Tumour necrosis factor binding ligands
The present invention relates to ligands which bind to human tumour necrosis factor alpha (TNF) in a manner such that upon binding of these ligands to TNF the biological activity of TNF is modified. In preferred forms the ligand binds to TNF in a manner such that the induction of fibrin deposition in the tumour and induction of endothelial procoagulant activity of the TNF is inhibited; the binding of TNF to receptors on endothelial cells, tumour regression, cytotoxicity and receptor binding activities of the TNF on tumour cells are unaffected. The ligand is preferably an antibody, F(ab) fragment, single domain antibody (dABs), single chain antibody or a serum binding protein. It is preferred, however, that the ligand is a monoclonal antibody or F(ab) fragment thereof.
1. An isolated antibody or fragment thereof that specifically binds to mature human TNF-α,
wherein the antibody or fragment thereof competitively inhibits MAb 42 (ECACC Accession No. 89080304) for specific binding to mature human TNF-α and,
wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited, and the cytotoxicity, tumor regression and tumor receptor binding to TNF-α are not effected.
2. The antibody or fragment thereof according to claim 1 ,
wherein the antibody or fragment thereof competitively inhibits the binding of MAb 42 (ECACC Accession No. 89080304) to mature human TNF-α, where comparative binding specificity is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
3. The antibody or fragment thereof according to claim 1 wherein the antibody is a monoclonal antibody.
4. The antibody or fragment thereof according to any one of claims 1 - 3 , wherein the antibody is a humanized antibody.
5. The antibody or fragment thereof according to any one of claims 1 - 3 , wherein the antibody is a chimeric antibody.
6. A composition comprising an isolated antibody or fragment thereof that specifically binds to mature human TNF-α,
wherein the antibody or fragment thereof competitively inhibits MAb 42 (ECACC Accession No. 89080304) for specific binding to mature human TNF-α and,
wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited, and the cytotoxicity, tumor regression and tumor receptor binding to TNF-α are not effected.
7. The composition according to claim 6 , wherein the antibody or fragment thereof competitively inhibits the binding of MAb 42 (ECACC Accession No. 89080304) to mature human TNF-α, where comparative binding specificity is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
8. The composition according to claim 7 wherein the antibody is a monoclonal antibody.
9. The composition according to any one of claims 6 - 8 , wherein the antibody is a humanized antibody.
10. The composition according to any one of claims 6 - 8 , wherein the antibody is a chimeric antibody.
11. An isolated single chain antibody that specifically binds to mature human TNF-α,
wherein the antibody competitively inhibits MAb 42 (ECACC Accession No. 89080304) for specific binding to mature human TNF-α and,
wherein when the antibody binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited, and the cytotoxicity, tumor regression and tumor receptor binding to TNF-α are not effected.
12. The antibody according to claim 11 , wherein the antibody competitively inhibits the binding of MAb 42 (ECACC Accession No. 89080304) to mature human TNF-α, where comparative binding specificity is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
13. The antibody according to claim 11 or 12 , wherein the antibody is a humanized antibody.
14. The antibody according to claim 11 or 12 , wherein the antibody is a chimeric antibody.
15. A composition comprising an isolated single chain antibody that specifically binds to mature human TNF-α,
wherein the antibody competitively inhibits MAb 42 (ECACC Accession No. 89080304) for specific binding to mature human TNF-α and,
wherein when the antibody binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited, and the cytotoxicity, tumor regression and tumor receptor binding to TNF-α are not effected.
16. The composition according to claim 15 , wherein the antibody competitively inhibits the binding of MAb 42 (ECACC Accession No. 89080304) to mature human TNF-α, where comparative binding specificity is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
17. The composition according to claim 15 or 16 , wherein the antibody is a humanized antibody.
18. The composition according to claim 15 or 16 , wherein the antibody is a chimeric antibody.
19. An isolated single domain antibody or fragment thereof that specifically binds to mature human TNF-α,
wherein the antibody or fragment thereof competitively inhibits MAb 42 (ECACC Accession No. 89080304) for specific binding to mature human TNF-α and,
wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited, and the cytotoxicity, tumor regression and tumor receptor binding to TNF-α are not effected.
