US2006204499A1PendingUtilityA1

Tumour necrosis factor binding ligands

66
Assignee: PEPTECH LTDPriority: Aug 7, 1989Filed: May 8, 2006Published: Sep 14, 2006
Est. expiryAug 7, 2009(expired)· nominal 20-yr term from priority
Inventors:Deborah RathjenRoger Aston
C07K 16/241A61K 47/6813C07K 2317/76A61P 35/00C07K 2317/75C07K 2317/622C07K 2317/21A61K 38/00C07K 2317/24A61K 47/68C07K 2319/00C07K 2317/55C07K 2317/73
66
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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 the antibody or fragment thereof is characterized in that when the antibody or fragment thereof binds TNF-α the induction of tumor fibrin deposition and induction of endothelial procoagulant activity are inhibited; and cytotoxicity, tumor regression and tumor receptor binding are unaffected; and,    wherein the antibody or fragment thereof binds to TNF-α such that the epitope defined by the topographic regions 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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  is prevented from binding to mature human TNF-α receptor.    
     
     
         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 . An antibody or fragment thereof according to  claim 2 , wherein the antibody is MAb 42, as produced by hybridoma cell line ECACC Accession No. 89080304.  
     
     
         7 . A composition comprising an isolated antibody or fragment thereof that binds to mature human TNF-α
 wherein the antibody or fragment thereof is characterized in that when the antibody or fragment thereof binds TNF-α the induction of tumor fibrin deposition and induction of endothelial procoagulant activity are inhibited; and cytotoxicity, tumor regression and tumor receptor binding are unaffected; and,    wherein the antibody or fragment thereof binds to TNF-α such that the epitope defined by the topographic regions 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 -Val 41 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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  is prevented from binding to mature human TNF-α receptor.    
     
     
         8 . A composition according to  claim 7  wherein the antibody is a monoclonal antibody.  
     
     
         9 . A composition according to  claim 7  or  8 , wherein the antibody is a humanized antibody.  
     
     
         10 . A composition according to  claim 7  or  8 , wherein the antibody is a chimeric antibody.  
     
     
         11 . A composition according to  claim 7  or  8 , wherein the antibody is a human antibody.  
     
     
         12 . A composition according to  claim 8 , wherein the antibody is MAb 42, as produced by hybridoma cell line ECACC Accession No. 89080304.  
     
     
         13 . An isolated single chain antibody that binds to mature human TNF-α
 wherein the antibody or fragment thereof is characterized in that when the antibody or fragment thereof binds TNF-α the induction of tumor fibrin deposition and induction of endothelial procoagulant activity are inhibited; and cytotoxicity, tumor regression and tumor receptor binding are unaffected; and,    wherein the antibody or fragment thereof binds to TNF-α such that the epitope defined by the topographic regions 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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  is prevented from binding to mature human TNF-α receptor.    
     
     
         14 . An antibody according to  claim 13 , wherein the antibody is a humanized antibody.  
     
     
         15 . An antibody according to  claim 13 , wherein the antibody is a chimeric antibody.  
     
     
         16 . An antibody according to  claim 13 , wherein the antibody is a human antibody.  
     
     
         17 . A composition comprising an isolated single chain antibody that binds to mature human TNF-α
 wherein the antibody or fragment thereof is characterized in that when the antibody or fragment thereof binds TNF-α the induction of tumor fibrin deposition and induction of endothelial procoagulant activity are inhibited; and cytotoxicity, tumor regression and tumor receptor binding are unaffected; and,    wherein the antibody or fragment thereof binds to TNF-α such that the epitope defined by the topographic regions 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 -Val 41 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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  is prevented from binding to mature human TNF-α receptor.    
     
     
         18 . A composition according to  claim 17 , wherein the antibody is a humanized antibody.  
     
     
         19 . A composition according to  claim 17 , wherein the antibody is a chimeric antibody.  
     
     
         20 . A composition according to  claim 17 , wherein the antibody is a human antibody.  
     
     
         21 . An isolated antibody or fragment thereof that binds to a topographical region of mature human TNF-α containing amino acid residues 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 -Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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 .  
     
     
         22 . An antibody or fragment thereof according to  claim 21 , wherein the antibody is a monoclonal antibody.  
     
