IL-12/p40 binding proteins

• US 7,700,739 B2
• Filed: 06/29/2006
• Issued: 04/20/2010
• Est. Priority Date: 06/30/2005
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories
• Inventors: Dixon, Richard W., Kumar, Shankar, Belk, Jonathan P., Hinton, Paul R., Roguska, Michael, Fung, Emma, Lacy, Susan E.
• Primary Examiner(s): Helms; Larry H.
• Assistant Examiner(s): Natarajan; Meera
• Application Number:
  US11/478,096
• Publication Number:
  US 20100047245A1
• Time in Patent Office: 1,391 Days
• Field of Search: None
• US Class Current: 530/387.1
• 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 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 11/06 Antiasthmatics
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 25/32 : Alcohol-abuse
• 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 3/10 : 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 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 33/6869 : Interleukin

Abstract

The present invention encompasses IL-12p40 binding proteins, particularly antibodies that bind human interleukin-12 (hIL-12) and/or human IL-23 (hIL-23). Specifically, the invention relates to antibodies that are chimeric, CDR grafted and humanized antibodies. Preferred antibodies have high affinity for hIL-12 and/or hIL-23 and neutralize h IL-12 and/or hIL-23 activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Method of making and method of using the antibodies of the invention are also provided. The antibodies, or antibody portions, of the invention are useful for detecting hIL-12 and/or hIL-23 and for inhibiting hIL-12 and/or hIL-23 activity, e.g., in a human subject suffering from a disorder in which hIL-12 and/or hIL-23 activity is detrimental.

Claims

1. An isolated binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of IL-12, said antigen binding domain comprising six CDRs:

CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below;

CDR-H1. X₁-X₂-X₃-X₄-X₅-X₆-X₇ (SEQ ID NO;

     55), wherein;

X₁ is D, K, T, or S;

X₂ is Y, S, or T;

X₃ is Y, V, G, W, S, or F;

X₄ is I, or M;

X is H, G, E, or V;

X₆ is V, or is not present; and

X₇ is S, or is not present;

CDR-H2. X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉-X₁₀-X₁₁-X₁₂-X₁₃-X₁₄-X₁₅-X₁₆-X₁₇-X₁₈-X₁₉-X₂₀ (SEQ ID NO;

     56), wherein;

X₁ is H, D, G, W, S, Y or R;

X₂ is I, or F;

X₃ is Y, W, L, S, N, D or G;

X₄ is W, P, H, T, or S;

X₅ is D, G, E, A, or I;

X₆ is D, G, S, T, or N;

X₇ is D, G, S, or P;

X₈ is K, N, S, E, T, or H;

X₉ is Y, T, P, I, or N;

X₁₀ is Y, N, T, H, K, S, or G;

X₁₁ is N, or Y;

X₁₂ is P, N, A, D, or S;

X₁₃ is S, E, D, or P;

X₁₄ is L, K, D, T, or Y;

X₁₅ is K, F, V, M, R, or A;

X₁₆ is S, K, Q, P, or is not present;

X₁₇ is D, G, R, or is not present;

X₁₈ is F, or is not present;

X₁₉ is Q, or is not present; and

X₂₀ is D, or is not present;

CDR-H3. X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉-X₁₀-X₁₁-X₁₂-X₁₃ (SEQ ID NO;

     57), wherein;

X₁ is R, N, or W;

X₂ is G, T, R, P, or H;

X₃ is I, R, F, Y, or Q;

X₄ is R, V, Y, F, or A;

X₅ is S, N, G, A, or R;

X₆ is A, Y, L, F, or M;

X₇ is M, A, D, L, or F;

X₈ is D, M, Y, or W;

X₉ is Y, D, or N;

X₁₀ is Y, A, or is not present;

X₁₁ is M, or is not present;

X₁₂ is D, or is not present; and

X₁₃ is Y, or is not present;

CDR-L1. X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉-X₁₀-X₁₁-X₁₂-X₁₃-X₁₄-X₁₅ (SEQ ID NO;

     58)_r wherein;

X₁ is K, or R;

X₂ is A;

