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WO2022060208A1 - Oligonucléotides antisens - Google Patents

Oligonucléotides antisens Download PDF

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Publication number
WO2022060208A1
WO2022060208A1 PCT/KR2021/012989 KR2021012989W WO2022060208A1 WO 2022060208 A1 WO2022060208 A1 WO 2022060208A1 KR 2021012989 W KR2021012989 W KR 2021012989W WO 2022060208 A1 WO2022060208 A1 WO 2022060208A1
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Prior art keywords
modified nucleotides
oligonucleotide
nucleotides
aso
modified
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Ceased
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English (en)
Korean (ko)
Inventor
박창희
구지혜
김지혜
홍수정
남경완
박전의
김태훈
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Autotelic Bio Inc
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Autotelic Bio Inc
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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
    • 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
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • the present invention relates to an antisense oligonucleotide and a pharmaceutical composition comprising the same.
  • tRNA fetches the corresponding amino acid according to the mRNA information from the ribosome, and the protein is produced through the process of linking it with a peptide bond.
  • the complementary DNA or RNA binds to mRNA to form a double strand, thereby preventing protein production.
  • RNA oligonucleotide capable of inhibiting its function by binding to an mRNA (sense RNA) that can be transcribed and translated into a protein is referred to as an antisense RNA or an antisense oligonucleotide.
  • an antisense oligonucleotide of SEQ ID NO: 1 and the like are known as an antisense oligonucleotide targeting TGF- ⁇ , a tumor promoting factor.
  • the antisense oligonucleotide itself needs to solve the problem of rapid degradation in vivo and also improve specificity so that it binds only to the mRNA of the target gene, so that it can be developed as a drug that can treat actual diseases.
  • the present inventors have studied to develop an antisense oligonucleotide with improved ability to inhibit TGF- ⁇ protein expression.
  • a novel antisense oligonucleotide in which the structure of some sugars among known antisense oligonucleotides is modified has excellent TGF- ⁇ inhibitory effect, and , it was confirmed that the stability was high.
  • the present invention is to provide a novel antisense oligonucleotide and a pharmaceutical composition containing the same.
  • the present invention relates to a novel antisense oligonucleotide comprising at least one modified nucleoside among the oligonucleotides of 5'-CGGCATGTCTATTTTGTA-3' of SEQ ID NO: 1.
  • the present invention relates to an antisense oligonucleotide of SEQ ID NO: 1, wherein at least one nucleoside of the oligonucleotide has a modified nucleotide.
  • nucleoside-modified nucleotide is a nucleoside is 2'-O-methoxyethyl (MOE) modified nucleotide, 2'-fluoro (F) modified nucleotide, 2'-O-methyl ( O-Me) modified nucleotides, locked nucleic acid (LNA) modified nucleotides, ethylene-bridged nucleic acid (ENA) modified nucleotides, restricted ethyl (cET: (R/S)-constrained ethyl ) modified nucleotides or polyalkylene oxide (eg, triethylene glycol (TEG)) modified nucleotides.
  • MOE methoxyethyl
  • F fluoro
  • O-Me 2'-O-methyl
  • LNA locked nucleic acid
  • ENA ethylene-bridged nucleic acid
  • cET restricted ethyl
  • R/S restricted ethyl
  • TAG triethylene glycol
  • the 2' position of the ribose pentose of the nucleoside to be modified is 2'-O-methoxyethyl (MOE) form, 2'-fluoro form, or 2' -O-methyl form, or LNA or ENA form in which the oxygen at the 2' position of the ribose pentose of the modified nucleoside is connected to the carbon at the 4' position, or the oxygen at the 2' position and the 4' position of the LNA It may be in the form of cET in which a bridge connecting carbons is replaced with a methyl group.
  • MOE 2'-O-methoxyethyl
  • the oligonucleotides of the invention comprise one or more modified nucleosides at the 5'-end and/or the 3' end.
  • each of the 5'-end or the 3'-end of the oligonucleotide of the present invention may include one or more modified nucleosides.
  • the oligonucleotides of the present invention may include nucleotides having one or more modified nucleosides at the 5'-end or the 3'-end, respectively, ie, "modified nucleotides".
  • the oligonucleotide according to the present invention is an oligonucleotide in which one or more nucleotides of the 5'-end or one or more nucleotides of the 3'-end of the oligonucleotide are modified nucleotides.
  • the oligonucleotide according to the present invention is an oligonucleotide in which one or more nucleotides of the 5'-end and one or more nucleotides of the 3'-end of the oligonucleotide are modified nucleotides.
