Antibodies to IL-6 and use thereof

• US 20090028784A1
• Filed: 05/21/2008
• Published: 01/29/2009
• Est. Priority Date: 05/21/2007
• Status: Active Grant

• Current Assignee: Vitaeris Inc. (CSL Limited)
• Original Assignee: Alder Biopharmaceuticals, Inc. (Lundbeck Foundation)
• Inventors: Smith, Jeffrey T. L., Latham, John, Jensen, Anne Elisabeth Carvalho, Garcia-Martinez, Leon, Kovacevich, Brian, Dutzar, Ben, Olson, Katie, Ojala, Ethan
• Granted Patent: US 7,935,340 B2
• Time in Patent Office: Days
• US Class Current: 424/1.110
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/248 : IL-6
• CPC Class Codes: C07K 2317/20 : characterized by taxonomic origin
• 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 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention is directed to antibodies and fragments thereof having binding specificity for IL-6. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the V_H, V_L and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-IL-6 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-IL-6 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-IL-6 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with IL-6. These antibodies may bind at least one of soluble IL-6, cell surface expressed IL-6, IL-6/IL-6R and/or prevent the association of IL-6 and IL-6R, the association of IL-6/IL-6R and gp130 and or the formation of IL-6/IL-6R/gp130 multimers and thereby inhibit a biological effect associated with any of the foregoing.

Claims

1. ) An anti-human IL-6 antibody or antibody fragment which 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 fragment thereof as an anti-human 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.

2. ) The anti-human IL-6 antibody or fragment of claim 1 which 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 a fragment thereof as Ab1.

3. ) The anti-human IL-6 antibody or fragment of claim 1 which specifically binds to the same linear or conformational epitope(s) on an intact human IL-6 polypeptide or fragment thereof as an anti-human 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 anti-human IL-6 antibody or fragment of claim 3 which 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 anti-human IL-6 antibody of claim 1 which specifically binds to the same linear or conformational epitopes on an intact IL-6 polypeptide or 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.

6. ) The anti-human IL-6 antibody of claim 1 which 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 an anti-human 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.

7. ) The anti-human IL-6 antibody of claim 6 which 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.

8. ) The anti-human IL-6 antibody of claim 6 wherein all of the CDRs are identical to the CDRs contained in an anti-human 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.

9. ) The anti-human IL-6 antibody of claim 6 wherein all of the CDRs are identical to the CDRs contained in Ab1.

10. ) The anti-human IL-6 antibody or fragment of claim 1 which is aglycosylated.

11. ) The anti-human IL-6 antibody of claim 1 which contains an Fc region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation.

12. ) The anti-human IL-6 antibody or fragment of claim 1 which is a human, humanized, single chain or chimeric antibody.

13. ) The anti-human IL-6 antibody of claim 12 which is a humanized antibody derived from a rabbit (parent) anti-human IL-6 antibody.

14. ) The anti-human IL-6 antibody of claim 13 wherein the framework regions (FRs) in the variable light region and the variable heavy regions of said antibody respectively are human FRs which are unmodified or which have been modified by the substitution of at most 2 or 3 human FR residues in the variable light or heavy chain region with the corresponding FR residues of the parent rabbit antibody, and wherein said human FRs have been derived from human variable heavy and light chain antibody sequences which have been selected from a library of human germline antibody sequences based on their high level of homology to the corresponding rabbit variable heavy or light chain regions relative to other human germline antibody sequences contained in the library.

15. ) The anti-human IL-6 antibody or fragment of claim 1 which specifically binds to IL-6 expressing human cells and/or to circulating soluble IL-6 molecules in vivo.

16. ) The anti-human IL-6 antibody or fragment of claim 15 which specifically binds to IL-6 expressed on or by human cells in a patient with a disease associated with cells that express IL-6.