X₃ is S;

X₄ is Q, or E;

X₅ is S, or N;

X₆ is V, or I;

X₇ is S, G, or D;

X₈ is N, T, or K;

X₉ is D, N, or Y;

X₁₀ is V, G, or L;

X₁₁ is A, I, or H;

X₁₂ is S, or is not present;

X₁₃ is F, or is not present;

X₁₄ is M, or is not present; and

X₁₅ is N, or is not present;

CDR-L2. X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈ (SEQ ID NO;

     59), wherein;

X₁ is Y, or S;

X₂ is A, or T;

X₃ is S, or A;

X₄ is N, H, S, or Q;

X₅ is R, N, or S;

X₆ is Y, Q, or I;

X₇ is T, S, or G; and

X₈ is S, or is not present;

and

CDR-L3. X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉ (SEQ ID NO;

     60), wherein;

X₁ is Q;

X₂ is Q;

X₃ is D, Y, or S;

X₄ is Y, N, K, or I;

X₅ is N, T, S, or E;

X₆ is S, Y, V, or W;

X₇ is P;

X₈ is W, F, Y, L, or P; and

X₉ is T, or S.

5. The binding protein according to claim 1, further comprising a human acceptor framework.

9. The binding protein according to claim 5, wherein said human acceptor framework comprises an amino acid sequence selected from the group consisting of:

13. The binding protein according to claim 1, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:

14. The binding protein according to claim 13 wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from the group consisting of:

SEQ ID NO.;

61 &

SEQ ID NO.;

62,

SEQ ID NO.;

63 &

SEQ ID NO.;

64,

SEQ ID NO.;

65 &

SEQ ID NO.;

66,

SEQ ID NO.;

67 &

SEQ ID NO.;

68,

SEQ ID NO.;

69 &

SEQ ID NO.;

70

SEQ ID NO.;

67 &

SEQ ID NO.;

70, AND

SEQ ID NO.;

69 &

SEQ ID NO.;

68.

15. The binding protein according to claim 5, wherein said human acceptor framework comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of:

a residue adjacent to a CDR;

a glycosylation site residue;

a rare residue;

a residue capable of interacting with a p40 subunit of human IL-12;

a residue capable of interacting with a CDR;

a canonical residue;

a contact residue between heavy chain variable region and light chain variable region;

a residue within a Vernier zone; and

a residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and a Kabat-defined first heavy chain framework.

18. The binding protein according to claim 15, wherein key residue selected from the group consisting of 3H, 5H, 10H, 11H, 12H, 13H, 15H, 16H, 18H, 19H, 23H, 24H, 25H, 30H, 41H, 44H, 46H, 49H, 66H, 68H, 71H, 73H, 74H, 75H, 76H, 77H, 78H, 79H, 81H, 82H, 82AH, 82BH, 82CH, 83H, 84H, 85H, 86H, 87H, 89H, 93H, 98H, 108H, 109H, 1L, 2L, 3L, 7L, 8L, 9L, 10L, 11L, 12L, 13L, 15L, 17L, 19L, 20L, 21L, 22L, 36L, 41L, 42L, 43L, 45L, 46L, 58L, 60L, 62L, 63L, 67L, 70L, 73L, 74L, 77L, 78L, 79L, 80L, 83L, 85L, 87L, 104L, and 106L.

21. The binding protein according to claim 15, wherein the binding protein is a consensus human variable domain.

24. The binding protein according to claim 5, wherein said human acceptor framework comprises at least one Framework Region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework.

27. The binding protein according to claim 1, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:

28. The binding protein according to claim 27 wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from the group consisting of:

SEQ ID NO.;

67 &

SEQ ID NO.;

79,

SEQ ID NO.;

80 &

SEQ ID NO.;

81,

SEQ ID NO.;

82 &

SEQ ID NO.;

83,

SEQ ID NO.;

84 &

SEQ ID NO.;

85,

SEQ ID NO.;

86 &

SEQ ID NO.;

87,

SEQ ID NO.;

98 &

SEQ ID NO.;

99,

SEQ ID NO.;

100 &

SEQ ID NO.;

101, and

SEQ ID NO.;

102 &

SEQ ID NO.;

103.

