Use Of Low Doses Of Oligonucleotides Antisense To TGF-Beta, VEGF, Interleukin-10, C-Jun, C-Fos Or Prostaglandin E2 Genes In The Treatment Of Tumors

• US 20090306176A1
• Filed: 05/04/2006
• Published: 12/10/2009
• Est. Priority Date: 05/05/2005
• Status: Active Grant

• Current Assignee: Antisense Pharma GmbH
• Original Assignee: Antisense Pharma GmbH
• Inventors: Schlingensiepen, Reimar, Schlingensiepen, Karl-Hermann
• Granted Patent: US 8,097,597 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

This invention is related to the use of at least one oligonucleotide with a length of from about 8 to about 30 nucleotide building blocks for manufacturing a pharmaceutical preparation for the prophylaxis and/or the treatment of diseases, that are modulated by TGF-beta2, TGF-beta1, TGF-beta3, VEGF, interleukin-10, c-jun, c-fos, and/or prostaglandin E2 in a mammal, wherein said oligonucleotide hybridizes with a messenger RNA of a TGF-beta2, TGF-beta1, TGF-beta3, VEGF, interleukin-10, c-jun, c-fos and/or prostaglandin E2 gene and wherein said preparation comprises said oligonucleotide in a concentration of about 1 microM to about 25 microM.

Claims

1-14. -14. (canceled)

15. A method of treating a patient suffering from a neoplasm comprising the step of administering a pharmaceutical composition comprising an oligonucleotide having the sequence identified in the sequence listing as Seq. ID No. 5 in a concentration of about 5 to about 12.5 μ

M at a flow rate of about 2 μ

l/min to about 10 μ

l/min for a time of about 4 to about 7 days.

16. The method of claim 15 wherein the oligonucleotide has one or more chemical modifications at the sugar, the base moiety and/or the internucleoside linkages.

17. The method of claim 15, wherein at least one linkage between two consecutive nucleotide building blocks is a phosphorothioate or a methylphosphonate.

18. A method of treating a patient suffering from a disease that is modulated by TGF-beta2, TGF-beta1, TGF-beta3, VEGF, interleukin-10, c-jun, c-fos, and/or prostaglandin E2 comprising the step of administering a pharmaceutical preparation comprising an oligonucleotide with the length of from 8 to 30 nucleotide building blocks in a concentration of about 1 μ

M to about 25 μ

M wherein said oligonucleotide hybridizes with a messenger RNA of a TGF-beta2, TGF-beta1, TGF-beta3, VEGF, interleukin-10, c-jun, c-fos and/or prostaglandin E2 gene.

19. The method of claim 18, wherein the pharmaceutical preparation comprises the oligonucleotide in a concentration of about 1 microM to about 15 microM, more preferred of about 2.5 microM to about 14 microM, even more preferably of about 4 microM to about 13 microM, even more preferably of about 5 microM to 12.5 microM, most preferably of about 20 microM, 10 microM or 5 microM.

20. The method of claim 18, wherein at least one linkage between two consecutive nucleotide building blocks is a phosphorothioate or a methylphosphonate.

21. The method of claim 18, wherein said oligonucleotide is a single stranded oligonucleotide.

22. The method of claim 18, wherein at least one nucleotide building block comprises a nucleotide with a 2′

-modification of the ribonucleotide, in a preferred embodiment the 2′

-modification is a methoxy- or a methoxyethyloxy-group.

23. The method of claim 18, wherein the oligonucleotide is one of the sequences identified in the sequence listing with SEQ ID NOs 1 to 93, most preferred are sequences with SEQ ID NOs 5 and/or 2.

24. The method of claim 18 for the prophylaxis and/or the treatment of a disease selected from the group consisting of cancer, metastases, disease of the nervous system, and immunosuppression.

25. The method of claim 18, wherein said preparation is used for administering an infusion into a tissue, a tumor, or a body cavity.

26. The method of claim 25, wherein said tissue is selected from the group of bile duct, bladder, bone, bone marrow, brain, breast, colon, endometrium, epithelium, gall, gall bladder, head, head and neck, heart, intestine, joints, kidney, larynx, liver, lung, lymphatic node, lymphatic vessels, muscle, oesophagus, ovary, pancreas, prostate, rectum, urinary duct, skin and its layers, spleen, stomach, testis, thymus, thyroid, tonsil, or uterus or the tumor is selected from the group of adamantinoma of long bones, adenoma, ameloblastoma, astrocytoma, bile duct carcinoma, bladder carcinoma, bone carcinoma, bone marrow carcinoma, brain tumor, breast cancer, bronchogenic carcinoma, cervical cancer, cervical cancer of uteri, chondroma, chorio carcinoma, colon carcinoma, colorectal carcinoma, cystadeno carcinoma, embryonal carcinoma, endometrial cancer, ependymoma, esophageal cancer, fibroma, follicular thymoma, gallbladder cancer, gastric cancer, glioblastoma, glioma, head and neck cancer, cancer of the heart, hepatocellular cancer, cancer in the intraperitoneal cavity, cancer of the intestine, carcinoma of the kidney, larynx cancer, lipoma, liver carcinoma, lung carcinoma, cancer of the lymphatic node, cancer of the lymphatic vessels, malignant glioma, mesenthelioma, menigioma, medullary carcinoma, myoma, neuroblastoma, non-small-cell bronchogenic/lung carcinoma, oesophagus cancer, osteosarcoma, ovarian cancer, pancreas carcinoma, papillary carcinoma, papillary adenocarcinoma, papillar thymoma, pheochromocytoma, prostate cancer, rectal cancer, renal cancer, renal cell carcinoma, urinary duct carcinoma, sebaceous gland carcinoma, seminoma, skin cancer, small-cell lung carcinoma, small intestine carcinoma, soft tissue cancer, spleen carcinoma, squamous cell carcinoma, stomach carcinoma, teratoma, testicular carcinoma, testis carcinoma, thymoma, thyroid cancer, thyroid gland tumors, and corpus cancer of the uterus or the body cavity is joint cavity or ventricular space.

27. The method of claim 25, wherein the body cavity is the intraperitoneal space or the pleural cavity.

28. The method of claim 18, wherein the preparation is for administering at a flow rate of about 0.1 microL/min to about 0.1 mL/min, more preferably about 0.5 microL/min to about 0.05 microL/min, even more preferably of about 0.8 microL/min to about 0.04 mL/min, even more preferred of about 1 microL/min to about 0.02 mL/min, even more preferred of about 2 microL/min to about 10 microL/min, most preferred 4 microL/min.

29. The method of claim 18 wherein the preparation is for administering at a flow rate of about 5 microL/min to about 2 mL/min, more preferably about 0.05 mL/min to about 1 mL/min, even more preferably of about 0.1 mL/min to about 0.5 mL/min, even more preferred of about 0.3 mL/min to about 0.4 mL/min, most preferred about 0.35 mL/min.

30. The method of claim 18, wherein said preparation is for administering into a brain tumor, more preferred into astrocytoma including glioblastoma and oligoastrocytoma.

31. The method of claim 18, wherein said preparation is for administering for about 4 days to about 14 days, more preferred for about 3 to 8 days.

32. The method of claim 18, wherein said preparation is for administering a plurality of courses, more preferred about 2 to 20 times, each of said courses being separated by an interval of between one day and 12 weeks, more preferred about 2 days to about 8 weeks, even more preferred about 4 days to about 4 weeks, and even more preferred about 6 days to about 12 days.

33. The method of claim 18 for the treatment of a mammal, more preferred a human being.