Compositions and methods of use of targeting peptides for diagnosis and therapy of human cancer
The present invention concerns compositions comprising and methods of identification and use of targeting peptides selective for cancer tissue, particularly prostate or ovarian cancer tissue. The method may comprise identifying endogenous mimeotopes of such peptides, such as GRP78, IL-11Rα and hsp90. Antibodies against such targeting peptides or their mimeotopes may be used for detection, diagnosis and/or staging of prostate or ovarian cancer. In other embodiments, the compositions and methods concern a novel type of gene therapy vector, known as adeno-associated phage (AAP). AAP are of use for targeted delivery of therapeutic agents to particular tissues, organs or cell types, such as prostate or ovarian cancer. In still other embodiments, targeting peptides selective for low-grade lipomas may be used for detection, diagnosis and targeted delivery of therapeutic agents.
1. An isolated peptide of 50 amino acids or less in size, comprising an IL-11Rα targeting motif having the amino acid sequence of any of SEQ ID NO:5 through SEQ ID NO:29, SEQ ID NO:34, or SEQ ID NO:37, or an isolated peptide of 40 amino acids or less in size comprising an IL-11Rα targeting motif having the amino acid sequence of SEQ ID NO:35, wherein the peptide is conjugated or fused to a second agent.
2. The peptide of claim 1 , wherein the second agent is a polypeptide.
3. The peptide of claim 1 , wherein the second agent is a therapeutic or diagnostic agent.
4. The peptide of claim 3 , wherein the therapeutic agent is a drug, a chemotherapeutic agent, a radioisotope, a pro-apoptosis agent, an anti-angiogenic agent, a survival factor, an anti-apoptotic agent, an enzyme, a hormone, a hormone antagonist, a cytokine, a cytotoxic agent, a cytocidal agent, a cytostatic agent, a growth factor, a peptide, a protein, an antibiotic, an antibody, a Fab fragment of an antibody, a hormone antagonist, a nucleic acid, an antigen, a virus, a bacteriophage, a bacterium, a liposome, a microparticle, a microcapsule, a magnetic bead, a microdevice, a yeast cell, a mammalian cell, a cell or an expression vector.
5. The peptide of claim 4 , wherein the second agent is an anti-angiogenic agent selected from the group consisting of thrombospondin, angiostatin, pigment epithelium-derived factor, angiotensin, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin 12, platelet factor 4, IP-10, Gro-β, thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CM101, Marimastat, pentosan polysulphate, angiopoietin 2 (Regeneron), interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, Linomide, thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, Docetaxel, polyamines, a proteasome inhibitor, a kinase inhibitor, a signaling peptide, accutin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4, and minocycline.
6. The peptide of claim 4 , wherein the second agent is a pro-apoptosis agent selected from the group consisting of gramicidin, magainin, mellitin, defensin, cecropin, (KLAKLAK) 2 (SEQ ID NO:1), (KLAKKLA) 2 (SEQ ID NO:2), (KAAKKAA) 2 (SEQ ID NO:3) and (KLGKKLG) 3 (SEQ ID NO:4).
7. The peptide of claim 6 , wherein the pro-apoptosis agent is (KLAKLAK) 2 (SEQ ID NO:1).
8. The peptide of claim 4 , wherein the second agent is a cytokine selected from the group consisting of interleukin 1 (IL-1), IL-2, IL-5, IL-10, IL-12, IL-18, interferon-γ (IF-γ), IF α, IF-β, tumor necrosis factor-α (TNF-α), or GM-CSF (granulocyte macrophage colony stimulating factor).
9. The peptide of claim 1 , wherein the second agent is a molecular complex.
10. The peptide of claim 9 , wherein the complex is a virus, a bacteriophage, a bacterium, a liposome, a microparticle, a microcapsule, a magnetic bead, a yeast cell, a mammalian cell or a cell.
11. The peptide of claim 10 , wherein the complex is a virus or a bacteriophage.
12. The peptide of claim 11 , wherein the virus is chosen from the group consisting of adenovirus, retrovirus adeno-associated virus (AAV), and AAVP.
13. The peptide of claim 3 , wherein the second agent is a diagnostic agent.
14. The peptide of claim 13 , wherein the diagnostic agent is an imaging agent.
15. The peptide of claim 14 , wherein the imaging agent, wherein the imaging agent comprises chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) erbium (III), lanthanum (III), gold (III), lead (II), or bismuth (III).
16. The peptide of claim 13 , wherein the agent comprises a radioisotope, and the radioisotope is astatine 211 , 14carbon, 51 chromium, 36 chlorine, 57 cobalt, 58 cobalt, copper 67 , 152 Eu, gallium 67 , 3 hydrogen, iodine 123 , iodine 125 , iodine 131 , indium 111 , 59 iron, 32 phosphorus, phosphorus, rhenium 186 , rhenium 188 , 75 selenium, 35 sulphur, technicium 99m or yttrium 90 .
17. The peptide of claim 1 , wherein said peptide is 25 amino acids or less in size.
18. The peptide of claim 17 , wherein said peptide is 10 amino acids or less in size.
19. The peptide of claim 17 , wherein said peptide is cyclic.
20. The peptide of claim 18 , wherein said peptide is 7 amino acids or less in size.
21. The peptide of claim 1 , wherein the peptide comprises an amino acid sequence selected from SEQ ID NO:34 or SEQ ID NO:37.
22. The peptide of claim 1 , further defined as comprising SEQ ID NO:5 and SEQ ID NO: 1.
23. A pharmaceutical composition comprising the peptide of claim 1 or 22 , in a pharmaceutically acceptable medium.