     
         23 . An antibody of fragment thereof according to  claim 21 , wherein the antibody or fragment thereof inhibits the induction of tumor fibrin deposition.  
     
     
         24 . An antibody or fragment thereof according to  claim 21 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         25 . An antibody or fragment thereof according to  claim 21 , wherein the antibody or fragment thereof has no effect on cytotoxicity.  
     
     
         26 . An antibody or fragment thereof according to  claim 21 , wherein the antibody or fragment thereof has no effect on tumor regression.  
     
     
         27 . An antibody or fragment thereof according to  claim 21 , wherein the antibody or fragment thereof has no effect on tumor receptor binding.  
     
     
         28 . An antibody or fragment thereof according to any one of claims  21 - 27 , wherein the antibody is a humanized antibody.  
     
     
         29 . An antibody or fragment thereof according to any one of claims  21 - 27 , wherein the antibody is a chimeric antibody.  
     
     
         30 . An antibody or fragment thereof according to any one of claims  21 - 27 , wherein the antibody is a human antibody.  
     
     
         31 . A composition comprising an isolated antibody or fragment thereof that binds to a topographical region of mature human TNF-α containing amino acid residues 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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 .  
     
     
         32 . A composition according to  claim 31 , wherein the antibody is a monoclonal antibody.  
     
     
         33 . A composition according to  claim 31 , wherein the antibody or fragment thereof inhibits the induction of tumor fibrin deposition.  
     
     
         34 . A composition according to  claim 31 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         35 . A composition according to  claim 31 , wherein the antibody or fragment thereof has no effect on cytotoxicity.  
     
     
         36 . A composition according to  claim 31 , wherein the antibody or fragment thereof has no effect on tumor regression.  
     
     
         37 . A composition according to  claim 31 , wherein the antibody or fragment thereof has no effect on tumor receptor binding.  
     
     
         38 . A composition according to any one of claims  31 - 37 , wherein the antibody is a humanized antibody.  
     
     
         39 . A composition according to any one of claims  31 - 37 , wherein the antibody is a chimeric antibody.  
     
     
         40 . A composition according to any one of claims  31 - 37 , wherein the antibody is a human antibody.  
     
     
         41 . An isolated single chain antibody that binds to a topographical region of mature human TNF-α containing amino acid residues 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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 .  
     
     
         42 . An antibody according to  claim 41 , wherein the antibody inhibits the induction of tumor fibrin deposition.  
     
     
         43 . An antibody according to  claim 41 , wherein the antibody inhibits the induction of procoagulant activity.  
     
     
         44 . An antibody according to  claim 41 , wherein the antibody has no effect on cytotoxicity.  
     
     
         45 . An antibody according to  claim 41 , wherein the antibody has no effect on tumor regression.  
     
     
         46 . An antibody according to  claim 41 , wherein the antibody has no effect on tumor receptor binding.  
     
     
         47 . An antibody according to any one of claims  41 - 46 , wherein the antibody is a humanized antibody.  
     
     
         48 . An antibody according to any one of claims  41 - 46 , wherein the antibody is a chimeric antibody.  
     
     
         49 . An antibody according to any one of claims  41 - 46 , wherein the antibody is a human antibody.  
     
     
         50 . A composition comprising an isolated single chain antibody that binds to a topographical region of mature human TNF-α containing amino acid residues 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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 .  
     
     
         51 . A composition according to  claim 50 , wherein the antibody inhibits the induction of tumor fibrin deposition.  
     
     
         52 . A composition according to  claim 50 , wherein the antibody inhibits the induction of procoagulant activity.  
     
     
         53 . A composition according to  claim 50 , wherein the antibody has no effect on cytotoxicity.  
     
     
         54 . A composition according to  claim 50 , wherein the antibody has no effect on tumor regression.  
     
     
         55 . A composition according to  claim 50 , wherein the antibody has no effect on tumor receptor binding.  
     
     
         56 . A composition according to any one of claims  50 - 55 , wherein the antibody is a humanized antibody.  
     
     
         57 . A composition according to any one of claims  50 - 55 , wherein the antibody is a chimeric antibody.  
     
     
         58 . A composition according to any one of claims  50 - 55 , wherein the antibody is a human antibody.  
     
