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WO2025119007A1 - Groupe d'oligonucléotides antisens qui inhibent spécifiquement le récepteur des androgènes et utilisation associée - Google Patents

Groupe d'oligonucléotides antisens qui inhibent spécifiquement le récepteur des androgènes et utilisation associée Download PDF

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Publication number
WO2025119007A1
WO2025119007A1 PCT/CN2024/133958 CN2024133958W WO2025119007A1 WO 2025119007 A1 WO2025119007 A1 WO 2025119007A1 CN 2024133958 W CN2024133958 W CN 2024133958W WO 2025119007 A1 WO2025119007 A1 WO 2025119007A1
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WIPO (PCT)
Prior art keywords
aso
modification
exon
antisense oligonucleotide
preparation
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Pending
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Chinese (zh)
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WO2025119007A8 (fr
Inventor
陈浩东
张瑞
李弯弯
张海霖
朱祎君
张星河
张丹
蒋小兵
李艳
朱红林
寇俊闯
邬丽娜
郑鑫
黎俊
张蕾
杜稼
格雷米·马克西米利安
徐晓雪
牛振峰
刘玉
张进阳
黄西芳
黄婷婷
袁翀
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Lnctac Co Ltd
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Lnctac Co Ltd
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Publication of WO2025119007A1 publication Critical patent/WO2025119007A1/fr
Publication of WO2025119007A8 publication Critical patent/WO2025119007A8/fr
Pending legal-status Critical Current
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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
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • 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

  • the present invention belongs to the field of biotechnology, and specifically relates to a group of antisense oligonucleotides for specifically inhibiting androgen receptors and applications thereof.
  • AR is a nuclear receptor that exists in the cytoplasm when not activated. It forms a complex with heat shock proteins and other molecular chaperone proteins in the form of dimers. After AR binds to androgen, the complex dissociates, the AR dimer is phosphorylated, binds to other regulatory proteins, and then translocates into the cell nucleus. Subsequently, the DNA binding domain in AR binds to the DNA sequence of the androgen response element (ARE; the most typical is TGTTCT), transcribes downstream genes, and then plays its role in regulating the growth, immune and endocrine systems.
  • ARE DNA sequence of the androgen response element
  • AR can combine with testosterone and the highly active metabolite dihydrotestosterone (DHT) converted by type II 5 ⁇ reductase to produce an effect, shortening the hair growth period, miniaturizing and even shrinking the hair follicles, and ultimately causing hair loss.
  • DHT highly active metabolite dihydrotestosterone
  • the present invention firstly relates to a group of antisense oligonucleotides (ASO) that specifically inhibit androgen receptor (AR), wherein the antisense oligonucleotides are 14-22 bases in length, the target gene is AR mRNA, and the ASO specifically pairs with a specific region of the target gene, wherein the starting site of the specific region is located at:
  • ASO antisense oligonucleotides
  • AR androgen receptor
  • the AR target gene is numbered: ENST00000374690.9, and the sequence is shown in SEQ ID NO.63.
  • the ASO comprises a chemical modification
  • the modifications are: thiolation of phosphate bonds, methoxyethyl modification (2'-MOE modification) of the 2' position of the base, and 5-methyl modification of cytosine;
  • the modifications are: monothiolation of the phosphate bonds of all nucleotides in the ASO sequence, 2'-MOE modification of 3 to 5 bases symmetrically at the 3' and 5' ends, and 5-methyl modification of all cytosines.
  • ASO is selected from the oligonucleotides shown in any sequence in the following table;
  • the phosphate bonds of all nucleotides in the ASO described in the table are monothiolated, and there are symmetrical 4-5 bases at the 3' end and 5' end for MOE modification and 5-methyl modification of all cytosines.
  • the motif of the ASO is 4-8-4, 4-9-4, 5-8-5, 5-10-5, or 5-12-5.
  • the present invention also relates to the following applications of the antisense oligonucleotide (ASO) or its modified form:
  • Treating diseases caused by overexpression or overactivation of AR protein including but not limited to: tumors, hair loss or acne caused by overexpression or overactivation of AR protein; preferably, the tumor is prostate cancer.
  • the medicine or pharmaceutical composition comprises a therapeutically effective amount of the antisense oligonucleotide (ASO) or a modified form thereof, and necessary pharmaceutical excipients or delivery carriers.
