Compositions and methods for inhibiting expression of CD274/PD-L1 gene

Patent metadata

Field	Value
Publication number	US-10745704-B2
Application number	US-201815906267-A
Country	US
Kind code	B2
Filing date	Feb 27, 2018
Priority date	Apr 6, 2010
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

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.

First claim

We claim:

1. A double-stranded ribonucleic acid (dsRNA), wherein said dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′-UGUCAUAUUGCUACCAUAC-3′ (SEQ ID NO: 138), wherein said antisense strand further comprises a 2′-deoxythymidine nucleotide at the 3′ end and each strand is no more than 30 nucleotides in length.

2. The dsRNA of claim 1 , wherein said dsRNA comprises: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, or a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group.

3. The dsRNA of claim 1 , wherein said dsRNA comprises: a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, or a non-natural base comprising nucleotide.

4. The dsRNA of a claim 1 , wherein the sense strand is complementary to the antisense strand, and the region of complementarity is between 19 and 21 nucleotides in length.

5. The dsRNA of claim 4 , wherein the region of complementarity is 19 nucleotides in length.

6. The dsRNA of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.

7. The dsRNA of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 2 nucleotides.

8. The dsRNA of claim 1 , further comprising a ligand.

9. The dsRNA of claim 1 , wherein the region of complementarity consists of SEQ ID NO: 138.

10. The dsRNA of claim 1 , wherein the sense strand consists of 5′-GuAuGGuAGcAAuAuGAcAdTsdT-3′ (SEQ ID NO: 569) and the antisense strand consists of 5′-UGUcAuAUUGCuACcAuACdTsdT-3′ (SEQ ID NO: 570);
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.

11. A cell containing the dsRNA of claim 1 .

12. A pharmaceutical composition comprising a dsRNA of claim 1 and a pharmaceutically acceptable carrier.

13. 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.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Defougerolles Antonin
• Novobrantseva Tatiana
• Bettencourt Brian

Classifications

• C12N2320/30

  Special therapeutic applications · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61P31/10

  Antimycotics · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• A61P31/04

  Antibacterial agents · CPC title