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 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 1 (ECACC Accession No. 89080301) 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, cytotoxicity, tumor regression and tumor receptor binding to TNF-α and induction of tumor fibrin deposition are inhibited. 
   
   
       2 . The antibody or fragment thereof according to  claim 1 , wherein the antibody or fragment thereof competitively inhibits the binding of MAb 1 (ECACC Accession No. 89080301) 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  claim 1  wherein the antibody is a humanized antibody. 
   
   
       5 . 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 1 (ECACC Accession No. 89080301) for specific binding to mature human TNF-αand, wherein when the antibody or fragment thereof binds mature human TNF-α, the induction of endothelial procoagulant activity, cytotoxicity, tumor regression and tumor receptor binding to TNF-α and induction of tumor fibrin deposition are inhibited. 
   
   
       6 . The composition according to  claim 5 , wherein the antibody or fragment thereof competitively inhibits the binding of MAb 1 (ECACC Accession No. 89080301) to mature human TNF-α, where comparative binding specificity is determined by antibody-antibody competition assays in the presence of mature human TNF-α. 
   
   
       7 . The composition according to  claim 6  wherein the antibody is a monoclonal antibody. 
   
   
       8 . The composition according to  claim 5  wherein the antibody is a humanized antibody. 
   
   
       9 . 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 1 (ECACC Accession No. 89080301). 
   
   
       10 . The antibody or fragment thereof according to  claim 9 , wherein the antibody is a monoclonal antibody. 
   
   
       11 . The antibody or fragment thereof according to  claim 9 , where comparative binding specificity between the antibody or fragment thereof and MAb 1 (ECACC Accession No. 89080301) is determined by antibody-antibody competition assays in the presence of mature human TNF-α.