  • ASO antisense oligonucleotide
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the antisense oligonucleotide (ASO) or a modified form thereof, wherein the pharmaceutical composition comprises: a therapeutically effective amount of the antisense oligonucleotide (ASO) or a modified form thereof, and necessary pharmaceutical excipients or delivery carriers; preferably, the pharmaceutical composition is a transdermal administration preparation.
  • the present invention also relates to an externally applied smear-type preparation containing ASO/ASO modification, wherein the smear-type preparation comprises:
  • the antisense oligonucleotide (ASO) or the chemically modified antisense oligonucleotide (ASO) 1-50 mg/mL; preferably 2-20 mg/mL; more preferably 4-10 mg/mL;
  • dimethyl isosorbide (DMI) 5-60 mg/mL, preferably 40 mg/mL;
  • Vitamin E polyethylene glycol succinate 2-20 mg/mL, preferably 10 mg/mL;
  • Vitamin C 2-20 mg/mL, preferably 10 mg/mL.
  • the chemically modified antisense oligonucleotide (ASO) in the smearable preparation is
  • A, G, C, T 2’-O-methoxyethyl; 2’-MOE modification;
  • C base or c base are both 5-methyl modified cytosine
  • HSA is a modification module:
  • C base or c base are both 5-methyl modified cytosine
  • HSA is a modification module:
  • C base or c base are both 5-methyl modified cytosine
  • RA is a modification module:
  • the present invention also relates to a method for preparing the smearable preparation, which specifically comprises the following steps:
  • Dissolved oxygen balance Take purified water and fill it with nitrogen at a nitrogen pressure of 0.1-0.2 MPa to balance the dissolved oxygen in the water;
  • API active pharmaceutical ingredient
  • an optional step (4) canning and labeling: transferring the preparation into a borosilicate vial, filling it with nitrogen, covering it with a rubber stopper and an aluminum cap, sealing it, pressing the cap and labeling it.
  • the present invention also relates to the following applications of the smearable preparation:
  • FIG4 After cells were treated with antisense oligonucleotides (ASO), the mRNA expression of cytokines related to inflammatory response was detected.
  • ASO antisense oligonucleotides
  • Example 1 Design, synthesis and modification of ASO targeting AR target gene
  • ASOs antisense oligonucleotide sequences
  • 349 of the above ASO sequences were chemically modified in the following ways: monothiolation of the phospholipid bonds of all nucleotides in the sequence, and MOE modification of 3 to 5 bases at the 3' and 5' ends respectively (i.e., methoxyethyl modification of the 2' position of the base).
  • Example 2 Testing the activity of ASO in in vitro cell models (HaCaT cells, human immortalized epidermal cells or LNCaP human prostate cancer cells)
  • suspension transfection reagent Dissolve ASO dry powder in sterile water to a concentration of 10 ⁇ M. Dilute 10 ⁇ M ASO stock solution to the required concentration with reduced serum medium for transfection (Basalmedia, L530KJ), dilute Lipofectamine 2000 transfection reagent (Invitrogen, 11668-019) with reduced serum medium, mix the transfection reagent diluent and ASO diluent to prepare ASO transfection complexes of preset concentration or concentration gradient, pipette 10 times to mix, and let stand at room temperature for 20 min.
  • the PCR primers and probes used to amplify the internal reference gene Actin and the target gene AR are shown in Table 2:
  • the relative gene expression was calculated using the 2 ⁇ - ⁇ CT method (Livak method), and the inhibition rate of antisense oligonucleotide mRNA expression level was calculated according to the following equation:
  • Inhibition rate (1-2 ⁇ - ⁇ CT) ⁇ 100%.
  • the experimental groups are:
  • the blank control group was cells that were not treated with any ASO.
  • Table 3-1 Inhibition rate of AR mRNA after antisense oligonucleotide treatment of HaCaT cells (%) Note: Motif indicates the MOE modification of the 3' and/or 5' bases, for example, 4-8-4, means: 4 bases at the 3' end are MOE-modified, and 4 bases at the 5' end are MOE-modified; 5-10-5 means: 5 bases at the 3' end are MOE modified, and 5 bases at the 5' end are MOE modified.
  • Example 3 Testing the activity of ASO in an in vitro cell model (LNCaP human prostate cancer cells)
  • Proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then transferred to a PVDF membrane. After blocking with 5% skim milk powder, the membrane was incubated with AR antibody (Abcam, AB133273) and Actin antibody (Abcam, ab49900) at 4°C overnight. The next day, the membrane was incubated with secondary antibody (CST, 7074S) at room temperature for 1 h. The expression of proteins was observed using a multifunctional imaging system (Tanon 5200Multi).