29. The binding protein according to claim 18, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of;

32. The binding protein according to claim 1, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

35. The binding protein according to claim 5, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

36. The binding protein according to claim 9, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

37. The binding protein according to claim 13, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

38. The binding protein according to claim 15, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

39. The binding protein according to claim 18, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

40. The binding protein according to claim 24, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

41. The binding protein according to claim 27, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

42. The binding protein according to claim 32, wherein the binding protein is capable of modulating a biological function of a target selected from the group consisting of IL-12 and IL-23.

43. The binding protein according to claim 37, wherein the binding protein is capable of modulating a biological function of a target selected from the group consisting of IL-12 and IL-23.

44. The binding protein according to claim 41, wherein the binding protein is capable of modulating a biological function of a target selected from the group consisting of IL-12 and IL-23.

45. The binding protein according to claim 32, wherein the binding protein is capable of neutralizing a target selected from the group consisting of IL-12 and IL-23.

46. The binding protein according to claim 37, wherein the binding protein is capable of neutralizing a target selected from the group consisting of IL-12 and IL-23.

47. The binding protein according to claim 41, wherein the binding protein is capable of neutralizing a target selected from the group consisting of IL-12 and IL-23.

48. The binding protein according to claim 32, wherein said binding protein has an on rate constant (Kon) to said target selected from the group consisting of:

at least about 10²M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10³M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁴M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁵M<sup>−

1</sup>s<sup>−

1</sup>; and

at least about 10⁶M<sup>−

1</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

49. The binding protein according to claim 37, wherein said binding protein has an on rate constant (Kon) to said target selected from the group consisting of:

at least about 10²M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10³M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁴M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁵M<sup>−

1</sup>s<sup>−

1</sup>; and

at least about 10⁶M<sup>−

1</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

50. The binding protein according to claim 40, wherein said binding protein has an on rate constant (Kon) to said target selected from the group consisting of:

at least about 10²M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10³M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁴M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁵M<sup>−

1</sup>s<sup>−

1</sup>; and

at least about 10⁶M<sup>−

1</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

51. The binding protein according to claim 41, wherein said binding protein has an on rate constant (Kon) to said target selected from the group consisting of:

at least about 10²M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10³M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁴M<sup>−

1</sup>s<sup>−

1</sup>;

at least about 10⁵M<sup>−

1</sup>s<sup>−

1</sup>; and

at least about 10⁶M<sup>−

1</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

52. The binding protein according to claim 32, wherein said binding protein has an off rate constant (Koff) to said target selected from the group consisting of:

at most about 10<sup>−

3</sup>s<sup>−

1</sup>;

at most about 10<sup>−

4</sup>s<sup>−

1</sup>;

at most about 10<sup>−

5</sup>s<sup>−

1</sup>; and

at most about 10<sup>−

6</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

53. The binding protein according to claim 37, wherein said binding protein has an off rate constant (Koff) to said target selected from the group consisting of:

at most about 10<sup>−

3</sup>s<sup>−

1</sup>;

at most about 10<sup>−

4</sup>s<sup>−

1</sup>;

at most about 10<sup>−

5</sup>s<sup>−

1</sup>; and

at most about 10<sup>−

6</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

54. The binding protein according to claim 40, wherein said binding protein has an off rate constant (Koff) to said target selected from the group consisting of:

at most about 10<sup>−

3</sup>s<sup>−

1</sup>;

at most about 10<sup>−

4</sup>s<sup>−

1</sup>;

at most about 10<sup>−

5</sup>s<sup>−

1</sup>; and

at most about 10<sup>−

6</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

55. The binding protein according to claim 41, wherein said binding protein has an off rate constant (Koff) to said target selected from the group consisting of:

at most about 10<sup>−

3</sup>s<sup>−

1</sup>;

at most about 10<sup>−

4</sup>s<sup>−

1</sup>;

at most about 10<sup>−

5</sup>s<sup>−

1</sup>; and

at most about 10<sup>−

6</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

56. The binding protein according to claim 32, wherein said binding protein has a dissociation constant (K_D) to said target selected from the group consisting of:

at most about 10<sup>−

7</sup> M;

at most about 10<sup>−

8</sup> M;

at most about 10<sup>−

9</sup> M;

at most about 10<sup>−

10</sup> M;

at most about 10<sup>−

11</sup> M;

at most about 10<sup>−

12</sup> M; and

at most 10<sup>−

13</sup>M.