     
         59 . An isolated single domain antibody or fragment thereof that binds to mature human TNF-α
 wherein the antibody or fragment thereof is characterized in that when the antibody or fragment thereof binds TNF-α the induction of tumor fibrin deposition and induction of endothelial procoagulant activity are inhibited; and cytotoxicity, tumor regression and tumor receptor binding are unaffected; and,    wherein the antibody or fragment thereof binds to TNF-α such that the epitope defined by the topographic regions 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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  is prevented from binding to mature human TNF-α receptor.    
     
     
         60 . An antibody or fragment thereof according to  claim 59 , wherein the antibody is a humanized antibody.  
     
     
         61 . An antibody or fragment thereof according to  claim 59 , wherein the antibody is a chimeric antibody.  
     
     
         62 . An antibody or fragment thereof according to  claim 59 , wherein the antibody is a human antibody.  
     
     
         63 . A composition comprising an isolated single domain antibody or fragment thereof that binds to mature human TNF-α
 wherein the antibody or fragment thereof is characterized in that when the antibody or fragment thereof binds TNF-α the induction of tumor fibrin deposition and induction of endothelial procoagulant activity are inhibited; and cytotoxicity, tumor regression and tumor receptor binding are unaffected; and,    wherein the antibody or fragment thereof binds to TNF-α such that the epitope defined by the topographic regions 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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  is prevented from binding to mature human TNF-α receptor.    
     
     
         64 . A composition according to  claim 63 , wherein the antibody is a humanized antibody.  
     
     
         65 . A composition according to  claim 63 , wherein the antibody is a chimeric antibody.  
     
     
         66 . A composition according to  claim 63 , wherein the antibody is a human antibody.  
     
     
         67 . An isolated single domain antibody or fragment thereof that binds to a topographical region of mature human TNF-α containing amino acid residues 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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.    
     
     
         68 . An antibody of fragment thereof according to  claim 67 , wherein the antibody or fragment thereof inhibits the induction of tumor fibrin deposition.  
     
     
         69 . An antibody or fragment thereof according to  claim 67 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         70 . An antibody or fragment thereof according to  claim 67 , wherein the antibody or fragment thereof has no effect on cytotoxicity.  
     
     
         71 . An antibody or fragment thereof according to  claim 67 , wherein the antibody or fragment thereof has no effect on tumor regression.  
     
     
         72 . An antibody or fragment thereof according to  claim 67 , wherein the antibody or fragment thereof has no effect on tumor receptor binding.  
     
     
         73 . An antibody or fragment thereof according to any one of claims  67 - 72 , wherein the antibody is a humanized antibody.  
     
     
         74 . An antibody or fragment thereof according to any one of claims  67 - 72 , wherein the antibody is a chimeric antibody.  
     
     
         75 . An antibody or fragment thereof according to any one of claims  67 - 72 , wherein the antibody is a human antibody.  
     
     
         76 . A composition comprising an isolated single domain antibody or fragment thereof that binds to a topographical region of mature human TNF-α containing amino acid residues 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 , Val 49 -Val 50 -Pro 51 -Ser 52 -Glu 53 -Gly 54 -Leu 55 -Tyr 56 -Leu 57 -Ile 58 -Tyr 59 -Ser 60 -Gln 61 -Val 62 -Leu 63 -Phe 64 -Lys 65 -Gly 66 -Gln 67 -Gly 68 -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 , 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 , and 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 .  
     
     
         77 . A composition according to  claim 76 , wherein the antibody or fragment thereof inhibits the induction of tumor fibrin deposition.  
     
     
         78 . A composition according to  claim 76 , wherein the antibody or fragment thereof inhibits the induction of endothelial procoagulant activity.  
     
     
         79 . A composition according to  claim 76 , wherein the antibody or fragment thereof has no effect on cytotoxicity.  
     
     
         80 . A composition according to  claim 76 , wherein the antibody or fragment thereof has no effect on tumor regression.  
     
     
         81 . A composition according to  claim 76 , wherein the antibody or fragment thereof has no effect on tumor receptor binding.  
     
     
         82 . A composition according to any one of claims  76 - 81 , wherein the antibody is a humanized antibody.  
     
     
         83 . A composition according to any one of claims  76 - 81 , wherein the antibody is a chimeric antibody.  
     
     
         84 . A composition according to any one of claims  76 - 81 , wherein the antibody is a human antibody.

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