20. The antibody or fragment thereof according to claim 19 ,
wherein the antibody or fragment thereof competitively inhibits the binding of MAb 42 (ECACC Accession No. 89080304) to mature human TNF-α, where comparative binding specificity is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
21. The antibody or fragment thereof according to claim 19 or 20 , wherein the antibody is a humanized antibody.
22. The antibody or fragment thereof according to claim 19 or 20 , wherein the antibody is a chimeric antibody.
23. A composition comprising an isolated single domain antibody or fragment thereof that specifically binds to mature human TNF-α,
wherein the antibody or fragment thereof competitively inhibits MAb 42 (ECACC Accession No. 89080304) for specific binding to mature human TNF-α and,
wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited, and the cytotoxicity, tumor regression and tumor receptor binding to TNF-α are not effected.
24. The composition according to claim 23 , wherein the antibody or fragment thereof competitively inhibits the binding of MAb 42 (ECACC Accession No. 89080304) to mature human TNF-α, where comparative binding specificity is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
25. The composition according to claim 23 or 24 , wherein the antibody is a humanized antibody.
26. The composition according to claim 23 or 24 , wherein the antibody is a chimeric antibody.
27. An isolated antibody or fragment thereof that specifically binds to mature human TNF-α,
wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited,
wherein the antibody or fragment thereof competitively inhibits a second antibody or fragment thereof for specific binding to mature human TNF-α; and,
wherein the second antibody is MAb 42 (ECACC Accession No. 89080304).
28. The antibody or fragment thereof according to claim 27 , wherein the antibody is a monoclonal antibody.
29. The antibody or fragment thereof according to claim 27 , wherein the antibody or fragment thereof inhibits the induction of tumor fibrin deposition activity.
30. The antibody or fragment thereof according to claim 27 , wherein the antibody or fragment thereof has no effect on tumor receptor binding to TNF-α.
31. The antibody or fragment thereof according to claim 30 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
32. The antibody or fragment thereof according to claim 27 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
33. The antibody or fragment thereof according to claim 32 , wherein the antibody or fragment thereof has no effect on tumor regression.
34. The antibody or fragment thereof according to claim 31 , wherein the antibody or fragment thereof has no effect on tumor regression.
35. The antibody or fragment thereof according to claim 30 , wherein the antibody or fragment thereof has no effect on tumor regression.
36. The antibody or fragment thereof according to claim 27 , wherein the antibody or fragment thereof has no effect on tumor regression.
37. The antibody or fragment thereof according to claim 27 , where comparative binding specificity between the antibody or fragment thereof and MAb 42 (ECACC Accession No. 89080304) is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
38. The antibody or fragment thereof according to claim 37 , wherein the antibody or fragment thereof has no effect on tumor receptor binding to TNF-α.
39. The antibody or fragment thereof according to claim 38 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
40. The antibody or fragment thereof according to claim 37 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
41. The antibody or fragment thereof according to claim 39 , wherein the antibody or fragment thereof has no effect on tumor regression.
42. The antibody or fragment thereof according to claim 37 , wherein the antibody or fragment thereof has no effect on tumor regression.
43. The antibody or fragment thereof according to any one of claims 27 - 42 , wherein the antibody is a humanized antibody.
44. The antibody or fragment thereof according to any one of claims 27 - 42 , wherein the antibody is a chimeric antibody.
45. A composition comprising an isolated antibody or fragment thereof that specifically binds to mature human TNF-α,
wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited,
wherein the antibody or fragment thereof competitively inhibits a second antibody or fragment thereof for specific binding to mature human TNF-α, and,
wherein the second antibody is MAb 42 (ECACC Accession No. 89080304).
46. The composition according to claim 45 , wherein the antibody is a monoclonal antibody.
47. The composition according to claim 45 , wherein the antibody or fragment thereof inhibits the induction of tumor fibrin deposition activity.
48. The composition according to claim 45 , wherein the antibody or fragment thereof has no effect on tumor receptor binding to TNF-α.
