USE OF TNFALPHA INHIBITOR FOR TREATMENT OF EROSIVE POLYARTHRITIS

• US 20140286867A1
• Filed: 04/30/2014
• Published: 09/25/2014
• Est. Priority Date: 07/19/2002
• 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
• Granted Patent: US 8,906,373 B2
• Time in Patent Office: Days
• US Class Current: 424/9.2
• 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 treating a human subject suffering from erosive polyarthritis, comprising administering to the subject a TNFα

antibody, or antigen-binding portion thereof, such that erosive polyarthritis is treated.

2. The method of claim 1, wherein the TNFα

antibody, or antigen-binding portion thereof, is an antibody selected from the group consisting of a humanized antibody, a chimeric antibody, and a multivalent antibody.

3. The method of claim 1, wherein the TNFα

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

4. The method of claim 1, wherein the TNFα

antibody, or antigen-binding portion thereof, is a human antibody.

5. The method of claim 4, wherein the human 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.

6. The method of claim 4, wherein the human antibody, or an antigen-binding portion thereof, has the following characteristics:

a) dissociates from human TNFα

with a K_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less, as determined by surface plasmon resonance;

b) has a light chain CDR3 domain comprising 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 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;

c) has a heavy chain CDR3 domain comprising 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.

7. The method of claim 4, wherein the human antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) having a CDR3 domain comprising 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 or 8, and comprises a heavy chain variable region (HCVR) having a CDR3 domain comprising 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.

8. The method of claim 4, wherein the human 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.

9. The method of claim 4, wherein the human antibody, or an antigen-binding portion thereof, is adalimumab.

10. The method of claim 1, wherein the TNFα

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

11. The method of claim 1, wherein the subject has a disorder in which TNFα

activity is detrimental.

12. The method of claim 11, wherein the disorder in which TNFα

activity is detrimental is selected from the group consisting of psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis.

13. The method of claim 11, wherein the disorder in which TNFα

activity is detrimental is psoriatic arthritis.

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

15. The method of claim 14, wherein the additional therapeutic agent is methotrexate.

16. A method for testing the efficacy of a TNFα

antibody, or antigen-binding portion thereof, for decreasing radiographic progression of joint disease associated with erosive polyarthritis comprising determining the efficacy of the TNFα

antibody, or antigen-binding portion thereof, using a modified Total Sharp Score (mTSS) of a patient population having joint disease associated with erosive polyarthritis and a mTSS of the patient population following administration of the TNFα

antibody, or antigen-binding portion thereof, wherein no change or a decrease in the mTSS indicates that the TNFα

antibody, or antigen-binding portion thereof, is efficacious for decreasing radiographic progression of joint disease associated with erosive polyarthritis.

17. The method of claim 16, wherein the patient population further has a disorder in which TNFα

is detrimental.

18. The method of claim 17, wherein the disorder in which TNFα

activity is detrimental is selected from the group consisting of psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis.

19. The method of claim 16, wherein the decrease in the mTSS is about −

0.2.

20. The method of claim 16, wherein the TNFα

antibody, or antigen-binding portion thereof, is an antibody selected from the group consisting of a humanized antibody, a chimeric antibody, a multivalent antibody, and a human antibody.

21. The method of claim 16, wherein the TNFα

antibody, or antigen-binding portion thereof, is selected from the group consisting of infliximab, golimumab, and adalimumab.

22. The method of claim 20, wherein the human 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 20, wherein the human antibody, or an antigen-binding portion thereof, has the following characteristics:

a) dissociates from human TNFα

with a K_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less, as determined by surface plasmon resonance;

b) has a light chain CDR3 domain comprising 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 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;

c) has a heavy chain CDR3 domain comprising 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.

24. The method of claim 20, wherein the human 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 16, wherein the TNFα

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

26. The method of claim 16, wherein the antibody, or antigen-binding portion thereof, is administered in combination with an additional therapeutic agent.

27. The method of claim 26, wherein the additional therapeutic agent is methotrexate.

28. A method for monitoring the effectiveness of a TNFα

antibody, or antigen-binding portion thereof, for the treatment of erosive polyarthritis in a human subject comprising determining the effectiveness of the TNFα

antibody, or antigen-binding portion thereof, using a baseline modified Total Sharp Score (mTSS) of a patient population having erosive polyarthritis and a mTSS score of a patient population following administration of the TNFα

antibody, or antigen-binding portion thereof, wherein a result selected from the group consisting of

i) a decrease in the mTSS in about 9-27% of the patient population;

ii) no change in the mTSS in about 65-73% of the patient population; and

iii) an increase in the mTSS in about 9-28% of the patient population indicates that the TNFα

antibody, or antigen-binding portion thereof, is effective at treating erosive polyarthritis.

29. A method for testing the efficacy of a TNFα

antibody, or antigen-binding portion thereof, to treat erosive polyarthritis associated with psoriatic arthritis comprising determining the efficacy of the TNFα

antibody, or antigen-binding portion thereof, using a baseline modified Total Sharp Score (mTSS) and either a baseline Psoriasis Area and Severity Index (PASI) score or a baseline ACR score of a patient population having erosive polyarthritis in comparison with the mTSS and either the PASI or the ACR score of the patient population following administration of the NF.alpha. antibody, or antigen-binding portion thereof, wherein no change or a decrease in the mTSS and either an ACR20 response achieved in at least about 57% or a PASI 50 response achieved in at least about 75% of the patient population, indicates that the TNFα

antibody, or antigen-binding portion thereof, is efficacious for the treatment of erosive polyarthritis associated with psoriatic arthritis.

30. A method of treating a human subject suffering from psoriasis, comprising administering to the subject a therapeutically effective amount of a human TNFα

antibody, wherein the human antibody 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.