WO2023013990A1 - 변형된 rt-let7을 유효성분으로 포함하는 간암의 예방 또는 치료용 조성물 - Google Patents
변형된 rt-let7을 유효성분으로 포함하는 간암의 예방 또는 치료용 조성물 Download PDFInfo
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- let7
- nucleic acid
- modified
- liver cancer
- acid molecule
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
- C12N2310/113—Antisense targeting other non-coding nucleic acids, e.g. antagomirs
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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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
Definitions
- the present invention relates to a pharmaceutical composition for preventing or treating liver cancer, and specifically, liver cancer comprising modified RT-LET7, which is an expression inhibitor of Let-7i-5p, or modified RT-LET7 equipped with a delivery system as an active ingredient. It relates to a pharmaceutical composition for the prevention or treatment of.
- Liver cancer is the 5th most frequent cancer worldwide, but it is an aggressive cancer with a mortality rate of 3rd (Ahn J, Flamm SL Hepatocellular carcinoma Dis Mon 2004;50:556-573). It is possible in only about 25% of patients, and most liver cancer patients die in a relatively short period of time due to locally advanced or metastatic diseases (Roberts LR, Gores GJ Hepatocellular carcinoma: molecular pathways and new therapeutic targets Semin Liver Dis 2005;25: 212-225) Hepatitis B virus, hepatitis C virus, and aflatoxin B1 are well known as major causes of liver cancer.
- liver cancer patients have not increased significantly over the past 20 years, and the mechanisms of development and progression of liver cancer are still unknown (Bruix J, et al Focus on hepatocellular carcinoma Cancer Cell 2004; 5:215-219) So far, molecular targeted therapy has been shown to be effective in the treatment of mature liver cancer (Shen YC, Hsu C, Cheng AL Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives J Gastroenterol; 45:794-807), it is unclear how these genetic alterations cause the clinical features observed in individual liver cancer patients.
- Histone deacetylases can be attached to gene promoters, often by corepressors or multi-protein transcriptional complexes, where they modify chromatin without directly binding to DNA.
- Histone deacetylases There are 18 HDACs, which are Class I (HDAC 1, 2, 3 and 8), Class II (HDAC 4, 5, 6, 7, 9 and 10), Class III (SIRT 1-7), and Class IV ( HDAC11) enzymes (Yang XJ, Seto E The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men Nat Rev Mol Cell Biol 2008;9:206-218) Histone acetyltransferases and HDACs are known to be involved in cell proliferation, differentiation and cell cycle regulation (Wita)
- HDAC6 is a member of the class IIb family of HDACs and acts as a cytoplasmic deacetylase associated with microtubules (MTs) and deacetylates ⁇ -tubulin ( Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, et al HDAC6 is a microtubule-associated Mis18 ⁇ . Nature 2002;417:455-458).
- miRNA is a type of endogenous small RNA with a length of 20-25 nucleotides present in cells. It is derived from DNA that does not synthesize proteins and is generated from hairpin-shaped transcripts. do. miRNA binds to the complementary sequence of the 3'-UTR of the target mRNA, induces translational inhibition or destabilization of the mRNA, and ultimately acts as a repressor to suppress protein synthesis of the target mRNA. It is known that one miRNA targets multiple mRNAs, and mRNAs can also be regulated by multiple miRNAs.
- macrophages phagocytose diseased cells (cancer cells) by phagocytosis, which occurs by mediating the binding of Fc fragments of antibodies to Fc receptors on the membrane surface of macrophages.
- tumors can escape the attack of immune cells, including macrophages, by subverting the normal immune regulatory machinery.
- CD47 a protein expressed in normal cells.
- CD47 interacts with a macrophage receptor called SIRP ⁇ (signal-regulatory protein ⁇ ), which leads to the transmission of a signal to the macrophages to "don't eat me (phagocytic blockade)", causing normal cells to leave.
