Conjugated antisense compounds and their use

• US 10,570,169 B2
• Filed: 05/21/2015
• Issued: 02/25/2020
• Est. Priority Date: 05/22/2014
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Seth, Punit P., Prakash, Thazha P., Migawa, Michael T., Swayze, Eric E.
• Primary Examiner(s): Lewis, Patrick T
• Application Number:
  US15/311,436
• Publication Number:
  US 20170355727A1
• Time in Patent Office: 1,741 Days
• Field of Search: None
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: C07H 13/04 having the esterifying carboxyl radicals attached to acyclic carbon atoms
• CPC Class Codes: C07H 13/08 having the esterifying carboxyl radicals directly attached to carbocyclic rings
• CPC Class Codes: C07H 13/10 having the esterifying carboxyl radicals directly attached to heterocyclic rings
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 15/14 attached to a sulfur, selenium or tellurium atom of a saccharide radical
• CPC Class Codes: C07H 19/056 Triazole or tetrazole radicals
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. 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 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12P 19/34 Polynucleotides, e.g. nucleic acids, oligoribonucleotides

Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the gomeric compounds are conjugated to N-Acetylgalactosamine or to N-Acetylgalactosamine analogues.

Claims

1. A compound comprising an oligomer and a conjugate group having Formula II:

2. The compound of claim 1 wherein R₁ is selected from CH₂NJ1J2 and CH₂SJ₃ wherein J₁, J₂ and J₃ are each independently selected from H and CH₃.

3. The compound of claim 2 wherein J₁, J₂ and J₃ are each H.

4. The compound of claim 1 wherein L optionally comprises one or more amides and wherein L attaches to T₁ through a group selected from among:

5. The compound of claim 1 wherein L comprises a phosphorus linking group, NH₂, or N(CH₃)₂.

6. The compound of claim 1 having the configuration:

7. The compound of claim 1, wherein the oligomer comprises at least one modified nucleoside comprising a modified base and or a modified sugar.

8. The compound of claim 7 having at least one modified nucleoside comprising a modified sugar selected from a bicyclic nucleoside and a 2′

-modified nucleoside.

9. The compound of claim 8, 4′

-C(CH₃)H-O-2′

or 4′

-CH₂—

O-2′

bridged bicyclic nucleoside.

10. The compound of claim 8, comprising at least one 2′

-O(CH₂)₂OCH₃ substituted 2′

-modified nucleoside.

11. The compound of claim 1, wherein the conjugate group is attached to the 5′

-terminal nucleoside of the oligomer.

12. The compound of claim 1, wherein the conjugate group is attached to the 3′

-terminal nucleoside of the oligomer.

13. The compound of claim 1, wherein the oligomer has a sugar motif comprising:

a 5′

-region consisting of 2-8 linked 5′

-region nucleosides, wherein at least two 5′

-region nucleosides are modified nucleosides and wherein the 3′

-most 5′

-region nucleoside is a modified nucleoside;

a 3′

-region consisting of 2-8 linked 3′

-region nucleosides, wherein at least two 3′

-region nucleosides are modified nucleosides and wherein the 5′

-most 3′

-region nucleoside is a modified nucleoside; and

a central region between the 5′

-region and the 3′

-region consisting of 5-10 linked central region nucleosides, each independently selected from among;

a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′

-most central region nucleoside is an unmodified deoxynucleoside and the 3′

-most central region nucleoside is an unmodified deoxynucleoside.

14. The compound of claim 1, wherein the oligomer comprises at least one modified internucleoside linkage.

15. The compound of claim 1, wherein each internucleoside linkage of the oligomer is independently a phosphodiester or a phosphorothioate internucleoside linkage.

16. The compound of claim 1, wherein the oligomer has a nucleobase sequence comprising an at least 14 or 16 nucleobase portion complementary to an equal length portion of a target nucleic acid.

17. A pharmaceutical composition comprising a compound or oligomer according to claim 1 and a pharmaceutically acceptable carrier or diluent.

18. The compound of claim 1 comprising an oligomer and three conjugate groups having Formula II attached to said oligomer through a single connecting group.