  • the first to n-th nucleotides of the 5'-end of the oligonucleotide or the first to m-th nucleotides of the 3'-end of the oligonucleotide may be modified nucleotides.
  • the first to n-th nucleotides of the 5'-end of the oligonucleotide and the first to m-th nucleotides of the 3'-end of the oligonucleotide may be modified nucleotides.
  • n and m are each independently an integer of any one of 1 to 9, and preferably, n and m are each independently an integer of any one of 1 to 6.
  • the oligonucleotide of the present invention may further include a modified nucleotide between the modified nucleosides present at the 5'-end or the 3'-end.
  • the oligonucleotide may further include one or more modified nucleotides between the (n+1)-th nucleotide of the 5'-end and the (m+1)-th nucleotide of the 3'-end.
  • Preferred examples of the oligonucleotide of the present invention may be any one of the antisense oligonucleotides of SEQ ID NO: 1 shown in Nos. 1 to 25 of the table below.
  • modified nucleotides of the oligonucleotides shown in Nos. 1 to 21 of the Table are 2'-O-methoxyethyl (MOE) modified nucleotides
  • the modified nucleotides of the oligonucleotides shown in Nos. 22 to 25 of the Table are locked nucleic acids ( LNA) is preferably an oligonucleotide that is a modified nucleotide.
  • LNA locked nucleic acids
  • the bond between nucleosides, whether or not the nucleosides are modified may be phosphodiester or phosphothioate.
  • oligonucleotide should be understood as a concept that also includes pharmaceutically acceptable salts of oligonucleotides.
  • the modification of the nucleoside as described above may be prepared through organic chemical synthesis methods known in the art to which the present invention pertains.
  • the present invention also relates to a pharmaceutical composition comprising the modified antisense oligonucleotide as described above.
  • the present invention contains the modified antisense oligonucleotide as described above, and diseases (eg, malignant tumors, benign tumors, immune diseases, fibrosis or ophthalmic diseases, etc.) related to overexpression of TGF- ⁇ 2 protein It relates to a pharmaceutical composition for preventing or treating.
  • diseases eg, malignant tumors, benign tumors, immune diseases, fibrosis or ophthalmic diseases, etc.
  • the oligonucleotide of the present invention was treated in a solid cancer cell line, it was confirmed that the effect of inhibiting the expression of TGF- ⁇ 2 protein was more excellent, the effect of killing cancer cells was excellent, and the stability in plasma was also improved.
  • the oligonucleotide of the present invention can be usefully used as a pharmaceutical composition for treating diseases related to TGF- ⁇ expression, for example, malignant tumors, benign tumors, immune diseases, fibrosis, ophthalmic diseases, and the like.
  • 1 is a graph confirming the change in TGF- ⁇ 2 mRNA expression by treating A549 with 20 nM of ASO.
  • FIG. 2 is a graph confirming the change in TGF- ⁇ 2 mRNA expression by treating PANC-1 with ASO 20 nM.
  • 3 is a graph confirming the change in TGF- ⁇ 2 mRNA expression by treating A549 with 5 nM of ASO.
  • FIGS. 5 and 6 show changes in human TGF- ⁇ 2 mRNA level (level) when A549, PANC-1 is treated with ASO at 1 uM (Free uptake (meaning no transfection reagent)).
  • TGF- ⁇ 2 mRNA expression levels for each cell line of 4 types of carcinoma (Breast cancer, Pancreatic cancer, Lung cancer, and Melanoma).
  • Figure 11 shows changes in human TGF- ⁇ 2 mRNA level after ASO treatment in 4 types of carcinoma (Lung adenocarcinoma (A549), Pancreatic cancer (Panc-1), Breast cancer (MDA-MB-231), Melanoma (Hs294T)) .
  • carcinoma Lung adenocarcinoma (A549), Pancreatic cancer (Panc-1), Breast cancer (MDA-MB-231), Melanoma (Hs294T)
  • FIG. 12 is a diagram showing changes in body weight after administration of ASO to xenograft mice.
  • FIG. 13 is a diagram showing tumor volume after administration of ASO to xenograft mice.
  • FIG. 14 is a diagram showing the tumor suppression rate after administration of ASO to xenograft mice.
  • the oligonucleotide of the present invention was treated in a solid cancer cell line, it was confirmed that the effect of inhibiting the expression of TGF- ⁇ 2 protein was more excellent, the effect of killing cancer cells was excellent, and the stability in plasma was also improved.