17. ) The anti-human IL-6 antibody or fragment of claim 16 wherein the disease is selected from general fatigue, exercise-induced fatigue, cancer-related fatigue, inflammatory disease-related fatigue, chronic fatigue syndrome, cancer-related cachexia, cardiac-related cachexia, respiratory-related cachexia, renal-related cachexia, age-related cachexia, rheumatoid arthritis, systemic lupus erythematosis (SLE), systemic juvenile idiopathic arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, inflammatory bowel disease (IBD), polymyalgia rheumatica, giant cell arteritis, autoimmune vasculitis, graft versus host disease (GVHD), Sjogren'"'"'s syndrome, adult onset Still'"'"'s disease, rheumatoid arthritis, systemic juvenile idiopathic arthritis, osteoarthritis, osteoporosis, Paget'"'"'s disease of bone, osteoarthritis, multiple myeloma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, prostate cancer, leukemia, renal cell cancer, multicentric Castleman'"'"'s disease, ovarian cancer, drug resistance in cancer chemotherapy, cancer chemotherapy toxicity, ischemic heart disease, atherosclerosis, obesity, diabetes, asthma, multiple sclerosis, Alzheimer'"'"'s disease, cerebrovascular disease, fever, acute phase response, allergies, anemia, anemia of inflammation (anemia of chronic disease), hypertension, depression, depression associated with a chronic illness, thrombosis, thrombocytosis, acute heart failure, metabolic syndrome, miscarriage, obesity, chronic prostatitis, glomerulonephritis, pelvic inflammatory disease, reperfusion injury, transplant rejection, graft versus host disease (GVHD), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

18. ) The anti-human IL-6 antibody or fragment of claim 16 wherein the disease is selected from a cancer, inflammatory disorder, viral disorder, or autoimmune disorder.

19. ) The anti-human IL-6 antibody or fragment of claim 16 wherein the disease is selected from arthritis, cachexia, and wasting syndrome.

20. ) The anti-human IL-6 antibody or fragment of claim 1 which is directly or indirectly attached to a detectable label or therapeutic agent.

21. ) A nucleic acid sequence or nucleic acid sequences which result in the expression of an anti-human IL-6 antibody or antibody fragment according to claim 1.

22. ) The nucleic acid sequence or sequences of claim 21 which are comprised of yeast or human preferred codons.

23. ) A vector comprising a nucleic acid sequence or sequences according to claim 21.

24. ) The vector of claim 23 which is a plasmid or recombinant viral vector.

25. ) A recombinant cell which expresses an antibody or antibody fragment according to claim 1.

26. ) The cell of claim 25 which is selected from a mammalian, yeast, bacterial, and insect cell.

27. ) The cell of claim 26 which is a yeast cell.

28. ) The cell of claim 27 which is a diploidal yeast cell.

29. ) The yeast cell of claim 28 which is a Pichia yeast.

30. ) A method of treatment comprising administering to a patient with a disease or condition associated with IL-6 expressing cells a therapeutically effective amount of at least one anti-human IL-6 antibody or fragment according to claim 1.

31. ) The method of claim 30 wherein the disease is selected from general fatigue, exercise-induced fatigue, cancer-related fatigue, inflammatory disease-related fatigue, chronic fatigue syndrome, cancer-related cachexia, cardiac-related cachexia, respiratory-related cachexia, renal-related cachexia, age-related cachexia, rheumatoid arthritis, systemic lupus erythematosis (SLE), systemic juvenile idiopathic arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, inflammatory bowel disease (IBD), polymyalgia rheumatica, giant cell arteritis, autoimmune vasculitis, graft versus host disease (GVHD), Sjogren'"'"'s syndrome, adult onset Still'"'"'s disease, rheumatoid arthritis, systemic juvenile idiopathic arthritis, osteoarthritis, osteoporosis, Paget'"'"'s disease of bone, osteoarthritis, multiple myeloma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, prostate cancer, leukemia, renal cell cancer, multicentric Castleman'"'"'s disease, ovarian cancer, drug resistance in cancer chemotherapy, cancer chemotherapy toxicity, ischemic heart disease, atherosclerosis, obesity, diabetes, asthma, multiple sclerosis, Alzheimer'"'"'s disease, cerebrovascular disease, fever, acute phase response, allergies, anemia, anemia of inflammation (anemia of chronic disease), hypertension, depression, depression associated with a chronic illness, thrombosis, thrombocytosis, acute heart failure, metabolic syndrome, miscarriage, obesity, chronic prostatitis, glomerulonephritis, pelvic inflammatory disease, reperfusion injury, transplant rejection, graft versus host disease (GVHD), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

32. ) The method of claim 30 wherein the disease or condition is a cancer, autoimmune disease, or inflammatory condition.

