Anti-IL-6 antibodies, compositions, methods and uses

• US 20060257407A1
• Filed: 04/28/2006
• Published: 11/16/2006
• Est. Priority Date: 04/29/2005
• Status: Active Grant

• Current Assignee: Janssen Biotech, Inc. (Johnson & Johnson)
• Original Assignee: Ortho Biotech Inc. (Johnson & Johnson)
• Inventors: Marquis, David Matthew, Knight, David M., Wu, Sheng-Jiun, Yang, Jing, Vasserot, Alain Philippe, Chen, Yan, Smith, Eric Michael, Stojanovic-Susulic, Vedrana, Song, Xiao-Yu R., Gardner, Debra, Shealy, David J., Liang, Bailin, Tam, Susan H., Lark, Michael W., Sweet, Raymond W.
• Granted Patent: US 7,560,112 B2
• Time in Patent Office: Days
• US Class Current: 424/145.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• 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 25/00 Drugs for disorders of the nervous system
• 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 27/02 Ophthalmic agents
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• 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 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: C07K 16/248 : IL-6
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• 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 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• 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

Abstract

An anti-IL-6 antibody, including isolated nucleic acids that encode at least one anti-IL-6 antibody, vectors, host cells, transgenic animals or plants, and methods of making and using thereof have applications in diagnostic and/or therapeutic compositions, methods and devices.

Claims

1. An isolated IL-6 antibody comprising at least one complementarity determining region having an amino acid sequence selected from the group consisting of SEQ ID NOS:

132-137, wherein said antibody binds to human IL-6 or a fragment thereof.

2. The isolated antibody of claim 1, wherein X₁ is A or G, X₂ is S or R, X₃ is H, I, S, or Y, X₄ is S or Y, X₅ is S or F, X₆ is F, L, M, or T, X₇ is N or E, X₈ is A or T, X₉ is M, C, S or Q, X₁₀ is Q or C, X₁₁ is T or Q, X₁₂ is F, S, or T, X₁₃ is S or P, X₁₄ is L or M, X₁₅ is A or I, X₁₆ is S or P, X₁₇ is Y or W, X₁₈ is T, E, or Y, X₁₉ is Y or F, X₂₀ is P, S, D, or Y, X₂₁ is V or D, X₂₂ is T or A, X₂₃ is G or P, X₂₄ is S, Y, T, or N, and X₂₅ is Y, T, F, or I.

40. An IL-6 antibody according to any one of claims 1-7, wherein said antibody binds IL-6 with at least one affinity selected from at least 10⁻

9 M, at least 10<sup>−

10</sup> M, at least 10<sup>−

11</sup> M, and at least 10<sup>−

12</sup> M, at least 10<sup>−

13</sup> M, at least 10<sup>−

14</sup> M, and at least 10<sup>−

15</sup> M, as determined by surface plasmon resonance or the Kinexa method.

41. The IL-6 antibody of claim 40, wherein said antibody substantially modulates at least one activity of at least one IL-6 polypeptide.

42. An isolated nucleic acid molecule encoding at least one isolated IL-6 antibody according to any one of claims 1-7.

43. An isolated nucleic acid vector comprising the isolated nucleic acid molecule according to claim 42.

44. A prokaryotic or eukaryotic host cell comprising the isolated nucleic acid molecule according to claim 42.

45. The host cell according to claim 44, wherein said host cell is at least one selected from COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2, 653, SP2/0, 293, HeLa, myeloma, or lymphoma cells, or any derivative, immortalized or transformed cell thereof.

46. A method for producing at least one IL-6 antibody, comprising translating the nucleic acid molecule according to claim 42 under conditions in vitro, in vivo or in situ, such that the IL-6 antibody is expressed in detectable or recoverable amounts.

47. A composition comprising at least one isolated IL-6 antibody according to any one of claims 1-7 and at least one pharmaceutically acceptable carrier or diluent.

