Modified cytokines for use in cancer therapy
View Patent ↗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 TNF and a ligand of the CD13 receptor, wherein the ligand is a peptide comprising the NGR motif.
2. A conjugation product as claimed in claim 1 , wherein said TNF is TNFα or TNFβ.
3. A conjugation product as claimed in claim 1 , 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), CNGRCG (SEQ ID NO:18), cyclo CVLNGRMEC (SEQ ID NO:11), linear CNGRC (SEQ ID NO:13), and cyclic CNGRC (SEQ ID NO:12).
4. A conjugation product according to claim 1 , wherein the TNF is linked to the peptide through a spacer.
5. A conjugation product according to claim 4 , wherein said peptide is linear or cyclic CNGRC and wherein said peptide is linked to TNF through the spacer G.
6. A conjugation product according to claim 4 , wherein:
(a) the peptide is linear or cyclic CNGRC; and
(b) the peptide is linked to the amino terminal of TNF through the spacer G.
7. A conjugation product as claimed in claim 1 , wherein TNF is derivatized with polyethylene glycol or an acyl residue.
8. A conjugation product as claimed in claim 1 , wherein TNF is further conjugated with a compound selected from the group consisting of an antibody, an 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.
9. A conjugation product according to claim 8 , wherein TNF is conjugated to both a peptide comprising the NGR motif and the compound on different subunits.
10. A pharmaceutical composition comprising an effective amount of a conjugation product as claimed in claim 1 , together with pharmaceutically acceptable carriers and excipients.
11. A composition as claimed in claim 10 , in the form of an injectable solution or suspension or a liquid for infusions.
12. A composition as claimed in claim 11 , in the form of liposomes.
13. A cDNA encoding for TNF and bearing a 5′ or 3′ contiguous sequence encoding a ligand of the CD13 receptor, wherein the ligand is a peptide comprising the NGR motif.
14. A cDNA according to claim 13 , wherein said peptide comprising the NGR motif is a peptide selected from the group consisting of CNGRCVSGCAGRC (SEQ ID NO:8), NGRAHA (SEQ ID NO:9), GNGRG (SEQ ID NO:10), CNGRCG (SEQ ID NO:18), cyclo CVLNGRMEC (SEQ ID NO:11), linear CNGRC (SEQ ID NO:13), and cyclic CNGRC (SEQ ID NO:12).
15. A cDNA encoding a conjugation product as defined in claim 4 .
16. A cDNA encoding a conjugation product as defined in claim 5 .
17. A method of treating a patient having a tumor that expresses CD 13 in angiogenic endothelium comprising administering the conjugation product of claim 1 to said patient.
18. The method of claim 17 , comprising additionally administering other antitumor agents.