33. ) The method of claim 30 wherein the treatment further includes the administration of another therapeutic agent or regimen selected from chemotherapy, radiotherapy, cytokine administration or gene therapy.

34. ) The method of claim 30 which is used to treat a side effect of cancer or viral infection.

35. ) The method of claim 34 wherein the side effect is fatigue or weight loss (wasting syndrome).

36. ) A method of in vivo imaging which detects the presence of cells which express IL-6 comprising administering a diagnostically effective amount of at least one anti-human IL-6 antibody according to claim 1.

37. ) The method of claim 36 wherein said administration further includes the administration of a radionuclide or fluorophore that facilitates detection of the antibody at IL-6 expressing disease sites.

38. ) The method of claim 36 which is used to detect IL-6 expressing tumors or metastases.

39. ) The method of claim 36 which is used to detect the presence of sites of inflammation associated with IL-6 expressing cells.

40. ) The method of claim 36 wherein the results are used to facilitate design of an appropriate therapeutic regimen.

41. ) The method of claim 40 wherein said therapeutic regimen includes radiotherapy, chemotherapy or a combination thereof.

119. ) A pharmaceutical or diagnostic composition containing at least one IL-6 antibody or fragment according to one of claims 1 or 82-89 and a pharmaceutically acceptable carrier.

120. ) The pharmaceutical or diagnostic composition of claim 119 which further comprises at least one stabilizer.

121. ) The pharmaceutical or diagnostic composition of claim 119 which is lyophilized.

122. ) The pharmaceutical or diagnostic composition of claim 119 which comprises one or more anti-IL-6 antibodies selected from 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, or a chimeric, humanized antibody or fragment derived therefrom.

123. ) The pharmaceutical or diagnostic composition of claim 122 wherein said antibody comprises Ab1 or Ab7 or a humanized or chimeric antibody or fragment derived therefrom.

124. ) A method of treating an IL-6 associated disease comprising administering a therapeutically effective amount of a pharmaceutical composition according to one of claims 120-123.

125. ) The method of claim 124, wherein the disease is selected from a cancerous condition, autoimmune condition and an inflammatory disease.

126. ) The method of claim 125, wherein the disease is cancer-associated fatigue, cachexia or arthritis.

127. ) A method of in vivo imaging which detects the presence of cells which express IL-6 comprising administering a diagnostically effective amount of a diagnostic composition according to any one of claims 120-123.

128. ) The method of claim 127 which is used to detect or image IL-6 expressing tumors or metastases.

129. ) The method of claim 127 which is used to detect or image IL-6 expressing inflammatory sites.

130. ) The method of claim 128 or 129 which is used as part of a planning regimen for design of an effective cancer or arthritis treatment protocol.

131. ) The method of claim 130 wherein the treatment protocol includes one or more of radiation, chemotherapy, cytokine therapy, gene therapy, and antibody therapy.

132. ) The method of claim 131 wherein the antibody comprises an anti-IL-6 antibody or fragment according to one of claims 1 or 82-89.

42. ) An isolated anti-IL-6 antibody comprising 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 comprising 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 that specifically binds IL-6.

43. ) The isolated antibody of claim 42 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.

44. ) The antibody of claim 42, wherein said antibody is humanized.

45. ) The antibody of claim 42, wherein said antibody is chimeric.

46. ) The antibody of claim 45, wherein said chimeric antibody comprises a human F_c.

47. ) The antibody of claim 46, wherein said human F_c is derived from IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19.