48. A composition according to claim 47, further comprising at least one compound or polypeptide selected from a detectable label or reporter, a TNF antagonist, an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplastic, an immunomodulation drug, an opthalmic, otic or nasal drug, a topical drug, a nutritional drug, a cytokine, and a cytokine antagonist.

49. An anti-idiotype antibody or fragment that specifically binds at least one IL-6 antibody according to any one of claims 1-7.

50. A method for diagnosing or treating an IL-6 related condition in a cell, tissue, organ or animal, comprising

contacting or administering a composition comprising an effective amount of at least one antibody according to any one of claims 1-7, with, or to, said cell, tissue, organ or animal.

51. The method according to claim 50, wherein the IL-6 related condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, osteolysis, aseptic loosening of orthopedic implants, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, type 2 diabetes melitus, chronic obstructive pulmonary disease, and renal cell carcinoma.

52. The method according to claim 50, wherein said effective amount is about 0.001-50 mg/kilogram of said cells, tissue, organ or animal.

53. The method according to claim 50, wherein said contacting or said administrating is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.

54. A method according to 50, further comprising administering, prior, concurrently or after said contacting or administering, at least one composition comprising an effective amount of at least one compound or polypeptide selected from a detectable label or reporter, an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplastic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug, a cytokine, and a cytokine antagonist.

55. A medical device, comprising an IL-6 antibody according to any one of claims 1-7, wherein said device is suitable for contacting or administering said IL-6 antibody by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.

56. An article of manufacture for human pharmaceutical or diagnostic use, comprising packaging material and a container comprising a solution or a lyophilized form of an IL-6 antibody according to any one of claims 1-7.

57. The article of manufacture of claim 56, wherein said container is a component of a parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal delivery device or system.

58. A method for producing an isolated IL-6 antibody according to any one of claims 1-7, comprising providing a host cell or transgenic animal or transgenic plant or plant cell capable of expressing in recoverable amounts said antibody.

59. An IL-6 antibody produced by the method according to claim 58.

80. An IL-6 antibody according to any one of claims 1-7, wherein said antibody has an EC₅₀ value of about 2.7×

10<sup>−

11</sup> M or less.

81. The antibody according to claim 80, wherein the EC₅₀ value is about 2.7×

10<sup>−

12</sup> or less.

3. An isolated human engineered antibody comprising at least one complementarity determining region, wherein said antibody binds to human IL-6 or a fragment thereof.

4. An isolated IL-6 antibody, comprising at least one heavy chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOS:

95, 99, 103, 118, 122, 126, and 130 and/or at least one light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOS;

93, 97, 101, 116, 120, 124, and 128.

5. An isolated IL-6 antibody, comprising at least one light chain variable region, said light chain variable region comprising at least one member from the group consisting of:

(a) a complementarity determining region light chain 1 (CDRL1) amino acid sequence selected from the group consisting of SEQ ID NOS;

1, 3, 5, 7, 9, 11, 13, and 15;

(b) a CDRL2 amino acid sequence selected from the group consisting of SEQ ID NOS;

17, 19, 21, 23, 25, and 27; and

(c) a CDRL3 amino acid sequence selected from the group consisting of SEQ ID NOS;

29, 31, 33, 35, and 138.

7. The isolated IL-6 antibody of claim 5, further comprising a heavy chain variable region comprising at least one member from the group consisting of:

(a) a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) a CDRH3 amino acid sequence selected from the group consisting of SEQ ID NOS;

79, 81, 83, 85, 87, 89, 91, and 114.

8. The isolated IL-6 antibody of claim 7, further comprising at least one human framework region adjacent to the at least one complementarity determining region.

9. The isolated IL-6 antibody of claim 8, wherein the at least one human framework region is selected from SEQ ID NOS:

105-112.