- SIRP ⁇ signal-regulatory protein ⁇
- CD47 expression by cancer cells also makes them resistant to macrophages even when cancer cells are bound with antibodies.
- phagocytic block signal is turned off.
- One treatment strategy for this is to block the “phagocytic block” signal using a monoclonal antibody to CD47.
- RT-LET7 an expression inhibitor of Let-7i-5p
- RT-LET7 can be used as a pharmaceutical composition for the prevention or treatment of liver cancer by modifying the RT-LET7 to increase the effect compared to the existing RT-LET7.
- RT-LET7 inhibits Let-7i-5p in liver cancer cells and increases TSP1, and the increased TSP1 binds to CD47 and blocks the interaction with SIRP ⁇ of macrophages.
- CD47 of liver cancer cells and SIRP ⁇ of macrophages The present invention was completed by confirming that it can be used as an immuno-anticancer agent for the treatment of CD47-positive liver cancer by significantly increasing macrophage phagocytic activity through a mechanism that increases the immune activity of macrophages against cancer cells and exhibits an anticancer effect.
- An object of the present invention is to provide a nucleic acid molecule targeting Let-7i-5p.
- Another object of the present invention is to provide a nucleic acid molecule characterized in that a hepatocyte targeting moiety is bound to the nucleic acid molecule.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating liver cancer comprising the nucleic acid molecule as an active ingredient.
- Another object of the present invention is to provide an immunotherapeutic agent for the treatment of CD47-positive liver cancer comprising the nucleic acid molecule as an active ingredient.
- Another object of the present invention is to provide a method for preventing or treating liver cancer comprising administering the pharmaceutical composition to a subject.
- nucleic acid molecule represented by SEQ ID NO: 1 the nucleotide sequence is modified by 2'-O-Methoxyethyl (methoxyethyl), and a part of the backbone is phosphorothioate (phosphorothioate) It is to provide a nucleic acid molecule targeting Let-7i-5p, characterized in that a hepatocyte targeting moiety is bound thereto.
- the present invention is a nucleic acid molecule targeting Let-7i-5p, wherein the nucleic acid molecule is represented by the nucleotide sequence of SEQ ID NO: 1, and the nucleotide sequence is 2'-O-Methoxyethyl (methoxyethyl) It is characterized in that it is a modified nucleic acid, and provides a nucleic acid molecule characterized in that part or the entire backbone is modified with phosphorothioate.
- the present invention is a nucleic acid molecule targeting Let-7i-5p, wherein the nucleic acid molecule is represented by the nucleotide sequence of SEQ ID NO: 1, and the nucleotide sequence is modified by 2'-O-Methoxyethyl (methoxyethyl) nucleic acid It is characterized in that, part or the entire backbone is modified with phosphorothioate, and a hepatocyte targeting moiety is coupled to the nucleic acid molecule.
- the present invention provides a pharmaceutical composition for preventing or treating liver cancer comprising modified RT-LET7 as an active ingredient.
- the present invention provides a pharmaceutical composition for preventing or treating liver cancer comprising, as an active ingredient, a modified RT-LET7 to which a hepatocyte targeting moiety is bound.
- the present invention provides an immuno-anticancer pharmaceutical composition for the treatment of CD47-positive liver cancer comprising modified RT-LET7 as an active ingredient.
- the present invention provides an immunotherapeutic agent for the treatment of CD47-positive liver cancer comprising a modified RT-LET7 coupled with a hepatocyte targeting moiety as an active ingredient.
- the present invention provides a method for preventing or treating liver cancer comprising administering the pharmaceutical composition to a subject.
- the modified RT-LET7 according to the present invention or the modified RT-LET7 to which the hepatocyte targeting moiety is bound is compared to RT-LET7, which is an antisense microRNA (AS-miRNA) that inhibits Let-7i-5p. It has the effects of increasing the inhibition of 7i-5p expression, increasing the inhibition of liver cancer cell growth, increasing TSP1 expression, and increasing macrophage phagocytic activity.
