Colon and pancreas cancer peptidomimetics
The invention relates to a peptidomimetic of an NPC-1 epitope on the MUC5AC protein which is differentially expressed in pancreatic and colorectal cancer, and diagnostic and therapeutic usages. Further, antibodies that selectively bind the NPC-1 epitope peptidomimetics and may be used in diagnostic and therapeutic methods.
1. An isolated polypeptide comprising a polypeptide having at least 90% identity to the amino acid sequence of SX 1 PX 2 DX 3 FRYX 4 NX 5 (SEQ ID NO: 1), wherein X 1 is L; X 2 is E or D; X 3 is Y or W; X 4 is T or I and X 5 is Q or Y; SX 1 PX 2 DX 3 FRYX 4 NX 5 K (SEQ ID NO: 2), wherein X 1 is L; X 2 is E or D; X 3 is Y or W; X 4 is T or I and X 5 is Q or Y; SLPDDWFRYINY (SEQ ID NO: 5); YSHSSLPDDWFRYINYGGGS (SEQ ID NO:20); or SLPDDWFRYINYSLPDDWFRYINY (SEQ ID NO:24).
2. The isolated polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of SX 1 PX 2 DX 3 FRYX 4 NX 5 (SEQ ID NO: 1), wherein X 1 is for L; X 2 is E or D; X 3 is Y or W; X 4 is T or I and X 5 is Q or Y; SX 1 PX 2 DX 3 FRYX 4 NX 5 K (SEQ ID NO: 2), wherein X 1 is for L; X 2 is E or D; X 3 is Y or W; X 4 is T or I and X 5 is Q or Y; SLPDDWFRYINY (SEQ ID NO: 5); YSHSSLPDDWFRYINYGGGS (SEQ ID NO:20); or SLPDDWFRYINYSLPDDWFRYINY (SEQ ID NO:24).
3. A fusion protein comprising the polypeptide of claim 1 .
4. The fusion protein of claim 3 , wherein said fusion protein comprises a detectable label covalently or non-covalently directly or indirectly attached thereto.
5. The fusion protein of claim 4 , wherein the detectable label is selected from the group consisting of polyHis tag, FLAG tag, MBP, GST protein, and GFP.
6. A conjugate comprising the polypeptide of claim 1 , directly or indirectly, conjugated to a cytotoxic agent, a therapeutic agent, label, carbohydrate, carrier, immunoglobulin or immunoglobulin fragment, or an immunomodulatory agent.
7. The conjugate of claim 6 , wherein said carbohydrate is mannose, fucose, glucose, GlcNAs, or maltose.
8. The conjugate of claim 6 , wherein said carrier is Keyhole Limpet Hemocyanin (KLH), diphtheria toxoid, cholera toxoid, ovalbumin, bovine serum albumin (BSA), Pseudomonas exoprotein A, or microbial outer membrane proteins (OMPS).
9. The conjugate of claim 6 , wherein said label is a chemiluminescent label, paramagnetic label, MRI contrast agent, fluorescent label, bioluminescent label, or radioactive label.
10. The conjugate of claim 9 , wherein said paramagnetic label is aluminum, manganese, platinum, oxygen, lanthanum, lutetium, scandium, yttrium, or gallium.
11. The conjugate of claim 6 , wherein the cytotoxic agent is a moiety that inhibits DNA, RNA, or protein synthesis, a radionuclide, or ribosomal inhibiting protein.
12. The conjugate of claim 11 , wherein the cytotoxic agent is 212 Bi, 131 I, 188 Re, 90 Y, vindesine, methotrexate, adriamycin, cisplatin, pokeweed antiviral protein, Pseudomonas exotoxin A, ricin, diphtheria toxin, ricin A chain, or cytotoxic phospholipase enzyme.
13. A composition comprising the polypeptide of claim 1 .
14. The composition of claim 13 , further comprising a pharmaceutically acceptable carrier, diagnostically acceptable carrier, adjuvant, or excipient.
15. A composition for treating cancer comprising an effective amount of the polypeptide of claim 1 .
16. A diagnostic kit comprising the polypeptide of claim 1 .
17. A method for treating cancer comprising administering an effective amount of a polypeptide of claim 1 to a subject in need thereof, thereby eliciting an immune response against said polypeptide.
18. The method of claim 17 , wherein said polypeptide is administered in combination with another antibody, a lymphokine, or a hematopoietic growth factor.
19. The method of claim 18 , wherein said agent is administered simultaneously or sequentially with the antibody.
20. The method of claim 17 , wherein said cancer is lung, breast, ovarian, stomach, pancreas, uterine, esophageal, colorectal, or liver cancer.
21. The method of claim 20 , wherein said cancer is a stage 1, 2, 3 or 4 cancer.
22. The method of claim 20 , wherein said cancer has metastasized.
23. The method of claim 17 , wherein the patient expresses detectable levels of a NPC-1 epitope.
24. The method of claim 23 , wherein the antigen is detected in a tumor biopsy sample or in the blood, stool, urine, or lymph fluid.
25. A method for activating dendritic cells comprising removing dendritic cells from a patient, contacting cells ex vivo with an effective amount of a polypeptide of claim 1 , and reintroducing activated the dendritic cells into said patient.
26. A method for activating antigen-specific immunity comprising administering to a patient an effective amount of a polypeptide of claim 1 .