Human antibodies that bind human IL-12 and methods for producing

• US 6,914,128 B1
• Filed: 03/24/2000
• Issued: 07/05/2005
• Est. Priority Date: 03/25/1999
• Status: Expired due to Term

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories Incorporated)
• Inventors: Friedrich, Stuart, Banerjee, Subhashis, Sakorafas, Paul, Warne, Nicholas W., Holtet, Thor Las, Carmen, Sara, Derbyshire, Elaine Joy, Du Fou, Sarah Leila, Paskind, Michael, White, Michael, Salfeld, Jochen, Venturini, Amy, Duncan, Alexander Robert, Widom, Angela, Smith, Stephen, Veldman, Geertruida M., Roguska, Michael, Elvin, John Gawain, Kaymakcalan, Zehra, Labkovsky, Boris, Myles, Angela, Tracey, Daniel
• Primary Examiner(s): Andries, Janet
• Assistant Examiner(s): HAMUD, FOZIA M
• Application Number:
  US09/534,717
• Time in Patent Office: 1,929 Days
• Field of Search: 530/387.3, 530/387.1, 530/387.9, 530/388.15, 530/388.24, 530/389.2, 530/351
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• 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: C07K 14/5434 : IL-12
• CPC Class Codes: C07K 16/00 : Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• 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 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

Human antibodies, preferably recombinant human antibodies, that specifically bind to human interleukin-12 (hIL-12) are disclosed. Preferred antibodies have high affinity for hIL-12 and neutralize hIL-12 activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. The antibodies, or antibody portions, of the invention are useful for detecting hIL-12 and for inhibiting hIL-12 activity, e.g., in a human subject suffering from a disorder in which hIL-12 activity is detrimental. Nucleic acids, vectors and host cells for expressing the recombinant human antibodies of the invention, and methods of synthesizing the recombinant human antibodies, are also encompassed by the invention.

Claims

1. An isolated human antibody, or antigen-binding portion thereof that binds to human IL-12 and dissociates from human IL-12 with a K₄ of 1×

10<sup>−

10</sup>M or less and a k_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less, as determined by surface plasmon resonance.

2. The isolated human antibody of claim 1, or an antigen-binding portion thereof, which disassociates from human IL-12 with a k_off rate constant of 1×

10<sup>−

4</sup> s<sup>−

1</sup> or less.

3. The isolated human antibody of claim 1, or an antigen-binding portion thereof, which disassociates from human IL-12 with a k_off rate constant of 1×

10<sup>−

5</sup>s<sup>−

1</sup> or less.

4. The isolated human antibody of claim 1, or an antigen-binding portion thereof, that binds to human IL-12 and disassociates from human IL-12 with a K₄ of 1.34×

10<sup>−

10</sup> M or less.

5. The isolated human antibody of claim 1, or an antigen-binding portion thereof, that binds to human IL-12 and disassociates from human IL-12 with a K₄ of 1.34×

10<sup>−

11</sup> M or less.

6. The isolated human antibody, or antigen-binding portion thereof, of claim 1, which is a recombinant antibody, or antigen-binding portion thereof.

7. The isolated human antibody of any one of claims 1 to 3, wherein the antibody is a neutralizing antibody.

8. The neutralizing antibody of claim 7, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

9</sup>M or less.

9. The neutralizing antibody of claim 7, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

10</sup>M or less.

10. The neutralizing antibody of claim 7, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

11</sup>M or less.

11. The neutralizing antibody of claim 7, or an antigen-binding portion thereof which inhibits phytohemagglutinin blast proliferation in an in vitro phytohemagglutinin blast proliferation assay (PHA assay) with an IC₅₀ of 1×

10<sup>−

7</sup> M or less.

12. The neutralizing antibody of claim 7, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA, assay with an IC₅₀ of 1×

10<sup>−

8</sup> M or less.

13. The neutralizing antibody of claim 7, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 1×

10<sup>−

10</sup> M or less.

14. The neutralizing antibody of claim 7, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 1×

10<sup>−

11</sup> M or less.

15. The neutralizing antibody of claim 7, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 1×

10<sup>−

12</sup> M or less.

64. A pharmaceutical composition comprising the antibody or an antigen binding portion thereof of claims 1, 16, 21, 27, 29, 41, 44, 45, 48, 50, 51, and a pharmaceutically acceptable carrier.