- AS-miRNA antisense microRNA
- FIG. 1 is a diagram showing various modified structures (Fig. 1a) and inhibitory efficiency (Fig. 1b) of RT-LET7, which is an expression inhibitor of Let-7i-5p, according to an embodiment of the present invention (basic type: RT-LET7, Variants: RT-LET7-2, RT-LET7-4, RT-LET7-6 and RT-LET7-8).
- Figure 2 is a diagram confirming the effect of RT-LET7-8, which is the modified RT-LET7 of the present invention, to significantly and continuously inhibit Let-7i-5p in HCC cell lines, according to an embodiment of the present invention (FIG. 2a ; SNU-387, Fig. 2b; SNU-368, Fig. 2c; SNU-423).
- Figure 3 is a diagram confirming the growth inhibition of HCC cell lines and the increase in macrophage activity by RT-LET7-8, which is a modified RT-LET7 of the present invention, according to an embodiment of the present invention (FIG. 3a; MTT and cells Characteristics of Let-7i-5p tumor formation through survival analysis, Fig. 3b; TSP1 expression change after treatment with basic RT-LET7 and modified RT-LET7-8 through Western blot analysis, Fig. 3c; Basic RT-LET7 and Macrophage phagocytic activity of HCC cells treated with modified RT-LET7-8).
- Figure 4 is a diagram confirming the effect of inhibiting Let-7i-5p expression and the effect of continuously inhibiting Let-7i-5p in HCC cells of RT-LET7-8 combined with GalNAc.
- FIG. 5 is a diagram confirming the efficiency of inhibiting Let-7i-5p expression and the effect of continuously inhibiting Let-7i-5p in HCC cells of RT-LET7-8 coupled with Gal-LNP, according to an embodiment of the present invention; am.
- FIG. 6 is a diagram confirming the growth inhibition of HCC cell lines and the increase in macrophage activity by GalNAc-coupled RT-LET7-8 in an embodiment of the present invention (FIG. 6a; Let through MTT and cell viability assays). Characteristics of -7i-5p tumorigenesis, Fig. 6b; GalNAc-conjugated RT-LET7-8 after treatment and TSP1 expression change through Western blot analysis, Fig. 6c; GalNAc-conjugated RT-LET7-8 treatment macrophage phagocytic activity of HCC cells).
- Figure 7 is a diagram confirming the growth inhibition of HCC cell lines and the increase in macrophage activity by Gal-LNP-coupled RT-LET7-8 in one embodiment of the present invention (FIG. 6a; MTT and cell viability assays). Characteristics of Let-7i-5p tumorigenesis via Western blot analysis after treatment with Gal-LNP-coupled RT-LET7-8, Figure 6c; Gal-LNP-coupled RT- Macrophage phagocytic activity of HCC cells treated with LET7-8).
- FIG. 8 is a schematic diagram showing simple binding of hepatocyte target delivery systems (GalNAc and Gal-LNP) according to an embodiment of the present invention (FIG. 8a; Gal-LNP binding; FIG. 8b; Old-GalNAc binding; FIG. 8c; D-GalNAc binding).
- Figure 9 shows the efficiency of inhibiting Let-7i-5p expression and the continuous expression of Let-7i-5p in HCC cells of RT-LET7-8 to which GalNAc (D-GalNAc) having a different structure is bound, according to an embodiment of the present invention. This is a diagram confirming the inhibitory effect.
- FIG. 10 is a diagram confirming growth inhibition of HCC cell lines by RT-LET7-8 to which GalNAc (D-GalNAc) having a different structure is bound, according to an embodiment of the present invention.
- FIG. 11 is a diagram confirming the change in TSP1 expression and the increase in macrophage activity in HCC cell lines by RT-LET7-8 to which GalNAc (D-GalNAc) having a different structure is bound, according to an embodiment of the present invention.
- the present invention relates to a nucleic acid molecule represented by SEQ ID NO: 1, which targets Let-7i-5p.
