Oligonucleotide conjugates

Patent metadata

Field	Value
Publication number	US-10077443-B2
Application number	US-201314443367-A
Country	US
Kind code	B2
Filing date	Nov 14, 2013
Priority date	Nov 15, 2012
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

The invention relates to the field of oligonucleotide therapeutics, and in particular to the use of a cleavable, e.g. a phosphodiester region covalently attached to a conjugate, a targeting group or blocking group to enhance the properties of the oligonucleotides, for example to improve the therapeutic index.

First claim

The invention claimed is:

1. An oligomeric compound of 8-35 nucleotides in length, comprising three regions:
i) a first region (region A), which is an antisense oligomer of 7-26 contiguous nucleotides complementary to a nucleic acid target, wherein the first region comprises at least four nucleoside analogues and wherein the internucleoside linkages of the first region are internucleoside linkage other than phosphodiester;
ii) a second region (region B) which is covalently linked to the 5′ or 3′ nucleotide of the first region via a phosphodiester internucleoside linkage, wherein the second region consists of 2-10 phosphodiester linked DNA or RNA nucleosides; and
iii) a third region which comprises a conjugate moiety or a targeting moiety, wherein the third region is covalent linked to the second region.

2. The oligomeric compound according to claim 1 , wherein the internucleoside linkages other than phosphodiester are selected from the group consisting of phosphorothioate, phosphorodithioate and boranophosphate.

3. The oligomeric compound according to claim 1 , wherein the nucleic acid target is selected from the group consisting of a microRNA, a mRNA, a lncRNA (long non-coding RNA), a snRNA, snoRNA, and a viral RNA.

4. The oligomeric compound according to claim 1 , wherein the first region is a gapmer, a mixmer, or a totalmer.

5. The oligomeric compound according of claim 1 , wherein the first region comprises at least one bicyclic nucleotide analogue (LNA).

6. The oligomeric compound according to claim 1 , wherein the first region and the second region form a contiguous nucleotide sequence.

7. The oligomeric compound according to claim 1 , wherein the second region is 5′ to the first region.

8. The oligomeric compound according to claim 1 , wherein the second region is 3′ to the first region.

9. The oligomeric compound according to claim 1 , wherein the second region is covalently linked to the third region at the terminal nucleoside of the second region.

10. The oligomeric compound according to claim 1 , wherein the third region comprises a non-nucleotide moiety selected from a sterol and a carbohydrate.

11. The oligomeric compound according to claim 10 , wherein the third region comprises a moiety selected from the group consisting of: a lipophilic group, a protein, a peptide, an antibody or fragment thereof, a polymer, a reporter group, a dye, a receptor ligand, a small molecule drug, a prodrug, and a vitamin.

12. The oligomeric compound according to claim 1 , wherein the third region comprises a targeting group.

13. The oligomeric compound according to claim 1 , wherein the second and third regions are covalently joined by a linker group.

14. The oligomeric compound according to claim 13 , wherein the linker group between the second and third regions comprises a group selected from phosphodiester, a phosphorothioate, a phosphorodithioate and a boranophosphate group.

15. A pharmaceutical composition comprising the oligomeric compound of claim 1 , and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.

16. The oligomeric compound according to claim 1 for use in the inhibition of a nucleic acid target in a cell.

17. The oligomeric compound according to claim 1 for use in medicine.

18. The oligomeric compound according to claim 1 for use in the treatment of a medical disease or disorder.

19. The oligomeric compound according to claim 1 , wherein region B consists of a dinucleotide of sequence AA, AT, AC, AG, TA, TT, TC, TG, CA, CT, CC, CG, GA, GT, GC, or GG.

20. The oligomeric compound according to claim 1 , wherein region B consists of a trinucleotide of sequence AAA, AAT, AAC, AAG, ATA, ATT, ATC, ATG, ACA, ACT, ACC, ACG, AGA, AGT, AGC, AGG, TAA, TAT, TAC, TAG, TTA, TTT, TTC, TAG, TCA, TCT, TCC, TCG, TGA, TGT, TGC, TGG, CAA, CAT, CAC, CAG, CTA, CTG, CTC, CTT, CCA, CCT, CCC, CCG, CGA, CGT, CGC, CGG, GAA, GAT, GAC, CAG, GTA, GTT, GTC, GTG, GCA, GCT, GCC, GCG, GGA, GGT, GGC, or GGG.

21. The oligomeric compound according to claim 10 , wherein the third region comprises cholesterol.

22. The oligomeric compound according to claim 10 , wherein the third region comprises a GalNac cluster.

Assignees

• Roche Innovation Ct Copenhagen As

Inventors

• Albæk Nanna
• Hansen Henrik Frydenlund
• Kammler Susanne
• Ravn Jacob
• Orum Henrik

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title