Dual-specific IL-1α/IL-1β antibodies

1. An isolated, dual-specific antibody, or an antigen-binding portion thereof, with the following characteristics:

a) dissociates from human IL-1α with a K D of 3×10 −7 M or less;

b) dissociates from human IL-1β with a K D of 5×10 −5 M or less; and

c) does not bind mouse IL-1α or mouse IL-1β,

wherein the dual-specific antibody, or antigen-binding portion thereof, comprises

a heavy chain variable region comprising all three complementary determining regions (CDRs) as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 16; SEQ ID NO: 52; SEQ ID NO: 44; SEQ ID NO: 32; SEQ ID NO: 20; SEQ ID NO: 4; and

a light chain variable region comprising all three CDRs as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 36; SEQ ID NO: 24; SEQ ID NO: 28; SEQ ID NO: 40; SEQ ID NO: 12; SEQ ID NO: 48.

2. An isolated, dual-specific antibody, or an antigen-binding portion thereof, with the following characteristics:

a) dissociates from human IL-1α with a K D of 3×10 −7 M or less;

b) dissociates from human IL-1β with a K D of 5×10 −5 M or less; and

c) does not bind mouse IL-1α or mouse IL-1β,

wherein the dual-specific antibody, or antigen-binding portion thereof, comprises

at least two heavy chain variable regions each comprising all three CDRs as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 16; SEQ ID NO: 32; and SEQ ID NO: 4.

3. The antibody, or antigen-binding portion of claim 1 or 2 , which neutralizes human IL-1α in a standard in vitro assay with an ND 50 of 900 nM or less.

4. The antibody, or antigen-binding portion of claim 1 or 2 , which neutralizes human IL-1β in a standard in vitro assay with an ND 50 of 800 nM or less.

5. The antibody, or antigen-binding portion thereof, of claim 4 , which neutralizes IL-1α in a standard in vitro assay with an ND 50 of 10 nM or less.

6. The antibody, or antigen-binding portion of claim 1 or 2 , which neutralizes human IL-1α in a standard in vitro assay with an ND 50 of 900 nM or less, and neutralizes human IL-1β in a standard in vitro assay with an ND 50 of 800 nM or less.

7. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 1×10 −8 M or less.

8. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1β with a K D of 5.4×10 −5 M or less.

9. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 1×10 −8 M or less.

10. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 40-86 nM or less.

11. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 20-42 nM or less.

12. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 32-42 nM or less.

13. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 7-12 nM or less.

14. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 3.0×10 −7 M or less.

15. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 1.1×10 −7 M or less.

16. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 6.1×10 −8 M or less.

17. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 6×10 −8 M or less.

18. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 4.2×10 −8 M or less.

19. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 1.3×10 −8 M or less.

20. The antibody, or antigen-binding portion, of claim 8 , which dissociates from IL-1α with a K D of 1.1×10 −9 M or less.

21. The antibody, or antigen-binding portion, of claim 1 or 2 , which neutralizes human IL-1β in a standard in vitro assay with an ND 50 of 200 nM or less.

22. The antibody, or antigen-binding portion of claim 1 or 2 , which has an IgG1 heavy chain constant region.

23. The antibody, or antigen-binding portion of claim 1 or 2 , which is a Fab.

24. The antibody, or antigen-binding portion of claim 1 or 2 , wherein the antibody, or antigen-binding portion thereof, is human.

25. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 1 or 2 , and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition of claim 25 , which further comprises at least one additional therapeutic agent for treating a disorder in which IL-1α/IL-1β activity is detrimental.

27. The antibody, or antigen-binding portion of claim 1 or 2 , which has an IgG4 heavy chain constant region.

28. The antibody, or antigen-binding portion of claim 1 or 2 , which is a domain antibody (dAb).

29. The antibody, or antigen-binding portion of claim 1 or 2 , which is a Fab′.

30. The antibody, or antigen-binding portion of claim 1 or 2 , which is a Fab 2 .

31. The antibody, or antigen-binding portion of claim 1 or 2 , which is a Fab′ 2 .

32. The antibody, or antigen-binding portion of claim 1 or 2 , which is an Fd.

33. The antibody, or antigen-binding portion of claim 1 or 2 , which is a single chain Fv (scFv).

34. The antibody, or antigen-binding portion of claim 1 or 2 , which is an scFv a .

35. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 1×10 −9 M or less.

36. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 40-86 nM or less.

37. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 20-42 nM or less.

38. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 32-42 nM or less.

39. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 7-12 nM or less.

40. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 3.0×10 −7 M or less.

41. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 1.1×10 −7 M or less.

42. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 6.1×10 −8 M or less.

43. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 6×10 −8 M or less.

44. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 4.2×10 −8 M or less.

45. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 1.3×10 −8 M or less.

46. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 1.1×10 −9 M or less.

47. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1β with a K D of 2.8×10 −6 M or less.

48. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1β with a K D of 1.3×10 −6 M or less.

49. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1β with a K D of 9.3×10 −7 M or less.

50. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1β with a K D of 2×10 −7 M or less.

51. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1β with a K D of 1.1×10 −7 M or less.

52. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1β with a K D of 2.8×10 −8 M or less.

53. The antibody, or antigen-binding portion of claim 1 or 2 , which dissociates from IL-1α with a K D of 1×10 −9 M or less.

54. An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β comprising

a light chain variable region comprising all three complementary determining regions (CDRs) as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 24, and SEQ ID NO: 28, and

a heavy chain variable region comprising all three CDRs set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 16, and SEQ ID NO: 20.

55. The antibody, or antigen-binding portion thereof, of claim 54 which dissociates from human IL-1β with a K D of 5×10 −5 M or less.

56. The antibody, or antigen-binding portion thereof, of claim 54 , which neutralizes human IL-1β in a standard in vitro assay with an ND 50 of 800 nM or less.

57. The antibody, or antigen-binding portion thereof, of claim 54 , which neutralizes IL-1β in a standard in vitro assay with an ND 50 of 200 nM or less.

58. The antibody, or antigen-binding portion thereof, of claim 54 , which dissociates from human IL-1β with a K D of 5×10 −5 M or less and neutralizes human IL-1β in a standard in vitro MRC5 assay with an ND 50 of 800 nM or less.

59. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 54 and a pharmaceutically acceptable carrier.

60. The antibody, or antigen-binding portion thereof, of claim 54 which dissociates from human IL-1β with a K D of 5.4×10 −5 M or less.

61. The antibody, or antigen-binding portion thereof, of claim 54 which dissociates from human IL-1β with a K D of 2.8×10 −6 M or less.

62. The antibody, or antigen-binding portion thereof, of claim 54 which dissociates from human IL-1β with a K D of 1.3×10 −6 M or less.

63. The antibody, or antigen-binding portion thereof, of claim 54 which dissociates from human IL-1β with a K D of 9.3×10 −7 M or less.

64. The antibody, or antigen-binding portion thereof, of claim 54 which dissociates from human IL-1β with a K D of 2×10 −7 M or less.

65. The antibody, or antigen-binding portion thereof, of claim 54 which dissociates from human IL-1β with a K D of 1.1×10 −7 M or less.

66. The antibody, or antigen-binding portion thereof, of claim 54 which dissociates from human IL-1β with a K D of 2.8×10 −8 M or less.

67. An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β comprising

a variable light chain comprising all three CDRs as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 40, and SEQ ID NO: 48, and a variable heavy chain comprising all three CDRs set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 16, and SEQ ID NO: 20.

68. An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β comprising

a variable light chain comprising all three CDRs as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 40, and SEQ ID NO: 48, and

a variable heavy chain comprising all three CDRs as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 32, SEQ ID NO: 44, SEQ ID NO: 52.

69. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 68 and a pharmaceutically acceptable carrier.

70. The antibody, or antigen-binding portion thereof, of claim 68 , which dissociates from IL-1α with a K D selected from the group consisting of 3.0×10 −7 M or less; 1.1×10 −7 M or less; 6×10 −8 M or less; 4.2×10 −8 M or less; 1×10 −8 M or less; 1×10 −9 M or less.

71. The antibody, or antigen-binding portion thereof, of claim 68 , wherein the isolated antibody, or antigen-binding portion thereof, dissociates from human IL-1α with a K D of 1×10 −7 M or less and neutralizes human IL-1α in a standard in vitro assay with an ND 50 of 900 nM or less.

72. An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β, said antibody, or antigen-binding portion thereof, comprising

a variable light chain comprising all three CDRs as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 24, and SEQ ID NO: 28, and a variable heavy chain comprising all three CDRs as set forth in the amino acid sequence selected from the group consisting of SEQ ID NO: 32, SEQ ID NO: 44, SEQ ID NO: 52.

