WO2023013818A1 - Composition pour la prévention ou le traitement du cancer hépatique comprenant du rt-let7 modifié comme principe actif - Google Patents

Composition pour la prévention ou le traitement du cancer hépatique comprenant du rt-let7 modifié comme principe actif Download PDF

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WO2023013818A1
WO2023013818A1 PCT/KR2021/014873 KR2021014873W WO2023013818A1 WO 2023013818 A1 WO2023013818 A1 WO 2023013818A1 KR 2021014873 W KR2021014873 W KR 2021014873W WO 2023013818 A1 WO2023013818 A1 WO 2023013818A1
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let7
modified
liver cancer
present
nucleic acid
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PCT/KR2021/014873
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English (en)
Korean (ko)
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남석우
양희두
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주식회사 네오나
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Priority claimed from KR1020210103567A external-priority patent/KR102329524B1/ko
Priority claimed from KR1020210140386A external-priority patent/KR102428121B1/ko
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Publication of WO2023013818A1 publication Critical patent/WO2023013818A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • 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.
  • 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.
  • 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 an immuno-anticancer pharmaceutical composition for the treatment of CD47-positive liver cancer comprising the nucleic acid molecule as an active ingredient.
  • nucleic acid molecule represented by SEQ ID NO: 1 the nucleotide sequence is modified by 2'-O-Methoxyethyl (methoxyethyl), and a part or the entire backbone is phosphorothioate ( phosphorothioate) to provide a nucleic acid molecule targeting Let-7i-5p.
  • 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.
  • the present invention provides an immuno-anticancer pharmaceutical composition for the treatment of CD47-positive liver cancer comprising, as an active ingredient, a modified RT-LET7 to which a hepatocyte targeting moiety is bound.
  • the present invention provides a method for preventing or treating liver cancer comprising administering the pharmaceutical composition to a subject.
  • Figure 1 is a diagram showing various modified structures (Fig. 1a) and inhibitory efficiency (Fig. 1b) of RT-LET7, an expression inhibitor of Let-7i-5p (default: RT-LET7, modified: RT-LET7-2, RT -LET7-4, RT-LET7-6 and RT-LET7-8).
  • Figure 3 is a diagram confirming the growth inhibition of HCC cell lines and the increase in macrophage activity by RT-LET7-8, the modified RT-LET7 of the present invention ( Figure 3a; Let-7i-5p through MTT and cell survival assays) Characteristics of tumor formation, Fig. 3b; TSP1 expression change through Western blot analysis after treatment with basic RT-LET7 and modified RT-LET7-8, Fig. 3c; Basic RT-LET7 and modified RT-LET7-8 treated macrophage phagocytic activity of HCC cells).
  • FIG. 5 is a diagram confirming the effect of inhibiting Let-7i-5p expression and the effect of continuously suppressing Let-7i-5p in HCC cells of RT-LET7-8 combined with Gal-LNP.
  • Figure 6 is a diagram confirming the growth inhibition of HCC cell lines and the increase in macrophage activity by GalNAc-coupled RT-LET7-8 (Figure 6a; tumor formation of Let-7i-5p through MTT and cell survival assays). Characteristics, Fig. 6b; TSP1 expression change through Western blot analysis after treatment with GalNAc-conjugated RT-LET7-8, Fig. 6c; macrophage phagocytic activity of HCC cells treated with GalNAc-conjugated RT-LET7-8).
  • 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 (Fig. 6a; tumor formation of Let-7i-5p through MTT and cell survival analysis) Characteristics of HCC cells treated with Gal-LNP-conjugated RT-LET7-8 and then treated with Gal-LNP-conjugated RT-LET7-8 and TSP1 expression through Western blot analysis, Figure 6c; Gal-LNP-conjugated RT-LET7-8 treated macrophage phagocytic activity).
  • nucleic acid molecule of the present invention may be modified by 2'-O-Methoxyethyl (methoxyethyl) all sequences of nucleotides.
  • the "nucleic acid molecule" of the present invention may be modified with phosphorothioate at 3' of some or all of the nucleotides.
  • 3' of the nucleotide from the 5' end to the 4th nucleotide of SEQ ID NO: 1 is modified with phosphorothioate, and 3' of the nucleotide from the 3' end to the 4th nucleotide is 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 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.
  • the present invention relates to an immuno-anticancer pharmaceutical composition 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 reduction in the expression (into mRNA) or translation (into protein) of a target gene, preferably by which the expression of the target gene is undetectable or insignificant. means to exist.
  • 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.
  • 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 preventing or treating liver cancer comprising administering the pharmaceutical composition for preventing or treating liver cancer to a subject.
  • the pharmaceutical composition of the present invention can be administered in a therapeutically effective amount or a pharmaceutically effective amount.
  • the term "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 the patient's Health condition, type and severity of disease, 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 concurrently, 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.
  • 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, genetically engineered mice, etc. there is. More specifically, it refers to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cows.
  • 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 was synthesized by combining alkylepoxide (Sigma-Aldrich) and polyamine (Sigma-Aldrich), C12-SPM, DSPC (Distearoylphosphatidylcholine) (Sigma-Aldrich), cholesterol (Sigma-Aldrich), -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.
  • GalNac is a delivery system that binds to the ASGPR receptor on the surface of liver cells and is effective only in ASGPR postive cells, but Gal-LNP has a structure similar to that of a cell membrane, 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
  • RT-LET7-8 coupled with the hepatocyte targeting moiety (GalNac or Gal-LNP) for 7 days was performed in Hep3B cells.
  • the effect of suppressing the expression of Let-7i-5p was maintained until day 7, and the expression of Let-7i-5p was stably inhibited even compared to Lipo-RT-LET7-8 (FIGS. 4b and 5b). ).
  • 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.
  • the hepatocyte-targeted delivery system is loaded on the modified RT-LET7-8, the transferability to the liver, which is the target organ, is increased, and the Let-7i-5p expression inhibitory effect in hepatocytes, tumor formation inhibitory effect in liver cancer, and macrophage phagocytosis activity It can be seen that the efficacy is significantly increased.