48. ) The antibody of any one of claims 42-46, wherein said antibody binds at least one of soluble IL-6, cell-surface expressed IL-6, IL-6/IL-6R, IL-6/IL-6R/gp130 complexes and or multimers thereof and/or antagonizes the biological effects of one or more of the foregoing.

49. ) An isolated anti-IL-6 antibody comprising a polypeptide sequence having at least 90% or greater homology to any one of the polypeptide sequences of claim 42.

50. ) The antibody of claim 48, wherein said antibody binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

7</sup>, 10<sup>−

7</sup>, 5×

10<sup>−

8</sup>, 10<sup>−

8</sup>, 5×

10<sup>−

9</sup>, 10<sup>−

9</sup>, 5×

10<sup>−

10</sup>, 10<sup>−

10</sup>, 5×

10<sup>−

11</sup>, 10<sup>−

11</sup>, 5×

10<sup>−

12</sup>, 10<sup>−

12</sup>, 5×

10<sup>−

13</sup>, or 10<sup>−

13</sup>.

51. ) The antibody of claim 50, wherein said antibody binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

10</sup>.

52. ) The antibody of claim 48, wherein said antibody binds to IL-6 with an off-rate (K_off) of less than or equal to 10⁻

4 S<sup>−

1</sup>, 5×

10<sup>−

5</sup> S<sup>−

1</sup>, 10<sup>−

5</sup> S<sup>−

1</sup>, 5×

10<sup>−

6</sup> S<sup>−

1</sup>, 10<sup>−

6</sup> S<sup>−

1</sup>, 5×

10<sup>−

7</sup> S<sup>−

1</sup>, or 10<sup>−

7</sup> S<sup>−

1</sup>.

53. ) The antibody of claim 42, wherein the V_H or V_L polypeptides contained in said antibody originated from one or more rabbit B cell populations.

54. ) The antibody of any one of claims 42-45, wherein the antibody has binding specificity for primate homologs of human IL-6.

55. ) The antibody of claim 54, wherein the primate is Macaca fascicularis.

56. ) The antibody of any one of claims 42-45, wherein said antibody does not have binding specificity for IL-6R or gp130.

57. ) The antibody of any one of claims 42-45, wherein said antibody inhibits the association of IL-6 with IL-6R, and/or the production of IL-6/IL-6R/gp130 complexes and/or the production of IL-6/IL-6R/gp130 multimers.

58. ) The antibody of claim 56, wherein the IL-6R is soluble IL-6R (sIL-6R).

59. ) The antibody of claim 57, wherein the IL-6R is soluble IL-6R (sIL-6R).

60. ) A fragment of the antibody of any one of claims 42-45, wherein said fragment is selected from an F_ab fragment, an F_ab′

fragment, or an F<sub>(ab′

)2</sub> fragment.

61. ) The antibody of any one of claims 42-45, wherein said antibody further comprises an effector moiety.

62. ) The antibody of claim 61, wherein the effector moiety is a detectable moiety or a functional moiety.

63. ) The antibody of claim 62, wherein said detectable moiety is a fluorescent dye, an enzyme, a substrate, a bioluminescent material, a radioactive material, or a chemiluminescent material.

64. ) The antibody of claim 62, wherein said functional moiety is streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, or a radioactive material.

65. ) A method of ameliorating or reducing symptoms of a disease or disorder associated with IL-6, comprising administering to a patient exhibiting symptoms of a disease or disorder associated with IL-6 a therapeutically effective amount of the antibody of any one of claims 42-47.

66. ) The method of claim 65, wherein said disease or disorder associated with IL-6 is cancer associated fatigue or cachexia or arthritis.