10. The isolated IL-6 antibody of claim 5, comprising at least one light chain variable region, said light chain variable region comprising:

(a) a complementarity determining region light chain 1 (CDRL1) amino acid sequence selected from the group consisting of SEQ ID NOS;

1, 3, 5, 7, 9, 11, 13, and 15;

(b) a CDRL2 amino acid sequence selected from the group consisting of SEQ ID NOS;

17, 19, 21, 23, 25, and 27; and

(c) a CDRL3 amino acid sequence selected from the group consisting of SEQ ID NOS;

29, 31, 33, 35, and 138.

12. The isolated IL-6 antibody of claim 10, further comprising a heavy chain variable region comprising:

(a) a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) a CDRH3 amino acid sequence selected from the group consisting of SEQ ID NOS;

79, 81, 83, 85, 87, 89, 91, and 114.

13. The isolated IL-6 antibody of claim 12, further comprising, interspersed between the complementarity determining regions, a human light chain framework region 1 (FRL1) of SEQ ID NO:

105, a FRL2 of SEQ ID NO;

106, a FRL3 of SEQ ID NO;

107, a FRL4 of SEQ ID NO;

108, a human heavy chain framework region 1 (FRH1) of SEQ ID NO;

109, a FRH2 of SEQ ID NO;

110, a FRH3 of SEQ ID NO;

111, and a FRH4 of SEQ ID NO;

112.

14. The isolated antibody of claim 12, wherein the light chain variable region comprises:

(a) a CDRL1 amino acid sequence selected from the group consisting of SEQ ID NOS;

1, 3, 5, 7, 9, 11, 13, and 15;

(b) a CDRL2 amino acid sequence selected from the group consisting of SEQ ID NOS;

17, 19, 21, 23, 25, and 27; and

(c) the CDRL3 amino acid sequence of SEQ ID NO;

29.

15. The isolated antibody of claim 12, wherein the light chain variable region comprises:

(a) a CDRL1 amino acid sequence selected from the group consisting of SEQ ID NOS;

1, 3, 5, 7, 9, 11, 13, and 15;

(b) a CDRL2 amino acid sequence selected from the group consisting of SEQ ID NOS;

17, 19, 21, 23, 25, and 27; and

(c) the CDRL3 amino acid sequence of SEQ ID NO;

35.

16. The isolated antibody of claims 14 or 15, further comprising, interspersed between the CDRLs, a human light chain framework region 1 (FRL1) of SEQ ID NO:

105, a FRL2 of SEQ ID NO;

106, a FRL3 of SEQ ID NO;

107, and a FRL4 of SEQ ID NO;

108.

17. The isolated antibody of claim 12, wherein the heavy chain variable region comprises:

(a) a CDRH1 amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) the CDRH3 amino acid sequence of SEQ ID NO;

87.

18. The isolated antibody of claim 12, wherein the heavy chain variable region comprises:

(a) a CDRH1 amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) the CDRH3 amino acid sequence of SEQ ID NO;

89.

19. The isolated antibody of claim 12, wherein the heavy chain variable region comprises:

(a) a CDRH1 amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) the CDRH3 amino acid sequence of SEQ ID NO;

91.

20. The isolated antibody of claim 12, wherein the heavy chain variable region comprises:

(a) a CDRH1 amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) the CDRH3 amino acid sequence of SEQ ID NO;

114.

21. The isolated antibody according to any one of claims 17-20, further comprising, interspersed between the CDRHs, a human heavy chain framework region 1 (FRH1) of SEQ ID NO:

109, a FRH2 of SEQ ID NO;

110, a FRH3 of SEQ ID NO;

111, and a FRH4 of SEQ ID NO;

112.

22. The isolated antibody of claim 12, wherein the CDRL1 comprises the amino acid sequence of SEQ ID NO:

7, the CDRL2 comprises the amino acid sequence of SEQ ID NO;

21, the CDRL3 comprises the amino acid sequence of SEQ ID NO;

29, the CDRH1 comprises the amino acid sequence of SEQ ID NO;

41, the CDRH2 comprises the amino acid sequence of SEQ ID NO;

75, and the CDRH3 comprises the amino acid sequence of SEQ ID NO;

87.