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement du cancer hépatique, comprenant du RT-LET7 modifié comme principe actif. Le RT-LET7 modifié selon la présente invention a été avéré pour augmenter l'inhibition de l'expression de Let-7i-5p, augmenter l'inhibition de la croissance des cellules cancéreuses hépatiques, augmenter l'expression de TSP1, et augmenter l'activité de phagocytose des macrophages, par comparaison avec le RT-LET7 conventionnel. Par conséquent, le RT-LET7 modifié peut être utilisé dans une composition pharmaceutique pour la prévention ou le traitement du cancer hépatique.
PCT/KR2021/014873 2021-08-06 2021-10-22 Composition pour la prévention ou le traitement du cancer hépatique comprenant du rt-let7 modifié comme principe actif WO2023013818A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2021-0103567 2021-08-06
KR1020210103567A KR102329524B1 (ko) 2021-08-06 2021-08-06 변형된 rt-let7을 유효성분으로 포함하는 간암의 예방 또는 치료용 조성물
KR10-2021-0140386 2021-10-20
KR1020210140386A KR102428121B1 (ko) 2021-10-20 2021-10-20 변형된 rt-let7을 유효성분으로 포함하는 간암의 예방 또는 치료를 위한 딜리버리 시스템

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007112754A2 (fr) * 2006-04-03 2007-10-11 Santaris Pharma A/S Composition pharmaceutique
WO2012119051A2 (fr) * 2011-03-02 2012-09-07 Groove Biopharma Corporation Biodistribution améliorée d'oligomères
KR20150006742A (ko) * 2013-07-09 2015-01-19 (주)바이오니아 간암 연관 유전자 특이적 siRNA, 그러한 siRNA를 포함하는 이중나선 올리고 RNA 구조체 및 이를 포함하는 암 예방 또는 치료용 조성물
KR20150095349A (ko) * 2014-02-13 2015-08-21 서울대학교산학협력단 마이크로알엔에이를 표적으로 하는 신경변성 질환 예방 또는 치료용 약학 조성물 및 방법
KR20200119538A (ko) * 2019-04-10 2020-10-20 가톨릭대학교 산학협력단 간암의 예방 또는 치료용 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007112754A2 (fr) * 2006-04-03 2007-10-11 Santaris Pharma A/S Composition pharmaceutique
WO2012119051A2 (fr) * 2011-03-02 2012-09-07 Groove Biopharma Corporation Biodistribution améliorée d'oligomères
KR20150006742A (ko) * 2013-07-09 2015-01-19 (주)바이오니아 간암 연관 유전자 특이적 siRNA, 그러한 siRNA를 포함하는 이중나선 올리고 RNA 구조체 및 이를 포함하는 암 예방 또는 치료용 조성물
KR20150095349A (ko) * 2014-02-13 2015-08-21 서울대학교산학협력단 마이크로알엔에이를 표적으로 하는 신경변성 질환 예방 또는 치료용 약학 조성물 및 방법
KR20200119538A (ko) * 2019-04-10 2020-10-20 가톨릭대학교 산학협력단 간암의 예방 또는 치료용 조성물

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