereof, is administered to the subject on a biweekly dosing regimen.

21. The method of claim 8, wherein the human anti-TNFα

antibody, or antigen-binding portion thereof, is administered at a dose of about 40 mg.

31. The method of claim 8, wherein the human anti-TNFα

antibody, or antigen-binding portion thereof, comprises;

a light chain variable region (LCVR) comprising a CDR3 domain set forth in the amino acid sequence of SEQ ID NO;

3, or modified from SEQ ID NO;

3 by a single alanine substitution at position 1, 4, 5, 7, and/or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9, a CDR2 domain set forth in the amino acid sequence of SEQ ID NO;

5, and a CDR1 domain set forth in the amino acid sequence of SEQ ID NO;

7; and

a heavy chain variable region (HCVR) comprising a CDR3 domain set forth in the amino acid sequence of SEQ ID NO;

4, or modified from SEQ ID NO;

4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12, a CDR2 domain set forth in the amino acid sequence of SEQ ID NO;

6, and a CDR1 domain set forth in the amino acid sequence of SEQ ID NO;

8.

14. A method for inhibiting radiographic progression of joint disease associated with erosive polyarthritis in a subject having erosive polyarthritis associated with psoriatic arthritis or rheumatoid arthritis, said method comprising administering to the subject having erosive polyarthritis, adalimumab on a biweekly dosing regimen, such that radiographic progression is inhibited, wherein a Total Sharp Score (TSS) of the subject is maintained or decreased following administration of adalimumab.

32. The method of claim 14, wherein the human anti-TNFα

antibody, or antigen-binding portion thereof, comprises;

a light chain variable region (LCVR) comprising a CDR3 domain set forth in the amino acid sequence of SEQ ID NO;

3, or modified from SEQ ID NO;

3 by a single alanine substitution at position 1, 4, 5, 7, and/or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9, a CDR2 domain set forth in the amino acid sequence of SEQ ID NO;

5, and a CDR1 domain set forth in the amino acid sequence of SEQ ID NO;

7; and

a heavy chain variable region (HCVR) comprising a CDR3 domain set forth in the amino acid sequence of SEQ ID NO;

4, or modified from SEQ ID NO;

4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12, a CDR2 domain set forth in the amino acid sequence of SEQ ID NO;

6, and a CDR1 domain set forth in the amino acid sequence of SEQ ID NO;

8.

22. A method for treating erosive polyarthritis associated with a disorder in which TNFα

activity is detrimental, said method comprising identifying a subject having erosive polyarthritis associated with a disorder in which TNFα

activity is detrimental and administering to the subject an amount of an isolated human anti-TNFα

antibody, or an antigen-binding portion thereof, such that erosive polyarthritis is treated, wherein the human anti-TNFα

antibody, or an antigen-binding portion thereof, dissociates from human TNFα

with a K_d of 1×

10<sup>−

8</sup> M or less and a K_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less, both determined by surface plasmon resonance, and neutralizes human TNFα

cytotoxicity in a standard in vitro L929 assay with an IC₅₀ of 1×

10<sup>−

7</sup> M or less.

23. The method of claim 22, wherein the human anti-TNFα

antibody is golimumab, or an antigen-binding portion thereof.

24. The method of claim 22, wherein the human anti-TNFα

antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO;

1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO;

2.

25. The method of claim 22, wherein the human anti-TNFα

antibody is adalimumab, or an antigen-binding portion thereof.

26. The method of claim 22, wherein the human anti-TNFα

antibody, or antigen-binding portion thereof, is administered to the subject on a biweekly dosing regimen.

27. The method of claim 22, wherein the disorder is rheumatoid arthritis, or juvenile rheumatoid arthritis.

28. The method of claim 22, further comprising administering an additional therapeutic agent to the subject.

29. The method of claim 28, wherein the additional therapeutic agent is methotrexate.

33. The method of claim 22, wherein the human anti-TNFα

antibody, or antigen-binding portion thereof, comprises;

a light chain variable region (LCVR) comprising a CDR3 domain set forth in the amino acid sequence of SEQ ID NO;

3, or modified from SEQ ID NO;

3 by a single alanine substitution at position 1, 4, 5, 7, and/or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9, a CDR2 domain set forth in the amino acid sequence of SEQ ID NO;

5, and a CDR1 domain set forth in the amino acid sequence of SEQ ID NO;

7; and

a heavy chain variable region (HCVR) comprising a CDR3 domain set forth in the amino acid sequence of SEQ ID NO;

4, or modified from SEQ ID NO;

4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12, a CDR2 domain set forth in the amino acid sequence of SEQ ID NO;

6, and a CDR1 domain set forth in the amino acid sequence of SEQ ID NO;

8.