US2007065426A1PendingUtilityA1

Tumor necrosis factor binding ligands

65
Assignee: PEPTECH LTDPriority: Aug 7, 1989Filed: Feb 28, 2006Published: Mar 22, 2007
Est. expiryAug 7, 2009(expired)· nominal 20-yr term from priority
Inventors:Deborah RathjenRoger Aston
C07K 2317/55C07K 2317/622A61K 38/00A61K 47/68C07K 2317/73C07K 2317/75C07K 2317/76A61P 35/00C07K 2319/00A61K 47/6813C07K 2317/24C07K 16/241C07K 2317/21
65
PatentIndex Score
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Claims

Abstract

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 endothelial procoagulant activity of the TNF is inhibited; the binding of TNF to receptors on endothelial cells is inhibited; the induction of fibrin deposition in the tumour and tumour regression activities of the TNF are enhanced; and the cytotoxicity and receptor binding activities of the TNF are unaffected or enhanced on tumour cells. 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.

Claims

exact text as granted — not AI-modified
1 . An isolated antibody or fragment thereof that binds to mature human TNF-α, 
 wherein when the antibody binds TNF-α, the induction of tumor fibrin deposition is unaffected, and the induction of endothelial procoagulant activity, cytotoxicity, tumor regression and tumor receptor binding activities are inhibited; and,    wherein the antibody binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.    
     
     
         2 . An antibody or fragment thereof according to  claim 1  wherein the antibody is a monoclonal antibody.  
     
     
         3 . An antibody or fragment thereof according to  claim 1  or  2 , wherein the antibody is a humanized antibody.  
     
     
         4 . An antibody or fragment thereof according to  claim 1  or  2  wherein the antibody is a chimeric antibody.  
     
     
         5 . An antibody or fragment thereof according to  claim 1  or  2  wherein the antibody is a human antibody.  
     
     
         6 . A composition comprising an isolated antibody or fragment thereof that binds to mature human TNF-α, 
 wherein when the antibody binds TNF-α, the induction of tumor fibrin deposition is unaffected, and the induction of endothelial procoagulant activity, cytotoxicity, tumor regression and tumor receptor binding activities are inhibited; and,    wherein the antibody binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108-Ala   109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.    
     
     
         7 . A composition according to  claim 6  wherein the antibody is a monoclonal antibody.  
     
     
         8 . A composition according to  claim 6  or  7 , wherein the antibody is a humanized antibody.  
     
     
         9 . A composition according to  claim 6  or  7 , wherein the antibody is a chimeric antibody.  
     
     
         10 . A composition according to  claim 6  or  7 , wherein the antibody is a human antibody.  
     
     
         11 . An isolated single chain antibody that binds to mature human TNF-α, 
 wherein when the antibody binds TNF-α, the induction of tumor fibrin deposition is unaffected, and the induction of endothelial procoagulant activity, cytotoxicity, tumor regression and tumor receptor binding activities are inhibited; and,    wherein the antibody binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.    
     
     
         12 . An antibody according to  claim 11 , wherein the antibody is a humanized antibody.  
     
     
         13 . An antibody according to  claim 11 , wherein the antibody is a chimeric antibody.  
     
     
         14 . An antibody according to  claim 11 , wherein the antibody is a human antibody.  
     
     
         15 . A composition comprising an isolated single chain antibody that binds to mature human TNF-α, 
 wherein when the antibody binds TNF-α, the induction of tumor fibrin deposition is unaffected, and the induction of endothelial procoagulant, cytotoxicity, tumor regression and tumor receptor binding activities are inhibited; and,    wherein the antibody binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.    
     
     
         16 . A composition according to  claim 15 , wherein the antibody is a humanized antibody.  
     
     
         17 . A composition according to  claim 15 , wherein the antibody is a chimeric antibody.  
     
     
         18 . A composition according to  claim 15 , wherein the antibody is a human antibody.  
     
