Antagonists of IL-6 to raise Albumin and/or lower CRP

• US 20090291082A1
• Filed: 11/25/2008
• Published: 11/26/2009
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Smith, Jeffrey T.L.
• Granted Patent: US 8,404,235 B2
• Time in Patent Office: Days
• US Class Current: 424/139.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/248 IL-6
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• 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: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 2333/4737 C-reactive protein
• CPC Class Codes: G01N 2333/765 Serum albumin, e.g. HSA
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Abstract

The present invention is directed to therapeutic methods using IL-6 antagonists such as antibodies and fragments thereof having binding specificity for IL-6 to improve survivability or quality of life of a patient in need thereof. In preferred embodiments these patients will comprise those exhibiting (or at risk of developing) an elevated serum C-reactive protein level or a reduced serum albumin level prior to treatment. In another preferred embodiment, the patient'"'"'s Glasgow Prognostic Score will be increased and survivability will preferably be improved.

Claims

1. A method of improving survivability or quality of life of a patient in need thereof, comprising administering to the patient an IL-6 antagonist, whereby the patient'"'"'s serum C-reactive protein (“

CRP”

) level is reduced, and monitoring the patient to assess the reduction in the patient'"'"'s serum CRP level.

4. The method of claim 1 or 3, wherein said patient has an elevated serum CRP level prior to treatment.

11. The method of claims 1 or 2, wherein the antagonist comprises an anti-IL-6 antibody or antibody fragment.

12. The method of claim 11, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitope(s) and/or competes for binding to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or antibody fragment thereof as an anti-IL-6 antibody selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36.

14. The method of claim 12, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or antibody fragment thereof as an anti-IL-6 antibody selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36.

15. The method of claim 12, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or a fragment thereof as Ab1.

16. The method of claim 12, wherein the anti-IL-6 antibody or antibody fragment specifically binds to the same linear or conformational epitopes on an intact IL-6 polypeptide or antibody fragment thereof that is (are) specifically bound by Ab1 and wherein said epitope(s) when ascertained by epitopic mapping using overlapping linear peptide fragments which span the full length of the native human IL-6 polypeptide includes one or more residues comprised in IL-6 fragments selected from those respectively encompassing amino acid residues 37-51, amino acid residues 70-84, amino acid residues 169-183, amino acid residues 31-45 and/or amino acid residues 58-72.

18. The method of claim 12, wherein the anti-IL-6 antibody or antibody fragment comprises at least 2 complementarity determining regions (CDRs) in each the variable light and the variable heavy regions which are identical to those contained in Ab1.

26. The method of claim 12, wherein the anti-IL-6 antibody or antibody fragment is administered to the patient with a frequency at most once per period of approximately four weeks.

30. The method of claim 26, wherein the patient'"'"'s serum CRP level remains decreased and/or serum albumin level remains raised for an entire period intervening two consecutive anti-IL-6 antibody administrations.

33. The method claim 12, wherein the anti-IL-6 antibody or antibody fragment comprises a V_H polypeptide sequence selected from the group consisting of:

SEQ ID NO;

3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555 and SEQ ID NO;

571; and

further comprises a V_L polypeptide sequence selected from the group consisting of;

SEQ ID NO;

2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554 and SEQ ID NO;

570 or a variant thereof wherein one or more of the framework residues (FR residues) in said V_H or V_L polypeptide has been substituted with another amino acid residue resulting in an anti-IL-6 antibody or antibody fragment that specifically binds human IL-6.

34. The method of claim 33, wherein one or more of said FR residues are substituted with an amino acid present at the corresponding site in a parent rabbit anti-IL-6 antibody from which the complementarity determining regions (CDRs) contained in said V_H or V_L polypeptides have been derived or by a conservative amino acid substitution.

39. The method of claim 12, wherein the anti-IL-6 antibody or antibody fragment comprises a polypeptide having at least 90% sequence homology to one or more of the polypeptide sequences of SEQ ID NO:

3, 18, 19, 22, 38, 54, 70, 86, 102, 117, 118, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, 571, 2, 20, 21, 37, 53, 69, 85, 101, 119, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, and 570.

40. The method of claim 12, wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days.

48. The method of claim 12, wherein the anti-IL-6 antibody or antibody fragment is Ab1 or a fragment thereof.

57. The method of claim 1 or 3, further comprising:

measuring the patient'"'"'s serum CRP level prior to administration of the IL-6 antagonist, and administering the IL-6 antagonist if the patient'"'"'s serum CRP level is at least approximately 5 mg/L.

58. The method of claim 57, wherein the patient'"'"'s serum CRP level is reduced to less than approximately 5 mg/L within 1 week of administration of the IL-6 antagonist.

61. The method of claim 1 or 3, wherein the patient'"'"'s serum CRP level is reduced to below 10 mg/L within about 1 week of IL-6 antagonist administration.

80. The method of any of claims 1 through 3, further comprising administration of one or more statins to the patient.

2. A method of improving survivability or quality of life of a patient in need thereof, comprising administering to the patient an IL-6 antagonist, whereby the patient'"'"'s serum albumin level is increased, and monitoring the patient to assess the increase in the patient'"'"'s serum albumin level.

70. The method of claim 2 or 3, further comprising:

measuring the patient'"'"'s serum albumin level prior to administration of the IL-6 antagonist, and administering the IL-6 antagonist if the patient'"'"'s serum albumin level is less than approximately 35 g/L.

71. The method of claim 70, wherein the patient'"'"'s serum albumin level is increased to more than approximately 35 g/L within about 5 weeks of administration of the IL-6 antagonist.

3. A method of improving survivability or quality of life of a patient in need thereof, comprising administering to the patient an IL-6 antagonist, whereby the patient'"'"'s serum CRP level is reduced and the patient'"'"'s serum albumin level is increased, and monitoring the patient to assess the reduction in the patient'"'"'s serum CRP level and the increase in the patient'"'"'s serum albumin level.

5-10. -10. (canceled)

13. (canceled)

17. (canceled)

19-25. -25. (canceled)

27-29. -29. (canceled)

31. (canceled)

32. (canceled)

35-38. -38. (canceled)

41-47. -47. (canceled)

49-56. -56. (canceled)

59. (canceled)

60. (canceled)

62-69. -69. (canceled)

72-79. -79. (canceled)

81. (canceled)