Methods and compositions for targeting PD-L1
Inventors
Beigelman, Leonid • Fitzgerald, Megan Elizabeth • MONTERO, Saul MARTINEZ • Bhattacharya, Aneerban
Assignees
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Publication Number
US-11939581-B2
Publication Date
2024-03-26
Expiration Date
Abstract
The present disclosure relates to small interfering RNA (siRNA) molecules directed to mRNA transcripts of CD274 to cause downregulation of programmed death-ligand 1 (PD-L1) expression in humans. The siRNA can be constructed of unmodified nucleotides or modified nucleotides that exhibit modified sugars, nucleobases, linkages, or covalently bound targeting moieties. Also disclosed herein are pharmaceutical compositions of siRNAs and uses of or methods of using the siRNAs for the treatment of PD-L1 related diseases including but not limited to liver diseases, cancer, hepatocellular carcinoma, viral diseases, or hepatitis B.
Core Innovation
The invention provides a small interfering RNA (siRNA) that targets human CD274 mRNA (PD-L1). The siRNA comprises a sense strand and an antisense strand, and the antisense strand comprises nucleotides selected from unmodified nucleotides and modified nucleosides. Each modified nucleoside contains a modified sugar, contains a modified nucleobase or is abasic, or both contains a modified sugar and contains a modified nucleobase or is abasic.
Linkages between the nucleosides are phosphorothioate, phosphodiester, phosphoramidate, thiophosphoramidate, methylphosphate, methylphosphonate, phosphonoacetate, amide, boranophosphate, or any combination thereof. The antisense strand comprises a 5′-phosphate mimic. The siRNA has a sequence as set forth in SEQ ID NO:303 and is at least 85% complementary to a fragment of human CD274 mRNA.
The disclosure also describes mismatch constraints relative to a fragment of human CD274 mRNA, a 2-nucleotide overhang, targeting-moiety conjugation at the 5′ end, the 3′ end, or both ends, and pharmaceutical compositions containing an effective amount of the siRNA together with a pharmaceutically acceptable carrier, diluent, excipient, or combinations thereof.
Claims Coverage
The claims coverage centers on one independent claim directed to an siRNA targeting human CD274 mRNA, with eight inventive features identified across the claim set.
Cd274-targeting sirna with defined sense/antisense structure
An siRNA that targets human CD274 mRNA, comprising a sense strand and an antisense strand, wherein the antisense strand comprises nucleotides selected from unmodified nucleotides and modified nucleosides.
Modified nucleoside content in the antisense strand
Each modified nucleoside contains a modified sugar, contains a modified nucleobase or is abasic, or both contains a modified sugar and contains a modified nucleobase or is abasic.
Selected backbone linkage chemistry and 5′-phosphate mimic
Each linkage between the nucleosides is phosphorothioate, phosphodiester, phosphoramidate, thiophosphoramidate, methylphosphate, methylphosphonate, phosphonoacetate, amide, boranophosphate, or any combination thereof, and the antisense strand comprises a 5′-phosphate mimic.
Seq id no:303 sequence with ≥85% complementarity to cd274 mrna fragment
The siRNA has a sequence as set forth in SEQ ID NO:303, and is at least 85% complementary to a fragment of human CD274 mRNA.
Mismatch limitation and seed-region mismatch exclusion
The siRNA has zero, one, or two mismatches relative to a fragment of human CD274 mRNA, and any mismatches are not present in the siRNA seed region.
2-nucleotide overhang
The siRNA further includes a 2-nucleotide overhang.
End conjugation of a targeting moiety
The antisense strand comprises a targeting moiety that is conjugated to the siRNA at the 5′ end, the 3′ end, or both ends.
Pharmaceutical composition including the sirna
A pharmaceutical composition that includes an effective amount of the siRNA together with a pharmaceutically acceptable carrier, diluent, excipient, or combinations thereof.
The claims define a CD274-targeting siRNA with modified nucleosides, specified linkage chemistry, a 5′-phosphate mimic, a required SEQ ID NO:303 sequence with at least 85% complementarity to human CD274 mRNA, and further limitations on mismatches, overhang structure, targeting-moiety end conjugation, and pharmaceutical composition inclusion.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating PD-L1 (CD274)-related diseases, including liver disease, cancers including hepatocellular carcinoma (HCC), hepatitis B (HBV), and viral diseases.
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