Tetragalnac containing conjugates and methods for delivery of oligonucleotides

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:

optionally, 3) one or more linkers, which may be the same or different; and

optionally, 4) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents,

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 of the tetraGalNAc ligands to the oligonucleotide, either directly or through one or more optionally present linkers.

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) 1-16 linkers, which may be the same or different; and

optionally, 4) 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,

3) 1-16 linkers, which may be the same or different; and

optionally, 4) 1-8 targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents,

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 of the tetraGalNAc ligands to the oligonucleotide, either directly or through one or more optionally present linkers.

4. The modular composition of claim 3 , wherein the tetraGalNAc ligands 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 are attached to the siRNA optionally via linkers.

5. The modular composition of claim 3 , wherein X of Formula (II) 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 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.

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 terminal 3′ and/or 5′-positions.

9. 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.

10. The modular composition of claim 3 , wherein the composition comprises 2-8 tetraGalNAc ligands of Formula (II), which may be the same or different; and the tetraGalNAc ligands are attached to the same strand of the siRNA.

11. The modular composition of claim 3 , wherein the composition comprises 2-8 tetraGalNAc ligands of Formula (II), which may be the same or different; and the tetraGalNAc ligands are attached to different strands of the siRNA.

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

13. The modular composition of claim 12 , 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.

14. The modular composition of claim 12 , 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.

15. 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 strand or different strands of the siRNA via linkers.

16. A modular composition comprising

1) a double stranded siRNA;

2) 1-8 tetraGalNAc ligands of Formula (IV), (V) or (VI):

optionally, 3) 1-16 linkers, which may be the same or different; and

optionally, 4) 1-8 targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents,

wherein the bond with “ ” indicates the point of attachment of the tetraGalNAc ligands to the oligonucleotide, either directly or through one or more optionally present linkers.

17. The modular composition of claim 16 comprising:

1) a double stranded siRNA;

2) 1-3 tetraGalNAc ligands of Formula (V);

optionally, 3) 1 -6 linkers, which may be the same or different; and

optionally, 4) 1-3 targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents;

wherein the tetraGalNAc ligands 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 are attached to the siRNA optionally via linkers.

18. The modular composition of claim 17 comprising 2-3 tetraGalNAc ligands, wherein the tetraGalNAc ligands are attached to the same strand or different strands of the siRNA via linkers.

19. The modular composition of claim 17 comprising:

1) a double stranded siRNA;

2) 1 -2 tetraGalNAc ligands of Formula (V);

3) 1-4 linkers, which may be the same or different; and

optionally, 4) 1-2 targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents;

wherein the tetraGalNAc ligands 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 are attached to the siRNA via linkers.

20. The modular composition of claim 19 comprising 2 tetraGalNAc ligands, wherein the tetraGalNAc ligands are attached to the same strand or different strands of the siRNA via linkers.

21. The modular composition of claim 19 comprising 1 tetraGalNAc ligand, wherein the tetraGalNAc ligand is attached to the siRNA via a linker.

22. A pharmaceutical composition comprising the modular composition of claim 1 and a pharmaceutically acceptable excipient.