65. The pharmaceutical composition of claim 64, further comprising an additional therapeutic agent selected from the group consisting of budenoside, corticosteroids, cyclosporin, sulfasalazine, aminosalicylares, 6-mercaptopurine, azathioprine, metronidazole, anti-IL-1β

monoclonal antibodies, anti-IL-6 monoclonal antibodies, pyridinyl-imidazole compounds, anti-TNF antibodies, or fragments thereof, and anti-LT antibodies.

66. The pharmaceutical composition of claim 64, further comprising an additional therapeutic agent selected from the group consisting of anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-6 antibodies, anti-IL-7 antibodies, anti-IL-8 antibodies, anti-IL-15 antibodies, anti-IL-16 antibodies, anti-IL-18 antibodies, anti-EMAP-II antibodies, anti-GM-CSF antibodies, anti-FGF antibodies, anti-PDGF antibodies, anti-CD2 antibodies, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD8 antibodies, anti-CD25 antibodies, anti-CD28 antibodies, anti-CD30 antibodies, anti-CD40 antibodies, anti-CD45 antibodies, anti-CD69 antibodies, anti CD80 (B7:

1) antibodies, anti-CD86 (B7.2) antibodies, and anti-CD90 antibodies.

67. The pharmaceutical composition of claim 64, further comprising an additional therapeutic agent selected from the group consisting of methotrexate, FK506, rapamycin, mycophenolate mofetil, leflunomide, non-steroidal anti-inflamatory drugs (NSAIDs), ibuprofen predisolone, 6-mercaptopurines, soluble p55 TNF receptor, soluble p75 TNF receptor, sIL-1RI, sIL-1RII, sIL-6R, sIL-13, antiinflammatory cytokines, IL-4, IL-10, IL-11, IL-13, TGFβ

, Vx740, anti-P7s, p-selection glycoprotein ligand (PSGL), p75TNFRIgG (Enbrel™

), p55TNFRIgG (Lenercept™

), pyridinyl-imidazole compounds, anti-gp39 antibodies, anti-CD40L antibodies, methotrexate, cytokine suppressive anti-inflamatory drugs (CSAIDs), leflunomide, MP, mesalazine, chloroquinine/hydroxychloroquine, pencillamine aurothiomalate, cochicine, salbutamol, terbutaline, salmeteral, theophylline, aminophylline, cromoglycate, nedocromil, ketotifen, ipratropium, and oxitropium.

68. The pharmaceutical composition of claim 64, further comprising an additional therapeutic agent selected from the group consisting of anti-IRAK antibodies, anti-NIK antibodies, anti-IKK antibodies, anti-p38 antibodies, D2E7, cA2 (Remicade™

), CDP 571, 5-aminosalicylic acid, TNFR-Ig constructs, dexamethasone, aminosalicylic acid, IL-1ra, methylprednisolone, cyclophosphamide, methotrexate, 4-aminopyridine, tizanidine, interferon-β

1a (Avonex™

), interferon-β

1b (Betaseron™

), Copolymer 1 (Cop-1;

Copaxone™

), hyperbaric oxygen, clabribine, anti-EMAP-II antibodies, IFNβ

1a, IFNβ

1b, and IL-1.

70. A pharmaceutical composition comprising the antibody or antigen binding portion thereof of claim 7, and a pharmaceutically acceptable carrier.

71. The pharmaceutical composition of claim 70, further comprising an additional therapeutic agent selected from the group consisting of budenoside, corticosteroids, cyclosporin sulfasalazine, aminosalicylates, 6-mercaptopurine, azathioprine, metronidazole, mesalamine, olsalazine, balsalazide, antioxidants, antibodies to IL-1 receptor, anti-IL-1β

monoclonal antibodies, anti-IL-6 monoclonal antibodies, pyridinyl-imidazole compounds, anti-TNF antibodies, or fragments thereof, and anti-LT antibodies.

72. The pharmaceutical composition of claim 70, further comprising an additional therapeutic agent selected from the group consisting of anti-IL-1 antibodies, anti-IL-2 antibodies, anti IL-6 antibodies, anti-IL-7 antibodies, anti-IL-8 antibodies, anti-IL-15 antibodies, anti IL-16 antibodies, anti-IL-18 antibodies anti-EMAP-II antibodies, anti-GM-CSF antibodies, anti-FGF antibodies, anti-PDGF antibodies, anti-CD2 antibodies, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD8 antibodies, anti-CD25 antibodies, anti-CD28 antibodies, anti-CD30 antibodies, anti-CD40 antibodies, anti-CD45 antibodies, anti-CD69 antibodies, anti-CD80(B7.1) antibodies, anti-CD86 (B7.2) antibodies, and anti-CD90 antibodies.

