Modified cytokines for use in cancer therapy

Abstract

Cytokine derivatives capable of homing the tumoral vessels and the antigen presenting cells and the use thereof as antitumoral agents.

1 . A conjugation product between a cytokine selected from TNF or IFNγ and a ligand of the CD13 receptor. 
     
     
         2 . A conjugation product as claimed in  claim 1 , wherein said cytokine is TNFα or TNF β. 
     
     
         3 . A conjugation product as claimed in  claim 1 , wherein the ligand of the CD13 receptor is selected from the group consisting of antibodies or active fragments thereof, peptides or peptido-mimetics. 
     
     
         4 . A conjugation product as claimed in  claim 3 , wherein said ligand is a peptide containing the NGR motif. 
     
     
         5 . A conjugation product as claimed in  claim 4 , wherein said peptide is selected from the group consisting of CNGRCVSGCAGRC (SEQ ID NO: 8), NGRAHA (SEQ ID NO: 9), GNGRG (SEQ ID NO: 10), cycloCVLNGRMEC (SEQ ID NO: 11), linear CNGRC (SEQ ID NO: 13), and cyclic CNGRC (SEQ ID NO: 12). 
     
     
         6 . A conjugation product as claimed in  claim 1 , wherein the cytokine is derivatized with polyethylene glycol or an acyl residue. 
     
     
         7 . A conjugation product as claimed in  claim 1 , wherein the cytokine is further conjugated with a compound selected from the group consisting of an antibody, and antibody fragment, and biotin, wherein said antibody or fragment thereof is directed to a compound selected from the group consisting of a tumoral antigen, a tumoral angiogenic marker, and a component of the extracellular matrix. 
     
     
         8 . A conjugation product according to  claim 7 , wherein the cytokine is TNF and is conjugated to both a CD13 ligand and a compound selected from the group consisting of an antibody, and antibody fragment, and biotin. 
     
     
         9 . A cDNA encoding for a cytokine selected from TNF and IFNγ bearing a 5′ or 3′ contiguous sequence encoding a CD13 ligand. 
     
     
         10 . A cDNA according to  claim 9 , wherein said CD13 ligand is a peptide selected from the group consisting of CNGRCVSGCAGRC (SEQ ID NO: 8), NGRAHA (SEQ ID NO: 9), GNGRG (SEQ ID NO: 10), cycloCVLNGRMEC (SEQ ID NO: 11), linear CNGRC (SEQ ID NO: 13), and cyclic CNGRC (SEQ ID NO: 12). 
     
     
         11 . A vector for gene therapy containing the cDNA of  claim 9 . 
     
     
         12 . Pharmaceutical composition comprising an effective amount of a conjugation product as claimed in  claim 1 , together with pharmaceutically acceptable carriers and excipients. 
     
     
         13 . A composition as claimed in  claim 12 , in the form of an injectable solution or suspension or a liquid for infusions. 
     
     
         14 . A composition as claimed in  claim 12 , in the form of liposomes. 
     
     
         15 . A method of treating or diagnosing a cancer patient comprising administering the conjugation product of  claim 1 . 
     
     
         16 . The method of  claim 15 , comprising additionally administering other antitumor agents or diagnostic tumor-imaging compounds.