49. The composition according to claim 48 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
50. The composition according to claim 45 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
51. The composition according to claim 50 , wherein the antibody or fragment thereof has no effect on tumor regression.
52. The composition according to claim 49 , wherein the antibody or fragment thereof has no effect on tumor regression.
53. The composition according to claim 48 , wherein the antibody or fragment thereof has no effect on tumor regression.
54. The composition according to claim 45 , wherein the antibody or fragment thereof has no effect on tumor regression.
55. The composition according to claim 45 , where comparative binding specificity between the antibody or fragment thereof and MAb 42 (ECACC Accession No. 89080304) is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
56. The composition according to claim 55 , wherein the antibody or fragment thereof has no effect on tumor receptor binding to TNF-α.
57. The composition according to claim 56 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
58. The composition according to claim 55 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
59. The composition according to claim 57 , wherein the antibody or fragment thereof has no effect on tumor regression.
60. The composition according to claim 57 , wherein the antibody or fragment thereof has no effect on tumor regression.
61. The composition according to any one of 52 - 60 , wherein the antibody is a humanized antibody.
62. The composition according to any one of claims 52 - 60 , wherein the antibody is a chimeric antibody.
63. An isolated single chain antibody that specifically binds to mature human TNF-α,
wherein when the antibody binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited,
wherein the antibody competitively inhibits a second antibody or fragment thereof for specific binding to mature human TNF-α; and,
wherein the second antibody is MAb 42 (ECACC Accession No. 89080304).
64. The antibody according to claim 63 , wherein the antibody inhibits the induction of tumor fibrin deposition activity.
65. The antibody according to claim 63 , wherein the antibody has no effect on tumor receptor binding to TNF-α.
66. The antibody according to claim 65 , wherein the antibody has no effect on cytotoxicity.
67. The antibody according to claim 63 , wherein the antibody has no effect on cytotoxicity.
68. The antibody according to claim 67 , wherein the antibody has no effect on tumor regression.
69. The antibody according to claim 66 , wherein the antibody has no effect on tumor regression.
70. The antibody according to claim 65 , wherein the antibody has no effect on tumor regression.
71. The antibody according to claim 63 , wherein the antibody has no effect on tumor regression.
72. The antibody according to claim 63 , where comparative binding specificity between the antibody and MAb 42 (ECACC Accession No. 89080304) is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
73. The antibody according to claim 72 , wherein the antibody has no effect on tumor receptor binding to TNF-α.
74. The antibody according to claim 73 , wherein the antibody has no effect on cytotoxicity.
75. The antibody according to claim 72 , wherein the antibody has no effect on cytotoxicity.
76. The antibody according to claim 74 , wherein the antibody has no effect on tumor regression.
77. The antibody according to claim 72 , wherein the antibody has no effect on tumor regression.
78. The antibody according to any one of claims 63 - 77 , wherein the antibody is a humanized antibody.
79. The antibody according to any one of claims 63 - 77 , wherein the antibody is a chimeric antibody.
80. A composition comprising an isolated single chain antibody that specifically binds to mature human TNF-α,
wherein when the antibody binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited,
wherein the isolated antibody competitively inhibits a second antibody or fragment thereof for specific binding to mature human TNF-α; and
wherein the second antibody is MAb 42 (ECACC Accession No. 89080304).
81. The composition according to claim 80 , wherein the antibody inhibits the induction of tumor fibrin deposition activity.
82. The composition according to claim 80 , wherein the antibody has no effect on tumor receptor binding to TNF-α.
83. The composition according to claim 82 , wherein the antibody has no effect on cytotoxicity.
84. The composition according to claim 80 , wherein the antibody has no effect on cytotoxicity.
85. The composition according to claim 84 , wherein the antibody has no effect on tumor regression.
86. The composition according to claim 83 , wherein the antibody has no effect on tumor regression.
87. The composition according to claim 82 , wherein the antibody has no effect on tumor regression.
88. The composition according to claim 80 , wherein the antibody has no effect on tumor regression.
89. The composition according to claim 70 , where comparative binding specificity between the antibody and MAb 42 (ECACC Accession No. 89080304) is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
90. The composition according to claim 89 , wherein the antibody has no effect on tumor receptor binding to TNF-α.
91. The composition according to claim 90 , wherein the antibody has no effect on cytotoxicity.
92. The composition according to claim 89 , wherein the antibody has no effect on cytotoxicity.
93. The composition according to claim 91 , wherein the antibody has no effect on tumor regression.
94. The composition according to claim 89 , wherein the antibody inhibits tumor regression.
95. The composition according to any one of claims 80 - 94 , wherein the antibody is a humanized antibody.
96. The composition according to any one of claims 80 - 94 , wherein the antibody is a chimeric antibody.
97. An isolated single domain antibody or fragment thereof that specifically binds to mature human TNF-α,
wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited,
wherein the isolated antibody or fragment thereof competitively inhibits a second antibody or fragment thereof for specific binding to mature human TNF-α; and,
wherein the second antibody is MAb 42 (ECACC Accession No. 89080304).