  • Human lung cancer cell line A549 and human pancreatic cancer cell line PANC-1 were each treated with antisense oligonucleotide (ASO) 20 nM (w/transfection reagent), and changes in human TGF- ⁇ 2 mRNA level were confirmed.
  • ASO antisense oligonucleotide
  • A549 and PANC-1 cell lines was treated with ASO 1 ⁇ M (free uptake (meaning no transfection reagent)), and then human TGF- ⁇ 2 mRNA level changes were confirmed.
  • RPMI 1640 (10% FBS, 1% Antibiotic-Antimycotic)
  • DMEM 1% Antibiotic-Antimycotic
  • McCoy's 5A 10% FBS, 1% Antibiotic-Antimycotic
  • the mixture containing ASO and the mixture containing the transfection reagent were mixed 1:1 and reacted at room temperature for 5 minutes. This mixture was dispensed to the cell line in which the medium was replaced, and incubated in an incubator (37° C., CO 2 5%) for 24 hours or 48 hours depending on the purpose of the test.
  • RNAiMAX total volume 6 well 200,000 to 300,000 7.5 ⁇ l 2 ml 96 wells 5,000 to 10,000 0.3 ⁇ l 100 ⁇ l
  • An appropriate number of cells were seeded according to the characteristics of the cells and the plate size, and cultured for 24 hours.
  • ASO was put in a medium containing 10% FBS according to the concentration.
  • the mixture containing ASO was dispensed on the cell-seeded plate, it was cultured in an incubator (37° C., CO 2 5%) for 24 hours or 48 hours depending on the purpose of the test.
  • cDNA was synthesized with 2 ⁇ g of the extracted RNA using a cDNA synthesis kit (RevertAid First Strand cDNA Synthesis kit, Thermo Sceientific, K1622). Synthesis was carried out under synthetic conditions according to the manufacturer's instructions, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20ng/ ⁇ l.
  • a cDNA synthesis kit RevertAid First Strand cDNA Synthesis kit, Thermo Sceientific, K1622. Synthesis was carried out under synthetic conditions according to the manufacturer's instructions, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20ng/ ⁇ l.
  • PCR was performed by preparing a mixture under the composition and conditions as shown in Tables 4 to 6 below.
  • the supernatant was recovered and centrifuged (13,000 rpm, 1 min).
  • nucleotides in bold underlined text indicate modified nucleotides.
  • A001 is the known antisense oligonucleotide of SEQ ID NO: 1, and A001-01M to A001-021M and A001-01L, A001-04L, A001-06L and A001-10L below are modified according to the present invention Examples of antisense oligonucleotides comprising nucleotides.
  • the modified nucleotides of the oligonucleotides indicated by A001-01M to A001-021M in the table above are 2'-O-methoxyethyl (MOE) modified nucleotides, and A001-01L, A001-04L, A001-06L and
  • the modified nucleotides of the oligonucleotides designated A001-10L are oligonucleotides that are locked nucleic acid (LNA) modified nucleotides.
  • LNA locked nucleic acid
  • the bond between nucleosides in the oligonucleotides of the table above is a phosphothioate bond, whether or not the nucleoside is modified.
  • the change in the mRNA level of TGF- ⁇ 2 was compared for each candidate, and the efficacy of the ASO of the present invention was compared with A001 did
  • the culture medium for cell line A549 (Lung carcinoma) was RPMI1640+10%FBS+1% Antibiotics, and the culture medium for cell line PANC-1 (Pancreas Epithelioid carcinoma) was DMEM+10%FBS+1% Antibiotics.
  • Transfection Change the medium 24 hours after cell seeding (after removing the existing culture, add 1.8 ml of media containing no antibiotics and 10% FBS), 20 times the final concentration of ASO to be tested (400 nM) It was put in plain media without addition of anything, and the transfection reagent (Lipofectamine RNAiMAX) was also put in plain media without addition to a concentration of 7.5 ul/100 ul. The mixture containing ASO and the mixture containing the transfection reagent were mixed 1:1 and reacted at room temperature for 5 minutes (at this time, the concentration of ASO becomes 200 nM).
  • RNA extraction and quantification After removing all the culture medium 24 hours after transfection, RNA was extracted using an RNA preparation kit (Rneasy Plus Mini Kit, Qiagen, Cat# 74136). After RNA extraction, RNA was quantified by absorptiometry using a micro-volume plate (Take 3, Biotek) and a multi plate reader (Synergy H1, Biotek).