  • Example 4 Testing the activity of antisense oligonucleotide-fatty acid construct (ASO-S1) in in vitro cell model (HaCaT cells, human immortalized epidermal cells/NCaP cells, human prostate cancer cells)
  • Preparation of incubation reagents Prepare DMEM (HaCaT) or RPMI 1640 (LNCaP) culture medium containing 1% FBS and 1% insulin-transferrin-selenium-aminoethanol (GIBCO, 51500056). Dissolve ASO-S1 dry powder in sterile water to a concentration of 1 mM. Dilute 1 mM ASO-S1 stock solution with the prepared culture medium to prepare ASO-S1 incubation complexes of a preset concentration or concentration gradient, and pipette 10 times to mix.
  • HaCaT DMEM
  • LNCaP RPMI 1640
  • GEBCO insulin-transferrin-selenium-aminoethanol
  • Example 6 Serum stability of antisense oligonucleotides (ASOs) (fetal bovine serum and rat serum)
  • Serum with a concentration of 10% or 50% was prepared with sterile water. 0.3 ⁇ g of ASO solution was added to 50 ⁇ L of serum of each concentration and mixed evenly. The mixture was then incubated at 37°C for 0 h, 4 h, or 24 h.
  • Example 7 In vitro cell model (PBMC peripheral blood mononuclear cells) to detect the levels of cytokines associated with inflammatory response after treatment with ASO and the corresponding ASO-S1 construct
  • Cell treatment Cells were revived and plated one day before incubation. 1 ⁇ 10 6 cells/well were plated in a 12-well plate. 100 ⁇ L of RPMI 1640 medium containing 1% FBS and 1% insulin-transferrin-selenium-aminoethanol (GIBCO, 51500056) was added to each well.
  • the PCR primers used to amplify the internal reference gene RPL13A and the target genes IL-6 and IL-1 ⁇ are shown in Table 6.
  • Example 8 Testing the tumor cell killing effect of ASO-S1 using an in vitro cell model (LNCaP human prostate cancer cells)
  • Preparation of incubation reagents Prepare RPMI 1640 medium containing 1% FBS and 1% insulin-transferrin-selenium-aminoethanol (GIBCO, 51500056). Dissolve ASO-S1 dry powder in sterile water to a concentration of 1 mM. Dilute 1 mM ASO-S1 stock solution with the prepared medium to prepare a concentration gradient of ASO-S1 incubation complexes. Pipet 10 times to mix.
  • Vitamin E polyethylene glycol succinate TPGS
  • the ASO or chemically modified ASO is selected from the ASO or chemically modified products thereof in the aforementioned examples.
  • the preparation method of the smearable preparation containing ASO/ASO modification comprises the following steps:
  • API ASO or modified form of ASO
  • the volume is made up with oxygen-balanced water, and nitrogen is filled for 2 hours after the volume is made up to balance, thereby preparing the ASO/ASO modified body-containing smearable preparation.
  • the preparation was transferred into a borosilicate vial, filled with nitrogen, and sealed with a rubber stopper and an aluminum cap, capped, and labeled.
  • Example 10 Testing of the hair growth function of external smear preparations
  • This product is a local external product applied with a massage applicator. Before each use, you need to wash your hair and blow dry it with hot air before applying it immediately. When using, pour the product into the applicator, apply the product evenly on the hair loss area on the head with the applicator, and massage with the applicator for 3 to 5 minutes. After application, wait for the scalp to dry naturally. It is also recommended not to wash your hair within 24 hours.
  • Table 9-1 Statistical table of information of placebo patients before and after medication
  • the average increase in non-vellus hair density in the placebo group was -2.44%.
  • the calculation formula is: (183.6-188.2)/188.2*100% (the same below).
  • Table 9-2 Statistical table of information before and after medication of patients in the preparation (4 mg/mL LT010-0390) group
  • the average increase in non-vellus hair density after use of this preparation group was -0.11%.
  • Table 9-3 Statistical table of information before and after medication of patients in the preparation (10 mg/mL LT010-0390) group
  • the average increase in non-vellus hair density after use of this preparation was 1.77%.
  • Table 9-4 Statistical table of information before and after medication of patients in the preparation (4 mg/mL LT010-0410) group
  • the average increase in non-vellus hair density after use of this preparation was 2.60%.
