APOB Antisense Conjugate Compounds

Patent metadata

Field	Value
Publication number	US-2016289677-A1
Application number	US-201415036218-A
Country	US
Kind code	A1
Filing date	Nov 14, 2014
Priority date	Nov 14, 2013
Publication date	Oct 6, 2016
Grant date	—

Abstract

The present invention relates to conjugates of antisense oligonucleotides (oligomers) that target the APOB gene at position 2265 to 2277.

First claim

1 . An antisense oligonucleotide conjugate comprising an oligomer with the oligonucleotide motif of SEQ ID NO 2 joined with a conjugate moiety (region C), where the conjugate moiety comprises one or more N-acetylgalactosamine moieties.

2 . The antisense oligonucleotide conjugate according to claim 1 , wherein the oligomer comprises at least 2 affinity enhancing nucleotide analogues selected from the group consisting of: Locked Nucleic Acid (LNA) units; 2′-O-alkyl-RNA units, 2′-OMe-RNA units, 2′-amino-DNA units, and 2′-fluoro-DNA units.

3 . The antisense oligonucleotide conjugate according to claim 1 , wherein the oligomer corresponds to SEQ ID NO 27: 5′ GsTstsgsascsascstsgsTsC 3′, wherein capital letters represent beta-D-oxy LNA, lower case letters represent DNA nucleosides, LNA cytosines are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate indicated by s.

4 . The antisense oligonucleotide conjugate according to claim 1 , wherein the oligomer is capable of down regulating the expression of ApoB in a cell which is expressing ApoB.

5 . The antisense oligonucleotide conjugate according to claim 1 , wherein said conjugate moiety is joined to said oligomer, via a cleavable linker (B).

6 . The antisense oligonucleotide conjugate according to claim 5 , wherein the cleavable linker comprises a cleavable lysine linker.

7 . The antisense oligonucleotide conjugate according to claim 1 , wherein the conjugate moiety comprises 1 to 3 N-acetylgalactosamine moiety(s).

8 . The antisense oligonucleotide conjugate according to claim 1 , wherein the oligonucleotide conjugate comprises a linker Y which covalently links the conjugate moiety to the oligomer.

9 . The antisense oligomer conjugate according to claim 8 , wherein the linker region Y comprises a fatty acid, such as a C6 linker.

10 . The antisense oligonucleotide according to claim 1 , wherein conjugate moiety comprises a PEG spacer between the N-acetylgalactosamine moiety(s) and the linker (B and/or Y) or the oligomer.

11 . The antisense oligonucleotide conjugate according to claim 1 , wherein the conjugate moiety comprises three N-acetylgalactosamine moieties each independently linked via a PEG spacer to a cleavable di-lysine linker.

12 . The antisense oligonucleotide conjugate according to claim 1 , wherein the conjugate comprises a conjugate moiety selected from the group consisting of Conj1, Conj2, Conj3, Conj4, Conj1 a, Conj2a, Conj3a and Conj4a.

13 . The antisense oligonucleotide conjugate according to claim 1 , which consists of SEQ ID NO 29 or SEQ ID NO 31.

14 . A pharmaceutical composition comprising the antisense oligonucleotide conjugate according to claim 1 , and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.

15 . The antisense oligonucleotide conjugate or pharmaceutical composition according to claim 1 , for use as a medicament.

16 . An in vivo or in vitro method for the inhibition of ApoB in a cell which is expressing ApoB, said method comprising administering an oligonucleotide conjugate or pharmaceutical composition according to claim 1 to said cell so as to inhibit ApoB in said cell.

Assignees

• Roche Innovation Ct Copenhagen As

Inventors

• Albæk Nanna
• Hansen Henrik Frydenlund
• Kammler Susanne
• Lindholm Marie
• Turner Mark
• Orum Henrik

Classifications

• C12N2310/351

  Conjugate · CPC title

• C12N15/113 Primary

  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 title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61K31/712 Primary

  Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose · CPC title

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · CPC title