- nucleic acid molecule of the present invention may be modified by 2'-O-Methoxyethyl (methoxyethyl) nucleotide sequence.
- the "nucleic acid molecule" of the present invention may have a part or the entire backbone modified with phosphorothioate, preferably from 1 to 5' end of the nucleotide of SEQ ID NO: 1.
- the backbone of the 4th nucleotide and 1 to 4 nucleotides from the 3' end may be modified with phosphorothioate, but is not limited thereto.
- the "nucleic acid molecule" of the present invention may be a hepatocyte-targeting moiety bound thereto.
- the hepatocyte-targeting moiety can be used without limitation as long as it is known as a liver tissue-targeting drug delivery system, for example, N-Acetylgalactosamine (GalNAc), Galactosyl lipidoid nanoparticle (Gal-LNP), Lipid-siRNA, Antibody -SiRNA, Peptide-ASO, Stable nucleic acid lipid particle, Exosome, Spherical nucleic acid, DNA cage, etc. (Nat Rev Drug Discov. 2020 Oct;19(10):673-694.).
- GalNAc N-Acetylgalactosamine
- Gal-LNP Galactosyl lipidoid nanoparticle
- Lipid-siRNA Lipid-siRNA
- Antibody -SiRNA Peptide-ASO
- Stable nucleic acid lipid particle Exosome
- Spherical nucleic acid DNA cage, etc.
- the Galactosyl lipidoid nanoparticle may be composed of cholesterol, DSPC, C16-PET2000-ceramide and ⁇ -galactosyl ceramide.
- N-Acetylgalactosamine may be represented by Chemical Formula 1 or 2, preferably represented by Chemical Formula 2, but is not limited thereto.
- the present invention relates to a pharmaceutical composition for preventing or treating liver cancer comprising the nucleic acid molecule as an active ingredient.
- composition of the present invention may inhibit the expression of Let-7i-5p.
- composition of the present invention may inhibit liver cancer cell growth.
- compositions of the present invention may increase the expression of thrombospondin-1 (TSP1).
- composition of the present invention may be one that increases macrophage phagocytic activity.
- the present invention relates to an immuno-anticancer agent for the treatment of CD47-positive liver cancer comprising the nucleic acid molecule as an active ingredient.
- TSP1 of the present invention can occupy the CD47 receptor and interfere with the interaction of CD47-SIRP ⁇ .
- the "nucleic acid molecule" of the present invention can modulate the let-7i-p-TSP1 signaling axis, and converts the CD47-SIRP ⁇ interaction between macrophages and HCC into CD47-TSP1 interaction, thereby increasing macrophage It may be to re-activate phagocytosis on HCC cells.
- the "liver cancer" of the present invention may be Let-7i-5p high expression liver cancer, it may be hepatocellular carcinoma, stage I, II, III, IVA or IVB stage hepatocellular carcinoma It may be carcinoma, more preferably stage III to IV hepatocellular carcinoma, which is more difficult to treat than the initial stage.
- liver cancer of the present invention may be TSP1 low expression liver cancer, it may be hepatocellular carcinoma, it may be stage I, II, III, IVA or IVB phase hepatocellular carcinoma, and it may be more advanced than the initial stage. More preferably, it is hepatocellular carcinoma of stage III to IV stage, which is difficult to treat.
- expression inhibition means to cause a decrease in expression (into mRNA) or translation (into protein) of a target gene, preferably thereby rendering target gene expression undetectable or insignificant. means to exist.
- prevention refers to any action that suppresses or delays the occurrence, development, and recurrence of liver cancer by administration of the composition according to the present invention.
- treatment means any action that improves or beneficially changes the symptoms of liver cancer and its complications by administration of the composition according to the present invention.
- Those of ordinary skill in the art to which the present invention pertains will be able to determine the degree of improvement, enhancement and treatment by knowing the exact criteria of the disease for which the composition of the present application is effective by referring to the data presented by the Korean Medical Association, etc. will be.