  • Table 9-5 Statistical table of information before and after medication of patients in the preparation (10 mg/mL LT010-0410) group
  • the average increase in non-vellus hair density after use of this preparation was 3.64%.
  • Table 9-6 Statistical table of information before and after medication of patients in the preparation (4 mg/mL LT010-0449) group
  • the average increase in non-vellus hair density after use of this preparation was 3.44%.
  • Table 9-7 Statistical table of information before and after medication of patients in the preparation (10 mg/mL LT010-0449) group
  • the average increase in non-vellus hair density after use of this preparation was 1.91%.
  • the modification methods are:
  • A, G, C, T 2’-O-methoxyethyl; 2’-MOE modification;
  • C base or c base are both 5-methyl modified cytosine
  • HSA is a modification module:
  • the specific API can be hydrogen form, sodium salt form or S - form, and the structure is shown below
  • the modification methods are:
  • C base or c base are both methyl type C bases
  • C base or c base are both 5-methyl modified cytosine
  • HSA is a modification module:
  • the specific API can be hydrogen form, sodium salt form or S - form, and the structure is shown below
  • the modification methods are:
  • C base or c base are both 5-methyl modified cytosine
  • RA is a modification module:
  • the specific API can be hydrogen form, sodium salt form or S - form, and the structure is shown below

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Abstract

L'invention concerne un groupe d'oligonucléotides antisens qui inhibent spécifiquement un récepteur des androgènes et une utilisation associée. Les oligonucléotides antisens ont une longueur de 14 à 22 bases. Les oligonucléotides antisens (OAS) ont les utilisations suivantes : (1) préparer une préparation qui inhibe le niveau d'expression d'une protéine AR; et (2) préparer un médicament ou une composition pharmaceutique pour le traitement de l'alopécie induite par les androgènes; ou (3) préparer un médicament ou une composition pharmaceutique pour le traitement de l'acné induite par les androgènes; ou (4) inhiber l'expression ou l'activation de la protéine AR; et (5) traiter des maladies provoquées par la surexpression ou l'activation excessive de la protéine AR, les maladies comprenant, mais sans s'y limiter, les tumeurs, l'alopécie ou l'acné provoquées par la surexpression ou l'activation excessive de la protéine AR.
PCT/CN2024/133958 2023-12-05 2024-11-22 Groupe d'oligonucléotides antisens qui inhibent spécifiquement le récepteur des androgènes et utilisation associée Pending WO2025119007A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110072879A (zh) * 2016-08-08 2019-07-30 奥利通公司 雄激素受体反义寡核苷酸
CN113271980A (zh) * 2018-11-28 2021-08-17 柏业公司 包含雄激素受体特异性序列的双链寡核苷酸构建体以及包含其的用于预防脱发和促进头发生长的组合物
CN114585742A (zh) * 2019-10-03 2022-06-03 牛津大学创新有限公司 治疗
CN116370491A (zh) * 2021-09-22 2023-07-04 北京瑞博开拓医药科技有限公司 反义寡核苷酸剂在治疗冠状病毒相关疾病中的应用
CN118421625A (zh) * 2024-04-24 2024-08-02 浙江海昶生物医药技术有限公司 反义寡核苷酸、雄激素受体抑制剂及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110072879A (zh) * 2016-08-08 2019-07-30 奥利通公司 雄激素受体反义寡核苷酸
CN113271980A (zh) * 2018-11-28 2021-08-17 柏业公司 包含雄激素受体特异性序列的双链寡核苷酸构建体以及包含其的用于预防脱发和促进头发生长的组合物
CN114585742A (zh) * 2019-10-03 2022-06-03 牛津大学创新有限公司 治疗
CN116370491A (zh) * 2021-09-22 2023-07-04 北京瑞博开拓医药科技有限公司 反义寡核苷酸剂在治疗冠状病毒相关疾病中的应用
CN118421625A (zh) * 2024-04-24 2024-08-02 浙江海昶生物医药技术有限公司 反义寡核苷酸、雄激素受体抑制剂及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAMAMOTO, Y. ET AL.: "Generation 2.5 Antisense Oligonucleotides Targeting the Androgen Receptor and Its Splice Variants Suppress Enzalutamide-Resistant Prostate Cancer Cell Growth", CLINICAL CANCER RESEARCH, vol. 21, no. 7, 1 April 2015 (2015-04-01), XP055500439, DOI: 10.1158/1078-0432.CCR-14-1108 *

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