WO2025143001A1 - Ｃ５ ｒｎａ配列に基づく新規二本鎖ｒｎａ及びその利用 - Google Patents

Ｃ５ ｒｎａ配列に基づく新規二本鎖ｒｎａ及びその利用 Download PDF

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WO2025143001A1
WO2025143001A1 PCT/JP2024/045860 JP2024045860W WO2025143001A1 WO 2025143001 A1 WO2025143001 A1 WO 2025143001A1 JP 2024045860 W JP2024045860 W JP 2024045860W WO 2025143001 A1 WO2025143001 A1 WO 2025143001A1
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double
stranded rna
sequence
strand
cell
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French (fr)
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菜穂子 ベイリー小林
徹彦 吉田
エリック ネルソン ベイリー
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Toagosei Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation

Definitions

  • the present disclosure relates to double-stranded RNA and compositions containing the double-stranded RNA, and methods of using the same. Specifically, the present disclosure relates to double-stranded RNA used to suppress or inhibit tumor cell proliferation or metastasis, and compositions comprising the double-stranded RNA.
  • This application claims priority based on Japanese Patent Application No. 2023-221597, filed on December 27, 2023, the entire contents of which are incorporated herein by reference.
  • the complement system is a part of the innate immune system that protects the body from infection by pathogens such as bacteria and viruses. It is made up of dozens of interacting proteins. Complement system proteins are mainly produced in the liver and circulate in the blood and extracellular fluid. Most of the complement system proteins are normally inactive, but are activated by infection with bacterial and viral pathogens. There are three complement activation pathways: the classical pathway (first pathway), the lectin pathway (mannose-binding lectin pathway), and the alternative pathway (second pathway). Activation of the complement system leads to opsonization, migration of phagocytes and lymphocytes, and elimination of pathogens by the membrane attack complex (MAC). However, excessive activation and inappropriate regulation of complement have been suggested to be involved in autoimmune diseases, inflammatory diseases, and tumor cell proliferation and metastasis.
  • C5 complement component C5
  • C5a acts alone as a diffusible signal, attracting phagocytes and lymphocytes to the site of infection and promoting inflammatory reactions.
  • C5 plays an important role as a late component of the complement activation pathway, and pharmaceutical compositions that inhibit the activation and expression of C5 have also been disclosed.
  • JP 2018-123125 A discloses an antibody pharmaceutical composition targeting C5.
  • JP 2019-518028 A discloses siRNA targeting C5.
  • the double-stranded RNA disclosed herein is composed of a first strand and a second strand complementary to the first strand.
  • the first strand has a main sequence consisting of 19 to 23 bases, the 5'-terminal base of which is guanine (G) or cytosine (C), and an additional sequence consisting of 2 to 4 bases added to the 3'-terminal side of the main sequence.
  • the main sequence is determined from the base sequence encoding the signal peptide region of complement component C5.
  • RNAi small interfering RNA
  • This effect is to inhibit the proliferation of cells in which complement components are involved, at least by suppressing the expression of complement component C5.
  • the base sequence constituting the additional sequence is thymine-thymine (TT). This can improve the stability of the double-stranded RNA.
  • the present disclosure provides a composition capable of inhibiting the proliferation of at least one type of cell.
  • One embodiment of the composition disclosed herein comprises a first strand and a second strand complementary to the first strand, the first strand having a main sequence of 19 to 23 bases, the 5'-terminal base of which is guanine (G) or cytosine (C), and an additional sequence of 2 to 4 bases added to the 3'-terminal side of the main sequence.
  • the main sequence includes a double-stranded RNA determined from a base sequence encoding a signal peptide region of complement system factor C5.
  • the cell type whose proliferation is inhibited by the composition is a tumor cell. This allows for more reliable inhibition of cell proliferation.
  • composition disclosed herein includes a peptide fragment that has cell membrane permeability and can pass through the cell membrane from the outside of the cell to introduce a foreign substance into the cytoplasm. This makes it easier to introduce the double-stranded RNA into the target cell.
  • the present disclosure provides a method for inhibiting the proliferation of at least one type of cell.
