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Publication Number
US-12539310-B2
Publication Date
2026-02-03
Expiration Date
Abstract
A hetero-structured RNA with two 3′-overhangs and use thereof as an immune stimulant are provided.
Core Innovation
The invention relates to a hetero-structured RNA (hsRNA) comprising a heteropolymeric double-stranded RNA (dsRNA) region and single-stranded RNA (ssRNA) regions. The ssRNA regions are positioned at the 3′-end of the first strand and the 3′-end of the second strand, and the hsRNA is a RNase T1 cleaved product of a double-stranded RNA formed by base pairing a nucleotide sequence of SEQ ID NO: 30 with a nucleotide sequence of SEQ ID NO: 61.
The ssRNA region includes the UAUAG sequence at the 3′-end of the first strand and the second strand. The disclosed concept uses defined-length ss overhangs flanking a heteropolymeric dsRNA core, producing a hetero-structured RNA with a defined overhang sequence relative to the dsRNA region. The document further provides an hsRNA production concept involving bidirectional transcription using opposing promoters on a template and RNase T1 cleavage to generate the defined-length ssRNA overhangs.
The hsRNA is positioned as a TLR3 ligand with potential TLR7/8-like activity. The disclosure also describes formulation and use concepts in pharmaceutical compositions and methods for treating infections and cancer, and for enhancing antigen-specific immune responses.
Extensive evidence in the disclosure describes that hsRNA activates dendritic cells, skews immunity, and includes Th1 marker and cytokine profiles, as well as length-dependent immune activity. The disclosure also describes improved physicochemical homogeneity and stability versus PolyIC derivatives, and documents in vivo adjuvant effects in vaccine contexts, including dose sparing, along with anti-tumor effects and synergy with immune checkpoint/agonist antibodies (PD-1 and OX40).
Claims Coverage
The independent claim is clm-00001. The main inventive features center on the structural definition of the hsRNA and its derivation as an RNase T1 cleaved product, including specific placement of ssRNA regions at 3′ ends and the UAUAG sequence within those ssRNA regions. Dependent claims further cover immune-response enhancement by administering the hsRNA, and pharmaceutical composition use for infection/cancer and antigen immune response elicitation, including narrowing to viral versus bacterial infections and adding an antigen or therapeutic agent.
Hetero-structured RNA with 3′-end ssRNA overhangs flanking a heteropolymeric dsRNA core
A hetero-structured RNA (hsRNA) comprising a heteropolymeric double-stranded RNA (dsRNA) region with a first strand and a second strand and single-stranded RNA (ssRNA) regions, wherein the ssRNA regions are positioned at the 3′-end of the first strand and the 3′-end of the second strand.
RNase T1 cleaved defined dsRNA base pairing between SEQ ID NO: 30 and SEQ ID NO: 61
The hsRNA is a RNase T1 cleaved product of a double-stranded RNA formed by base pairing the nucleotide sequence of SEQ ID NO: 30 with the nucleotide sequence of SEQ ID NO: 61.
UAUAG ssRNA overhang sequence at the 3′ ends of both dsRNA strands
The ssRNA region is the UAUAG sequence at the 3′-end of the first strand and the second strand.
Administering hsRNA to enhance an immune response to an antigen
A method for enhancing an immune response to an antigen by administering a therapeutically effective amount of the hsRNA of claim 1 to a subject in need of treatment.
Pharmaceutical composition comprising hsRNA
A pharmaceutical composition containing the hsRNA from claim 1.
Using the pharmaceutical composition for infection or cancer and/or eliciting antigen immune response
A pharmaceutical composition used for preventing or treating an infection or cancer, or for eliciting an immune response to an antigen.
Treating viral versus bacterial infections
The pharmaceutical composition for preventing or treating an infection is used for treating either a viral or bacterial infection.
Pharmaceutical composition further including an antigen or therapeutic agent
The pharmaceutical composition further includes an antigen or a therapeutic agent.
Across the independent claim and dependents, the claimed innovation is the structural and sequence-defined hsRNA in which UAUAG ssRNA regions are positioned at the 3′ ends of a heteropolymeric dsRNA core, and the hsRNA is defined as an RNase T1 cleaved product derived from base pairing SEQ ID NO: 30 and SEQ ID NO: 61. Coverage then extends to immune-response enhancement to an antigen and pharmaceutical-composition use for infection/cancer treatment and antigen immune response elicitation, with further narrowing to viral versus bacterial infections and addition of an antigen or therapeutic agent.
Stated Advantages
Activates dendritic cells and skews immunity, including Th1 marker and cytokine profiles.
Shows length-dependent immune activity.
Improved physicochemical homogeneity and stability versus PolyIC derivatives.
Provides in vivo vaccine adjuvant effects, including dose sparing for influenza and meningococcal vaccines.
Provides anti-tumor effects and synergy with immune checkpoint/agonist antibodies (PD-1, OX40).
Documented Applications
Enhancing an immune response to an antigen by administering hsRNA to a subject in need of treatment.
Preventing or treating an infection.
Preventing or treating cancer.
Eliciting an immune response to an antigen using a pharmaceutical composition containing hsRNA.
Treating either a viral or a bacterial infection using the pharmaceutical composition.
Vaccine adjuvant use including influenza vaccine contexts and meningococcal vaccine contexts with dose-sparing effects.
Anti-tumor use in melanoma, colorectal cancer, lung cancer, and TNBC contexts described in the document, including synergy with PD-1 and OX40.
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