Uses and compositions for treatment of rheumatoid arthritis

• US 20080166348A1
• Filed: 04/10/2007
• Published: 07/10/2008
• Est. Priority Date: 04/10/2006
• Status: Active Grant

• Current Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Original Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Inventors: Burmester, Gerd R., Cifaldi, Mary A., Keystone, Edward, Mease, Philip, Kavanaugh, Arthur, Lovell, Daniel J., Kupper, Hartmut, Kent, Jeffrey D., Perez, John L.
• Granted Patent: US 9,399,061 B2
• Time in Patent Office: Days
• US Class Current: 424/136.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/55 characterised by the host/recipient, e.g. newborn with maternal antibodies
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/092 Streptococcus
• CPC Class Codes: A61K 39/145 Orthomyxoviridae, e.g. influenza virus
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/30 characterized by aspects of specificity or valency
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C12N 2760/16034 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/16071 Demonstrated in vivo effect
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: G01N 33/15 : Medicinal preparations ; Physical properties thereof, e.g. dissolubility drug screening with animal cells G01N33/5008
• 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 provides methods, uses and compositions for the treatment of rheumatoid arthritis. The invention describes methods and uses for treating rheumatoid arthritis wherein a TNFα inhibitor, such as a human TNFα antibody, or antigen-binding portion thereof. Also described are methods for determining the efficacy of a TNFα inhibitor for treatment of rheumatoid arthritis in a subject.

Claims

1. A method of preventing Pneumococcal disease and treating rheumatoid arthritis (RA) in a subject comprising administering a pneumococcal vaccine and a human TNFα

antibody, or antigen-binding portion thereof, to the subject, such that Pneumococcal disease is prevented and rheumatoid arthritis is treated.

4. The method of claim 1 or 2, wherein the human TNFα

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

5. The method of claim 1 or 2, wherein the human TNFα

antibody, or antigen-binding portion thereof, is administered to the subject in a dose of 40 mg.

6. The method of claim 1 or 2, wherein the human TNFα

antibody, or antigen-binding portion thereof, is administered to the subject subcutaneously.

46. The method of any one of claims 1, 2, 31, 36, or 39, wherein the human TNFα

antibody, or an antigen-binding portion thereof, is selected from the group consisting of

a) a human antibody, or antigen-binding portion thereof, that 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;

b) a human antibody, or antigen-binding portion thereof, having the following characteristics;

i) 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;

ii) 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, 8 and/or 9;

iii) 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,

c) a human TNFα

antibody, or antigen-binding portion thereof, comprising 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 comprising 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;

d) a human TNFα

antibody, or 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; and

e) adalimumab.

2. A method of treating late-onset RA comprising administering a human TNFα

antibody, or antigen-binding portion thereof, to a patient having late-onset RA.

3. The method of claim 2, wherein the subject is over 60 years old.

7. A method of determining the efficacy of a TNFα

inhibitor for treating RA in a subject comprising

determining an ACR response of a patient population having RA and who was administered the TNFα

inhibitor,

wherein an ACR response selected from the group consisting of an ACR20 response in at least about 80% of the patient population, an ACR50 response in at least about 62% of the patient population, and an ACR70 response in at least about 20% of the patient population, indicates that the TNFα

inhibitor is an effective TNFα

inhibitor for the treatment of RA in a subject.

8. The method of claim 7, an ACR20 response in at least about 85% of the patient population indicates that the TNFα

inhibitor is an effective TNFα

inhibitor for the treatment of RA in a subject.

10. The method of claim 7, wherein an ACR50 response in at least about 65% of the patient population indicates that the TNFα

inhibitor is an effective TNFα

inhibitor for the treatment of RA in a subject.

11. The method of claim 7, further comprising administering the effective TNFα

inhibitor to a subject for the treatment of RA.

