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Publication Number
US-12123003-B2
Publication Date
2024-10-22
Expiration Date
Abstract
The present disclosure relates to, inter alia, RNA molecules (e.g., RNA hairpin agonists) that bind to and agonize RIG-I-like receptors (RLRs), and to use of the molecules in methods for treating, or ameliorating one or more symptoms of, a disorder (e.g., cancer).
Core Innovation
The invention relates to synthetic RIG-I-like receptor (RLR) agonist hairpin RNAs. The agonist comprises a blunt-ended, hairpin RNA with a first polynucleotide connected to a second polynucleotide by a linker, where the first polynucleotide is sufficiently complementary to form a duplex with the second polynucleotide.
The duplex comprises less than 19 base pairs, and the 5′ most nucleotide of the first oligonucleotide comprises a 5′ diphosphate or triphosphate moiety, or a derivative or analog thereof. The agonist comprises a [AUCG]n repeat motif with n=3, where the 5′ most AUCG repeat motif is preceded by CG, or preceded by IG, or preceded by GG and each G in the AUCG motif is substituted by inosine.
The document further describes embodiments using specific nucleotide sequence motif frameworks and allowed nucleoside sets such as A, G, C, U, 5-methyluridine, and inosine. Additional described features include inosine–cytidine base pairing, modular first/second polynucleotide architecture, and allowed phosphate bioisosteres or derivatives, including phosphonate-, thiophosphonate-, phosphorothioate-, sulfate-, and sulfonate-like options.
Claims Coverage
The partial content identifies two independent claims: a first independent claim directed to contacting a cell with the RLR agonist to increase RLR-mediated functions, and a second independent claim directed to administering the same class of synthetic RLR agonists to stimulate immune responses and address cancer-related outcomes. Across these independent claims, the inventive elements focus on a blunt-ended hairpin RNA architecture, a short duplex less than 19 base pairs, a 5′ diphosphate or triphosphate moiety, and an AUCG repeat motif with inosine substitution and specified upstream nucleotide context.
Blunt-ended hairpin RNA agonist architecture that forms a short duplex
A method using a RLR agonist that specifically binds to an RLR, where the agonist comprises a blunt-ended, hairpin RNA comprising a first polynucleotide connected to a second polynucleotide by a linker, wherein the first polynucleotide is sufficiently complementary to the second polynucleotide to form a duplex, and wherein the duplex comprises less than 19 base pairs.
5′ diphosphate or triphosphate moiety at the 5′ end
A method wherein the 5′ most nucleotide of the first oligonucleotide comprises a 5′ diphosphate or triphosphate moiety, or derivative or analog thereof.
[AUCG]n repeat motif with n=3 and specified preceding context
A method wherein the agonist comprises a [AUCG]n repeat motif, wherein n=3, and wherein the 5′ most AUCG repeat motif is preceded by CG, or preceded by IG, or preceded by GG and each G in the AUCG motif is substituted by inosine.
Increasing RLR-mediated cytokine/ISG signaling or administering for immune stimulation and cancer outcomes
A method comprising contacting a cell with the RLR agonist to increase RLR-mediated production of one or more cytokines or increase RLR-mediated expression of one or more interferon-stimulated genes or to increase RLR-dependent intracellular signaling in the cell; or a method comprising administering to a subject an effective amount of the synthetic RLR agonist to stimulate an immune response, treat or delay progression of a cancer, or reduce or inhibit tumor growth.
The independent claims are grounded in a blunt-ended hairpin RNA RLR agonist with a short complementary duplex, a 5′ diphosphate or triphosphate moiety at the 5′ end, and an [AUCG]n repeat motif with specified preceding context including an inosine-substituted GG-preceded embodiment. The claims cover both cell-contact use to increase RLR-mediated cytokines, interferon-stimulated genes, or intracellular signaling, and subject administration to stimulate immune responses and address cancer progression or tumor growth.
Stated Advantages
Increases RLR-mediated production of one or more cytokines in a cell.
Increases RLR-mediated expression of one or more interferon-stimulated genes in a cell.
Increases RLR-dependent intracellular signaling in a cell.
Stimulates an immune response in a subject.
Treats or delays progression of a cancer in a subject.
Reduces or inhibits tumor growth in a subject.
Documented Applications
Increasing RIG-I-like receptor (RLR)-mediated production of one or more cytokines in a cell by contacting the cell with a synthetic RLR agonist hairpin RNA.
Increasing RLR-mediated expression of one or more interferon-stimulated genes in a cell by contacting the cell with the synthetic RLR agonist hairpin RNA.
Increasing RLR-dependent intracellular signaling in a cell by contacting the cell with the synthetic RLR agonist hairpin RNA.
Stimulating an immune response in a subject by administering an effective amount of the synthetic RLR agonist.
Treating or delaying progression of a cancer in a subject by administering an effective amount of the synthetic RLR agonist.
Reducing or inhibiting tumor growth in a subject by administering an effective amount of the synthetic RLR agonist.
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