Antagonists of IL-6 to prevent or treat Cachexia, weakness, fatigue, and/or fever

• US 20090291077A1
• 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: Schatzman, Randall C., Litton, Mark J., Latham, John, Smith, Jeffrey T.L.
• Granted Patent: US 7,906,117 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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 2317/52 Constant or Fc region; Isotype
• 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: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention is directed to therapeutic methods using antibodies and fragments thereof having binding specificity for IL-6 to prevent or treat cachexia, fever, weakness and/or fatigue in 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. In another preferred embodiment, the patient'"'"'s survivability or quality of life will preferably be improved.

Claims

1. A method of preventing or treating cachexia, weakness, fatigue, and/or fever in a patient diagnosed with an IL-6 associated disorder, comprising administering to the patient an anti-IL-6 antibody or antibody fragment, whereby the patient'"'"'s cachexia, weakness, fatigue, and/or fever is prevented or improved, and monitoring the patient to assess cachexia, weakness, fatigue, and/or fever, 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.

3. The method of claim 1, 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.

4. The method of claim 3, 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.

5. The method of claim 1, 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.

7. The method of claim 1, 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 Ab 1.

15. The method of claim 1, 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.

19. The method of claim 15, wherein the patient'"'"'s cachexia, weakness, fatigue, and/or fever remains improved for an entire period intervening two consecutive anti-IL-6 antibody administrations.

22. The method of claim 1, 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.

23. The method of claim 22 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.

28. The method of claim 1, 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.

29. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment has an elimination half-life of at least about 22 days.

37. The method of claim 1, wherein the anti-IL-6 antibody or antibody fragment is Ab1 or a fragment thereof.

39. The method of claim 1, further comprising administration of an antagonist of a cachexia-associated factor, weakness-associated factor, fatigue-associated factor, and/or fever-associated factor.

40. The method of claim 39, wherein the cachexia-associated factor, weakness-associated factor, fatigue-associated factor, and/or fever-associated factor is selected from tumor necrosis factor-alpha, Interferon gamma, Interleukin 1 alpha, Interleukin 1 beta, Interleukin 6, proteolysis inducing factor, leukemia-inhibitory factor, or any combination thereof.

46. The method of claim 1, further comprising:

measuring the patient'"'"'s body weight prior to administration of the anti-IL-6 antibody, and administering the anti-IL-6 antibody or antibody fragment if the patient'"'"'s weight has declined by greater than approximately 5% within approximately 30 days, or if the patient'"'"'s lean body mass index is less than about 17 kg/m² (male patient) or less than about 14 kg/m² (female patient).

47. The method of claim 1, further comprising:

measuring the patient'"'"'s muscular strength prior to administration of the anti-IL-6 antibody, and administering the anti-IL-6 antibody or antibody fragment if the patient'"'"'s muscular strength has declined by greater than approximately 20% within approximately 30 days.

48. The method of claim 1, that results in a prolonged improvement in cachexia, weakness, fatigue, and/or fever in the patient.

49. The method of claim 1, wherein the patient'"'"'s body mass is raised by approximately 1 kilogram within approximately 4 weeks of administration of the anti-IL-6 antibody or antibody fragment.

50. The method of claim 1, wherein the patient'"'"'s cachexia is measurably improved within about 4 weeks of anti-IL-6 antibody administration.

54. The method of claim 1, wherein the patient'"'"'s weakness is measurably improved within about 2 weeks of anti-IL-6 antibody administration.

55. The method of claim 54, wherein the patient'"'"'s weakness is measured by the hand grip strength test.

56. The method of claim 55, wherein the patient'"'"'s hand grip strength is improved by at least about 15%.

59. The method of claim 1, wherein the patient'"'"'s fatigue is measurably improved within about 1 week of anti-IL-6 antibody administration.

60. The method of claim 59, wherein the patient'"'"'s fatigue is measured by the FACIT-F FS test.

61. The method of claim 60, wherein the patient'"'"'s FACIT-F FS score is improved by at least about 10 points.

63. The method of claim 1, wherein the patient'"'"'s fever is measurably improved within about 1 week of anti-IL-6 antibody administration.

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