GLP-1 Receptor Ligand Moiety Conjugated Oligonucleotides and Uses Thereof

Patent metadata

Field	Value
Publication number	US-2021346509-A1
Application number	US-202117231409-A
Country	US
Kind code	A1
Filing date	Apr 15, 2021
Priority date	May 6, 2016
Publication date	Nov 11, 2021
Grant date	—

Abstract

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

First claim

1 - 90 . (canceled)

91 . A method of modulating the expression of a nucleic acid target in a cell comprising contacting the cell with a compound comprising a modified oligonucleotide, conjugate linker, and GLP-1 receptor ligand conjugate moiety, thereby modulating expression of the nucleic acid target in the cell.

92 . The method of claim 91 , wherein the cell is a pancreatic cell.

93 . The method of claim 92 , wherein the pancreatic cell is a beta-islet cell.

94 . The method of claim 91 , wherein the cell expresses GLP-1 receptor on the surface of the cell.

95 . The method of claim 91 , wherein contacting the cell with the compound inhibits expression of the nucleic acid target.

96 . The method of claim 91 , wherein the nucleic acid target is pre-mRNA, mRNA, non-coding RNA, or miRNA.

97 - 121 . (canceled)

122 . The method of claim 91 , wherein the conjugate linker links the modified oligonucleotide to the GLP-1 receptor ligand conjugate moiety.

123 . The method of claim 91 , wherein the modified oligonucleotide is 15 to 30 linked nucleosides in length.

124 . The method of claim 91 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.

125 . The method of claim 91 , 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.

126 . The method of claim 91 , wherein the modified oligonucleotide is single-stranded.

127 . The method of claim 91 , wherein the GLP-1 receptor ligand conjugate moiety is a peptide conjugate moiety, small molecule conjugate moiety, aptamer conjugate moiety, or antibody conjugate moiety targeted to GLP-1 receptor.

128 . The method of claim 127 , wherein the peptide conjugate moiety is a GLP-1 peptide conjugate moiety capable of binding to GLP-1 receptor.

129 . The method of claim 128 , wherein the GLP-1 peptide conjugate moiety is 8 to 50 amino acids in length.

130 . The compound of claim 91 , wherein the conjugate linker comprises 1-5 linker-nucleosides, 3 linker-nucleosides, or a TCA motif.

131 . The method of claim 91 , 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.

132 . The method of claim 91 , 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; or

(b)

wherein X directly or indirectly attaches to the GLP-1 receptor ligand conjugate moiety; and
wherein Y comprises a phosphate group and directly or indirectly attaches to the modified oligonucleotide; or

(c)

wherein X comprises a disulfide linkage and directly or indirectly attaches to the GLP-1 receptor ligand conjugate moiety; and
wherein T 1 comprises the modified oligonucleotide; and Bx is a modified or unmodified nucleobase; or
(d)

wherein the phosphate group is connected to the modified oligonucleotide and Y is connected to the conjugate group;
wherein Y is a phosphodiester or amino (—NH—) group; and
wherein Z is a pyrrolidinyl group having the formula:

j is 0 or 1;
n is from about 1 to about 10;
p is from 1 to about 10;
m is 0 or from 1 to 4; and
when Y is amino then m is 1; or

(e)

133 . The method of claim 129 , wherein the GLP-1 peptide conjugate moiety is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% homologous over its entire length to the amino acid sequence of any of SEQ ID NOs: 1-57.

134 . The method of claim 133 , wherein the GLP-1 peptide conjugate moiety is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical over its entire length to the amino acid sequence of any of SEQ ID NOs: 1-57.

135 . The method of claim 133 , wherein the GLP-1 peptide conjugate moiety comprises the amino acid sequence of GLP-1(7-37) (SEQ ID NO: 1).

136 . The method of claim 135 , wherein the GLP-1 peptide consists of the amino acid sequence of GLP-1(7-37) (SEQ ID NO: 1).

137 . The method of claim 133 , 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.

138 . The method of claim 137 , 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.

139 . The method of claim 133 , 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-Pen (SEQ ID NO: 23), wherein Aib is aminoisobutyric acid and Pen is penicillamine.

140 . The method of claim 139 , 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-Pen (SEQ ID NO: 23), wherein Aib is aminoisobutyric acid and Pen is penicillamine.

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

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C12N2310/3513

  Protein; Peptide · CPC title

• C12N2310/3341

  5-Methylcytosine · CPC title