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Publication Number
US-10907161-B2
Publication Date
2021-02-02
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
A synthetic RIG-I-like receptor (RLR) agonist is provided that specifically binds to an RLR. The agonist comprises a blunt-ended hairpin RNA comprising a first polynucleotide connected to a second polynucleotide by a linker, wherein the first and second polynucleotides are sufficiently complementary to form a duplex of less than 19 base pairs.
The 5 most nucleotide of the first oligonucleotide comprises a 5 diphosphate or triphosphate moiety, or a derivative or analog thereof. The agonist further comprises an [AUCG]n repeat motif where n=3, with the 5 most AUCG repeat preceded by CG, IG, or GG, and in one case each G in the AUCG motif is substituted by inosine.
The disclosed hairpin RNA includes linker embodiments comprising a nucleotide linker, including a tetraloop motif such as UUCG, or a non-nucleotide linker. The document also describes RLR binding and induction of cytokine and interferon-stimulated genes (ISGs), together with duplex stability and reduced off-target binding or immunogenicity.
Claims Coverage
The independent claim coverage centers on a synthetic RLR agonist with blunt-ended hairpin RNA, a duplex of less than 19 base pairs, a 5 diphosphate or triphosphate moiety at the 5 end, and an [AUCG]n repeat motif with n=3 and specified 5 precedence; linker refinements are also recited.
Synthetic RIG-I-like receptor agonist specifically binds an RLR
A synthetic RIG-I-like receptor (RLR) agonist that specifically binds to an RLR.
Blunt-ended hairpin RNA duplex of less than 19 base pairs
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 the duplex comprises less than 19 base pairs.
5 diphosphate or triphosphate at the 5 most nucleotide of the first oligonucleotide
The 5 most nucleotide of the first oligonucleotide comprises a 5 diphosphate or triphosphate moiety, or derivative or analog thereof.
AUCG repeat motif with n=3 and specified precedence
The agonist comprises an [AUCG]n repeat motif, wherein n=3, and the 5 most AUCG repeat is preceded by CG, IG, or GG; in one embodiment each G in the AUCG motif is substituted by inosine.
Linker refinements including UUCG tetraloop and non-nucleotide linkers
The linker can include a nucleotide linker with a tetraloop such as UUCG, or a non-nucleotide linker.
The claim set covers a blunt-ended hairpin RNA RLR agonist with a short duplex, a 5 diphosphate or triphosphate moiety at the 5 end, and an [AUCG]n repeat motif (n=3) with specified 5 precedence and, in one embodiment, inosine substitution at each G. It also includes linker embodiments such as tetraloop and non-nucleotide linkers.
Stated Advantages
RLR binding.
Cytokine and interferon-stimulated genes (ISGs) induction.
Improved RLR-mediated biological activity including cytokine production, ISG expression, and intracellular signaling.
Improved binding affinity.
Improved duplex stability.
Reduced off-target binding and/or immunogenicity.
Improved uptake/bioavailability/half-life.
Decreased immunogenicity.
Documented Applications
Immune stimulation.
Cancer treatment, including tumor growth inhibition as described in the disclosure.
Combination regimens with other immunotherapies and immunostimulatory agents.
Use and evaluation of the RLR agonists in human PBMC transfection experiments with measurements of IFN- induction.
Pharmaceutical composition use including an agonist together with a pharmaceutically acceptable carrier.
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