23. The isolated antibody of claim 12, wherein the CDRL1 comprises the amino acid sequence of SEQ ID NO:

3, the CDRL2 comprises the amino acid sequence of SEQ ID NO;

21, the CDRL3 comprises the amino acid sequence of SEQ ID NO;

29, the CDRH1 comprises the amino acid sequence of SEQ ID NO;

41, the CDRH2 comprises the amino acid sequence of SEQ ID NO;

75, and the CDRH3 comprises the amino acid sequence of SEQ ID NO;

89.

24. The isolated antibody of claim 12, wherein the CDRL1 comprises the amino acid sequence of SEQ ID NO:

15, the CDRL2 comprises the amino acid sequence of SEQ ID NO;

27, the CDRL3 comprises the amino acid sequence of SEQ ID NO;

35, the CDRH1 comprises the amino acid sequence of SEQ ID NO;

47, the CDRH2 comprises the amino acid sequence of SEQ ID NO;

61, and the CDRH3 comprises the amino acid sequence of SEQ ID NO;

91.

25. The isolated antibody of claim 12, wherein the CDRL1 comprises the amino acid sequence of SEQ ID NO:

15, the CDRL2 comprises the amino acid sequence of SEQ ID NO;

27, the CDRL3 comprises the amino acid sequence of SEQ ID NO;

35, the CDRH1 comprises the amino acid sequence of SEQ ID NO;

47, the CDRH2 comprises the amino acid sequence of SEQ ID NO;

57, and the CDRH3 comprises the amino acid sequence of SEQ ID NO;

91.

26. The isolated antibody of claim 12, wherein the CDRL1 comprises the amino acid sequence of SEQ ID NO:

15, the CDRL2 comprises the amino acid sequence of SEQ ID NO;

17, the CDRL3 comprises the amino acid sequence of SEQ ID NO;

29, the CDRH1 comprises the amino acid sequence of SEQ ID NO;

45, the CDRH2 comprises the amino acid sequence of SEQ ID NO;

59, and the CDRH3 comprises the amino acid sequence of SEQ ID NO;

89.

27. The isolated antibody of claim 12, wherein the CDRL1 comprises the amino acid sequence of SEQ ID NO:

7, the CDRL2 comprises the amino acid sequence of SEQ ID NO;

17, the CDRL3 comprises the amino acid sequence of SEQ ID NO;

29, the CDRH1 comprises the amino acid sequence of SEQ ID NO;

45, the CDRH2 comprises the amino acid sequence of SEQ ID NO;

77, and the CDRH3 comprises the amino acid sequence of SEQ ID NO;

87.

32. The isolated IL-6 antibody according to any one of claims 22-28 and 31, further comprising, interspersed between the complementarity determining regions, a human light chain framework region 1 (FRL1) of SEQ ID NO:

105, a FRL2 of SEQ ID NO;

106, a FRL3 of SEQ ID NO;

107, a FRL4 of SEQ ID NO;

108, a human heavy chain framework region 1 (FRH1) of SEQ ID NO;

109, a FRH2 of SEQ ID NO;

110, a FRH3 of SEQ ID NO;

111, and a FRH4 of SEQ ID NO;

112.

37. An isolated human or human engineered antibody that competitively binds to IL-6 with the isolated IL-6 antibody according to claim 12.

6. An isolated IL-6 antibody, comprising at least one heavy chain variable region, said heavy chain variable region comprising at least one member from the group consisting of:

(a) a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) a CDRH3 amino acid sequence selected from the group consisting of SEQ ID NOS;

79, 81, 83, 85, 87, 89, 91, and 114.

11. The isolated IL-6 antibody of claim 6, comprising at least one heavy chain variable region, said heavy chain variable region comprising:

(a) a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) a CDRH3 amino acid sequence selected from the group consisting of SEQ ID NOS;

79, 81, 83, 85, 87, 89, 91, and 114.

