Compositions and methods for treatment of angiogenesis in pathological lesions

Abstract

Treatment of lesions of pathological angiogenesis, especially tumors, rheumatoid arthritis, diabetic retinopathy, age-related muscular degeneration, and angiomas. A conjugate is used comprising a molecule that exerts a biocidal or cytotoxic effect on target cells in the lesions and an antibody directed against an extracellular matrix component which is present in such lesions. The antibody may be directed against fibronectin-2 (IL-2), doxorubicin, interleukin-12 (IL-12), Interferon-γ (IFN-γ), Tumor Necrosis Factor α (TNFα) or Tissue Factor protein (which may be truncated).

1 . A conjugate of (i) a specific binding member specific for an extracellular matrix component which is present in angiogenesis in pathological lesions, and (ii) a molecule selected from the group consisting of: interleukin-2 (IL-2), interleukin-12 (IL-12), Tumor Necrosis Factor α (TNFα), Interferon-γ (IFN-γ), Tissue Factor protein and doxorubicin, with the proviso that where said molecule is Tissue Factor protein the specific binding member comprises one or more VH and/or VL domains of antibody L19 and/or competes with antibody L19 for binding to fibronectin ED-B, the amino acid sequences of the VH and VL domains of antibody L19 being disclosed in Pini et al. (1998) J. Biol. Chem. 273: 21769-21776. 
     
     
         2 . A conjugate according to  claim 1  wherein said specific binding member is specific for an extracellular matrix component which is present in angiogenesis in tumors. 
     
     
         3 . A conjugate according to  claim 2  wherein said extracellular matrix component is fibronectin ED-B. 
     
     
         4 . A conjugate of (i) a specific binding member specific for an extracellular matrix component which is present in angiogenesis in pathological lesions, and (ii) a molecule which exerts a biocidal or cytotoxic effect on target cells by cellular interaction, characterised in that the specific binding member comprises one or more VH and/or VL domains of antibody L19 and/or competes with antibody L19 for binding to fibronectin ED-B, the amino acid sequences of the VH and VL domains of antibody L19 being disclosed in Pini et al. (1998) J. Biol. Chem. 273: 21769-21776. 
     
     
         5 . A conjugate according to  claim 4  wherein said molecule is selected from the group consisting of interleukin-2 (IL-2), interleukin-12 (IL-12), Tumor Necrosis Factor α (TNFα), Interferon-γ (IFN-γ), Tissue Factor protein and doxorubicin. 
     
     
         6 . A conjugate according to  claim 1  wherein the specific binding member is a single-chain. 
     
     
         7 . A conjugate according to  claim 6  which comprises a fusion protein of (a) said specific binding member and (b) said molecule or a polypeptide chain of said molecule that associates with a second polypeptide chain of said molecule. 
     
     
         8 . A conjugate according to  claim 1  wherein the specific binding member is multi-chain. 
     
     
         9 . A conjugate according to  claim 8  which comprises (a) a fusion protein of a first chain of the specific binding member and a chain of the molecule and (b) a fusion protein of a second chain of the specific binding member and a chain of the molecule. 
     
     
         10 . A conjugate according to  claim 1  for use in a method of treatment of the human or animal body by therapy. 
     
     
         11 . A conjugate according to  claim 10  for use in a method of treatment of angiogenesis in pathological lesions. 
     
     
         12 . A conjugate according to  claim 11  for use in a method of treatment of a tumor. 
     
     
         13 . Use of a conjugate according to  claim 1  in the manufacture of a medicament for treatment of angiogenesis in pathological lesions. 
     
     
         14 . Use according to  claim 13  wherein said medicament is for treatment of a tumor. 
     
     
         15 . A method of treating angiogenesis in pathological lesions, the method comprising administering a conjugate according to  claim 1 . 
     
     
         16 . A method according to  claim 15  comprising treating a tumor. 
     
     
         17 . A nucleic acid encoding a conjugate of:
 (i) an antibody or antibody fragment specific for fibronectin ED-B, and   (ii) interleukin-2 (IL-2) or tumor necrosis factor-alpha (TNF-α).   
     
     
         18 . A host cell comprising a nucleic acid of  claim 17 . 
     
     
         19 . A nucleic acid of  claim 17  wherein (ii) is IL-2. 
     
     
         20 . A host cell comprising a nucleic acid of  claim 19 .