     
         19 . An isolated antibody or fragment thereof that binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         20 . An antibody or fragment thereof according to  claim 19  wherein the antibody is a monoclonal antibody.  
     
     
         21 . An antibody of fragment thereof according to  claim 19  wherein the antibody or fragment thereof has no effect on the induction of tumor fibrin deposition activity.  
     
     
         22 . An antibody or fragment thereof according to  claim 19 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         23 . An antibody or fragment thereof according to  claim 19 , wherein the antibody or fragment thereof inhibits cytotoxicity.  
     
     
         24 . An antibody or fragment thereof according to  claim 19 , wherein the antibody or fragment thereof inhibits tumor regression.  
     
     
         25 . An antibody or fragment thereof according to  claim 19 , wherein the antibody or fragment thereof inhibits tumor receptor binding.  
     
     
         26 . An antibody or fragment thereof according to any one of claims  19 - 25  wherein the antibody is a humanized antibody.  
     
     
         27 . An antibody or fragment thereof according to any one of claims  19 - 25 , wherein the antibody is a chimeric antibody.  
     
     
         28 . An antibody or fragment thereof according to any one of claims  19 - 25 , wherein the antibody is a human antibody.  
     
     
         29 . A composition comprising an isolated antibody or fragment thereof that binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         30 . A composition according to  claim 29  wherein the antibody is a monoclonal antibody.  
     
     
         31 . A composition according to  claim 29 , wherein the antibody or fragment thereof has no effect on the induction of tumor fibrin deposition activity.  
     
     
         32 . A composition according to  claim 29 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         33 . A composition according to  claim 29 , wherein the antibody or fragment thereof inhibits cytotoxicity.  
     
     
         34 . A composition according to  claim 29 , wherein the antibody or fragment thereof inhibits tumor regression.  
     
     
         35 . A composition according to  claim 29 , wherein the antibody or fragment thereof inhibits tumor receptor binding.  
     
     
         36 . A composition according to any one of claims  29 - 35 , wherein the antibody is a humanized antibody.  
     
     
         37 . A composition according to any one of claims  29 - 35 , wherein the antibody is a chimeric antibody.  
     
     
         38 . A composition according to any one of claims  29 - 35 , wherein the antibody is a human antibody.  
     
     
         39 . An isolated single chain antibody that binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         40 . An antibody according to  claim 39 , wherein the antibody has no effect on the induction of tumor fibrin deposition activity.  
     
     
         41 . An antibody according to  claim 39 , wherein the antibody inhibits the induction of endothelial procoagulant activity.  
     
     
         42 . An antibody according to  claim 39 , wherein the antibody inhibits cytotoxicity.  
     
     
         43 . An antibody according to  claim 39 , wherein the antibody inhibits tumor regression.  
     
     
         44 . An antibody according to  claim 39 , wherein the antibody inhibits tumor receptor binding.  
     
     
         45 . An antibody according to any one of claims  39 - 44 , wherein the antibody is a humanized antibody.  
     
     
         46 . An antibody according to any one of claims  39 - 44 , wherein the antibody is a chimeric antibody.  
     
     
         47 . An antibody according to any one of claims  39 - 44 , wherein the antibody is a human antibody.  
     
     
         48 . A composition comprising an isolated single chain antibody that binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         49 . A composition according to  claim 48 , wherein the antibody has no effect on the induction of tumor fibrin deposition activity.  
     
     
         50 . A composition according to  claim 48 , wherein the antibody inhibits the induction of endothelial procoagulant activity.  
     
     
         51 . A composition according to  claim 48 , wherein the antibody inhibits cytotoxicity.  
     
     
         52 . A composition according to  claim 48 , wherein the antibody inhibits tumor regression.  
     
     
         53 . A composition according to  claim 48 , wherein the antibody inhibits tumor receptor binding.  
     
     
         54 . A composition according to any one of claims  48 - 53 , wherein the antibody is a humanized antibody.  
     