28. An isolated IL-6 antibody, comprising a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:

3, a CDRL2 amino acid sequence of SEQ ID NO;

21, a CDRL3 amino acid sequence of SEQ ID NO;

29, a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO;

39, a CDRH2 amino acid sequence of SEQ ID NO;

59, and a CDRH3 amino acid sequence of SEQ ID NO;

89.

29. An isolated IL-6 antibody, comprising at least one light chain variable region, said light chain variable region comprising:

(a) a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO;

132;

(b) a CDRL2 amino acid sequence of SEQ ID NO;

133; and

(c) a CDRL3 amino acid sequence selected from the group consisting of SEQ ID NO;

134, wherein X₁ is A or G, X₂ is S or R, X₃ is H, I, S, or Y, X₄ is S or Y, X₅ is S or F, X₆ is F, L, M, or T, X₇ is N or E, X₈ is A or T, X₉ is M, C, S or Q, and X₁₀ is Q or C.

31. The isolated IL-6 antibody of claim 29, further comprising a heavy chain variable region comprising:

(a) a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO;

135;

(b) a CDRH2 amino acid sequence of SEQ ID NO;

136; and

(c) a CDRH3 amino acid sequence of SEQ ID NO;

137, wherein X₁₁ is T or Q, X₁₂ is F, S, or T, X₁₃ is S or P, X₁₄ is L or M, X₁₅ is A or I, X₁₆ is S or P, X₁₇ is Y or W, X₁₈ is T, E, or Y, X₁₉ is Y or F, X₂₀ is P, S, D, or Y, X₂₁ is V or D, X₂₂ is T or A, X₂₃ is G or P, X₂₄ is S, Y, T, or N, and X₂₅ is Y, T, F, or I.

30. An isolated IL-6 antibody, comprising at least one heavy chain variable region, said heavy chain variable region comprising:

(a) a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO;

135;

(b) a CDRH2 amino acid sequence of SEQ ID NO;

136; and

(c) a CDRH3 amino acid sequence of SEQ ID NO;

137, wherein X₁₁ is T or Q, X₁₂ is F, S, or T, X₁₃ is S or P, X₁₄ is L or M, X₁₅ is A or I, X₁₆ is S or P, X₁₇ is Y or W, X₁₈ is T, E, or Y, X₁₉ is Y or F, X₂₀ is P, S, D, or Y, X₂₁ is V or D, X₂₂ is T or A, X₂₃ is G or P, X₂₄ is S, Y, T, or N, and X₂₅ is Y, T, F, or I.

33. An isolated IL-6 antibody, comprising at least one light chain variable region, said light chain variable region comprising a human light chain framework region 1 (FRL1) of SEQ ID NO:

105, a FRL2 of SEQ ID NO;

106, a FRL3 of SEQ ID NO;

107, and a FRL4 of SEQ ID NO;

108, and interspersed CDR regions, the CDR regions comprising;

(a) a CDRL1 amino acid sequence selected from the group consisting of SEQ ID NOS;

1, 3, 5, 7, 9, 11, 13, and 15;

(b) a CDRL2 amino acid sequence selected from the group consisting of SEQ ID NOS;

17, 19, 21, 23, 25, and 27; and

(c) a CDRL3 amino acid sequence selected from the group consisting of SEQ ID NOS;

29, 31, 33, 35, and 138.

35. The isolated IL-6 antibody of claim 33, further comprising a heavy chain variable region comprising a human heavy chain framework region 1 (FRH1) of SEQ ID NO:

109, a FRH2 of SEQ ID NO;

110, a FRH3 of SEQ ID NO;

111, and a FRH4 of SEQ ID NO;

112, and interspersed CDR regions, the CDR regions comprising;

(a) a CDRH1 amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) a CDRH3 amino acid sequence selected from the group consisting of SEQ ID NOS;

79, 81, 83, 85, 87, 89, 91, and 114.