57. The binding protein according to claim 37, wherein said binding protein has a dissociation constant (K_D) to said target selected from the group consisting of:

at most about 10<sup>−

7</sup> M;

at most about 10<sup>−

8</sup> M;

at most about 10<sup>−

9</sup> M;

at most about 10<sup>−

10</sup> M;

at most about 10<sup>−

11</sup> M;

at most about 10<sup>−

12</sup> M; and

at most 10<sup>−

13</sup>M.

58. The binding protein according to claim 40, wherein said binding protein has a dissociation constant (K_D) to said target selected from the group consisting of:

at most about 10<sup>−

7</sup> M;

at most about 10<sup>−

8</sup> M;

at most about 10<sup>−

9</sup> M;

at most about 10<sup>−

10</sup> M;

at most about 10<sup>−

11</sup> M;

at most about 10<sup>−

12</sup> M; and

at most 10<sup>−

13</sup> M.

59. The binding protein according to claim 41, wherein said binding protein has a dissociation constant (K_D) to said target selected from the group consisting of:

at most about 10<sup>−

7</sup> M;

at most about 10<sup>−

8</sup> M;

at most about 10<sup>−

9</sup> M;

at most about 10<sup>−

10</sup> M;

at most about 10<sup>−

11</sup> M;

at most about 10<sup>−

12</sup> M; and

at most 10<sup>−

13</sup> M.

60. An antibody construct comprising a binding protein as described in claim 1, 2, or 3, said antibody construct further comprising a linker polypeptide or an immunoglobulin constant domain.

61. The antibody construct according to claim 60, wherein said binding protein is selected from the group consisting of:

62. The antibody construct according to claim 60, wherein said binding protein comprises a heavy chain immunoglobulin constant domain selected from the group consisting of:

63. The antibody construct according to claim 60, comprising an immunoglobulin constant domain having an amino acid sequence selected from the group consisting of:

SEQ ID NO;

2

SEQ ID NO;

3

SEQ ID NO;

4

and

SEQ ID NO;

5.

64. An antibody conjugate comprising an antibody construct according to claim 60, said antibody conjugate further comprising an agent selected from the group consisting of:

an immunoadhension molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent.

65. The antibody conjugate according to claim 64, wherein said agent is an imaging agent selected from the group consisting of a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin.

66. The antibody conjugate according to claim 64, wherein said imaging agent is a radiolabel selected from the group consisting of:

³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, and ¹⁵³Sm.

67. The antibody conjugate according to claim 64, wherein said agent is a therapeutic or cytotoxic agent selected from the group consisting of:

an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, and an apoptotic agent.

68. The antibody construct according to claim 62, wherein said binding protein possesses a human glycosylation pattern.

69. The antibody conjugate according to claim 64, wherein said binding protein possesses a human glycosylation pattern.

70. The binding protein according to claim 1, wherein said binding protein exists as a crystal.

71. The antibody construct according to claim 60, wherein said antibody construct exists as a crystal.

72. The antibody conjugate according to claim 64, wherein said antibody conjugate exists as a crystal.

73. The binding protein according to claim 70, wherein said crystal is a carrier-free pharmaceutical controlled release crystal.

74. The antibody construct according to claim 71, wherein said crystal is a carrier-free pharmaceutical controlled release crystal.

75. The antibody conjugate according to claim 72, wherein said crystal is a carrier-free pharmaceutical controlled release crystal.

76. The binding protein according to claim 70, wherein said binding protein has a greater half life in vivo than the soluble counterpart of said binding protein.

77. The antibody construct according to claim 71, wherein said antibody construct has a greater half life in vivo than the soluble counterpart of said antibody construct.