  • One aspect of the method disclosed herein includes the steps of (1) preparing a composition disclosed herein, and (2) supplying the composition to a target cell in vitro. This makes it possible to inhibit the proliferation of cells in which a complement component is involved.
  • complement components refers to proteins involved in the complement pathway and its activation.
  • Examples of complement components include C1 (C1r, C1s, C1p), C2, C3, C4, C5, C6, C7, C8, C9, CFB, CFD, MBL, and MASP.
  • FIG. 1 is a schematic diagram showing an outline of complement activation.
  • C1, C2, C4, and the like are mainly involved.
  • the classical pathway begins with the binding of IgM or IgG antibody molecules to complement component C1q. C1r and C1s are activated, and C2 and C4 are degraded into C2a and C2b, and C4a and C4b, respectively.
  • the main sequence of the sense strand can be, for example, a part of the base sequence encoding the signal peptide region of C5. This allows the double-stranded RNA to function as an siRNA (small interfering RNA) targeting C5. In addition, since the base sequence of the signal peptide region of C5 is located upstream of the mRNA, when the double-stranded RNA functions as an siRNA, it can effectively suppress the expression of C5.
  • the base sequence shown in SEQ ID NO:1 (the DNA sequence corresponding to the RNA sequence of SEQ ID NO:21) is the 3rd to 21st bases of the base sequence encoding human C5 (i.e., the sequence from the start codon to the stop codon).
  • the base sequence shown in SEQ ID NO:2 (the DNA sequence corresponding to the RNA sequence of SEQ ID NO:22) is the 4th to 22nd bases of the base sequence encoding human C5.
  • the base sequence shown in SEQ ID NO:3 (the DNA sequence corresponding to the RNA sequence of SEQ ID NO:23) is the 6th to 24th bases of the base sequence encoding human C5.
  • the base sequence shown in SEQ ID NO:4 (the DNA sequence corresponding to the RNA sequence of SEQ ID NO:24) is the 7th to 25th bases of the base sequence encoding human C5.
  • the base sequence shown in SEQ ID NO:5 (the DNA sequence corresponding to the RNA sequence of SEQ ID NO:25) is the 13th to 21st bases of the base sequence encoding human C5.
  • the base sequences shown in SEQ ID NO:1 to 5 are part of the base sequence of the signal peptide region of human C5.
  • Double-stranded RNA composed of the main sequences shown in SEQ ID NOs: 21 to 25 can be supplied to at least one type of cell to suppress or inhibit the proliferation of the cell.
  • tumor cells e.g., neuroblastoma, breast cancer, lung cancer, etc.
  • C5 is expressed at low levels in normal cells other than tumor cells, but is overexpressed in tumor cells. Therefore, even if the double-stranded RNA disclosed herein is supplied to normal cells, the amount of C5 present in normal cells is relatively small, so it is considered that the double-stranded RNA will have little effect.
  • the sense strand may be, for example, composed of a base sequence of 21 to 27 bases, 21 to 25 bases, or 21 to 23 bases.
  • the sense strand is composed of 21 bases, consisting of a 19-base main sequence and 2-base additional sequence. In such an example, RNAi can be effectively induced.
  • the sense strand or antisense strand is typically composed of chemically unmodified ribonucleotides (RNA).
  • the double-stranded RNA of the present disclosure may contain DNA, chemically modified DNA or RNA, other known nucleotide analogs, etc., to the extent that the technology of the present disclosure is not significantly impaired. That is, one or more bases (e.g., two bases) of the sense strand or antisense strand may be replaced with chemically modified RNA (or DNA) such as methylated or pseudouridylated.
  • chemically modified RNA include pseudouridine, N1-methylpseudouridine, 5-methylcytosine, or inosine.
  • one or more bases (e.g., two bases) of uridine in the double-stranded RNA of the present disclosure may be replaced with pseudouridine.
  • the antisense strand may have a main sequence complementary to the sense strand, and an additional sequence consisting of 2 to 4 bases added to the 5' or 3' end of the complementary main sequence.
  • the additional sequence may be added to the 3' end of the complementary base sequence.
