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Novel ribonucleic acid and pharmaceutical composition based on same

A base and base sequence technology, applied in the field of novel ribonucleic acid, can solve the problems of low stability of RNaseT1 and the length of dsRNA analogs are not constant, and achieve the purpose of reducing antigenic mass, improving polarization cross-protection reaction, and enhancing innate immunity. Effect

Pending Publication Date: 2022-07-15
NA VACCINE INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In summary, the length of Poly(I:C)-based dsRNA analogs is not constant, and there are unspecified number of gaps in unspecified positions inside the dsRNA, resulting in low stability to RNase T1 (Patent Document 3, Non- Patent Document 2 and Non-Patent Document 5)

Method used

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  • Novel ribonucleic acid and pharmaceutical composition based on same
  • Novel ribonucleic acid and pharmaceutical composition based on same
  • Novel ribonucleic acid and pharmaceutical composition based on same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0213] In vivo dendritic cell (DC) activation by hsRNA-based next adjuvant

[0214] This example demonstrates in vivo innate immune activity by hsRNA-based next adjuvant (abbreviated as NA) by intraperitoneal (i.p: intraperitoneal) injection into C57BL / 6 mice ( figure 1 ).

[0215] An example of the NA (alias NVT or VP10) of the invention (Table 2) induces differentiation of dendritic cell markers (CD40, CD86 and MHC-II) to levels equal to or higher than 100 μg of Poly(I:C) ( figure 1 ). NA further induces type 1 interferon beta (IFN-β), which correlates with the skewness of naive CD4 T cells to Th1 CD4 T cells and the secretion of IL-6 and IL-12 ( figure 1 ). In addition, NA induced T-bet (a Th1 cell marker) and IFN-γ, but not Th2 cytokines (IL-4) and Th17 cytokines (IL-17A) ( figure 1 ). NA strongly activated DCs compared to the Poly(I:C) positive control group.

Embodiment 2

[0217] In vivo DC activation depends on hsRNA length rather than sequence

[0218] hsRNA was prepared from two independent backbones of different lengths, where the dsRNA region varied from 106 to 806 bp, but the ssRNA overhang at both ends in this Example 2 was constant at 17 bases ( figure 2 A and figure 2 B), and splenic DC activation was tested intraperitoneally in mice.

[0219] The level of DC activation increases with hsRNA length, as assessed by induction of CD40 and CD86, showing high activity at 400 to 900 bases ( figure 2 C and figure 2 D).

[0220] All hsRNAs showed better activity than the positive control Poly(I:C).

[0221] Because all ssRNA overhangs are non-complementary, with 17 bases at each end, for a total of 34 bases, differences in DC activation from hsRNAs must arise with increasing dsRNA length. Therefore, dsRNAs with a range of about 406 to 806 bp showed high activity.

[0222] When rechecking the 540hsRNA (506bp dsRNA), which showed high ac...

Embodiment 3

[0224] Antigen-specific antibody responses depend on hsRNA length

[0225] More hsRNAs with a broad range (353 to 1682 bases) were derived from a third backbone vector, different from the first two vectors shown in Example 2 ( image 3 A). After transient co-transfection of these RNAs with an IFN-β promoter-driven vector into HEK 293 cells, a surrogate reporter for innate immune activation was identified ( image 3 B). IFN-β promoter activity increased proportionally to the length of hsRNA and dsRNA, reaching a maximum in the range of 406 bp to 806 bp. Notably, this activity was independent of the specific RNA sequence, which is consistent with Example 2.

[0226] Some of these (R3, R5, R7 and R10) were complexed with the model antigen OVA and tested in vivo for their induction of anti-OVA IgG in mice.

[0227] Consistent with the above, high levels of anti-OVA IgG1 and Th1-mediated anti-OVA IgG2 ( image 3 C).

[0228] Taken together, hsRNA (140 to 1682 bp) and dsRNA (1...

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Abstract

The present invention relates to a heterostructured RNA (hsRNA) comprising ssRNA and dsRNA wherein the dsRNA has any length and sequence, has complete complementarity, acts as a TLR3 ligand, and is located in the middle of the hsRNA, and the ssRNA has any sequence (preferably a TLR7 ligand sequence), has a length, and is linked to the two 3'ends of the dsRNA. In addition, the present invention relates to a pharmaceutical composition for the prevention and treatment of viral or bacterial infections and cancer comprising the same.

Description

technical field [0001] The present invention relates to a novel ribonucleic acid (RNA: ribonucleic acid) that overcomes the problems of Poly(I:C), such as length heterogeneity, high toxicity and inconsistent activity. Specifically, the present invention relates to a so-called hetero-structured RNA (hsRNA: hetero-structured RNA) comprising a homopolymeric double-stranded RNA (dsRNA: double-stranded RNA) in the middle and a dsRNA pendant on both sides. Single-stranded RNA (ssRNA: single-stranded RNA) at each 3' end, wherein both dsRNA and ssRNA can have any specific sequence and a specific defined length. While the dsRNA regions are fully complementary and function as TLR3 ligands, the ssRNA sequences are characterized by preferentially TLR7-like ligands. hsRNAs are extremely uniform in length and have high innate immune activity and stability. The disclosed hsRNA and dsRNA are agents with few side effects and thus can be used as active ingredients of compositions for preventi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113A61K39/39A61K39/00A61K39/12A61K39/395A61P31/04A61P31/12A61P35/00
CPCC12N15/113A61K39/39A61P35/00A61P31/12A61P31/04A61K39/0011A61K39/39558A61K39/12A61K39/3955C12N2310/34A61K2039/55561A61K2039/585C12N15/117C12N2310/53C12N2310/17C12N2510/00A61K2039/5156C07K16/2818C07K16/2878C07K2317/76C07K2317/75A61K39/395A61K2300/00A61K31/7105
Inventor 金东镐姜命秀
Owner NA VACCINE INST
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