67. ) The method of claim 65, wherein said disease or disorder associated with IL-6 is selected from general fatigue, exercise-induced fatigue, cancer-related fatigue, inflammatory disease-related fatigue, chronic fatigue syndrome, cancer-related cachexia, cardiac-related cachexia, respiratory-related cachexia, renal-related cachexia, age-related cachexia, rheumatoid arthritis, systemic lupus erythematosis (SLE), systemic juvenile idiopathic arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, inflammatory bowel disease (IBD), polymyalgia rheumatica, giant cell arteritis, autoimmune vasculitis, graft versus host disease (GVHD), Sjogren'"'"'s syndrome, adult onset Still'"'"'s disease, rheumatoid arthritis, systemic juvenile idiopathic arthritis, osteoarthritis, osteoporosis, Paget'"'"'s disease of bone, osteoarthritis, multiple myeloma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, prostate cancer, leukemia, renal cell cancer, multicentric Castleman'"'"'s disease, ovarian cancer, drug resistance in cancer chemotherapy, cancer chemotherapy toxicity, ischemic heart disease, atherosclerosis, obesity, diabetes, asthma, multiple sclerosis, Alzheimer'"'"'s disease, cerebrovascular disease, fever, acute phase response, allergies, anemia, anemia of inflammation (anemia of chronic disease), hypertension, depression, depression associated with a chronic illness, thrombosis, thrombocytosis, acute heart failure, metabolic syndrome, miscarriage, obesity, chronic prostatitis, glomerulonephritis, pelvic inflammatory disease, reperfusion injury, transplant rejection, graft versus host disease (GVHD), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

68. ) A method of making the antibody of claim 42 in a polyploid yeast culture that stably expresses and secretes into the culture medium at least 10-25 mg/liter of said antibody, comprising:

(i) introducing at least one expression vector containing one or more heterologous polynucleotides encoding said antibody operably linked to a promoter and a signal sequence into a haploid yeast cell;

(ii) producing by mating or spheroplast fusion a polyploidal yeast from said first and/or second haploid yeast cell;

(iii) selecting polyploidal yeast cells that stably express said antibody; and

(iv) producing stable polyploidal yeast cultures from said polyploidal yeast cells that stably express at least 10-25 mg/liter of said antibody into the culture medium.

69. ) The method of claim 68, wherein said yeast is selected from the following genera:

Arxiozyma;

Ascobotryozyma;

Citeromyces;

Debaryomyces;

Dekkera;

Eremothecium;

Issatchenkia;

Kazachstania;

Kluyveromyces;

Kodamaea;

Lodderomyces;

Pachysolen;

Pichia;

Saccharomyces;

Saturnispora;

Tetrapisispora;

Torulaspora;

Williopsis; and

Zygosaccharomyces.

70. ) The method of claim 69, wherein said yeast genera is Pichia.

71. ) The method of claim 70, wherein the species of Pichia is selected from Pichia pastoris, Pichia methanolica and Hansenula polymorpha (Pichia angusta).

76. ) The method of claim 68, wherein said heterologous polynucleotide further comprises a polynucleotide sequence encoding a V_L amino acid sequence selected from 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 encoding a variant thereof wherein at least one framework residue (FR residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-IL-6 antibody V_L polypeptide or a conservative amino acid substitution.

81. ) The method of claim 68, wherein said heterologous polynucleotide comprises a sequence encoding the polypeptides contained in SEQ ID NO:

2 and SEQ ID NO;

3;

SEQ ID NO;

2 and SEQ ID NO;

18;

SEQ ID NO;

2 and SEQ ID NO;

19;

SEQ ID NO;

20 and SEQ ID NO;

3;

SEQ ID NO;

20 and SEQ ID NO;

18;

SEQ ID NO;

20 and SEQ ID NO;

19;

SEQ ID NO;

21 and SEQ ID NO;

22;

SEQ ID NO;

37 and SEQ ID NO;

38;

SEQ ID NO;

53 and SEQ ID NO;

54;

SEQ ID NO;

69 and SEQ ID NO;

70;

SEQ ID NO;

85 and SEQ ID NO;

86;

SEQ ID NO;

101 and SEQ ID NO;

102;

SEQ ID NO;

101 and SEQ ID NO;

117;

SEQ ID NO;

101 and SEQ ID NO;

118;

SEQ ID NO;

119 and SEQ ID NO;