73. An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β, said antibody, or antigen-binding portion thereof, comprising

an IL-1α antigen binding region comprising a light chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, wherein the amino acid sequence of the CDR3 domain is selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 23, and SEQ ID NO: 27, and

an IL-1β antigen binding region comprising a heavy chain variable region comprising a CDR1 domain, a CDR2 domain, and a CDR3 domain, wherein the amino acid sequence of the CDR3 domain is selected from the group consisting of SEQ ID NO: 31, SEQ ID NO: 43, and SEQ ID NO: 51.

74. The antibody, or antigen-binding portion thereof, of claim 73 , wherein the CDR2 domain of the light chain variable region of the IL-1α antigen binding region comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 22, and SEQ ID NO: 26.

75. The antibody, or antigen-binding portion thereof, of claim 74 , wherein the CDR1 domain of the light chain variable region of the IL-1α antigen binding region comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 21, and SEQ ID NO: 25.

76. The antibody, or antigen-binding portion thereof, of claim 73 , wherein the CDR2 domain of the heavy chain variable region of the IL-1β antigen binding region comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 30, SEQ ID NO: 42, and SEQ ID NO: 50.

77. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 73 and a pharmaceutically acceptable carrier.

78. The antibody, or antigen-binding portion thereof, of claim 76 , wherein the CDR1 domain of the heavy chain variable region of the IL-1β antigen binding region comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 29, SEQ ID NO: 41, and SEQ ID NO: 49.

79. A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises

a heavy chain variable region comprising all three CDRs as set forth in SEQ ID NO: 16 and a light chain variable region comprising all three CDRs as set forth in SEQ ID NO: 40.

80. A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of claim 79 and a pharmaceutically acceptable carrier.

81. A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising all three CDRs as set forth in SEQ ID NO: 24 and a heavy chain variable region comprising all three CDRs as set forth in SEQ ID NO: 52.

82. A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising all three CDRs as set forth in SEQ ID NO: 28 and a heavy chain variable region comprising all three CDRs as set forth in SEQ ID NO: 52.

83. A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising all three CDRs as set forth in SEQ ID NO: 28 and a heavy chain variable region comprising all three CDRs as set forth in SEQ ID NO: 44.

84. A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising all three CDRs as set forth in SEQ ID NO: 16 and a light chain variable region comprising all three CDRs as set forth in SEQ ID NO: 36.

85. A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising all three CDRs as set forth in SEQ ID NO: 12 and a heavy chain variable region comprising all three CDRs as set forth in SEQ ID NO: 32.

86. A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises a light chain variable region comprising all three CDRs as set forth in SEQ ID NO: 24 and a heavy chain variable region comprising all three CDRs as set forth in SEQ ID NO: 44.

87. A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region comprising all three CDRs as set forth in SEQ ID NO: 20 and a light chain variable region comprising all three CDRs as set forth in SEQ ID NO: 48.

88. An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β, comprising

an IL-1α antigen binding region comprising a heavy chain variable region comprising a CDR3 domain, a CDR2 domain, and a CDR1 domain, wherein the amino acid sequence of the CDR3 domain is selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 15, SEQ ID NO: 19, and

an IL-1β antigen binding region comprising a light chain variable region comprising a CDR3 domain, a CDR2 domain, and a CDR1 domain, wherein the amino acid sequence of the a CDR3 domain is selected from the group consisting of SEQ ID NO: 35, SEQ ID NO: 39, and SEQ ID NO: 47.

89. The antibody, or antigen-binding portion thereof, of claim 88 , wherein the CDR2 domain of the heavy chain variable region of the IL-1α antigen binding region comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 18.

90. The antibody, or antigen-binding portion thereof, of claim 89 , wherein the CDR1 domain of the heavy chain variable region of the IL-1α antigen binding region comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 13, and SEQ ID NO: 17.

91. The antibody, or antigen-binding portion thereof, of claim 88 , wherein the CDR2 domain of the light chain variable region of the IL-1β antigen binding region comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 34, SEQ ID NO: 38, and SEQ ID NO: 46.

92. The antibody, or antigen-binding portion thereof, of claim 91 , wherein the CDR1 domain of the light chain variable region of the IL-1β antigen binding region comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 33, SEQ ID NO: 37, and SEQ ID NO: 45.