HMGN2 peptides and related molecules that selectively home to tumor blood vessels and tumor cells
View Patent ↗The present invention provides a conjugate which contains a therapeutic moiety linked to a homing molecule that selectively homes to tumor blood vessels and tumor cells and that specifically binds the receptor bound by peptide KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK (SEQ ID NO: 9). Methods of directing a conjugate of the invention to tumor blood vessels and tumor cells and of using a conjugate to treat cancer also are provided.
1. A conjugate, comprising a therapeutic moiety linked to a homing peptide comprising the amino acid sequence KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK (SEQ ID NO: 9) or PQRRSARLSA (SEQ ID NO: 11), said peptide having a length of less than 70 residues, wherein said peptide specifically binds nucleolin on the surface of a tumor cell or selectively homes to tumor blood vessels or tumor cells.
2. The conjugate of claim 1 , wherein said homing peptide comprises the amino acid sequence SEQ ID NO: 9.
3. The conjugate of claim 1 , wherein said homing peptide comprises the amino acid sequence SEQ ID NO: 11.
4. The conjugate of claim 1 , wherein said peptide has a length of less than 60 residues.
5. The conjugate of claim 1 , wherein said peptide has a length of less than 50 residues.
6. The conjugate of claim 1 , wherein said peptide has a length of less than 45 residues.
7. The conjugate of claim 1 , wherein said peptide has a length of less than 40 residues.
8. The conjugate of claim 1 , wherein said peptide has a length of less than 35 residues.
9. The conjugate of claim 1 , wherein said peptide specifically binds nucleolin on the surface of a tumor cell.
10. The conjugate of claim 1 , wherein said peptide selectively homes to tumor blood vessels.
11. The conjugate of claim 1 , wherein said peptide selectively homes to tumor cells.
12. The conjugate of claim 1 , wherein said therapeutic moiety is an anti-angiogenic agent.
13. The conjugate of claim 1 , wherein said therapeutic moiety is a cytotoxic agent.
14. The conjugate of claim 13 , wherein said cytotoxic agent targets a DNA-associated process.
15. The conjugate of claim 14 , wherein said cytotoxic agent is selected from the group consisting of an alkylating agent, an anti-tumor antibiotic and a sequence-selective agent.
16. The conjugate of claim 14 , wherein said cytotoxic agent is selected from the group consisting of cyclophosphamide, melphalan, mitomycin C, bizelesin, cisplatin, doxorubicin, etoposide, mitoxantrone, SN-38, Et-743, actinomycin D, bleomycin and TLK286.
17. A multivalent conjugate, comprising at least two homing peptides linked to a moiety, wherein each of said peptides independently comprise the amino acid sequence KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK (SEQ ID NO: 9) or PQRRSARLSA (SEQ ID NO: 11), said peptides having a length of less than 70 residues, wherein said peptides specifically bind nucleolin on the surface of a tumor cell or selectively home to tumor blood vessels or tumor cells.
18. The multivalent conjugate of claim 17 , comprising at least ten of said homing peptides linked to a moiety.
19. The multivalent conjugate of claim 18 , comprising at least 100 homing peptides linked to a moiety.
20. The multivalent conjugate of claim 17 , wherein said homing peptides comprise the amino acid sequence SEQ ID NO: 9.
21. The multivalent conjugate of claim 17 , wherein said homing peptides comprise the amino acid sequence SEQ ID NO: 11.
22. The multivalent conjugate of claim 17 , wherein at least one of said homing peptides independently has a length of less than 60 residues.
23. The multivalent conjugate of claim 17 , wherein at least one of said homing peptides independently has a length of less than 50 residues.
24. The multivalent conjugate of claim 17 , wherein at least one of said homing peptides independently has a length of less than 45 residues.
25. The multivalent conjugate of claim 17 , wherein at least one of said homing peptides independently has a length of less than 40 residues.
26. The multivalent conjugate of claim 17 , wherein at least one of said homing peptides independently has a length of less than 35 residues.
27. The multivalent conjugate of claim 17 , wherein said peptides specifically bind nucleolin on the surface of a tumor cell.
28. The multivalent conjugate of claim 17 , wherein said peptides selectively home to tumor blood vessels.
29. The multivalent conjugate of claim 17 , wherein said peptides selectively home to tumor cells.
30. The multivalent conjugate of claim 17 , wherein said moiety is a therapeutic moiety.
31. The multivalent conjugate of claim 30 , wherein said therapeutic moiety is a phage.
32. A conjugate, comprising a detectable label linked to a homing peptide comprising the amino acid sequence KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK (SEQ ID NO: 9) or PQRRSARLSA (SEQ ID NO: 11), said peptide having a length of less than 70 residues, wherein said peptide specifically binds nucleolin on the surface of a tumor cell or selectively homes to tumor blood vessels or tumor cells.
33. The conjugate of claim 32 , wherein said homing peptide comprises the amino acid sequence SEQ ID NO: 9.
34. The conjugate of claim 32 , wherein said homing peptide comprises the amino acid sequence SEQ ID NO: 11.
35. The conjugate of claim 32 , wherein said peptide has a length of less than 60 residues.
36. The conjugate of claim 32 , wherein said peptide has a length of less than 50 residues.
37. The conjugate of claim 32 , wherein said peptide has a length of less than 45 residues.
38. The conjugate of claim 32 , wherein said peptide has a length of less than 40 residues.
39. The conjugate of claim 32 , wherein said peptide has a length of less than 35 residues.
40. The conjugate of claim 32 , wherein said peptide specifically binds nucleolin on the surface of a tumor cell.
41. The conjugate of claim 32 , wherein said peptide selectively homes to tumor blood vessels.
42. The conjugate of claim 32 , wherein said peptide selectively homes to tumor cells.
43. The conjugate of claim 32 , wherein said detectable label is a radionuclide.
44. The conjugate of claim 32 , wherein said detectable label is a fluorescent label.