- the pharmaceutical composition may be one or more formulations selected from the group consisting of oral formulations, external preparations, suppositories, sterile injection solutions, and sprays.
- composition of the present invention may also include a carrier, diluent, excipient or a combination of two or more commonly used in biological preparations.
- the pharmaceutically acceptable carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, for example, Merck Index, 13th ed., Merck & Co. Inc. , saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components may be mixed and used. Customary additives may be added.
- diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate formulations for injection, such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
- formulations for injection such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
- it can be preferably formulated according to each disease or component by using an appropriate method in the art or by using a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
- composition of the present invention includes 0.0001 to 10% by weight of the protein, preferably 0.001 to 1% by weight, based on the total weight of the composition.
- the pharmaceutical composition of the present invention may further include pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, Lactose, Mannitol, Taffy, Gum Arabic, Pregelatinized Starch, Corn Starch, Powdered Cellulose, Hydroxypropyl Cellulose, Opadry, Sodium Starch Glycolate, Carnauba Lead, Synthetic Aluminum Silicate, Stearic Acid, Magnesium Stearate, Aluminum Stearate, Stearic Acid Calcium, white sugar, dextrose, sorbitol, and talc may be used.
- the pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.1 part by weight to 90 parts by weight based on the composition, but is not limited thereto.
- composition of the present invention may be administered parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) or orally, depending on the desired method, and oral administration is most preferred.
- parenterally for example, intravenously, subcutaneously, intraperitoneally or topically
- oral administration is most preferred.
- the dosage varies depending on the subject's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.
- Liquid formulations for oral administration of the composition of the present invention include suspensions, internal solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, and preservatives in addition to water and liquid paraffin, which are commonly used simple diluents etc. may be included.
- Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, suppositories, and the like.
- the present invention relates to a method for treating liver cancer comprising administering the pharmaceutical composition or immuno-anticancer agent to a subject.
- the term "individual” means a subject in need of a method for preventing, controlling or treating a disease, and can be used without limitation, such as humans, dogs, monkeys, cats, rodents such as mice and genetically engineered mice. More specifically, it refers to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cows.
- the pharmaceutical composition of the present invention can be administered in a therapeutically effective amount or a pharmaceutically effective amount.
- the term "therapeutically effective amount” refers to an amount of a pharmaceutically acceptable salt of a composition effective for preventing or treating a target disease
- the therapeutically effective amount of the composition of the present invention is various factors, such as It may vary depending on the administration method, the target site, the condition of the patient, and the like. Therefore, when used in the human body, the dosage should be determined in an appropriate amount considering both safety and efficiency. It is also possible to estimate the amount to be used in humans from the effective amount determined through animal experiments. These considerations in determining effective amounts are discussed, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
- the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
- pharmaceutically effective amount means an amount that is sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects
- the effective dose level is Health condition, type and severity of infection, activity of drug, sensitivity to drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field can be determined according to
- the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. Considering all of the above factors, it is important to administer the amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
- RT-LET7 (SEQ ID NO: 1: AACAGCACAAACUACUACCUCA, an inhibitor of Let-7i-5p, proceeds one cycle at a time in 4 steps, RNA oligo 1mer from 3' end to 5' end Deblocking -> Coupling -> Oxidation -> Capping At this time, a modified base is used, and according to Nat Rev Drug Discov. 2020 Oct;19(10):673-694., modification of 2'-Ribose (2'-O-methyl , 2'-MOE) contributes to increased resistance to nucleases and increased stability in the cytoplasm, rather than unmodified RNA, and also increases the half-life in biological tissues, resulting in drug effects.
- 2'-Ribose 2'-O-methyl , 2'-MOE
- RNA base 2'-OMe rA Phosphoramidite (Glen Research, Sterling, VA, cat.
