GLP-1 receptor ligand moiety conjugated oligonucleotides and uses thereof

Patent metadata

Field	Value
Publication number	US-12115225-B2
Application number	US-202117231409-A
Country	US
Kind code	B2
Filing date	Apr 15, 2021
Priority date	May 6, 2016
Publication date	Oct 15, 2024
Grant date	Oct 15, 2024

Abstract

The present embodiments provide compounds and methods for targeting cells expressing GLP-1 receptor.

First claim

What is claimed:

1. A method of modulating the expression of a nucleic acid target in a pancreatic beta-islet cell, wherein the cell expresses GLP-1 receptor on the surface, the method comprising contacting the cell with a compound comprising a modified oligonucleotide, a GLP-1 peptide conjugate moiety capable of binding to the GLP-1 receptor and a conjugate linker linking the modified oligonucleotide to the GLP-1 peptide conjugate moiety, wherein the oligonucleotide has a nucleobase sequence complementary to that of the nucleic acid target, thereby modulating expression of the nucleic acid target in the cell.

2. The method of claim 1 , wherein contacting the cell with the compound inhibits expression of the nucleic acid target.

3. The method of claim 1 , wherein the nucleic acid target is pre-mRNA, mRNA, non-coding RNA, or miRNA.

4. The method of claim 1 , wherein the modified oligonucleotide is 15 to 30 linked nucleosides in length.

5. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.

6. The method of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides; and
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

7. The method of claim 1 , wherein the modified oligonucleotide is single-stranded.

8. The method of claim 1 , wherein the GLP-1 peptide conjugate moiety is 8 to 50 amino acids in length.

9. The method of claim 1 , wherein the conjugate linker comprises a disulfide linkage or group chosen from a cysteine group, a penicillamine group, a hexylamino group, a polyethylene glycol group, a triethylene glycol group, and a phosphate group.

10. The method of claim 1 , wherein the conjugate linker comprises:
(a)

wherein X directly or indirectly attaches to the GLP-1 receptor ligand conjugate moiety; and
wherein Y directly or indirectly attaches to the oligonucleotide

11. The method of claim 1 , wherein the GLP-1 peptide comprises the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Cys (SEQ ID NO: 22), wherein Aib is aminoisobutyric acid.

12. The method of claim 11 , wherein the GLP-1 peptide consists of the amino acid sequence: His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Cys (SEQ ID NO: 22), wherein Aib is aminoisobutyric acid.

Assignees

• Astrazeneca Ab
• Ionis Pharmaceuticals Inc

Inventors

• Monia Brett P
• Prakash Thazha P
• Kinberger Garth A
• Lee Richard
• Seth Punit P
• Andersson Shalini
• Ämmälä Eva Carina
• Knerr Daniel Laurent
• Ölwegård-Halvarsson Maria Astrid
• Valeur Eric
• Drury Iii William John

Classifications

• C07K19/00

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title

• C07K14/605

  Glucagons · CPC title

• C12N2310/3533

  Halogen · CPC title

• C12N2310/3525

  MOE, methoxyethoxy · CPC title

• C12N2310/3521

  Methyl · CPC title