Polynucleotide agents targeting programmed cell death 1 ligand 1 (PD-L1) and methods of use thereof
The invention relates to polynucleotide agents targeting programmed cell death 1 ligand 1 (PD-L1) gene, and methods of using such polynucleotide agents to inhibit expression of PD-L1 and to treat subjects having a PD-L1-associated disorder.
1. A single-stranded antisense polynucleotide agent for inhibiting expression of a Programmed cell death 1 ligand 1 (PD-L1) gene, wherein the agent is 10 to 40 contiguous nucleotides in length, wherein at least one of the contiguous nucleotides is a modified nucleotide, and wherein the nucleotide sequence of the agent is 80% complementary over its entire length to nucleotides 10-29 of SEQ ID NO: 1.
2. The agent of claim 1 , wherein the nucleotide sequence of the agent is fully complementary over its entire length to nucleotides 10-29 of SEQ ID NO: 1.
3. The agent of claim 1 , wherein substantially all of the nucleotides are modified nucleotides.
4. The agent of claim 1 , wherein all of the nucleotides are modified nucleotides.
5. The agent of claim 1 , which is 10 to 30 nucleotides in length; 18 to 30 nucleotides in length; 10 to 24 nucleotides in length; 18 to 24 nucleotides in length; 14 to 20 nucleotides in length; 14 nucleotides in length; or 20 nucleotides in length.
6. The agent of claim 1 , wherein the modified nucleotide comprises a modified sugar moiety selected from the group consisting of: a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, a bicyclic sugar moiety, a 5-methylcytosine, and a modified internucleoside linkage.
7. The agent of claim 6 , wherein the bicyclic sugar moiety has a (—CRH—)n group forming a bridge between the 2′ oxygen and the 4′ carbon atoms of the sugar ring, wherein n is 1 or 2 and wherein R is H, CH3 or CH3OCH3.
8. The agent of claim 6 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
9. The agent of claim 1 , wherein the agent is a gapmer comprising a plurality of 2′-deoxynucleotides flanked on each of a 5′ and a 3′ side by a wing segment comprising at least one nucleotide having a modified sugar moiety.
10. The agent of claim 9 , wherein the modified sugar moiety is selected from the group consisting of a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety.
11. The agent of claim 9 , wherein the 5′-wing segment is 1 to 6 nucleotides in length; 2 nucleotides in length; 3 nucleotides in length; 4 nucleotides in length; or 5 nucleotides in length.
12. The agent of claim 9 , wherein the 3′-wing segment is 1 to 6 nucleotides in length; 2 nucleotides in length; 3 nucleotides in length; 4 nucleotides in length; or 5 nucleotides in length.
13. The agent of claim 9 , wherein the gap segment is 5 to 14 nucleotides in length; or 10 nucleotides in length.
14. The agent of claim 1 , wherein the agent further comprises a ligand.
15. The agent of claim 14 , wherein the antisense polynucleotide agent is conjugated to the ligand at the 3′-terminus.
16. The agent of claim 14 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
17. The agent of claim 16 , wherein the ligand is
18. A pharmaceutical composition for inhibiting expression of a Programmed cell death 1 ligand 1 (PD-L1) gene comprising the agent of claim 1 .
19. A pharmaceutical composition comprising the agent of claim 1 , and a lipid formulation.
20. A method of inhibiting expression of a Programmed cell death 1 ligand 1 (PD-L1) gene in a cell, the method comprising:
(a) contacting the cell with the agent of claim 1 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain antisense inhibition of a PD-L1gene, thereby inhibiting expression of the PD-L1gene in the cell.