25. The method of claim 7 wherein an ACR70 response selected from the group consisting of an ACR70 response in at least about 25% of the patient population, an ACR70 response in at least about 30% of the patient population, an ACR70 response in at least about 35% of the patient population, or an ACR70 response in at least about 40% of the patient population, indicates that the human TNFα

antibody, or antigen-binding portion thereof, is an effective human TNFα

antibody, or antigen-binding portion thereof, for the treatment of RA in a subject.

9. (canceled)

12. A method of treating RA in a subject comprising administering an effective TNFα

inhibitor, wherein the effective TNFα

inhibitor was identified as providing an ACR response selected from the group consisting of an ACR20 response in at least about 80% of a patient population who received the effective TNFα

inhibitor for the treatment of RA, an ACR50 response in at least about 62% of a patient population who received the effective TNFα

inhibitor for the treatment of RA, and an ACR70 response in at least about 20% of a patient population who received the effective TNFα

inhibitor for the treatment of RA.

20. The method of any one of claims 7, 12, 14, or 19, wherein the TNFα

inhibitor is a TNFα

antibody, or antigen-binding portion thereof, a recombinant TNF binding protein, or a TNFα

fusion protein.

21. The method of claim 20, wherein the TNFα

fusion protein is etanercept.

22. The method of claim 20, 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 human antibody, and a multivalent antibody.

23. The method of claim 20, wherein the TNFα

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

60. The method of claim 22, wherein the human antibody, or antigen-binding portion thereof, is selected from the group consisting of:

a) a human antibody, or 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;

b) a human antibody, or antigen-binding portion thereof, having the following characteristics;

i) 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;

ii) 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;

iii) 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;

c) a human TNFα

antibody, or antigen-binding portion thereof, comprising 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 comprising 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;

d) a human TNFα

antibody, or antigen-binding portion thereof, comprising 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; and

e) adalimumab.

13. (canceled)

14. A method for predicting the efficacy of a TNFα

inhibitor for the treatment of rheumatoid arthritis (RA) in a subject comprising using the combination of a C-reactive protein (CRP) level of the subject and a Patient Activity Score (PAS) of the subject, wherein an improvement in the CRP level and the PAS score early in the treatment of the patient with the TNFα

inhibitor indicates that the TNFα

inhibitor is an effective TNFα

inhibitor for the treatment of RA in the subject.

15. The method of claim 14, wherein the improvement in the CRP level and the PAS score early in the treatment of the subject occurs at about two weeks following initiation of the treatment in the subject.

16. The method of claim 14, wherein the PAS score is determined using the Health Assessment Questionnaire (HAQ) of the subject.

18. The method of claim 16, wherein the improvement in the HAQ score is at least about 0.4.

17. (canceled)

19. A method for determining the efficacy of a TNFα

inhibitor for the treatment of rheumatoid arthritis (RA) in a subject comprising

determining a Simplified Disease Activity Score (SDAI) of a patient population having RA and who was administered the TNFα

inhibitor, wherein a mean SDAI of no greater than about 3.3 in at least about 11% of the patient population indicates that the TNFα

inhibitor is an effective TNFα

inhibitor for treating RA.

24. (canceled)

26-30. -30. (canceled)

31. A method for determining the efficacy of a human TNFα

antibody, or antigen-binding portion thereof, for treating RA in a subject comprising

determining a EULAR response of a patient population having RA and who was administered the human TNFα

antibody, or antigen-binding portion thereof,

wherein a moderate EULAR response in at least about 83% of the patient population or a good EULAR response in at least about 35% of the patient population, indicates that the human TNFα

antibody, or antigen-binding portion thereof, is an effective human TNFα

antibody, or antigen-binding portion thereof, for the treatment of RA.

32. The method of claim 31, wherein a moderate EULAR response selected from the group consisting of a moderate EULAR response in at least about 85% of the patient population, a moderate EULAR response in at least about 90% of the patient population, and a moderate EULAR response in at least about 92% of the patient population, indicates that the human TNFα

antibody, or antigen-binding portion thereof, is an effective human TNFα

antibody, or antigen-binding portion thereof, for the treatment of RA.