78. The antibody conjugate according to claim 72, wherein said antibody conjugate has a greater half life in vivo than the soluble counterpart of said antibody conjugate.

79. The binding protein according to claim 70, wherein said binding protein retains biological activity.

80. The antibody construct according to claim 71, wherein said antibody construct retains biological activity.

81. The antibody conjugate according to claim 72, wherein said antibody conjugate retains biological activity.

82. A binding protein described in claim 1 produced according to a method comprising culturing a host cell in culture medium under conditions sufficient to produce said binding protein wherein said host cell comprises a vector said vector comprising a nucleic acid encoding said binding protein.

83. A composition for the release of a binding protein said composition comprising:

(a) a formulation, wherein said formulation comprises a crystallized binding protein, according to claim 70, and an ingredient; and

(b) at least one polymeric carrier.

84. The composition according to claim 83, wherein said polymeric carrier is a polymer selected from one or more of the group consisting of:

poly (acrylic acid), poly (cyanoacrylates), poly (amino acids), poly (anhydrides), poly (depsipeptide), poly (esters), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b-hydroxybutryate), poly (caprolactone), poly (dioxanone);

poly (ethylene glycol), poly ((hydroxypropyl)methacrylamide, poly [(organo)phosphazene], poly (ortho esters), poly (vinyl alcohol), poly (vinylpyrrolidone), maleic anhydride-alkyl vinyl ether copolymers, pluronic polyols, albumin, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, hyaluronic acid, oligosaccharides, glycaminoglycans, sulfated polyeaccharides, blends and copolymers thereof.

85. The composition according to claim 83, wherein said ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β

-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.

86. A pharmaceutical composition comprising the binding protein according to claim 1 or claim 70, and a pharmaceutically acceptable carrier.

87. The pharmaceutical composition of claim 86 wherein said pharmaceutically acceptable carrier functions as adjuvant useful to increase the absorption, or dispersion of said binding protein.

88. The pharmaceutical composition of claim 87 wherein said adjuvant is hyaluronidase.

89. The pharmaceutical composition of claim 86 further comprising at least one additional therapeutic agent for treating a disorder in which IL-12 activity is detrimental.

90. The pharmaceutical composition of claim 86 comprising an additional agent, wherein said additional agent is selected from the group consisting of:

Therapeutic agent, imaging agent, cytotoxic agent, angiogenesis inhibitors;

kinase inhibitors;

co-stimulation molecule blockers;

adhesion molecule blockers;

anti-cytokine antibody or functional fragment thereof, methotrexate;

cyclosporin;

rapamycin;

FK506;

detectable label or reporter;

a TNF antagonist;

an antirheumatic;

a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, and a cytokine antagonist.

91. A method for reducing human IL-12 activity comprising contacting human IL-12 with the binding protein of claim 1 such that human IL-12 activity is reduced.

92. The binding protein comprising an antigen binding domain according to claim 1, said binding protein capable of binding the p40 subunit of human IL-12, wherein said binding protein has an on rate constant (Kon) to said target selected from the group consisting of:

between 10²M<sup>−

1</sup>s<sup>−

1</sup> to 10³M<sup>−

1</sup>s<sup>−

1</sup>;

between 10³M<sup>−

1</sup>s<sup>−

1</sup> to 10⁴M<sup>−

1</sup>s<sup>−

1</sup>;

between 10⁴M<sup>−

1</sup>s<sup>−

1</sup> to 10⁵M<sup>−

1</sup>s<sup>−

1</sup>; and

between 10⁵M<sup>−

1</sup>s<sup>−

1</sup> to 10⁶M<sup>−

1</sup>s<sup>−

1</sup>.