- RNA oligo In the synthesis process, parts that require substitution with phosphorothioate are synthesized using Sulfurizing Reagent II (Glen Research, cat. 40-4037-10) (Bioneer synthesis).
- Sulfurizing Reagent II Gibbon Research, cat. 40-4037-10 (Bioneer synthesis).
- the unmodified RNA oligo is RT-LET7
- all bases are modified with 2'-O-methyl
- the RNA oligo modified with phosphorothioate is RT-LET7-2, 5' and 3' ends 4 places
- the modified base was named RT-LET7-6.
- all bases were modified with 2'-MOE, and the phosphorothioate-modified RNA oligo was named RT-LET7-4, and the base modified at the 5' and 3' ends was named RT-LET7-8 (Fig. 1a).
- RNA from HCC cell lines SNU-387, SNU-368, and SNU-4283 transfected with the modified RT-LET7 made as shown in Figure 1a using TRIzol reagent (Invitrogen, Carlsbad, CA)
- cDNAs specific to the two miRNAs were synthesized using the micscipt II RT kit (Qiagen, Manchester, UK).
- qRT-PCR was performed with the SensiFASTTM SYBR-NoROX Kit (Bioline, London, UK).
- MTT assay was performed using RT-LET7. Specifically, for the MTT assay, SNU-387 cells were seeded in a 12-well plate and transfected with RT-LET7, RT-LET7-4, and RT-LET7-8, followed by MTT [3-(4,5 -dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] solution (Sigma) 0.5 mg/ml and after incubation for 1 hour, absorbance was measured using a SYNERGY H1 Multilabel plate reader (Bio-Tek, Winooski, VT). measured. As a result, it was confirmed that the experimental group treated with the modified RT-LET7-8 of RT-LET7 inhibited tumor cell growth most excellently (FIG. 3a).
- RT-LET7 and modified RT-LET7-8 were treated and expression changes were analyzed through Western blot analysis. Confirmed. As a result, it was confirmed that the expression of TSP1 was increased when RT-LET7 and RT-LET7-8 were treated respectively (FIG. 3b).
- TSP1 occupies the CD47 receptor and interferes with the CD47-SIRP ⁇ interaction, resulting in macrophages phagocytosing HCC.
- SIRP ⁇ signal regulatory protein ⁇
- an in vitro phagocytic assay was performed. Specifically, each HCC cell line, SNU-387, was made into a single cell suspension and then labeled with CFSE (abcam, Cambridge, UK). Then, peritoneal macrophages were obtained from C57BL/6 mice, co-cultured with SNU-387 for 2 hours, and then treated with RT-LET7 and modified RT-LET7-8, respectively.
- TSP1 recombinant protein was directly used as a positive control. compared to treated HCC cells.
- the phagocytic index was calculated by dividing the number of macrophages trapping tumor cells by the total number of macrophages.
- both HCC cells treated with RT-LET7 and modified RT-LET7-8 significantly increased macrophage phagocytic activity, and the modified RT-LET7-8 showed more macrophage phagocytic activity than RT-LET7. It was confirmed that it increased (FIG. 3c).
- RT-LET7-8 which is a modified RT-LET7, can modulate the let-7i-p-TSP1 signaling axis, converting the CD47-SIRP ⁇ interaction between macrophages and HCC into CD47-TSP1 interaction, thereby It can be seen that the phagocytic action of phagocytes on HCC cells is re-activated.
- N-Acetylgalactosamine (GalNAc) or Gal-LNP (Galactosyl lipidoid nanoparticle ) to RT-LET7-8 was delivered to positive ASGPR (asialoglycoprotein receptor) expression cells (Hep3B) and negative cells (SNU-449).
- ASGPR asialoglycoprotein receptor
- Gal-LNP-RT-LET7-8 is C12-SPM synthesized by combining alkylepoxide (Sigma-Aldrich) and polyamine (Sigma-Aldrich), DSPC (Distearoylphosphatidylcholine) (Sigma-Aldrich), cholesterol ( Sigma-Aldrich), C16-PEG2000-ceramide (Avanti Polar Lipids) and ⁇ -galactosyl ceramide (Avanti Polar Lipids) were mixed at a ratio of 50:10:38.5:0.75:0.75, respectively, to prepare Gal-LNP.
