MODIFIED CYTOKINES FOR USE IN CANCER THERAPY
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.