PROGRAMMED CELL DEATH 1 LIGAND 1 (PD-L1) iRNA COMPOSITIONS AND METHODS OF USE THEREOF
The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting the programmed cell death 1 ligand 1 (PD-L1) gene, and methods of using such RNAi agents to inhibit expression of a PD-L1 gene and methods of treating subjects having a PD-L1-associated disorder.
1 . A double stranded ribonucleic acid (dsRNAi) agent for inhibiting expression of programmed cell death 1 ligand 1 (PD-L1), wherein said RNAi-dsRNAi agent comprises a sense strand and an antisense strand, wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of nucleotides 3221-3243, 351-372, 618-641, 618-639, 619-640, 620-641, 1167-1188, 1293-1314, 1518-1539, 2103-2124, 2220-2261, 2220-2241, 2240-2261, 2648-2680, 2648-2669, 2658-2679, 2659-2680, 3143-3164, and 3198-3219, of the nucleotide sequence of SEQ ID NO:1 and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the complementary portion of the nucleotide sequence of SEQ ID NO:2, and wherein the RNAi agent comprises at least one modified nucleotide.
2 . A double stranded ribonucleic acid (dsRNAi) agent for inhibiting expression of programmed cell death 1 ligand 1 (PD-L1), wherein said dsRNAi agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense sequences in any one of the duplexes AD-67658, AD-67632, AD-67629, AD-67631, AD-67676, AD-67661, AD-67667, AD-67655, AD-67672, AD-67659, AD-67673, AD-67664, AD-67662, AD-67660, and AD-67656.
3 . The dsRNAi agent of claim 2 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of any one of the nucleotide sequences in any one of the duplexes AD-67658, AD-67632, AD-67629, AD-67631, AD-67676, AD-67661, AD-67667, AD-67655, AD-67672, AD-67659, AD-67673, AD-67664, AD-67662, AD-67660, and AD-67656.
4 . The dsRNAi agent of claim 1 , wherein substantially all of the nucleotides of said sense strand or substantially all of the nucleotides of said antisense strand comprise a nucleotide modification-.
5 . The dsRNAi agent of claim 1 , wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand comprise a modification.
6 .- 7 . (canceled)
8 . The dsRNAi agent of claim 5 , wherein at least one of said nucleotide modifications is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic.
9 .- 12 . (canceled)
13 . The dsRNAi agent of claim 1 , wherein each strand is no more than 30 nucleotides in length.
14 . The dsRNAi agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.
15 . (canceled)
16 . The dsRNAi agent of claim 1 , further comprising a ligand.
17 . The dsRNAi agent of claim 16 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.
18 . The dsRNAi agent of claim 16 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
19 . The dsRNAi agent of claim 18 , wherein the ligand is
20 . The dsRNAi agent of claim 18 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic
and wherein X is O or S.
21 . (canceled)
22 . The dsRNAi agent of claim 2 , wherein the region of complementarity comprises any one of the antisense sequences in Table 3 and Table 5.
23 .- 42 . (canceled)
43 . The dsRNAi agent of claim 1 , wherein the nucleotide modifications are selected from the group consisting of LNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-C-allyl, 2′-fluoro, 2′-deoxy, 2′-hydroxyl, and combinations thereof.
44 . (canceled)
45 . The dsRNAi agent of claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; or a cholesterol.
46 .- 77 . (canceled)
78 . A cell containing the dsRNAi agent of claim 1 .
79 . A pharmaceutical composition for inhibiting expression of a PD-L1 gene comprising the dsRNAi agent of claim 1 .
80 .- 87 . (canceled)
88 . A method of inhibiting PD-L1 expression in a cell, the method comprising:
contacting the cell with the dsRNAi agent of claim 1 , thereby inhibiting expression of the PD-L1 gene in the cell.
89 .- 91 . (canceled)
92 . A method of treating a subject having a disease or disorder that would benefit from reduction in PD-L1 expression, the method comprising administering to the subject a therapeutically effective amount of the dsRNAi agent of claim 1 , thereby treating said subject.
93 - 106 . (canceled)