  • cDNA was synthesized with 2 ug of the extracted RNA using a cDNA synthesis kit (RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622). Synthesis conditions were carried out according to the manufacturer's instruction, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • a cDNA synthesis kit RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622. Synthesis conditions were carried out according to the manufacturer's instruction, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • Figure 2 shows the inhibition ratio of human TGF- ⁇ 2 mRNA when PANC-1 is treated with ASO 20nM (with transfection reagent).
  • Example 5 Based on the experimental results of Example 5, ASO with relatively good efficacy was selected, and cell lines (A549, PANC-1) were treated at a concentration of 5 nM ASO in the presence of a transfection reagent, and then the mRNA level of TGF- ⁇ 2 was Changes were compared by ASO to compare the efficacy of ASO to the known A001 ASO.
  • the culture medium RPMI1640+10%FBS+1% Antibiotics was used, and for the cell line PANC-1 (Pancreas Epithelioid carcinoma), the culture medium DMEM+10%FBS+1% Antibiotics was used.
  • Cells were seeded at 2x10 5 cells / 2 ml per well in a 6 well plate.
  • RNA extraction and quantification After removing all the culture medium 24 hours after transfection, RNA was extracted using an RNA preparation kit (Rneasy Plus Mini Kit, Qiagen, Cat# 74136). After RNA extraction, RNA was quantified by absorptiometry using a micro-volume plate (Take 3, Biotek) and a multi-plate reader (Synergy H1, Biotek).
  • cDNA was synthesized with 2 ug of the extracted RNA using a cDNA synthesis kit (RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622). Synthesis conditions were carried out according to the manufacturer's instruction, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • a cDNA synthesis kit RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622. Synthesis conditions were carried out according to the manufacturer's instruction, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • 3 is a graph confirming the change in TGF- ⁇ 2 mRNA expression by treating A549 with 5 nM of ASO.
  • the culture medium RPMI1640+10%FBS+1% Antibiotics was used, and for the cell line Panc-1 (Pancreas Epithelioid carcinoma), the culture medium DMEM+10%FBS+1% Antibiotics was used.
  • RNA extraction and quantification After removing all the culture medium 24 hours after transfection, RNA was extracted using an RNA preparation kit (Rneasy Plus Mini Kit, Qiagen, Cat# 74136). After RNA extraction, RNA was quantified by absorptiometry using a micro-volume plate (Take 3, Biotek) and a multi-plate reader (Synergy H1, Biotek).
  • cDNA was synthesized with 2 ug of the extracted RNA using a cDNA synthesis kit (RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622). Synthesis conditions were carried out according to the manufacturer's instruction, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • a cDNA synthesis kit RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622. Synthesis conditions were carried out according to the manufacturer's instruction, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • the medium was replaced (after removing the existing culture medium, 1.8 ml of a medium containing 10% FBS without antibiotics was added).
  • the ASO to be tested was serially diluted with plain media without any addition so as to be 20 times the concentration to be treated (50-1600 nM).
  • the transfection reagent (Lipofectamine RNAiMAX) was also put in plain media to which nothing was added to a concentration of 7.5 ul/100 ul.
  • the mixture containing ASO and the mixture containing the transfection reagent were mixed 1:1 and reacted at room temperature for 5 minutes (at this time, the concentration of ASO becomes 10 times the concentration to be treated).
  • RNA extraction and quantification After collecting the culture medium 48 hours after transfection, RNA was extracted using an RNA preparation kit (Rneasy Plus Mini Kit, Qiagen, Cat# 74136). After RNA extraction, RNA was quantified by absorptiometry using a micro-volume plate (Take 3, Biotek) and a multi-plate reader (Synergy H1, Biotek).
  • cDNA was synthesized with 2ug of the extracted RNA using a cDNA synthesis kit (RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622). Synthesis conditions were carried out according to the manufacturer's instruction, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • a cDNA synthesis kit RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622. Synthesis conditions were carried out according to the manufacturer's instruction, and after PCR was completed, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • ASO spiked plasma was sampled and the amount of remaining ASO was analyzed by HPLC.
  • ASO containing nucleotides modified according to the present invention was maintained at 50% or more until 24 hours.
  • the amount of ASO detected even after 24 hours was about 80% or more.
  • the nucleotide according to the present invention has improved stability.
  • the transfection reagent (Lipofectamine RNAiMAX) was also put in plain media to which nothing was added to a concentration of 7.8 ul/100 ul.