102;

SEQ ID NO;

119 and SEQ ID NO;

117;

SEQ ID NO;

119 and SEQ ID NO;

118;

SEQ ID NO;

122 and SEQ ID NO;

123;

SEQ ID NO;

138 and SEQ ID NO;

139;

SEQ ID NO;

154 and SEQ ID NO;

155;

SEQ ID NO;

170 and SEQ ID NO;

171;

SEQ ID NO;

186 and SEQ ID NO;

187;

SEQ ID NO;

202 and SEQ ID NO;

203;

SEQ ID NO;

218 and SEQ ID NO;

219;

SEQ ID NO;

234 and SEQ ID NO;

235;

SEQ ID NO;

250 and SEQ ID NO;

251;

SEQ ID NO;

266 and SEQ ID NO;

267;

SEQ ID NO;

282 and SEQ ID NO;

283;

SEQ ID NO;

298 and SEQ ID NO;

299;

SEQ ID NO;

314 and SEQ ID NO;

315;

SEQ ID NO;

330 and SEQ ID NO;

331;

SEQ ID NO;

346 and SEQ ID NO;

347;

SEQ ID NO;

362 and SEQ ID NO;

363;

SEQ ID NO;

378 and SEQ ID NO;

379;

SEQ ID NO;

394 and SEQ ID NO;

395;

SEQ ID NO;

410 and SEQ ID NO;

411;

SEQ ID NO;

426 and SEQ ID NO;

427;

SEQ ID NO;

442 and SEQ ID NO;

443;

SEQ ID NO;

458 and SEQ ID NO;

459;

SEQ ID NO;

474 and SEQ ID NO;

475;

SEQ ID NO;

490 and SEQ ID NO;

491;

SEQ ID NO;

506 and SEQ ID NO;

507;

SEQ ID NO;

522 and SEQ ID NO;

523;

SEQ ID NO;

538 and SEQ ID NO;

539;

SEQ ID NO;

554 and SEQ ID NO;

555;

or SEQ ID NO;

570 and SEQ ID NO;

571.

82. ) An anti-IL-6 antibody that binds with the same IL-6 epitope and/or competes with an anti-IL-6 antibody for binding to IL-6 as an antibody or antibody fragment encoded by one of the polynucleotide sequences recited in claim 81.

83. ) The anti-IL-6 antibody of claim 82 which binds to the same IL-6 epitope as an anti-IL-6 antibody selected from 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.

85. ) The antibody of claim 83 or 84, wherein said antibody is humanized.

86. ) The antibody of claim 83 or 84, wherein said antibody is chimeric.

87. ) The antibody of claim 86, wherein said chimeric antibody comprises a human F_c.

88. ) The antibody of claim 83 or 84 which comprises a single chain antibody.

89. ) The antibody of claim 87 wherein said human F_c is derived from human IgG1, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19.

90. ) The antibody of any one of claims 82-89, wherein said antibody binds to at least one of soluble IL-6, cell surface expressed IL-6, IL-6/IL-6R, IL-6/IL-6R/gp130 complexes and/or IL-6/IL-6R/gp130 complex multimers.

91. ) The antibody of any one of claims 82-90, wherein said antibody binds to a linear or conformational IL-6 epitope.

92. ) An isolated anti-IL-6 antibody comprising a V_L or V_H polypeptide sequence having at least 90% or greater homology to any one of the polypeptide sequences recited in claim 83.

93. ) The antibody of claim 92, wherein said antibody binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

7</sup>, 10<sup>−

7</sup>, 5×

10<sup>−

8</sup>, 10<sup>−

8</sup>, 5×

10<sup>−

−

9</sup>, 10<sup>−

9</sup>, 5×

10<sup>−

10</sup>, 10<sup>−

10</sup>, 5×

10<sup>−

11</sup>, 10<sup>−

11</sup>, 5×

10<sup>−

12</sup>, 10<sup>−

12</sup>, 5×

10<sup>−

13</sup>, or 10<sup>−

13</sup>.