     
         55 . A composition according to any one of claims  48 - 53 , wherein the antibody is a chimeric antibody.  
     
     
         56 . A composition according to any one of claims  48 - 53 , wherein the antibody is a human antibody.  
     
     
         57 . An isolated single domain antibody or fragment thereof that binds to mature human TNF-α, 
 wherein when the antibody binds TNF-α, the induction of tumor fibrin deposition is unaffected, and the induction of endothelial procoagulant activity, cytotoxicity, tumor regression and tumor receptor binding activities are inhibited; and,    wherein the antibody binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.    
     
     
         58 . An antibody or fragment thereof according to  claim 57  wherein the antibody is a humanized antibody.  
     
     
         59 . An antibody or fragment thereof according to  claim 57 , wherein the antibody is a chimeric antibody.  
     
     
         60 . An antibody or fragment thereof according to  claim 57 , wherein the antibody is a human antibody.  
     
     
         61 . A composition comprising an isolated single domain antibody or fragment thereof that binds to mature human TNF-α, 
 wherein when the antibody binds TNF-α, the induction of tumor fibrin deposition is unaffected, and the induction of endothelial procoagulant activity, cytotoxicity, tumor regression and tumor receptor binding activities are inhibited; and,    wherein the antibody binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.    
     
     
         62 . A composition according to  claim 61 , wherein the antibody is a humanized antibody.  
     
     
         63 . A composition according to  claim 61 , wherein the antibody is a chimeric antibody.  
     
     
         64 . A composition according to  claim 61 , wherein the antibody is a human antibody.  
     
     
         65 . An isolated single domain antibody or fragment thereof that binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         66 . An antibody of fragment thereof according to  claim 65 , wherein the antibody or fragment thereof has no effect on the induction of tumor fibrin deposition activity.  
     
     
         67 . An antibody or fragment thereof according to  claim 65 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         68 . An antibody or fragment thereof according to  claim 65 , wherein the antibody or fragment thereof inhibits cytotoxicity.  
     
     
         69 . An antibody or fragment thereof according to  claim 65 , wherein the antibody or fragment thereof inhibits tumor regression.  
     
     
         70 . An antibody or fragment thereof according to  claim 65 , wherein the antibody or fragment thereof inhibits tumor receptor binding.  
     
     
         71 . An antibody or fragment thereof according to any one of claims  65 - 70 , wherein the antibody is a humanized antibody.  
     
     
         72 . An antibody or fragment thereof according to any one of claims  65 - 70 , wherein the antibody is a chimeric antibody.  
     
     
         73 . An antibody or fragment thereof according to any one of claims  65 - 70 , wherein the antibody is a human antibody.  
     
     
         74 . A composition comprising an isolated single domain antibody or fragment thereof that binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         75 . A composition according to  claim 74 , wherein the antibody or fragment thereof has no effect on the induction of tumor fibrin deposition activity.  
     
     
         76 . A composition according to  claim 74 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         77 . A composition according to  claim 74 , wherein the antibody or fragment thereof inhibits cytotoxicity.  
     
     
         78 . A composition according to  claim 74 , wherein the antibody or fragment thereof inhibits tumor regression.  
     
     
         79 . A composition according to  claim 74 , wherein the antibody or fragment thereof inhibits tumor receptor binding.  
     
     
         80 . A composition according to any one of claims  74 - 79 , wherein the antibody is a humanized antibody.  
     
     
         81 . A composition according to any one of claims  74 - 79 , wherein the antibody is a chimeric antibody.  
     
     
         82 . A composition according to any one of claims  74 - 79 , wherein the antibody is a human antibody.  
     
     
         83 . An isolated antibody or fragment thereof that binds to mature human TNF-α, and binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         84 . An antibody or fragment thereof according to  claim 83 ,wherein the antibody is a monoclonal antibody.  
     
     
         85 . An antibody of fragment thereof according to  claim 83 ,wherein the antibody or fragment thereof has no effect on the induction of tumor fibrin deposition activity.  
     