- RT-LET7-8 solution (10 mg / mL) with 10 mM citrate buffer (pH 3), mix Gal-LNP and RT-LET7-8 at a ratio of 7:1, and incubate at 37 °C for 30 minutes.
- Gal-LNP was loaded with RT-LET7-8.
- ethanol and RT-LET7-8 not loaded with Gal-LNP were removed by dialysis against PBS (Sigma-Aldrich, cat. P5368) for 75 minutes (see FIG. 8a).
- GalNAc-RT-LET7-8 is modified by conjugating Trebler phosphoramidite (GLEN Research) to the 5' end of modified RT-LET7-8 to modify RT-LET7-8, and then conjugating N-acetylgalactosamine (GLEN Research). GalNAc-RT-LET7-8 was synthesized (see Fig. 8b). Then, the expression level of Let-7i-5p in each cell was confirmed in the same manner as in Example 2.
- GalNAc is a delivery system that binds to ASGPR receptors on the surface of liver cells, so it is effective only in ASGPR postive cells, but Gal-LNP has a structure similar to that of cell membranes, so it is expected to show an effect regardless of ASGPR.
- Gal-LNP-coupled RT-LET7-8 (Gal-LNP-RT-LET7-8) showed a higher level of Let-7i-5p compared to lipofectamine-coupled RT-LET7-8 (Lipo-RT-LET7-8). expression was found to be significantly reduced. This is because lipofectamine is composed of simple phospholipids, so compared to Gal-LNP composed of cholesterol, DSPC, C16-PET2000-ceramide, and ⁇ -galactosyl ceramide, the liver delivery efficiency and in vivo stability are remarkably means to fall
- MTT assay was performed by the method of Example 3.
- the target protein of let-7i-5p by the decrease in the expression of let-7i-5p, the target microRNA of RT-LET7, the modified RT-LET7-8 and the hepatocyte targeting moiety After treating the conjugated RT-LET7-8, expression changes were confirmed through Western blot analysis.
- in vitro phagocytosis assay was performed by the method of Example 4 to confirm whether macrophages could phagocytose HCC.
- Example 5 it was confirmed that in the case of GalNAc, when combined with the modified RT-LET7-8, the liver delivery efficiency and in vivo stability were higher than that of Gal-LNP.
- RT-LET7-8 In order to search for an optimal GalNAc that can significantly improve the efficacy of RT-LET7-8 by combining with the modified RT-LET7-8, GalNAc (D-GalNAc) having a different structure was bound to the 5' end.
- RT-LET7-8 was fabricated, and the efficiency of the GalNAc-coupled modified RT-LET7-8 was compared through the following experiments.
- RT-LET7-8 in which GalNAc (Old-GalNAc) used in Example 5 and D-GalNAc, a new GalNAc, were combined, and the two Old-GalNAc-RT-LET7-8 (see FIG. 8b) and D-GalNAc-RT-LET7-8 (see FIG. 8c) was delivered to Hep3B cells, respectively, and the expression level of Let-7i-5p in each cell was confirmed in the same manner as in Example 2.
- the MTT assay was performed according to the method described in Example 3, and the BrdU assay was performed using the BrdU cell proliferation assay kit (Millipore) according to the manufacturer's protocol.
- a target protein of let-7i-5p by decreasing the expression of let-7i-5p, a target microRNA of RT-LET7, Hep3B cells were inoculated with Old-GalNAc-RT-LET7-8 and D- After each treatment with GalNAc-RT-LET7-8, expression changes were confirmed through Western blot analysis.
- in vitro phagocytosis assay was performed by the method of Example 4 to confirm whether macrophages could phagocytose HCC.