34. An isolated IL-6 antibody, comprising at least one heavy chain variable region, said heavy chain variable region comprising a human heavy chain framework region 1 (FRH1) of SEQ ID NO:

109, a FRH2 of SEQ ID NO;

110, a FRH3 of SEQ ID NO;

111, and a FRH4 of SEQ ID NO;

112, and interspersed CDR regions, the CDR regions comprising;

(a) a CDRH1 amino acid sequence selected from the group consisting of SEQ ID NOS;

37, 39, 41, 43, 45, and 47;

(b) a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS;

49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, and 113; and

(c) a CDRH3 amino acid sequence selected from the group consisting of SEQ ID NOS;

79, 81, 83, 85, 87, 89, 91, and 114.

36. An isolated human or human engineered antibody competitively binding to IL-6 with at least one isolated IL-6 antibody comprising at least one light chain variable region and at least one heavy chain variable region, said isolated IL-6 antibody comprising light and heavy chain variable regions selected from the group consisting of SEQ ID NOS:

93 and 95, SEQ ID NOS;

97 and 99, SEQ ID NOS;

101 and 103, SEQ ID NOS;

116 and 118, SEQ ID NOS;

120 and 122, SEQ ID NOS;

124 and 126, and SEQ ID NOS;

128 and 130.

39. The antibody of any one of claims 36-38, wherein the antibody is human engineered.

38. An isolated human or human engineered antibody that competitively binds to a region comprising amino acids 168-184 of SEQ ID NO:

115.

60. An isolated nucleic acid molecule encoding an IL-6 antibody, comprising at least one light chain variable region, said light chain variable region comprising at least one member of the group consisting of:

(a) a complementarity determining region light chain 1 (CDRL1) nucleotide sequence selected from the group consisting of SEQ ID NOS;

2, 4, 6, 8, 10, 12, 14, and 16;

(b) a CDRL2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

18, 20, 22, 24, 26, and 28; and

(c) a CDRL3 nucleotide sequence selected from the group consisting of SEQ ID NOS;

30, 32, 34, and 36.

62. The isolated nucleic acid molecule of claim 60, further comprising a heavy chain variable region nucleotide sequence comprising at least one member of the group consisting of:

(a) a complementarity determining region heavy chain 1 (CDRH1) nucleotide sequence selected from the group consisting of SEQ ID NOS;

38, 40, 42, 44, 46, and 48;

(b) a CDRH2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and

(c) a CDRH3 nucleotide sequence selected from the group consisting of SEQ ID NOS;

80, 82, 84, 86, 88, 90, and 92.

61. An isolated nucleic acid molecule encoding an IL-6 antibody, comprising at least one heavy chain variable region, said heavy chain variable region comprising at least one member of the group consisting of:

(a) a complementarity determining region heavy chain 1 (CDRH1) nucleotide sequence selected from the group consisting of SEQ ID NOS;

38, 40, 42, 44, 46, and 48;

(b) a CDRH2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and

(c) a CDRH3 nucleotide sequence selected from the group consisting of SEQ ID NOS;

80, 82, 84, 86, 88, 90, and 92.

63. An isolated nucleic acid molecule encoding an IL-6 antibody, comprising at least one light chain variable region, said light chain variable region comprising:

(a) a complementarity determining region light chain 1 (CDRL1) nucleotide sequence selected from the group consisting of SEQ ID NOS;

2, 4, 6, 8, 10, 12, 14, and 16;

(b) a CDRL2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

18, 20, 22, 24, 26, and 28; and

(c) a CDRL3 nucleotide sequence selected from the group consisting of SEQ ID NOS;

30, 32, 34, and 36.

65. The isolated nucleic acid molecule of claim 63, further comprising a heavy chain variable region nucleotide sequence comprising:

(a) a complementarity determining region heavy chain 1 (CDRH1) nucleotide sequence selected from the group consisting of SEQ ID NOS;

38, 40, 42, 44, 46, and 48;

(b) a CDRH2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and

(c) a CDRH3 nucleotide sequence selected from the group consisting of SEQ ID NOS;

80, 82, 84, 86, 88, 90, and 92.