     
         86 . An antibody or fragment thereof according to  claim 83 ,wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         87 . An antibody or fragment thereof according to  claim 83 ,wherein the antibody or fragment thereof inhibits cytotoxicity.  
     
     
         88 . An antibody or fragment thereof according to  claim 83 ,wherein the antibody or fragment thereof inhibits tumor regression.  
     
     
         89 . An antibody or fragment thereof according to  claim 83 ,wherein the antibody or fragment thereof inhibits tumor receptor binding.  
     
     
         90 . An antibody or fragment thereof according to any one of claims  83 - 89  wherein the antibody is a humanized antibody.  
     
     
         91 . An antibody or fragment thereof according to any one of claims  83 - 89 , wherein the antibody is a chimeric antibody.  
     
     
         92 . An antibody or fragment thereof according to any one of claims  83 - 89 , wherein the antibody is a human antibody.  
     
     
         93 . A composition comprising an isolated antibody or fragment thereof that binds to mature human TNF-α, and binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         94 . A composition according to  claim 93 , wherein the antibody is a monoclonal antibody.  
     
     
         95 . A composition according to  claim 93 , wherein the antibody or fragment thereof has no effect on the induction of tumor fibrin deposition activity.  
     
     
         96 . A composition according to  claim 93 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         97 . A composition according to  claim 93 , wherein the antibody or fragment thereof inhibits cytotoxicity.  
     
     
         98 . A composition according to  claim 93 , wherein the antibody or fragment thereof inhibits tumor regression.  
     
     
         99 . A composition according to  claim 93 , wherein the antibody or fragment thereof inhibits tumor receptor binding.  
     
     
         100 . A composition according to any one of claims  93 - 99 , wherein the antibody is a humanized antibody.  
     
     
         101 . A composition according to any one of claims  93 - 99 , wherein the antibody is a chimeric antibody.  
     
     
         102 . A composition according to any one of claims  93 - 99 , wherein the antibody is a human antibody.  
     
     
         103 . An isolated single chain antibody that binds to mature human TNF-α, and binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         104 . An antibody according to  claim 103 , wherein the antibody inhibits the induction of tumor fibrin deposition activity.  
     
     
         105 . An antibody according to  claim 103 , wherein the antibody has no effect on the induction of endothelial procoagulant activity.  
     
     
         106 . An antibody according to  claim 103 , wherein the antibody inhibits cytotoxicity.  
     
     
         107 . An antibody according to  claim 103 , wherein the antibody inhibits tumor regression.  
     
     
         108 . An antibody according to  claim 103 , wherein the antibody inhibits tumor receptor binding.  
     
     
         109 . An antibody according to any one of claims  103 - 108 , wherein the antibody is a humanized antibody.  
     
     
         110 . An antibody according to any one of claims  103 - 108 , wherein the antibody is a chimeric antibody.  
     
     
         111 . An antibody according to any one of claims  103 - 108 , wherein the antibody is a human antibody.  
     
     
         112 . A composition comprising an isolated single chain antibody that binds to mature human TNF-α, and binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         113 . A composition according to  claim 112 , wherein the antibody has no effect on the induction of tumor fibrin deposition activity.  
     
     
         114 . A composition according to  claim 112 , wherein the antibody inhibits the induction of endothelial procoagulant activity.  
     
     
         115 . A composition according to  claim 112 , wherein the antibody inhibits cytotoxicity.  
     
     
         116 . A composition according to  claim 112 , wherein the antibody inhibits tumor regression.  
     
     
         117 . A composition according to  claim 112 , wherein the antibody inhibits tumor receptor binding.  
     
     
         118 . A composition according to any one of claims  112 - 117 , wherein the antibody is a humanized antibody.  
     
     
         119 . A composition according to any one of claims  112 - 117 , wherein the antibody is a chimeric antibody.  
     