- modified RT-LET7-8 when the modified RT-LET7-8 is loaded with a hepatocyte-targeted delivery system, transmissibility to the target organ, the liver, is increased, and the effect of inhibiting Let-7i-5p expression in hepatocytes, the inhibitory effect on tumor formation in liver cancer, and the phagocytosis of macrophages It was confirmed that the action activity efficacy significantly increased.
- modified RT-LET7-8 coupled with D-GalNAc represented by Formula 2 among the hepatocyte targeting delivery systems it can be seen that the above-mentioned liver cancer prevention or treatment effect of RT-LET7-8 is significantly improved.
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Abstract
Description
Claims (12)
- Let-7i-5p를 표적화하는 핵산분자로서,상기 핵산분자는 서열번호 1의 염기서열로 표시되고,상기 핵산분자는 뉴클레오티드 서열이 2`-O-Methoxyethyl(메톡시에틸)화되어 변형된 핵산인 것을 특징으로 하며,상기 핵산분자는 일부 또는 전체 골격(backbone)이 포스포로티오에이트(phosphorothioate)로 개질된 것을 특징으로 하는, 핵산분자.
- 제1항에 있어서,상기 핵산분자는 서열번호 1의 뉴클레오티드 중 5‘말단으로부터 1 내지 4번째 뉴클레오티드의 골격(backbone)이 포스포로티오에이트(phosphorothioate)로 개질된 것인, 핵산분자.
- 제1항에 있어서,상기 핵산분자는 서열번호 1의 뉴클레오티드 중 3‘말단으로부터 1 내지 4번째 뉴클레오티드의 골격(backbone)이 포스포로티오에이트(phosphorothioate)로 개질된 것인, 핵산분자.
- Let-7i-5p를 표적화하는 핵산분자로서,상기 핵산분자는 서열번호 1의 염기서열로 표시되고,상기 핵산분자는 뉴클레오티드 서열이 2`-O-Methoxyethyl(메톡시에틸)화되어 변형된 핵산인 것을 특징으로 하며,상기 핵산분자는 일부 또는 전체 골격(backbone)이 포스포로티오에이트(phosphorothioate)로 개질된 것을 특징으로 하고,상기 핵산분자는 간세포 표적 모이어티(Moiety)가 결합된 것을 특징으로 하는, 핵산분자.
- 제1항에 있어서,상기 간세포 표적 모이어티(Moiety)는 N-Acetylgalactosamine (GalNAc) 또는 Gal-LNP(Galactosyl lipidoid nanoparticle)인 것을 특징으로 하는, 핵산분자.
- 제1항 내지 제6항 중 어느 한 항의 핵산분자를 유효성분으로 포함하는, 간암의 예방 또는 치료용 약학 조성물.
- 제7항에 있어서,상기 조성물은 Let-7i-5p의 발현을 억제하는 것인, 간암의 예방 또는 치료용 약학 조성물.
- 제7항에 있어서,상기 조성물은 TSP1(thrombospondin-1) 발현을 증가시키는 것인, 간암의 예방 또는 치료용 약학 조성물.
- 제7항에 있어서,상기 조성물은 대식세포 식작용 활성을 증가시키는 것인, 간암의 예방 또는 치료용 약학 조성물.
- 제1항 내지 제6항 중 어느 한 항의 핵산분자를 유효성분으로 포함하는, CD47-양성 간암의 치료용 면역항암제.
- 제7항의 약학 조성물 또는 제11항의 면역항암제를 개체에 투여하는 단계를 포함하는 간암를 치료하는 방법.
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CN202280054494.4A CN117795077A (zh) | 2021-08-06 | 2022-07-29 | 包含修饰的rt-let7作为有效成分的用于预防或治疗肝癌的组合物 |
CA3228077A CA3228077A1 (en) | 2021-08-06 | 2022-07-29 | Composition for prevention or treatment of liver cancer, comprising modified rt-let7 as active ingredient |
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