98. The antibody or fragment thereof according to claim 97 , wherein the antibody or fragment thereof inhibits the induction of tumor fibrin deposition activity.
99. The antibody or fragment thereof according to claim 97 , wherein the antibody or fragment thereof has no effect on tumor receptor binding to TNF-α.
100. The antibody or fragment thereof according to claim 99 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
101. The antibody or fragment thereof according to claim 97 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
102. The antibody or fragment thereof according to claim 101 , wherein the antibody or fragment thereof has no effect on tumor regression.
103. The antibody or fragment thereof according to claim 100 , wherein the antibody or fragment thereof has no effect on tumor regression.
104. The antibody or fragment thereof according to claim 99 , wherein the antibody or fragment thereof has no effect on tumor regression.
105. The antibody or fragment thereof according to claim 97 , wherein the antibody or fragment thereof has no effect on tumor regression.
106. The antibody or fragment thereof according to claim 97 , where comparative binding specificity between the antibody or fragment thereof and MAb 42 (ECACC Accession No. 89080304) is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
107. The antibody or fragment thereof according to claim 106 , wherein the antibody or fragment thereof has no effect on tumor receptor binding to TNF-α.
108. The antibody or fragment thereof according to claim 107 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
109. The antibody or fragment thereof according to claim 106 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
110. The antibody or fragment thereof according to claim 108 , wherein the antibody or fragment thereof has no effect on tumor regression.
111. The antibody or fragment thereof according to claim 106 , wherein the antibody or fragment thereof has no effect on tumor regression.
112. The antibody or fragment thereof according to any one of claims 97 - 111 , wherein the antibody is a humanized antibody.
113. The antibody or fragment thereof according to any one of claims 97 - 111 , wherein the antibody is a chimeric antibody.
114. A composition comprising an isolated single domain antibody or fragment thereof that specifically binds to mature human TNF-α,
wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity is inhibited,
wherein the antibody or fragment thereof competitively inhibits a second antibody or fragment thereof for specific binding to mature human TNF-α; and,
wherein the second antibody is MAb 42 (ECACC Accession No. 89080304).
115. The composition according to claim 114 , wherein the antibody or fragment thereof inhibits the induction of tumor fibrin deposition activity.
116. THE composition according to claim 114 , wherein the antibody or fragment thereof has no effect on tumor receptor binding to TNF-α.
117. The composition according to claim 116 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
118. The composition according to claim 114 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
119. The composition according to claim 118 , wherein the antibody or fragment thereof has no effect on tumor regression.
120. The composition according to claim 117 , wherein the antibody or fragment thereof has no effect on tumor regression.
121. The composition according to claim 116 , wherein the antibody or fragment thereof has no effect on tumor regression.
122. The composition according to claim 114 , wherein the antibody or fragment thereof has no effect on tumor regression.
123. The composition according to claim 114 , where comparative binding specificity between the antibody or fragment thereof and MAb 42 (ECACC Accession No. 90012248) is determined by antibody-antibody competition assays in the presence of mature human TNF-α.
124. The composition according to claim 123 , wherein the antibody or fragment thereof has no effect on tumor receptor binding to TNF-α.
125. The composition according to claim 124 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
126. The composition according to claim 123 , wherein the antibody or fragment thereof has no effect on cytotoxicity.
127. The composition according to claim 125 , wherein the antibody or fragment thereof has no effect on tumor regression.
128. The composition according to claim 123 , wherein the antibody or fragment thereof has no effect on tumor regression.
129. The composition according to any one of claims 114 - 128 , wherein the antibody is a humanized antibody.
130. The composition according to any one of claims 114 - 128 , wherein the antibody is a chimeric antibody.