     
         120 . A composition according to any one of claims  112 - 117 , wherein the antibody is a human antibody.  
     
     
         121 . An isolated single domain antibody or fragment thereof that binds to mature human TNF-α, and binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         122 . An antibody of fragment thereof according to  claim 121 , wherein the antibody or fragment thereof has no effect on the induction of tumor fibrin deposition activity.  
     
     
         123 . An antibody or fragment thereof according to  claim 121 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         124 . An antibody or fragment thereof according to  claim 121 , wherein the antibody or fragment thereof inhibits cytotoxicity.  
     
     
         125 . An antibody or fragment thereof according to  claim 121 , wherein the antibody or fragment thereof inhibits tumor regression.  
     
     
         126 . An antibody or fragment thereof according to  claim 121 , wherein the antibody or fragment thereof inhibits tumor receptor binding.  
     
     
         127 . An antibody or fragment thereof according to any one of claims  121 - 126  wherein the antibody is a humanized antibody.  
     
     
         128 . An antibody or fragment thereof according to any one of claims  121 - 126 , wherein the antibody is a chimeric antibody.  
     
     
         129 . An antibody or fragment thereof according to any one of claims  121 - 126 , wherein the antibody is a human antibody.  
     
     
         130 . A composition comprising an isolated single domain antibody or fragment thereof that binds to mature human TNF-α, and binds to peptides having amino acid sequences Ala 22 -Glu 23 -Gly 24 -Gln 25 -Leu 26 -Gln 27 -Trp 28 -Leu 29 -Asn 30 -Arg 31 -Arg 32 -Ala 33 -Asn 34 -Ala 35 -Leu 36 -Leu 37 -Ala 38 -Asn 39 -Gly 40 , Cys 69 -Pro 70 -Ser 71 -Thr 72 -His 73 -Val 74 -Leu 75 -Leu 76 -Thr 77 -His 78 -Thr 79 -Ile 80 -Ser 81 -Arg 82 -Ile 83 -Ala- 84 -Val 85 -Ser 86 -Tyr 87 -Gln 88 -Thr 89 -Lys 90 -Val 91 -Asn 92 -Leu 93 -Leu 94 -Ser 95 -Ala 96 -Ile 97 , Thr 105 -Pro 106 -Glu 107 -Gly 108 -Ala 109 -Glu 110 -Ala 111 -Lys 112 -Pro 113 -Trp 114 -Tyr 115 -Glu 116 -Pro 117 -Ile 118 -Tyr 119 -Leu 120 -Gly 121 -Gly 122 -Val 123 -Phe 124 -Gln 125 -Leu 126 -Glu 127 -Lys 128 , and Glu 135 -Ile 136 -Asn 137 -Arg 138 -Pro 139 -Asp 140 -Tyr 141 -Leu 142 -Asp 143 -Phe 144 -Ala 145 -Glu 146 -Ser 147 -Gly 148 -Gln 149 -Val 150 -Tyr 151 -Phe 152 -Gly 153 -Ile 154 -Ile 155  of the mature human TNF-α amino acid sequence.  
     
     
         131 . A composition according to  claim 130 , wherein the antibody or fragment thereof has no effect on the induction of tumor fibrin deposition activity.  
     
     
         132 . A composition according to  claim 130 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         133 . A composition according to  claim 130 , wherein the antibody or fragment thereof inhibits cytotoxicity.  
     
     
         134 . A composition according to  claim 130 , wherein the antibody or fragment thereof inhibits tumor regression.  
     
     
         135 . A composition according to  claim 130 , wherein the antibody or fragment thereof inhibits tumor receptor binding.  
     
     
         136 . A composition according to any one of claims  130 - 135 , wherein the antibody is a humanized antibody.  
     
     
         137 . A composition according to any one of claims  130 - 135 , wherein the antibody is a chimeric antibody.  
     
     
         138 . A composition according to any one of claims  130 - 135 , wherein the antibody is a human antibody.

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