  • the additional sequence of the antisense strand is added to the 3' end of the complementary base sequence.
  • the configuration of the additional sequence in the antisense strand may be the same as the configuration of the additional sequence of the sense strand described above.
  • the base sequence of the additional sequence of the antisense strand is the same as the additional sequence of the sense strand to which it hybridizes, but it may be a different base sequence.
  • the antisense strand is composed of a base sequence of, for example, 21 to 27 bases, and may be composed of 21 to 25 bases, or 21 to 23 bases.
  • the antisense strand is composed of a base sequence of the same length as the sense strand, and all or part of the base sequence, excluding the additional sequence, is composed of a base sequence complementary to the main sequence of the sense strand.
  • the antisense strand is composed of a base sequence of the same length as the sense strand, and all of the base sequence, excluding the additional sequence, is composed of a base sequence complementary to the main sequence of the sense strand.
  • the sense strand and antisense strand constituting the double-stranded RNA disclosed herein can be produced according to a general chemical synthesis method. For example, they can be synthesized using a commercially available DNA/RNA automatic synthesizer. In addition, the sense strand and antisense strand can be synthesized in vitro or in vivo based on genetic engineering techniques. In addition, the synthesized sense strand and antisense strand are preferably purified, and can be purified, for example, by HPLC or the like.
  • the double-stranded RNA disclosed herein can be produced, for example, by annealing (hybridizing) a sense strand and an antisense strand.
  • the annealing method may be any conventional method.
  • annealing can be performed by mixing equal amounts of a sense strand and an antisense strand in a solvent, heating at 90°C for 1 to 5 minutes, and then cooling to 4°C to room temperature.
  • a solvent include distilled water, pure water, ultrapure water, and buffers (e.g., HEPES-KOH buffer at pH 7.4, PBS, etc.).
  • buffers e.g., HEPES-KOH buffer at pH 7.4, PBS, etc.
  • composition includes the above-mentioned double-stranded RNA.
  • the composition may include various medicamentally (pharmacologically) acceptable carriers depending on the form of use.
  • a carrier generally used in medicine as a diluent, excipient, etc. is preferable.
  • a carrier varies appropriately depending on the use and form of the composition.
  • water, physiological buffer solutions, various organic solvents, etc. are included.
  • such a carrier may be an aqueous solution of alcohol (ethanol, etc.) of an appropriate concentration, glycerol, a non-drying oil such as olive oil, or a liposome.
  • secondary components that can be contained in the pharmaceutical composition include various fillers, extenders, binders, moisturizers, surfactants, dyes, fragrances, etc.
  • the composition may include carriers used in conventionally known drug delivery systems (DDS).
  • DDS drug delivery systems
  • compositions disclosed herein are not particularly limited.
  • typical forms of the composition include liquids, suspensions, emulsions, aerosols, foams, granules, powders, tablets, capsules, and ointments.
  • the composition may be freeze-dried or granulated to be dissolved in physiological saline or an appropriate buffer solution (e.g., PBS) immediately before use to prepare a medicinal solution.
  • compositions using double-stranded RNA (main component) and various carriers (secondary components) as materials may be in accordance with conventionally known methods, and such formulation methods themselves do not characterize the present disclosure, so detailed explanations are omitted.
  • main component double-stranded RNA
  • secondary components secondary components
  • the composition disclosed herein inhibits the proliferation of at least one type of cell.
  • the cells whose proliferation is inhibited are cells in which expression of C5 is involved, such as tumor cells (e.g., neuroblastoma, breast cancer, lung cancer, lymphoma, etc.), hepatic cells, eye cells, etc.
  • the composition disclosed herein preferably inhibits the proliferation of tumor cells.
  • the double-stranded RNA and composition disclosed herein can be preferably used as an antitumor agent (anticancer agent) that suppresses the proliferation of tumor cells.
  • composition disclosed herein includes, in addition to the double-stranded RNA described above, a peptide fragment (cell-penetrating peptide, CPP) that has cell membrane permeability and can pass through the cell membrane from outside the cell to introduce a foreign substance into the cytoplasm.
