LNA antisense oligonucleotides for the modulation of Myc expression

• US 9,506,060 B2
• Filed: 02/15/2013
• Issued: 11/29/2016
• Est. Priority Date: 02/15/2012
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Dana-Farber Cancer Institute, Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Bandaru, Rajanikanth, Zhang, Yixian, Qu, Zhengxing, Greenberger, Lee, Ott, Christopher, Bradner, James Elliott
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US14/378,698
• Publication Number:
  US 20160024495A1
• Time in Patent Office: 1,383 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/711 Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• 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 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

The disclosure relates to oligonucleotide compounds (oligomers) that target Myc mRNA in a cell, leading to reduced expression of Myc. Reduction of Myc expression is beneficial for the treatment of certain disorders, such as hyperproliferative disorders (e.g., cancer). The disclosure provides therapeutic compositions comprising oligomers and methods for modulating the expression of Myc using said oligomers, including methods of treatment.

Claims

1. An oligomer of between 10-30 nucleobases in length which comprises a contiguous nucleobase sequence of a total of between 10-16 nucleobases, wherein the contiguous nucleobase sequence comprises nucleotide analogues, and wherein the contiguous nucleobase sequence comprises between 0-2 mismatches to a corresponding region of a sequence selected from the group consisting of:

2. The oligomer according to claim 1 wherein the nucleotide analogues comprise one or more sugar modified nucleotides.

3. The oligomer according to claim 2 wherein the one or more nucleotide analogues comprise LNA units.

4. The oligomer according to claim 2 wherein the nucleotide comprises a gapmer design.

5. The oligomer according to claim 4 selected from the group consisting of:

6. The oligomer according to claim 5 wherein the LNA units consist of beta-D-oxy-LNA monomers.

7. A conjugate comprising the oligomer according claim 1 covalently attached to at least one moiety that is not a nucleic acid or a monomer.

8. A pharmaceutical composition comprising the oligomer according to claim 1 and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.

9. A method of inhibiting the expression of Myc in a cell, comprising contacting the cell with an effective amount of an oligomer according to claim 1.

10. The method of claim 9, wherein the cell is within a tissue of a mammal.

11. The method of claim 9, wherein the Myc is c-Myc.

12. The method of claim 9, wherein the Myc is N-Myc.

13. The method of claim 9, wherein the Myc is c-Myc and N-Myc.

14. A method of treating a cancer disease in a mammal, comprising administering to the mammal an effective amount of an oligomer according to claim 1, wherein the mammal is currently suffering from or at risk of suffering from the cancer disease.

15. The method of claim 14, wherein the mammal is a human.

16. The method of claim 14, wherein the cancer is selected from the group consisting of B-acute lymphocytic leukemia, Burkitt'"'"'s lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, neuroblastoma, oesophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma retinoblastoma, rhabdomyocarcoma and small cell lung carcinoma.

17. The method of claim 16, wherein the cancer is selected from the group consisting of Burkitt'"'"'s lymphoma, breast cancer, and multiple myeloma.

18. A pharmaceutical composition comprising a conjugate according to claim 7 and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.

19. A method of inhibiting the expression of Myc in a cell, comprising contacting the cell with an effective amount of a conjugate according to claim 7.

20. A method of treating a cancer disease in a mammal, comprising administering to the mammal an effective amount of a conjugate according to claim 7, wherein the mammal is currently suffering from or at risk of suffering from the cancer disease.