94. ) The antibody of claim 90, wherein said antibody binds to IL-6 with a dissociation constant (K_D) of less than or equal to 5×

10<sup>−

10</sup>.

95. ) The antibody of claim 91, wherein said antibody binds to IL-6 with an off-rate (k_off) of less than or equal to 10⁻

4 S<sup>−

1</sup>, 5×

10<sup>−

5</sup> S<sup>−

1</sup>, 10<sup>−

5</sup> S<sup>−

1</sup>, 5×

10<sup>−

6</sup> S<sup>−

1</sup>, 10<sup>−

6</sup> S<sup>−

1</sup>, 5×

10<sup>−

7</sup> S<sup>−

1</sup>, or 10<sup>−

7</sup> S<sup>−

1</sup>.

96. ) The antibody of claim 83 or 84, wherein the antibody originated from one or more rabbit B cell populations.

97. ) The antibody of any one of claims 82-89, wherein the antibody has binding specificity for primate homologs of human IL-6.

98. ) The antibody of claim 97, wherein the primate is Macaca fascicularis.

99. ) The antibody of any one of claims 82-89, wherein said antibody does not have binding specificity for IL-6R or gp130.

100. ) The antibody of any one of claims 82-89, wherein said antibody inhibits the association of IL-6 with IL-6R;

and/or the association of IL-6/IL-6R with gp130 and/or the formation of IL-6/IL-6R/gp130 multimers and/or inhibits a biological effect of any of the foregoing.

101. ) The antibody of claim 100, wherein the IL-6R is soluble IL-6R (sIL-6R).

102. ) A fragment of the antibody of any one of claims 82-89, wherein said fragment is selected from an F_ab fragment, an F_ab′

fragment, or an F<sub>(ab′

)2</sub> fragment.

103. ) The antibody of any one of claims 82-89, wherein said antibody further comprises an effector moiety.

104. ) The antibody of claim 101, wherein the effector moiety is a detectable moiety or a functional moiety.

105. ) The antibody of claim 104, wherein said detectable moiety is a fluorescent dye, an enzyme, a substrate, a bioluminescent material, a radioactive material, or a chemiluminescent material.

106. ) The antibody of claim 104, wherein said functional moiety is streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, or a radioactive material.

107. ) A method of ameliorating or reducing symptoms of a disease or disorder associated with IL-6, comprising administering to a patient exhibiting symptoms of a disease or disorder associated with IL-6 a therapeutically effective amount of the antibody of any one of claims 82-89.

108. ) The method of claim 107, wherein said disease or disorder associated with IL-6 is cancer-associated fatigue, cachexia or arthritis.

109. ) The method of claim 107, wherein said disease or disorder associated with IL-6 is selected from general fatigue, exercise-induced fatigue, cancer-related fatigue, inflammatory disease-related fatigue, chronic fatigue syndrome, cancer-related cachexia, cardiac-related cachexia, respiratory-related cachexia, renal-related cachexia, age-related cachexia, rheumatoid arthritis, systemic lupus erythematosis (SLE), systemic juvenile idiopathic arthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis, inflammatory bowel disease (IBD), polymyalgia rheumatica, giant cell arteritis, autoimmune vasculitis, graft versus host disease (GVHD), Sjogren'"'"'s syndrome, adult onset Still'"'"'s disease, rheumatoid arthritis, systemic juvenile idiopathic arthritis, osteoarthritis, osteoporosis, Paget'"'"'s disease of bone, osteoarthritis, multiple myeloma, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, prostate cancer, leukemia, renal cell cancer, multicentric Castleman'"'"'s disease, ovarian cancer, drug resistance in cancer chemotherapy, cancer chemotherapy toxicity, ischemic heart disease, atherosclerosis, obesity, diabetes, asthma, multiple sclerosis, Alzheimer'"'"'s disease, cerebrovascular disease, fever, acute phase response, allergies, anemia, anemia of inflammation (anemia of chronic disease), hypertension, depression, depression associated with a chronic illness, thrombosis, thrombocytosis, acute heart failure, metabolic syndrome, miscarriage, obesity, chronic prostatitis, glomerulonephritis, pelvic inflammatory disease, reperfusion injury, transplant rejection, graft versus host disease (GVHD), avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemic inflammatory response syndrome (SIRS).