93. The binding protein according to claim 92, where in the said binding protein has an on rate constant (Kon) to said target selected from the group consisting of:

at least about 1×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, at least about 1.2×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, 3.2×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, at least about 3.5×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, at least about 4.8×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, at least about 5.3×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, at least about 7.4×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, at least about 7.8×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, at least about 8.0×

10⁵M<sup>−

1</sup>s<sup>−

1</sup>, at least about 1.3×

10⁶M<sup>−

1</sup>s<sup>−

1</sup>, at least about 1.6×

10⁶M<sup>−

1</sup>s<sup>−

1</sup>, at least about 1.6×

10⁶M<sup>−

1</sup>s<sup>−

1</sup> and at least about 1.7×

10⁶M<sup>−

1</sup>s<sup>−

1</sup>.

94. The binding protein comprising an antigen binding domain according to claim 1, said binding protein capable of binding the p40 subunit of human IL-12, wherein said binding protein has an off rate constant (Koff) to said target selected from the group consisting of:

10<sup>−

3</sup>s<sup>−

1</sup> to 10<sup>−

4</sup>s<sup>−

1</sup>;

of 10⁴s<sup>−

1</sup> to 10<sup>−

5</sup>s<sup>−

1</sup>; and

of 10<sup>−

5</sup>s<sup>−

1</sup> to 10<sup>−

6</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

95. The binding protein according to claim 94, wherein said binding protein has an off rate constant (Koff) to said target selected from the group consisting of:

at most about 1×

10<sup>−

3</sup>s<sup>−

1</sup>, at most about 1.24×

10<sup>−

3</sup>s<sup>−

1</sup>, at most about 1.5×

10<sup>−

4</sup>s<sup>−

1</sup>;

3×

10⁴s<sup>−

1</sup>, at most about 1×

10<sup>−

5</sup>s<sup>−

1</sup>;

8×

10<sup>−

5</sup>s<sup>−

1</sup>, at most about 1×

10<sup>−

6</sup>s<sup>−

1</sup> and at most about 7.6×

10<sup>−

6</sup>s<sup>−

1</sup>, as measured by surface plasmon resonance.

96. The binding protein comprising an antigen binding domain according to claim 1, said binding protein capable of binding the p40 subunit of human IL-12, wherein said binding protein has a dissociation constant (K_D) to said target selected from the group consisting of:

10<sup>−

7</sup> M to 10<sup>−

8</sup> M;

of 10<sup>−

8</sup> M to 10<sup>−

9</sup> M;

of 10<sup>−

9</sup> M to 10<sup>−

10</sup> M;

of 10<sup>−

10</sup> to 10<sup>−

11</sup> M;

of 10<sup>−

11</sup> M to 10<sup>−

12</sup> M; and

of 10<sup>−

12</sup> to M 10<sup>−

13</sup> M.

97. The binding protein according to claim 96, wherein said binding protein has a dissociation constant (K_D) to said target selected from the group consisting of:

at most about 1.3×

10<sup>−

9</sup> M, at most about 2×

10<sup>−

10</sup> M, at most about 4×

10<sup>−

10</sup> M;

at most about 7.5×

10<sup>−

10</sup> M, at most about 7.6×

10<sup>−

10</sup>M, at most about 1×

10<sup>−

11</sup> M;

at most about 2.4×

10<sup>−

11</sup> M and at most about 4.6×

10<sup>−

11</sup>M.

98. The binding protein according to claim 96, wherein the binding protein is capable of neutralizing a target selected from the group consisting of IL-12 and IL-23.

99. The binding protein according to claim 96, wherein said binding protein is selected from the group consisting of:

an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab′

, a F(ab′

)2, a Fv, a disulfide linked Fv, a scFv, a diabody, a multispecific antibody, a dual specific antibody, and a bispecific antibody.

100. The binding protein according to claim 99, wherein said binding protein is a humanized antibody.

101. A pharmaceutical composition comprising the antibody construct according to claim 60 or claim 71, and a pharmaceutically acceptable carrier.

102. The pharmaceutical composition of claim 101 wherein said pharmaceutically acceptable carrier functions as adjuvant useful to increase the absorption, or dispersion of said binding protein.

103. The pharmaceutical composition of claim 102 wherein said adjuvant is hyaluronidase.

104. The pharmaceutical composition of claim 101 further comprising at least one additional therapeutic agent for treating a disorder in which IL-12 activity is detrimental.