73. The pharmaceutical composition of claim 70 further comprising an additional therapeutic agent selected from the group consisting of methotrexate, FK506, rapamycin, mycophenolate mofetil, letlunomide, non-steroidal anti-inflamatory drugs (NSAIDs), ibuprofen, prednisolone, 6-mercaptopurines, soluble p55 TNF receptor, soluble p75 TNF receptor, sIL-1RI, sIL-1RII, sIL-6R, sIL-13, antiinflamatory cytokines, IL-4, IL-10, IL-11, IL-13, TGFβ

, Vx740, anti-P7s, p-selection glycoprotein ligand (PSGL), p75TNFRIgG (Enbrel™

), p55TNFRIgG (Lenercept™

), pyridinyl-imidazole compounds, anti-gp39 antibodies, anti-CD40L antibodies methotrexate, cytokine suppressive anti-inflamatory drugs (CSAIDs), leflunomide, MP, mesalazine, chloroquinine/hydroxychloroquine, pencillamine, aurothiomalate, cochicine salbutamol, terbutaline, salmeteral, theophylline, aminophylline, cromoglycate, nedocromil, ketotifen, ipratropium, and oxitropium.

74. The pharmaceutical composition of claim 70, further comprising an additional therapeutic agent selected from the group consisting of anti-IRAK antibodies, anti-NIK antibodies, anti-IKK antibodies, anti-p38 antibodies D2E7, cA2(Remicade™

), CDP 571, 5-aminosalicylic acid, TNFR-Ig constructs, dexamethasone, aminonsalicylic acid, IL-1ra, methylprednisolone, cyclophosphamide, methotrexate, 4-aminopyridine, tizanidine, interferon-β

1a (AVONEX™

), interferon-β

1b (Betaseron™

), Copolymer 1 (Cop-1;

Copaxone™

), hyperbaric oxygen, clabribine, anti-EMAP-II antibodies, IFNβ

1a, IFNβ

1b, and IL-1.

16. An isolated human antibody, or an antigen-binding portion thereof, which:

a) inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

9</sup>M or less;

b) has a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO;

25; and

c) has a light chain CDR3 comprising the amino acid sequence of SEQ ID NO;

26.

17. The isolated human antibody, or an antigen-binding portion thereof, of claim 16 which further has a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:

27; and

a light chain CDR2 comprising the amino acid sequence of SEQ ID NO;

28.

18. The isolated human antibody, or an antigen-binding portion thereof, of claim 16 which further has a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:

29; and

a light chain CDR1 comprising the amino acid sequence of SEQ ID NO;

30.

19. The isolated human antibody, or antigen-binding portion thereof, of claim 16, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

10</sup>M or less.

20. The isolated human antibody, or antigen-binding portion thereof, of claim 16, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

11</sup> M or less.

21. An isolated human antibody, or an antigen-binding portion thereof, having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

31, and a light chain variable region comprising the amino acid sequence of SEQ ID NO;

32.

22. The isolated human antibody of claim 21, comprising a heavy chain constant region selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE constant regions.

23. The isolated human antibody of claim 22, wherein the antibody heavy chain constant region is IgG1.

24. The isolated human antibody of claim 21, which is a Fab fragment.

25. The isolated human antibody of claim 21, which is a F(ab′

)₂ fragment.

26. The isolated human antibody of claim 21, which is a single chain Fv fragment.

27. An isolated human antibody, or an antigen-binding portion thereof, which disassociates from human IL-12 with a K₄ of 1×

10<sup>−

10</sup> M or less and binds to an epitope on the p40 subunit of human IL-12.

28. The isolated human antibody of claim 27, which neutralizes the activity of human IL-12.

29. A neutralizing isolated human antibody, or antigen-binding portion thereof that binds to human IL-12 and disassociates from human IL-12 with a K_off rate constant of 1×

10<sup>−

2</sup>s<sup>−

1</sup> or less, as determined by surface plasmon resonance.

30. The neutralizing isolated human antibody of claim 29, or an antigen-binding portion thereof, which dissociates from human IL-12 with a k_off rate constant of 1×

10<sup>−

4</sup>s<sup>−

1</sup> or less.

31. The neutralizing isolated human antibody of claim 29, or an antigen-binding portion thereof, which disassociates from human IL-12 with a k_off rate constant of 1×

10<sup>−

5</sup>s<sup>−

1</sup> or less.

32. The neutralizing isolated human antibody of claim 29, or an antigen-binding portion thereof, which disassociates from human IL-12 with a K_off rate constant of 1×

10<sup>−

3</sup> s<sup>−

1</sup> or less.