  • the peptide fragment is directly or indirectly bound (linked) to the double-stranded RNA disclosed herein to construct a construct of the peptide fragment and the double-stranded RNA.
  • double-stranded RNA has a negative charge and cannot pass through the cell membrane.
  • the construct of the peptide fragment and the double-stranded RNA can be introduced into the cytoplasm.
  • the number of amino acid residues of the peptide fragment is not limited as long as the cell membrane permeability is not impaired.
  • the present disclosure may provide a method for inhibiting the proliferation of at least one type of cell using the composition disclosed herein, the method comprising the steps of preparing a composition disclosed herein and delivering the composition to a cell of interest.
  • the method of administration of the composition is not particularly limited, and may be similar to the method conventionally used for the treatment of animals.
  • the composition may be used in vivo in a manner and dosage appropriate to its form and purpose.
  • a liquid formulation it can be administered in a desired amount to the affected area (e.g., malignant tumor tissue, virus-infected tissue, inflammatory tissue, etc.) of a patient or an individual animal (i.e., a living body) by intravenous, intralymphatic, intramuscular, subcutaneous, intradermal, or intraperitoneal injection.
  • a solid form such as a tablet or a gel or aqueous jelly such as an ointment can be administered directly to a specific tissue (e.g., an affected area such as a tissue or organ containing tumor cells, inflammatory cells, etc.).
  • a solid form such as a tablet can be administered orally.
  • the amount of the composition to be supplied in vivo is not particularly limited.
  • the lower limit of the amount of double-stranded RNA per kg of an animal may be 0.01 mg or more, 0.05 mg or more, or 0.1 mg or more.
  • the upper limit of the amount of double-stranded RNA per kg of an animal may be, for example, 10 mg or less, 5 mg or less, or 1 mg or less.
  • the amount of the composition to be supplied in vitro is not particularly limited.
  • the lower limit of the double-stranded RNA concentration may be, for example, 1 nM or more, 5 nM or more, or 10 nM or more.
  • the upper limit of the double-stranded RNA concentration in such a culture medium may be, for example, 10 ⁇ M or less, 5 ⁇ M or less, 2 ⁇ M or less, 1 ⁇ M or less, or 100 nM or less.
  • the sense strand of the double-stranded RNA of sample 1 is composed of a main sequence (part of the base sequence encoding the signal peptide region of C5) consisting of SEQ ID NO: 21 and an additional sequence consisting of TT added to the 3' end of the main sequence.
  • the sense strand of the double-stranded RNA of samples 2 to 5 shown in Table 1 is composed of a main sequence (part of the base sequence encoding the signal peptide region of C5) consisting of SEQ ID NO: 22 to 25 and an additional sequence consisting of TT added to the 3' end of the main sequence.
  • the sense strand of the double-stranded RNA of sample 6 is composed of a main sequence (a random, artificially created sequence) consisting of SEQ ID NO: 8 and an additional sequence consisting of TT added to the 3' end of the main sequence.
  • the antisense strand of each example is composed of a sequence complementary to the main sequence and an additional sequence consisting of TT added to the 3' end of the sequence.
  • the SK-N-SH strain which is a human neuroblastoma cell, was used as the tumor cell.
  • the SK-N-SH cells were pre-cultured in a culture medium of 10% FBS (fetal bovine serum) + E-MEM (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Cat No. 051-07615) + 1% MEM non-essential amino acid solution (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Cat No. 139-15651). Note that 0.5% penicillin-streptomycin (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Cat No. 168-23191) was added to the culture medium only during pre-culture, but was not added during the following culture and evaluation.
  • the SK-N-SH cells that had adhered to the culture plate were washed with PBS, and then a 0.25% trypsin/EDTA solution was added and incubated at 37°C for 2 minutes. After the incubation, the above culture medium was added to inactivate the trypsin. Then, the cells were precipitated by centrifugation at 150 ⁇ g for 5 minutes. After removing the supernatant generated by centrifugation, the above culture medium was added to the precipitate (cell pellet) to prepare a cell suspension of approximately 5 ⁇ 10 4 cells/mL. A commercially available 96-well plate was prepared, and the cell suspension was seeded in each well at 5 ⁇ 10 3 cells/100 ⁇ L/well, and incubated overnight at 37°C under 5% CO 2 .