110. ) A method of making the antibody according to any one of claims 82-89 in a polyploid yeast culture that stably expresses and secretes into the culture medium at least 10-25 mg/liter of said antibody, comprising:

(i) introducing at least one expression vector containing one or more heterologous polynucleotides encoding said antibody operably linked to a promoter and a signal sequence into a haploid yeast cell;

(ii) producing by mating or spheroplast fusion a polyploidal yeast from said first and/or second haploid yeast cell;

(iii) selecting polyploidal yeast cells that stably express said antibody; and

(iv) producing stable polyploidal yeast cultures from said polyploidal yeast cells that stably express at least 10-25 mg/liter of said antibody into the culture medium.

111. ) The method of claim 110, wherein said yeast is selected from the following genera:

Arxiozyma;

Ascobotryozyma;

Citeromyces;

Debaryomyces;

Dekkera;

Eremothecium;

Issatchenkia;

Kazachstania;

Kluyveromyces;

Kodamaea;

Lodderomyces;

Pachysolen;

Pichia;

Saccharomyces;

Saturnispora;

Tetrapisispora;

Torulaspora;

Williopsis; and

Zygosaccharomyces.

112. ) The method of claim 111, wherein said yeast genera is Pichia.

113. ) The method of claim 112, wherein the species of Pichia is selected from Pichia pastoris, Pichia methanolica and Hansenula polymorpha (Pichia angusta).

118. ) The method of claim 110, wherein said heterologous polynucleotide comprises one or more of the polynucleotide sequences encoding at least one CDR contained in a V_L or V_H polypeptide 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;

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 SEQ ID NO;

570.

133. ) The antibody of claim 88 wherein the single chain antibody is selected from scFv, camelbody, nanobody, IgNAR, SMIP, and combinations thereof.

72. ) An isolated polynucleotide comprising a polynucleotide encoding an anti-IL-6 V_H antibody amino acid sequence selected from 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 or encoding a variant thereof wherein at least one framework residue (FR residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-IL-6 antibody V_H polypeptide or a conservative amino acid substitution.

73. ) A vector comprising the polynucleotide sequence of claim 72.

74. ) A host cell comprising the vector of claim 73.

75. ) The host cell of claim 74, wherein said host cell is a yeast cell belonging to the genus Pichia.

77. ) An isolated polynucleotide comprising the polynucleotide sequence encoding an anti-IL-6 V_L antibody amino acid sequence of 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 encoding a variant thereof wherein at least one framework residue (FR residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-IL-6 antibody V_L polypeptide or a conservative amino acid substitution.

78. ) A vector comprising the polynucleotide sequence of claim 77.

79. ) A host cell comprising the vector of claim 78.

80. ) The host cell of claim 79, wherein said host cell is a yeast cell belonging to the genus Pichia.

84. ) An isolated anti-IL-6 antibody or antibody fragment comprising one or more of the CDRs contained in the V_H polypeptide sequences 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/or one or more of the CDRs contained in the V_L polypeptide sequence consisting of;

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.

114. ) An isolated polynucleotide that expresses a polypeptide containing at least one CDR polypeptide derived from an anti-IL-6 antibody wherein said expressed polypeptide alone specifically binds IL-6 or specifically binds IL-6 when expressed in association with another polynucleotide sequence that expresses a polypeptide containing at least one CDR polypeptide derived from an anti-IL-6 antibody wherein said at least one CDR is selected from those contained in the V_L or V_H polypeptides contained in 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 SEQ ID NO;

570.

115. ) A vector comprising at least one of the polynucleotide sequences of claim 114.

116. ) A host cell comprising the vector of claim 115.

117. ) The host cell of claim 116, wherein said host cell is a yeast cell belonging to the genus Pichia.