66. The isolated nucleic acid molecule of claim 65, further comprising, interspersed between the complementarity determining region nucleotide sequences, nucleotide sequences encoding a human light chain framework region 1 (FRL1) of SEQ ID NO:

105, a FRL2 of SEQ ID NO;

106, a FRL3 of SEQ ID NO;

107, a FR4 of SEQ ID NO;

108, a human heavy chain framework region 1 (FRH1) of SEQ ID NO;

109, a FRH2 of SEQ ID NO;

110, a FRH3 of SEQ ID NO;

111, and a FRH4 of SEQ ID NO;

112.

67. The isolated nucleic acid molecule of claim 63, wherein the light chain variable region comprises:

(a) a CDRL1 nucleotide sequence selected from the group consisting of SEQ ID NOS;

2, 4, 6, 8, 10, 12, 14, and 16;

(b) a CDRL2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

18, 20, 22, 24, 26, and 28; and

(c) the CDRL3 nucleotide sequence of SEQ ID NO;

30.

68. The isolated nucleic acid molecule of claim 63, wherein the light chain variable region comprises:

(a) a CDRL1 nucleotide sequence selected from the group consisting of SEQ ID NOS;

2, 4, 6, 8, 10, 12, 14, and 16;

(b) a CDRL2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

18, 20, 22, 24, 26, and 28; and

(c) the CDRL3 nucleotide sequence of SEQ ID NO;

36.

73. The isolated nucleic acid molecule of claim 65, comprising the CDRL1 nucleotide sequence of SEQ ID NO:

8, the CDRL2 nucleotide sequence of SEQ ID NO;

22, the CDRL3 nucleotide sequence of SEQ ID NO;

30, the CDRH1 nucleotide sequence of SEQ ID NO;

42, the CDRH2 nucleotide sequence of SEQ ID NO;

76, and the CDRH3 nucleotide sequence of SEQ ID NO;

88.

74. The isolated nucleic acid molecule of claim 65, comprising the CDRL1 nucleotide sequence of SEQ ID NO:

4, the CDRL2 nucleotide sequence of SEQ ID NO;

22, the CDRL3 nucleotide sequence of SEQ ID NO;

30, the CDRH1 nucleotide sequence of SEQ ID NO;

40, the CDRH2 nucleotide sequence of SEQ ID NO;

60, and the CDRH3 nucleotide sequence of SEQ ID NO;

90.

75. The isolated nucleic acid molecule of claim 65, comprising the CDRL1 nucleotide sequence of SEQ ID NO:

4, the CDRL2 nucleotide sequence of SEQ ID NO;

22, the CDRL3 nucleotide sequence of SEQ ID NO;

30, the CDRH1 nucleotide sequence of SEQ ID NO;

42, the CDRH2 nucleotide sequence of SEQ ID NO;

76, and the CDRH3 nucleotide sequence of SEQ ID NO;

90.

76. The isolated nucleic acid molecule of claim 65, comprising the CDRL1 nucleotide sequence of SEQ ID NO:

16, the CDRL2 nucleotide sequence of SEQ ID NO;

28, the CDRL3 nucleotide sequence of SEQ ID NO;

36, the CDRH1 nucleotide sequence of SEQ ID NO;

48, the CDRH2 nucleotide sequence of SEQ ID NO;

62, and the CDRH3 nucleotide sequence of SEQ ID NO;

92.

77. The isolated nucleic acid molecule of claim 65, comprising the CDRL1 nucleotide sequence of SEQ ID NO:

16, the CDRL2 nucleotide sequence of SEQ ID NO;

28, the CDRL3 nucleotide sequence of SEQ ID NO;

36, the CDRH1 nucleotide sequence of SEQ ID NO;

48, the CDRH2 nucleotide sequence of SEQ ID NO;

58, and the CDRH3 nucleotide sequence of SEQ ID NO;

92.