  • RNA extraction and quantification After collecting the culture medium 48 hours after transfection, RNA was extracted using an RNA preparation kit (Rneasy Plus Mini Kit, Qiagen, Cat# 74136). After RNA extraction, RNA was quantified by absorptiometry using a micro-volume plate (Take 3, Biotek) and a multi-plate reader (Synergy H1, Biotek).
  • cDNA was synthesized with 2ug of the extracted RNA using a cDNA synthesis kit (RevertAid First Strand cDNA Synthesis Kit, Thermo Scientific, K1622). Synthesis conditions were performed according to the manufacturer’s instructions. After completion of PCR, cDNA was diluted with distilled water (DW) to 20 ng/ul.
  • DW distilled water
  • TGF- ⁇ 2 protein expression quantitative assay (ELISA):
  • TGF- ⁇ 2 mRNA expression levels for each cell line of 4 types of carcinoma (Breast cancer, Pancreatic cancer, Lung cancer, and Melanoma).
  • Figure 11 shows changes in human TGF- ⁇ 2 mRNA level after ASO treatment in 4 types of carcinoma (Lung adenocarcinoma (A549), Pancreatic cancer (Panc-1), Breast cancer (MDA-MB-231), Melanoma (Hs294T)) .
  • carcinoma Lung adenocarcinoma (A549), Pancreatic cancer (Panc-1), Breast cancer (MDA-MB-231), Melanoma (Hs294T)
  • the human TGF-b2 mRNA level was significantly reduced compared to the control group for 4 cell lines.
  • mice/group Balb/c nude mouse, male (5 weeks old), 6 mice/group
  • mice were acclimatized for one week after wearing, and tumor cells (A549) were transplanted 13 days before group separation (day 0).
  • Groups were separated 13 days after tumor cell transplantation.
  • the tumor size was about 80-100 mm 3 .
  • Treatment A total of 5 times (day 0, 2, 4, 7, 9) was administered at a dose of 15 mg/kg, 10 ml/kg by subcutaneous injection (s.c.) or intraperitoneal injection (i.p.).
  • the experimental schedule is as follows:
  • the oligonucleotide of the present invention can be usefully used as a pharmaceutical composition for treating diseases related to TGF- ⁇ expression, for example, malignant tumors, benign tumors, immune diseases, fibrosis, ophthalmic diseases, and the like.

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Abstract

Des oligonucléotides antisens sont divulgués.
PCT/KR2021/012989 2020-09-21 2021-09-23 Oligonucléotides antisens Ceased WO2022060208A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010512773A (ja) * 2006-12-22 2010-04-30 アンティセンス ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング オリゴヌクレオチド、タンパク、および／またはペプチド・ポリマー接合体
US20100160208A1 (en) * 2003-12-19 2010-06-24 Antisense Pharma Gmbh Pharmaceutical composition
KR20180103817A (ko) * 2016-02-09 2018-09-19 오토텔릭 엘엘씨 암을 치료하기 위한 조성물과 방법
KR102108599B1 (ko) * 2013-03-27 2020-05-08 이사르나 테라퓨틱스 게엠베하 변형된 tgf-베타 올리고뉴클레오타이드

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE211762T1 (de) 1993-04-30 2002-01-15 Biognostik Ges Antisense-oligonukleotide zur behandlung des immunsuppressiven effektes des transformierenden wachstumsfaktor-beta1(tgf-beta1)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100160208A1 (en) * 2003-12-19 2010-06-24 Antisense Pharma Gmbh Pharmaceutical composition
JP2010512773A (ja) * 2006-12-22 2010-04-30 アンティセンス ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング オリゴヌクレオチド、タンパク、および／またはペプチド・ポリマー接合体
KR102108599B1 (ko) * 2013-03-27 2020-05-08 이사르나 테라퓨틱스 게엠베하 변형된 tgf-베타 올리고뉴클레오타이드
KR20180103817A (ko) * 2016-02-09 2018-09-19 오토텔릭 엘엘씨 암을 치료하기 위한 조성물과 방법

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PETER HAU , PIOTR JACHIMCZAK ,ULRICH BOGDAHN: "Treatment of malignant gliomas with TGF-β2 antisense oligonucleotides. ", EXPERT REVIEW OF ANTICANCER THERAPY, vol. 9, no. 11, 1 January 2009 (2009-01-01), GB , pages 1663 - 1674, XP009535063, ISSN: 1473-7140, DOI: 10.1586/era.09.138 *

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