Tetragalnac and peptide containing conjugates and methods for delivery of oligonucleotides

Patent metadata

Field	Value
Publication number	US-9655976-B2
Application number	US-201314398369-A
Country	US
Kind code	B2
Filing date	May 1, 2013
Priority date	May 2, 2012
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

First claim

What is claimed is:

1. A modular composition comprising:
1) a single stranded or double stranded oligonucleotide;
2) one or more tetraGalNAc ligands of Formula (I), (II) or (III), which may be the same or different:

wherein X is —O—, —S—, —CR 1 R 2 — or —NR 1 —, wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl; n is 1, 2, 3, or 4; and the bond with “ ” indicates the point of attachment;
optionally, 3) one or more linkers, which may be the same or different;
optionally, 4) one or more peptides independently selected from SEQ ID No. 1-474, or the D-amino acid, retro-inverso, and cysteine conjugation point variants thereof, which may be the same or different, wherein the cysteine conjugation point variants thereof refers to variants of the peptides comprising conjugation through existing cysteines or through a cysteine residue added to a N- or C-terminus of the peptides; and
optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

2. The modular composition of claim 1 comprising:
1) a single stranded or double stranded oligonucleotide;
2) 1-8 tetraGalNAc ligands of Formula (II), which may be the same or different, wherein X is —O—, —S—, —CH 2 — or NH—; and n is 1, 2, 3, or 4;
3) 1-24 linkers, which may be the same or different;
4) 1-8 peptides independently selected from SEQ ID No. 1-474, which may be the same or different; and
optionally, 5) 1-8 targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

3. A modular composition comprising:
1) a single stranded or double stranded siRNA;
2) 1-8 tetraGalNAc ligands of Formula (I), (II) or (III), which may be the same or different, wherein X is —O—, —S—, —CH 2 — or NH—; and n is 1, 2, 3, or 4;
3) 1-24 linkers, which may be the same or different;
4) 1-12 peptides independently selected from SEQ ID No. 1-474, or the D-amino acid, retro-inverso, and cysteine conjugation point variants thereof, which may be the same or different, wherein the cysteine conjugation point variants thereof refers to variants of the peptides comprising conjugation through existing cysteines or through a cysteine residue added to a N- or C-terminus of the peptides; and
optionally, 5) 1-8 targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

4. The modular composition of claim 3 , wherein the tetraGalNAc ligands and/or the peptides are attached to the siRNA at different 2′-positions of the ribose rings and/or at different terminal 3′ and/or 5′-positions of the siRNA; and wherein the tetraGalNAc ligands and/or the peptides are attached to the siRNA optionally via linkers.

5. The modular composition of claim 3 , wherein X of Formula (I), (II) or (III) is —O—, —S— or —CH 2 —; and n is 1, 2 or 3.

6. The modular composition of claim 3 , wherein the composition comprises 1-4 tetraGalNAc ligands, which may be the same or different.

7. The modular composition of claim 3 , wherein the composition comprises 1-8 peptides, which may be the same or different.

8. The modular composition of claim 3 ,
wherein the siRNA is double stranded; and
wherein the tetraGalNAc ligands are attached to the guide strand or the passenger strand of the siRNA at different 2′-positions of the ribose rings of the siRNA.

9. The modular composition of claim 3 ,
wherein the siRNA is double stranded; and
wherein the tetraGalNAc ligands are attached to the guide strand or the passenger strand of the siRNA at different terminal 3′ and/or 5′-positions.

10. The modular composition of claim 3 ,
wherein the siRNA is double stranded; and
wherein the tetraGalNAc ligands are attached to both the guide strand and the passenger strand of the siRNA at different 2′-positions of the ribose rings and/or different terminal 3′ and/or 5′-positions.

11. The modular composition of claim 3 ,
wherein the siRNA is double stranded; and
wherein the peptides are attached to the guide strand or the passenger strand of the siRNA at different 2′-positions of the ribose rings of the siRNA.

12. The modular composition of claim 3 ,
wherein the siRNA is double stranded; and
wherein the peptides are attached to the guide strand or the passenger strand of the siRNA at different terminal 3′ and/or 5′-positions.

13. The modular composition of claim 3 ,
wherein the siRNA is double stranded; and
wherein the peptides are attached to both the guide strand and the passenger strand of the siRNA at different 2′-positions of the ribose rings and/or different terminal 3′ and/or 5′-positions.

14. The modular composition of claim 3 , wherein the tetraGalNAc ligands and the peptides are attached to the same strand of the siRNA.

15. The modular composition of claim 3 , wherein the tetraGalNAc ligands and the peptides are attached to different strands of the siRNA.

16. The modular composition of claim 3 , wherein the tetraGalNAc ligands and the peptides are attached to the same or different strands of the siRNA via linkers.

17. The modular composition of claim 16 , wherein each linker is independently selected from the group consisting of:

wherein:
each R is independently H, Boc (tert-butyloxycarbonyl), Cbz (carboxybenzyl), Ac (acetyl), a PEG, a lipid, a targeting ligand, linker(s), or peptide(s); and
each n is 0 to 750.

18. The modular composition of claim 16 , wherein each linker is independently selected from the group consisting of:

wherein:
each R is independently H, Boc (tert-butyloxycarbonyl), Cbz (carboxybenzyl), Ac (acetyl), a PEG, a lipid, a targeting ligand, linker(s), or peptide(s); and
each n is 0 to 750.

19. The modular composition of claim 18 , wherein the linker is a branching linker independently selected from the group consisting of:

wherein:
each R is independently H, Boc (tert-butyloxycarbonyl), Cbz (carboxybenzyl), Ac (acetyl), a PEG, a lipid, a targeting ligand, linker(s), or peptide(s); and
each n is 0 to 750.

20. The modular composition of claim 3 ,
wherein the siRNA is double stranded; and
wherein the optional targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents are attached to the same or different strands of the siRNA via linkers.

21. A modular composition comprising:
1) a double stranded siRNA;
2) 1-8 tetraGalNAc ligands of Formula (IV), (V) or (VI):

3) 1-24 linkers which may

Assignees

• Sirna Therapeutics Inc

Inventors

• Tellers David
• Colletti Steven L
• Dudkin Vadim
• Aaronson Jeffrey
• Momose Aaron
• Tucker Thomas Joseph
• Yuan Yu
• Calati Kathleen B
• Tian Lu
• Parmar Rubina G
• Shaw Anthony W
• Wang Weimin
• Storr Rachel Anne
• Busuek Marina
• Kowtoniuk Robert A

Classifications

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C12N15/113

  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 title

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title