Synthetic RIG-I-like receptor agonists
AssigneeCheckmate Pharmaceuticals, Inc.
InventorsArthur M. Krieg, Aaron Jay Morris
Life of this patent
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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).
Claims18
A method to increase RIG-I-like receptor (RLR)-mediated production of one or more cytokines in a cell or to increase RLR-mediated expression of one or more interferon-stimulated genes in a cell, the method comprising contacting the cell with a RLR agonist that specifically binds to a RLR,
- wherein 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,
- wherein the duplex comprises less than 19 base pairs, wherein the 5′ most nucleotide of the first oligonucleotide comprises a 5′ diphosphate or triphosphate moiety, or derivative or analog thereof;
- 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
- wherein the 5′ most AUCG repeat motif is preceded by IG, or
- wherein the 5′ most AUCG repeat motif is preceded by GG and each Gin the AUCG motif is substituted by inosine,
- wherein the agonist increases RLR-mediated cytokine production in the cell, increases RLR-mediated expression of one or more interferon-stimulated genes in the cell, or increases RLR-dependent intracellular signaling in the cell.
A method of stimulating an immune response, treating or delaying progression of a cancer, or reducing or inhibiting tumor growth in a subject, the method comprising administering to the subject an effective amount of a synthetic RIG-I-like receptor (RLR) agonist that specifically binds to a RIG-I-like receptor (RLR),
- wherein 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,
- wherein the duplex comprises less than 19 base pairs, wherein the 5′ most nucleotide of the first oligonucleotide comprises a 5′ diphosphate or triphosphate moiety, or derivative or analog thereof;
- 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
- wherein the agonist comprises a [AUCG]n repeat motif, wherein n=3, and wherein the 5′ most AUCG repeat motif is preceded by IG, or
- wherein the agonist comprises a [AUCG]n repeat motif, wherein n=3, and wherein the 5′ most AUCG repeat motif is preceded by GG, and wherein each Gin the AUCG motif is substituted by inosine.
Dependencies are inferred from the claim text.