78. The isolated-nucleic acid molecule of claim 65, comprising the CDRL1 nucleotide sequence of SEQ ID NO:

16, the CDRL2 nucleotide sequence of SEQ ID NO;

18, the CDRL3 nucleotide sequence of SEQ ID NO;

30, the CDRH1 nucleotide sequence of SEQ ID NO;

46, the CDRH2 nucleotide sequence of SEQ ID NO;

60, and the CDRH3 nucleotide sequence of SEQ ID NO;

90.

79. The isolated nucleic acid molecule of claim 65, comprising the CDRL1 nucleotide sequence of SEQ ID NO:

8, the CDRL2 nucleotide sequence of SEQ ID NO;

18, the CDRL3 nucleotide sequence of SEQ ID NO;

30, the CDRH1 nucleotide sequence of SEQ ID NO;

46, the CDRH2 nucleotide sequence of SEQ ID NO;

78, and the CDRH3 nucleotide sequence of SEQ ID NO;

88.

64. An isolated nucleic acid molecule encoding an IL-6 antibody, comprising at least one heavy chain variable region, said heavy chain variable region comprising:

(a) a complementarity determining region heavy chain 1 (CDRH1) nucleotide sequence selected from the group consisting of SEQ ID NOS;

38, 40, 42, 44, 46, and 48;

(b) a CDRH2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and

(c) a CDRH3 nucleotide sequence selected from the group consisting of SEQ ID NOS;

80, 82, 84, 86, 88, 90, and 92.

69. The isolated nucleic acid molecule of claim 64, wherein the heavy chain variable region comprises:

(a) a CDRH1 nucleotide sequence selected from the group consisting of SEQ ID NOS;

38, 40, 42, 44, 46, and 48;

(b) a CDRH2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and

(c) the CDRH3 nucleotide sequence of SEQ ID NO;

86.

70. The isolated nucleic acid molecule of claim 64, wherein the heavy chain variable region comprises:

(a) a CDRH1 nucleotide sequence selected from the group consisting of SEQ ID NOS;

38, 40, 42, 44, 46, and 48;

(b) a CDRH2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and

(c) the CDRH3 nucleotide sequence of SEQ ID NO;

88.

71. The isolated nucleic acid molecule of claim 64, wherein the heavy chain variable region comprises:

(a) a CDRH1 nucleotide sequence selected from the group consisting of SEQ ID NOS;

38, 40, 42, 44, 46, and 48;

(b) a CDRH2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and

(c) the CDRH3 nucleotide sequence of SEQ ID NO;

90.

72. The isolated nucleic acid molecule of claim 64, wherein the heavy chain variable region comprises:

(a) a CDRH1 nucleotide sequence selected from the group consisting of SEQ ID NOS;

38, 40, 42, 44, 46, and 48;

(b) a CDRH2 nucleotide sequence selected from the group consisting of SEQ ID NOS;

50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, and 78; and

(c) the CDRH3 nucleotide sequence of SEQ ID NO;

92.

82. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

93 and a heavy chain variable region amino acid sequence of SEQ ID NO;

95.

83. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

97 and a heavy chain variable region amino acid sequence of SEQ ID NO;

99.

84. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

101 and a heavy chain variable region amino acid sequence of SEQ ID NO;

103.

85. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

116 and a heavy chain variable region amino acid sequence of SEQ ID NO;

118.

86. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

120 and a heavy chain variable region amino acid sequence of SEQ ID NO;

122.

87. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

124 and a heavy chain variable region amino acid sequence of SEQ ID NO;

126.

88. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence of SEQ ID NO:

128 and a heavy chain variable region amino acid sequence of SEQ ID NO;

130.

89. An isolated IL-6 antibody, comprising a light chain variable region amino acid sequence encoded by one of the nucleotide sequences of SEQ ID NOS:

94, 98, 102, 117, 121, 125, and 129 and a heavy chain variable region amino acid sequence encoded by one of the nucleotide sequences of SEQ ID NOS;

96, 100, 104, 119, 123, 127, and 131.

90. Any invention described herein.