Method for Treating Liver Disorders with Receptor Associated Protein (RAP) Peptide-Fucosidase Inhibitor Conjugates

• US 20110189084A1
• Filed: 01/28/2011
• Published: 08/04/2011
• Est. Priority Date: 01/28/2010
• Status: Abandoned Application

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Biomarin Pharmaceutical Incorporated (Amgen Inc.)
• Inventors: Zankel, Todd C.
• Application Number:
  US13/016,135
• Publication Number:
  US 20110189084A1
• Time in Patent Office: Days
• US Class Current: 424/1.11
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/641 Branched, dendritic or hypercomb peptides
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates, in general, to methods and compositions for the treatment of liver disorders and liver tumors, such as hepatocellular carcinoma, with a peptide of the receptor associated protein (RAP) molecule conjugated to a fucosidase inhibitor.

Claims

1. A peptide conjugate comprising a receptor associated protein (RAP) peptide linked to a fucosidase inhibitor, the RAP peptide comprising a polypeptide sequence at least 80% homologous to amino acids 210-319 of RAP of SEQ ID NO:

1.

4. The peptide conjugate of any one of claims 1 to 3 wherein the fucosidase inhibitor is selected from the group consisting of L-deoxyfuconojirimycin (DFJ), beta-1-C-methyl deoxymannojirimycin, beta-1-C-ethyl deoxymannojirimycin, beta-1-C-phenyl deoxymannojirimycin and (3R,4R,5S,6S)-1-butyl-4,5,6-trihydroxyazepane-3-carboxylic acid (Faz).

5. The peptide conjugate of any one of claims 1 to 4, wherein the fucosidase inhibitor is conjugated via a peptide linker.

6. The peptide conjugate of claim 5, wherein the peptide linker is a lysine dendrimer.

7. The peptide conjugate of claim 6, wherein the peptide linker is a K4K2K lysine dendrimer.

8. The peptide conjugate of any one of claims 1 to 7, wherein at least 4 fucosidase inhibitors are conjugated per RAP peptide molecule.

9. The peptide conjugate of any one of claims 1 to 7, wherein at least 8 fucosidase inhibitors are conjugated per RAP peptide molecule.

10. A method for treating a liver tumor in a subject in need thereof comprising administering the peptide conjugate of any one of claims 1 to 9 in a therapeutically effective amount.

11. The method of claim 10, wherein the liver tumor is a result of hepatocellular carcinoma, hepatitis virus infection, cirrhosis, toxic liver damage, and hereditary hemochromatosis.

12. The method of claim 11, wherein the liver tumor is a result of hepatocellular carcinoma.

13. The method of any one of claims 10 to 12, wherein the treatment results in a decrease in liver tumor size in the subject.

14. The method of any one of claims 10 to 13, wherein the treatment results in a reduction of alpha-fetoprotein levels in blood of the subject compared to levels before treatment.

15. The method of claim any one of claims 10 to 14, wherein the peptide conjugate is administered intravenously.

16. The method of claim 15, wherein the peptide conjugate is administered via the hepatic artery.

17. The method of any one of claims 10 to 14, wherein the peptide conjugate is administered in combination with a second agent.

18. The method of claim 17, wherein the second agent is selected from the group consisting of a chemotherapeutic agent, a cytotoxic agent, a radioisotope, an anti-viral agent, an anti-fungal agent, an anti-inflammatory agent and an antibody.

19. The method of claim 18, wherein the chemotherapeutic agent is selected from the group consisting of doxorubicin and 5-fluorouracil.

20. The method of claim 18, wherein the second agent is a cytotoxic agent.

21. The method of claim 20, wherein the cytotoxic agent is selected from the group consisting of mechlorethamine hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, thiotepa, carmustine, lomustine, dacarbazine and streptozocin.

22. The method of claim 18, wherein the second agent is a radioisotope.

23. The method of claim 22, wherein the radioisotope is selected from the group consisting of ¹³¹I, ¹²⁵I, ¹¹¹In, ⁹⁰Y, ⁶⁷Cu, ¹²⁷Lu, ²¹²Bi, ²¹³Bi, ²⁵⁵Fm, ¹⁴⁹Tb, ²²³Rd, ²¹³Pb, ²¹²Pb, ²¹¹At, ⁸⁹Sr, ¹⁵³Sm, ¹⁶⁶Ho, ²²⁵Ac, ¹⁸⁶Re, ⁶⁷Ga, ⁶⁸Ga and ^99mTc.

24. The method of claim 18, wherein the liver tumor is associated with hepatitis virus infection, and the second agent is an antiviral agent.

2. A peptide conjugate comprising a receptor associated protein (RAP) peptide linked to a fucosidase inhibitor, the RAP peptide comprising a polypeptide at least 80% homologous to the amino acid sequence set out in SEQ ID NO:

2.

3. The peptide conjugate of claim 2, wherein the RAP peptide comprises the amino acid sequence set out in SEQ ID NO:

2.