Compositions and methods for inhibiting expression of cd274/pd-l1 gene

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the CD274/PD-L1 gene, and methods of using such dsRNA compositions to inhibit expression of CD274/PD-L1.

1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of CD274/PD-L1, comprising a sense strand and an antisense strand, wherein:
 (i) the antisense strand comprises a region of complementarity to a CD274/PD-L1 RNA transcript, the region of complementarity comprising at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NOs: 774, 776, 778, or 780;   (ii) the antisense strand comprises a 2′-deoxythymidine nucleotide at the 3′ end;   (iii) the sense strand is complementary to the antisense strand; and   (iv) each said strand is no more than 30 nucleotides in length.   
     
     
         2 .- 5 . (canceled) 
     
     
         6 . The dsRNA of  claim 1 , wherein the region of complementarity is between 19 and 21 nucleotides in length. 
     
     
         7 . The dsRNA of  claim 6 , wherein the region of complementarity is 19 nucleotides in length. 
     
     
         8 . (canceled) 
     
     
         9 . The dsRNA of  claim 21 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide. 
     
     
         10 . The dsRNA of  claim 1 , wherein at least one strand comprises a 3′ overhang of at least 2 nucleotides. 
     
     
         11 . The dsRNA of  claim 1 , further comprising a ligand. 
     
     
         12 . The dsRNA of  claim 1 , wherein the region of complementarity consists of the nucleotide sequence of SEQ ID NO: 774, 776, 778, or 780. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . A cell containing the dsRNA of  claim 1 . 
     
     
         17 . The dsRNA of  claim 1 , further comprising a pharmaceutically acceptable carrier. 
     
     
         18 . A method of inhibiting CD274/PD-L1 expression in a cell, the method comprising:
 (a) introducing into the cell a double-stranded ribonucleic acid (dsRNA) of  claim 1 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a CD274/PD-L1 gene, thereby inhibiting expression of the CD274/PD-L1 gene in the cell.   
     
     
         19 - 20 . (canceled) 
     
     
         21 . The dsRNA of  claim 1 , wherein the sense strand consists of 5′-AcAuuuGGAGGAGAcGuAAdTsdT-3′ (SEQ ID NO: 773) and the antisense strand consists of 5′-UuACGUCUCCUCcAAAUGUdTsdT-3′ (SEQ ID NO: 774);
 wherein A, C, G, and U are adenosine, cytidine, guanosine, and uridine, respectively; a, c, g, and u are 2′-O-methyladenosine, 2′-O-methylcytidine, 2′-O-methylguanosine, and 2′-O-methyluridine, respectively; dT is 2′-deoxythymidine; and s is a phosphorothioate linkage. 
 
     
     
         22 . The dsRNA of  claim 1 , wherein the sense strand consists of 5′-cAuuuGGAGGAGAcGuAAudTsdT-3′ (SEQ ID NO: 775) and the antisense strand consists of 5′-AUuACGUCUCCUCcAAAUGdTsdT-3′ (SEQ ID NO: 776);
 wherein A, C, G, and U are adenosine, cytidine, guanosine, and uridine, respectively; a, c, g, and u are 2′-O-methyladenosine, 2′-O-methylcytidine, 2′-O-methylguanosine, and 2′-O-methyluridine, respectively; dT is 2′-deoxythymidine; and s is a phosphorothioate linkage. 
 
     
     
         23 . The dsRNA of  claim 1 , wherein the sense strand consists of 5′-GGAGGAGAcGuAAuccAGcdTsdT-3′ (SEQ ID NO: 777) and the antisense strand consists of 5′-GCUGGAUuACGUCUCCUCCdTsdT-3′ (SEQ ID NO: 778);
 wherein A, C, G, and U are adenosine, cytidine, guanosine, and uridine, respectively; a, c, g, and u are 2′-O-methyladenosine, 2′-O-methylcytidine, 2′-O-methylguanosine, and 2′-O-methyluridine, respectively; dT is 2′-deoxythymidine; and s is a phosphorothioate linkage. 
 
     
     
         24 . The dsRNA of  claim 1 , wherein the sense strand consists of 5′-AcGuAAuccAGcAuuGGAAdTsdT-3′ (SEQ ID NO:779) and the antisense strand consists of 5′-UUCcAAUGCUGGAUuACGUdTsdT-3′ (SEQ ID NO: 780);
 wherein A, C, G, and U are adenosine, cytidine, guanosine, and uridine, respectively; a, c, g, and u are 2′-O-methyladenosine, 2′-O-methylcytidine, 2′-O-methylguanosine, and 2′-O-methyluridine, respectively; dT is 2′-deoxythymidine; and s is a phosphorothioate linkage.