Tumour necrosis factor binding ligands

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.

We claim:  
     
         1 . A ligand capable of binding to human TNF, the ligand being characterised in that when it binds to TNF the in vivo tumour regression activity of the TNF is enhanced.  
     
     
         2 . A ligand capable of binding to human TNF, the ligand being characterised in that when it binds to TNF the in vivo tumour regression activity of the TNF is enhanced; the ligand binding to the TNF such that the epitope of the TNF defined by the topographic region of residues 1-30, 117-128 and 141-153 is substantially prevented from binding to naturally occurring biologically active ligands.  
     
     
         3 . A ligand which binds to human TNF in the topographic regions of residues 1-30, 117-128 and 141-153.  
     
     
         4 . A ligand as claimed in  claim 3  in which the ligand binds to human TNF in the topographic regions of residues 1-26, 117-128 and 141-153.  
     
     
         5 . A ligand as claimed in  claim 1  in which the ligand is selected from the group consisting of antibodies, F(ab) fragments, single domain antibodies (dABs) restructured antibodies, single chain antibodies and serum binding proteins.  
     
     
         6 . A ligand as claimed in  claim 5  in which the ligand is a monoclonal antibody or F(ab) fragment thereof.  
     
     
         7 . A ligand as claimed in  claim 1  in which the ligand is MAb 32 (ECACC 89080302).  
     
     
         8 . A composition comprising TNF in combination with a ligand as claimed in  claim 1  in which the ligand is bound to the TNF.