ANTAGONISTS OF IL-6 TO PREVENT OR TREAT CACHEXIA, WEAKNESS, FATIGUE, AND/OR FEVER

• US 20110217303A1
• Filed: 03/14/2011
• Published: 09/08/2011
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: AlderBio Holdings, LLC (Lundbeck Seattle Biopharmaceuticals, Inc.)
• Inventors: Smith, Jeffrey T.L., Schatzman, Randall C., Litton, Mark J., Latham, John
• Granted Patent: US 9,546,213 B2
• Time in Patent Office: Days
• US Class Current: 424/135.1
• 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

1-66. -66. (canceled)

67. A method of treating cancer-related cachexia, weakness, fever or fatigue in a patient in need thereof by administering an anti-human IL-6 antibody or anti-human IL-6 antibody fragment which specifically competes for binding to the human IL-6 epitope specifically bound by the anti-IL-6 antibody comprising the variable light and heavy chain in SEQ ID NO:

3 and 2 respectively, wherein said competition can be detected in a competitive binding assay using said antibody or antibody fragment, the human IL-6 polypeptide in SEQ ID NO;

1, and the anti-IL-6 antibody comprising the variable light and heavy chain in SEQ ID NO;

3 and 2 respectively.

68. The method of claim 67 wherein said administered anti-human IL-6 antibody or antibody fragment, when used in a Western immunoblot assay that detects binding of the antibody or antibody fragment to peptides comprised in a library of overlapping peptides which each are 15 amino acids in length corresponding to the entirety of the human IL-6 polypeptide in SEQ ID NO:

1, specifically binds to the same peptides in said library as an anti-human IL-6 antibody comprising the variable heavy and variable light chain polypeptides in SEQ ID NO;

3 and 2 respectively, wherein specific binding of the antibody or antibody fragment is detected using a chemiluminescent label which emits a detectable chemiluminescent signal when specific binding of said antibody or antibody fragment to a peptide in said library occurs.

69. The method of claim 67 wherein the administered anti-human 11-6 antibody or antibody fragment blocks the interaction of human IL-6 with IL-6R1 and gp130.

70. The method of claim 68 wherein the administered anti-human 11-6 antibody or antibody fragment blocks the interaction of human IL-6 with IL-6R1 and gp130.

71. The method of claim 67 wherein the light chain said anti-human IL-6 antibody or anti-human IL-6 antibody fragment comprises the light chain complementarity-determining regions (CDRs) in SEQ ID NO:

4 (CDR1), SEQ ID NO;

5 (CDR2) and SEQ ID NO;

6 (CDR3) and the heavy chain of said antibody comprises;

the heavy chain complementarity-determining regions (CDRs) in SEQ ID NO;

7 (CDR1),;

SEQ ID NO;

8 or 120 (CDR2) and SEQ ID NO;

9 (CDR3).

72. The method of claim 71 wherein the administered anti-IL-6 antibody or IL-6 antibody fragment contains a humanized variable heavy chain contained in SEQ ID NO:

18, 19, 652, 653, 654, 655, 656, 657, 661, 664, 665, 657, 658, 704, or 708 and a humanized light chain region contained in SEQ ID NO;

2, 20, 647, 648, 649, 650, 651, 660, 666, 699, 702, 706, or 709.

73. The method of claim 71 wherein the administered anti-human IL-6 antibody or anti-human IL-6 antibody fragment contains a humanized variable light region contained in SEQ ID NO:

709 and a humanized heavy chain region contained in SEQ ID NO;

656 or 657.

74. The method of claim 67 wherein the patient has advanced cancer.

75. The method of claim 67 wherein the antibody or antibody fragment is selected from chimeric antibodies, human antibodies, humanized antibodies, rabbit antibodies, single chain antibodies selected from scFvs, camelbodies, nanobodies, IgNAR, and small-modular immunopharmaceuticals (SMIPs), and the antibody fragment is selected from Fab, Fab′

, and F(ab′

) fragments.

76. the method of claim 67 wheein the antibody contains constant regions selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19 constant regions.

77. The method of claim 76 wherein the administered antibody is an IgG1.

78. the method of claim 67 wherein the antibody or antibody fragment is non-glycosylated.

79. The method of claim 67, 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.

80. The method of claim 67, wherein the patient'"'"'s weakness or fatigue remains improved for an entire period intervening two consecutive anti-IL-6 antibody administrations.

81. The method of claim 67, wherein the anti-IL-6 antibody or antibody fragment comprises heavy and light chains having at least 90% sequence homology to the VH and VL polypeptides in SEQ ID NO:

18 and SEQ ID NO;

19 and 20 respectively. 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.

83. The method of claim 67, wherein the anti-11-6 antibody or antibody fragment is administered in combination with an antibody specific to a polypeptide selected from the group consisting of tumor necrosis factor-alpha, Interferon gamma, Interleukin 1 alpha, Interleukin 1 beta, proteolysis inducing factor, leukemia-inhibitory factor, or any combination thereof.

84. The method of claim 67, further comprising:

measuring the patient'"'"'s muscular strength prior to administration of the anti-IL-6 antibody or fragment, 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.

85. The method of claim 67, wherein the patient'"'"'s weakness is measured by the hand grip strength test before or after antibody administration.

86. The method of claim 67, wherein the patient'"'"'s fatigue is measured by the FACIT-F FS test before or after antibody administration.