105. The pharmaceutical composition of claim 101 comprising an additional agent, wherein said additional agent is selected from the group consisting of:

Therapeutic agent, imaging agent, cytotoxic agent, angiogenesis inhibitors;

kinase inhibitors;

co-stimulation molecule blockers;

adhesion molecule blockers;

anti-cytokine antibody or functional fragment thereof, methotrexate;

cyclosporin;

rapamycin;

FK506;

detectable label or reporter;

a TNF antagonist;

an antirheumatic;

a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, and a cytokine antagonist.

106. A pharmaceutical composition comprising the antibody conjugate according to claim 64 or claim 72, and a pharmaceutically acceptable carrier.

107. The pharmaceutical composition of claim 106 wherein said pharmaceutically acceptable carrier functions as adjuvant useful to increase the absorption, or dispersion of said binding protein.

108. The pharmaceutical composition of claim 107 wherein said adjuvant is hyaluronidase.

109. The pharmaceutical composition of claim 106 further comprising at least one additional therapeutic agent for treating a disorder in which IL-12 activity is detrimental.

110. The pharmaceutical composition of claim 106 comprising an additional agent, wherein said additional agent is selected from the group consisting of:

Therapeutic agent, imaging agent, cytotoxic agent, angiogenesis inhibitors;

kinase inhibitors;

co-stimulation molecule blockers;

adhesion molecule blockers;

anti-cytokine antibody or functional fragment thereof, methotrexate;

cyclosporin;

rapamycin;

FK506;

detectable label or reporter;

a TNF antagonist;

an antirheumatic;

a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, and a cytokine antagonist.

2. An isolated binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of IL-12 and said antigen binding domain comprising a CDR-H1CDR-H2CDR-H3CDR-L1 CDR-L2 and CDR-L3 amino acid sequence independently selected from the group consisting of:

6. The binding protein according to claim 2, further comprising a human acceptor framework.

10. The binding protein according to claim 6, wherein said human acceptor framework comprises an amino acid sequence selected from the group consisting of:

16. The binding protein according to claim 6, wherein said human acceptor framework comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of:

a residue adjacent to a CDR;

a glycosylation site residue;

a rare residue;

a residue capable of interacting with a p40 subunit of human IL-12;

a residue capable of interacting with a CDR;

a canonical residue;

a contact residue between heavy chain variable region and light chain variable region;

a residue within a Vernier zone; and

a residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and a Kabat-defined first heavy chain framework.

19. The binding protein according to claim 16, wherein key residue selected from the group consisting of 3H, 5H, 10H, 11H, 12H, 13H, 15H, 16H, 18H, 19H, 23H, 24H, 25H, 30H, 41H, 44H, 46H, 49H, 66H, 68H, 71H, 73H, 74H, 75H, 76H, 77H, 78H, 79H, 81H, 82H, 82AH, 82BH, 82CH, 83H, 84H, 85H, 86H, 87H, 89H, 93H, 98H, 108H, 109H, 1L, 2L, 3L, 7L, 8L, 9L, 10L, 11L, 12L, 13L, 15L, 17L, 19L, 20L, 21L, 22L, 36L, 41L, 42L, 43L, 45L, 46L, 58L, 60L, 62L, 63L, 67L, 70L, 73L, 74L, 77L, 78L, 79L, 80L, 83L, 85L, 87L, 104L, and 106L.

22. The binding protein according to claim 16, wherein the binding protein is a consensus human variable domain.

25. The binding protein according to claim 6, wherein said human acceptor framework comprises at least one Framework Region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework.

30. The binding protein according to claim 19, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:

111. The binding protein according to claim 2, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:

112. The binding protein according to claim 111 wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from the group consisting of:

SEQ ID NO.;

71 &

SEQ ID NO.;

72,

SEQ ID NO.;

73 &

SEQ ID NO.;

74,

SEQ ID NO.;

75 &

SEQ ID NO.;

76, and

SEQ ID NO.;

77 &

SEQ ID NO.;

78.