35. The method of claim 31, further comprising administering the effective human TNFα

antibody, or antigen-binding portion thereof, to a subject for the treatment of RA.

33-34. -34. (canceled)

36. A method of treating RA in a subject comprising administering an effective human TNFα

antibody, or antigen-binding portion thereof, for the treatment of RA in a subject, wherein the effective human TNFα

antibody, or antigen-binding portion thereof, was identified as achieving either a moderate EULAR response in at least about 83% of a patient population who was administered the human TNFα

antibody, or antigen-binding portion thereof, or a good EULAR response in at least about 35% of a patient population who was administered the human TNFα

antibody, or antigen-binding portion thereof.

38. The method of claim 36, wherein a good EULAR response in at least about 40% of the patient population indicates that the human TNFα

antibody, or antigen-binding portion thereof, is an effective human TNFα

antibody, or antigen-binding portion thereof, for the treatment of RA in a subject.

37. (canceled)

39. A method for determining the efficacy of a human TNFα

antibody, or antigen-binding portion thereof, for treating RA in a subject who has failed prior infliximab treatment comprising

determining an ACR20 response of a patient population having RA who has failed previous infliximab treatment and who was administered the human TNFα

antibody, or antigen-binding portion thereof,

wherein an ACR20 response in at least about 50% of the patient population indicates that the human TNFα

antibody, or antigen-binding portion thereof is an effective human TNFα

antibody, or antigen-binding portion thereof, for the treatment of RA in a subject who has failed prior infliximab treatment.

40. The method of claim 39, wherein an ACR20 response selected from the group consisting of an ACR20 response in at least about 50% of the patient population, an ACR20 response in at least about 55% of the patient population, an ACR20 response in at least about 60% of the patient population, an ACR20 response in at least about 65% of the patient population, and an ACR20 response in at least about 69% of the patient population, indicates that the human TNFα

antibody, or antigen-binding portion thereof, is an effective human TNFα

antibody, or antigen-binding portion thereof, for the treatment of RA in a subject who has failed prior infliximab treatment.

45. The method of claim 40, further comprising administering the effective human TNFα

antibody, or antigen-binding portion thereof, to a subject to maintain treat RA.

41-44. -44. (canceled)

47-50. -50. (canceled)

51. An article of manufacture comprising

a) a packaging material;

b) a TNFα

antibody, or antigen-binding portion thereof; and

c) a label or package insert indicating either that patients with RA receiving treatment with the TNFα

antibody, or antigen-binding portion thereof, can be administered a pneumonococcal vaccine concurrently with the TNFα

antibody, or antigen-binding portion thereof, or that in studies of the TNFα

antibody, or antigen-binding portion thereof, observed malignancies included melanoma and/or granulose cell tumor of the ovary.

52. The article of claim 51, wherein the pneumonococcal vaccine is a pneumonococcal polysaccharide vaccine.

55. The article of claim 51, wherein the TNFα

antibody, or antigen-binding portion thereof, is selected from the group consisting of

a) a human antibody, or antigen-binding portion thereof, that 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;

b) a human antibody, or antigen-binding portion thereof, having the following characteristics;

i) 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,

ii) 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;

iii) 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;

c) a human TNFα

antibody, or antigen-binding portion thereof, comprising 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 comprising 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;

d) a human TNFα

antibody, or antigen-binding portion thereof, comprising 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; and

e) adalimumab.

53. An article of manufacture comprising

a) a packaging material;

b) pneumonococcal or influenza virus vaccine; and

c) a label or package insert contained within the packaging material indicating that patients receiving the pneumonococcal or influenza virus vaccine can be safely administered a TNFα

inhibitor.

54. (canceled)

56-59. -59. (canceled)