  • RNA solution prepared to 2 mM with PBS was mixed with 75 ⁇ L of Opti-MEM (trademark) to prepare solution A.
  • Opti-MEM trademark
  • RNAiMAX Lipofectamine (trademark) RNAiMAX was mixed with 75 ⁇ L of Opti-MEM (trademark) to prepare solution B.
  • solution C equal amounts of solution A and solution B were mixed to prepare solution C, which was then incubated at room temperature for 5 minutes.
  • the prepared solution C was added to the wells in which SK-N-SH cells were cultured, at 11 ⁇ L/well (final concentration of double-stranded RNA was 4 ⁇ M). The mixture was then incubated at 37° C. under 5% CO 2 for 3 days.
  • Cell proliferation was evaluated using Cell Counting Kit-8 (CCK-8, Dojin Kagaku Kenkyusho).
  • CCK-8 Cell Counting Kit-8
  • siRNA siRNA
  • the 96-well plate in which SK-N-SH cells had been cultured was removed, 10 ⁇ L of CCK-8 was added to each well, and the plate was incubated at 37° C. under 5% CO 2 for 1.5 hours.
  • the absorbance of each well was measured at 450 nm.
  • the absorbance was the average value of three wells.
  • a well containing only the culture medium and CCK-8 reagent was provided as a blank. The value obtained by subtracting the absorbance of the blank from the absorbance of sample 1 was used as the measured value of sample 1.
  • Samples 2 to 6 were prepared in the same manner as Sample 1, except that the double-stranded RNA in Samples 2 to 6 was changed to the double-stranded RNA in Samples 2 to 6 shown in Table 1.
  • Comparative Example 1 was the same as sample 1, except that a PBS solution was used instead of the RNA solution in sample 1. That is, in the comparative example, no double-stranded RNA was introduced.
  • the double-stranded RNA of samples 1 and 2 showed a particularly excellent effect of inhibiting the proliferation of human neuroblastoma cells. Furthermore, the double-stranded RNA of samples 1 to 5 had the same or better cell inhibition function even at one-tenth the concentration. Of these, the double-stranded RNA of sample 2 had an improved function of inhibiting the proliferation of human neuroblastoma cells by lowering the concentration.

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PCT/JP2024/045860 2023-12-27 2024-12-25 Ｃ５ ｒｎａ配列に基づく新規二本鎖ｒｎａ及びその利用 Pending WO2025143001A1 (ja)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016518331A (ja) * 2013-03-14 2016-06-23 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 補体成分Ｃ５ｉＲＮＡ組成物及びその使用方法
JP2019518028A (ja) * 2016-06-10 2019-06-27 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 補体成分Ｃ５ｉＲＮＡ組成物及び発作性夜間血色素尿症（ＰＮＨ）を処置するためのその使用方法
US20190218550A1 (en) * 2015-02-17 2019-07-18 Dicerna Pharmaceuticals, Inc. Methods and compositions for the specific inhibition of complement component 5(c5) by double-stranded rna

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CA2936158C (en) * 2014-02-05 2023-06-13 Yeda Research And Development Co. Ltd. Use of mir-135 or precursor thereof for the treatment and diagnosis of a bipolar disease
JP2023013932A (ja) * 2021-07-14 2023-01-26 東亞合成株式会社 ＳＡＲＳ－ＣｏＶ－２ ＲＮＡ配列に基づく新規ｓｉＲＮＡ及びその利用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016518331A (ja) * 2013-03-14 2016-06-23 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 補体成分Ｃ５ｉＲＮＡ組成物及びその使用方法
US20190218550A1 (en) * 2015-02-17 2019-07-18 Dicerna Pharmaceuticals, Inc. Methods and compositions for the specific inhibition of complement component 5(c5) by double-stranded rna
JP2019518028A (ja) * 2016-06-10 2019-06-27 アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 補体成分Ｃ５ｉＲＮＡ組成物及び発作性夜間血色素尿症（ＰＮＨ）を処置するためのその使用方法

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