113. The binding protein according to claim 2, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:

114. The binding protein according to claim 113 wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from the group consisting of:

SEQ ID NO.;

88 &

SEQ ID NO.;

89,

SEQ ID NO.;

90 &

SEQ ID NO.;

91,

SEQ ID NO.;

104 &

SEQ ID NO.;

105,

SEQ ID NO.;

106 &

SEQ ID NO.;

107, and

SEQ ID NO.;

108 &

SEQ ID NO.;

109.

115. The binding protein according to claim 2, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

116. The binding protein according to claim 2, wherein the binding protein is capable of modulating a biological function of a target selected from the group consisting of IL-12 and IL-23.

117. The binding protein according to claim 2, wherein the binding protein is capable of neutralizing a target selected from the group consisting of IL-12 and IL-23.

3. An isolated binding protein comprising an antigen binding domain, said binding protein capable of binding a p40 subunit of IL-12 and said antigen binding domain comprising a variable heavy chain (VH) set of 3 CDRs and a variable light chain (VL) set of 3 CDRs wherein said VH set of 3 CDRs is selected from any one of the VH sets in the group below and said VL set of 3 CDRs is selected from any one of the VL sets in the group of below:

4. The binding protein according to claim 3, wherein said VH set of 3 CDRs and VL set of 3 CDRs are selected from a group consisting of:

VH 1D4 CDR Set &

VL 1D4 CDR Set;

VH 1A6 CDR Set &

VL 1A6 CDR Set;

VH 1D8 CDR Set &

VL 1D8 CDR Set;

VH 3G7 CDR Set &

VL 3G7 CDR Set;

VH 5E8 CDR Set &

VL 5E8 CDR Set;

VH 8E1 CDR Set &

VL 8E1 CDR Set;

VH 1H6 CDR Set &

VL 1H6 CDR Set;

VH 3A11 CDR Set &

VL 3A11 CDR Set;

VH 4B4 CDR Set &

VL 4B4 CDR Set; and

VH 7G3 CDR Set &

VL 7G3 CDR Set.

7. The binding protein according to claim 4, further comprising a human acceptor framework.

8. The binding protein according to claim 4, further comprising a human acceptor framework.

11. The binding protein according to claim 7, wherein said human acceptor framework comprises an amino acid sequence selected from the group consisting of:

12. The binding protein according to claim 8, wherein said human acceptor framework comprises an amino acid sequence selected from the group consisting of:

17. The binding protein according to claim 7, wherein said human acceptor framework comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of:

a residue adjacent to a CDR;

a glycosylation site residue;

a rare residue;

a residue capable of interacting with a p40 subunit of human IL-12;

a residue capable of interacting with a CDR;

a canonical residue;

a contact residue between heavy chain variable region and light chain variable region;

a residue within a Vernier zone; and

a residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and a Kabat-defined first heavy chain framework.

20. The binding protein according to claim 17, wherein key residue selected from the group consisting of 3H, 5H, 10H, H, 12H, 13H, 15H, 16H, 18H, 19H, 23H, 24H, 25H, 30H, 41H, 44H, 46H, 49H, 66H, 68H, 71H, 73H, 74H, 75H, 76H, 77H, 78H, 79H, 81H, 82H, 82AH, 82BH, 82CH, 83H, 84H, 85H, 86H, 87H, 89H, 93H, 98H, 108H, 109H, 1L, 2L, 3L, 7L, 8L, 9L, 10L, 11L, 12L, 13L, 15L, 17L, 19L, 20L, 21L, 22L, 36L, 41L, 42L, 43L, 45L, 46L, 58L, 60L, 62L, 63L, 67L, 70L, 73L, 74L, 77L, 78L, 79L, 80L, 83L, 85L, 87L, 104L, and 106L.

23. The binding protein according to claim 17, wherein the binding protein is a consensus human variable domain.

26. The binding protein according to claim 7, wherein said human acceptor framework comprises at least one Framework Region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework.

31. The binding protein according to claim 20, wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:

33. The binding protein according to claim 3, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.

34. The binding protein according to claim 4, wherein the binding protein is capable of binding a target selected from the group consisting of IL-12 and IL-23.