33. The neutralizing isolated human antibody of any one of claims 29 to 31 and 32, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ or 1×

10<sup>−

7</sup> M or less.

34. The neutralizing isolated human antibody of any one of claims 29 to 31 and 32, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

8</sup> M or less.

35. The neutralizing isolated human antibody of any one of claims 29 to 31 and 32 or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

9</sup> M or less.

36. The neutralizing isolated human antibody of any one of claims 29 to 31 and 32 or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

10</sup> M or less.

37. The neutralizing isolated human antibody of any one of claims 29 to 31 and 32, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

11</sup> M or less.

38. The neutralizing isolated human antibody of any one of claims 29 to 31 and 32, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 1×

10<sup>−

10</sup> M or less.

39. The neutralizing isolated human antibody of any one of claims 29 to 31 and 32, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 1×

10<sup>−

11</sup> M or less.

40. The neutralizing isolated human antibody of any one of claims 29 to 31 and 32, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 1×

10<sup>−

12</sup> M or less.

41. An isolated human antibody, or an antigen-binding portion thereof, which:

a) disassociates from human IL-12 with a k_off rate constant of 1×

10<sup>−

3</sup>S<sup>−

1</sup>or less, as determined by surface plasmon resonance;

b) has a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO;

25; and

c) has a light chain CDR3 comprising the amino acid sequence of SEQ ID NO;

26.

42. The isolated human antibody of claim 41, or an antigen-binding portion thereof, which disassociates from human IL-12 with a k_off rate constant of 1×

10<sup>−

4</sup> s<sup>−

1</sup> or less.

43. The isolated human antibody of claim 41, or an antigen-binding portion thereof, which disassociates from human IL-12 with a k_off rate constant of 1×

10<sup>−

5</sup> s<sup>−

1</sup> or less.

44. An isolated human antibody, or antigen-binding portion thereof, that binds to human IL-12 and comprises:

a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO;

26; and

a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO;

25.

45. An isolated human antibody, or antigen-binding portion thereof, with a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:

26, and with a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO;

25.

46. An isolated human antibody, or an antigen-binding portion thereof, of claim 45, wherein the LCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO:

28 and the HCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO;

27.

47. An isolated human antibody, or an antigen-binding portion thereof, of claim 46, wherein the LCVR further has CDR1 domain comprising the amino acid sequence of SEQ ID NO:

30 and the HCVR has a CDR1 domain comprising the amino acid sequence of SEQ ID NO;

29.

48. An isolated human antibody that binds human IL-12 and is the antibody J695, or an antigen binding portion thereof.

49. A pharmaceutical composition comprising the isolated human antibody of claim 48 and a pharmaceutically acceptable carrier.

50. An isolated human antibody, or antigen-binding portion thereof, that binds to human IL-12 and disassociates from human IL-12 with a K₄ of 1.34×

10<sup>−

10</sup> M or less, and neutralizes human IL-12.

51. The isolated human antibody of claim 50, or an antigen-binding portion thereof, which dissociates from human IL-12 with a K₄ of 9.74×

10<sup>−

11</sup> M or less.

52. The isolated human antibody, or antigen-binding portion thereof, of claim 50 or 51, which is a recombinant antibody, or antigen-binding portion thereof.

53. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

7</sup> M or less.

54. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PRA assay with an IC₅₀ of 1×

10<sup>−

8</sup> M or less.

55. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

9</sup> M or less.

56. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

10</sup>M or less.

57. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits phytohemagglutinin blast proliferation in an in vitro PHA assay with an IC₅₀ of 1×

10<sup>−

11</sup>M or less.

58. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 1×

10<sup>−

10</sup> M or less.

59. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 1×

10<sup>−

11</sup> M or less.

60. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits human IFNγ

production with an IC₅₀ of 5×

10<sup>−

12</sup> M or less.

61. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits IL-12 binding to its receptor in an IL-12 receptor binding assay (RBA) with an IC₅₀ of 1×

10<sup>−

9</sup> M or less.

62. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits IL-12 binding to its receptor in an IL-12 receptor binding assay (RBA) with an IC₅₀ of 1×

10<sup>−

10</sup> M or less.

63. The isolated human antibody of claim 52, or an antigen-binding portion thereof, which inhibits IL-12 binding to its receptor in an IL-12 receptor binding assay (RBA) with an IC₅₀ of 1×

10<sup>−

11</sup> M or less.

69. A pharmaceutical composition comprising an antibody or an antigen binding portion thereof, and a pharmaceutically acceptable carrier, wherein the antibody comprises:

a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO;

26; and

a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO;

25.