IL-11 antisense oligonucleotide

Abstract

To provide IL-11 antisense oligonucleotides capable of inhibiting the expression of IL-11 or IL-11 mRNA, pharmaceutically acceptable salts thereof, solvates thereof, pharmaceutical compositions characterized by containing them as active ingredients, and agents for the prevention and / or treatment of diseases involving IL-11. [Solution] The present invention relates to IL-11 antisense oligonucleotides that can inhibit the expression of IL-11 or IL-11 mRNA, and to pharmaceutical compositions characterized by containing them as active ingredients.

Description

[Technical Field]

[0001] The present invention relates to IL-11 antisense oligonucleotides, or pharmaceutically acceptable salts thereof, or solvates thereof, and to pharmaceutical compositions characterized by containing them as active ingredients. The invention also relates to agents for the prevention and / or treatment of diseases involving IL-11 (e.g., fibrotic diseases, gastrointestinal polyposis, etc.). [Background technology]

[0002] IL-11 (interleukin-11) is a type of cytokine and a member of the IL-6 family of cytokines. The IL-6 family of cytokines includes IL-6, IL-11, IL-27, IL-31, oncostatin, leukemia suppressor factor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), and neuropoetin (NP-1). When IL-11 was first discovered, it was isolated from bone marrow-derived stromal cells and was thought to be a cytokine involved in hematopoietic cell activation and platelet production. However, various studies to date have shown that IL-11 has a wide range of physiological effects in the body, including on the hematopoietic system, gastrointestinal tract, respiratory system, bone formation, cartilage and synovial membrane, and liver.

[0003] Regarding IL-11, the following are known: (1) its association with hematopoietic cell activation and platelet production; (2) its protective effects against graft-versus-host disease, inflammatory arthritis, and inflammatory bowel disease, and its role as an anti-inflammatory cytokine; (3) its suggestion of a relationship between tumor formation based on pro-inflammatory / anti-inflammatory and pro-angiogenic properties; (4) its detection in a mouse arthritis model and in virus-induced inflammation of cancer, suggesting that pathological stimuli induce IL-11 expression; and (5) its association with Stat3-dependent activation of tumor-promoting target genes in neoplastic gastrointestinal epithelium. It has been suggested that the expression of IL-11 in cells, tissues, and organs in the body can lead to the development of various diseases due to its physiological effects (Patent Document 4).

[0004] Based on these findings, if it becomes possible to create drugs that can inhibit IL-11 expression in cells, tissues, and organs in the body, or drugs that can inhibit IL-11 mRNA expression at the gene level, such as nucleic acid drugs like IL-11 antisense oligonucleotides (hereinafter also referred to as IL-11ASOs), then these drugs could potentially be applied to the prevention and / or treatment of diseases involving IL-11, and are expected to become a new type of preventive and / or therapeutic agent.

[0005] International Publication No. 2010 / 115868 (Patent Document 1) exemplifies siRNA, ASOs, antibodies, polypeptides, etc., as inhibitors of the expression and / or activity of IL-6 family cytokines (such as IL-11) for the treatment of cancer-related diseases. However, the examples only disclose an anti-LIF antibody against LIF, one of the IL-6 family cytokines, and the specific sequence of IL-11ASO is not disclosed.

[0006] International Publication No. 2019 / 207122 (Patent Document 2) exemplifies anti-IL-11 antibodies, oligonucleotides (aptamers, siRNAs, miRNAs, ASOs), and small molecules as antagonists of IL-11-mediated signaling that can block or reduce IL-11 expression for the treatment and / or prevention of ocular fibrosis, etc. However, only anti-IL-11 antibodies are specifically disclosed, and the specific sequence of IL-11ASO is not disclosed.

[0007] International Publication No. 2020 / 152122 (Patent Document 3) exemplifies oligonucleotides and small molecules as agents that can inhibit or reduce IL-11 expression for use in the treatment and / or prevention of hepatotoxicity and / or hepatotoxicity-related disorders, diseases, etc. However, only the sequence of IL-11 target siRNA is specifically disclosed, and the sequence of IL-11ASO is not disclosed.

[0008] International Publication No. 2020 / 225147 (Patent Document 4) exemplifies oligonucleotides and small molecules as agents that can inhibit or reduce IL-11 expression for use in the treatment and / or prevention of metabolic diseases. However, only the sequence of IL-11 target siRNA is specifically disclosed, and the sequence of IL-11ASO is not disclosed.

[0009] International Publication No. 2021 / 255182 (Patent Document 5) exemplifies oligonucleotides and small molecules as agents that can block or reduce IL-11 expression for use in the treatment and / or prevention of Alport syndrome. Specifically, the sequences of IL-11 target siRNAs are disclosed, but the sequences of IL-11 ASOs are not disclosed.

[0010] International Publication No. 2022 / 090509 (Patent Document 6) lists oligonucleotides as agents that can block or reduce the expression of IL-11 for use in extending healthy life expectancy and treating age-related diseases. However, only the sequence of IL-11 target siRNA is specifically disclosed, and the sequence of IL-11ASO is not disclosed.

[0011] International Publication No. 2023 / 006765 (Patent Document 7) exemplifies the following as agents capable of inhibiting IL-11-mediated signaling for the treatment or prevention of alcoholic liver disease: antibodies or their antigen-binding fragments, polypeptides, peptides, nucleic acids, oligonucleotides (ASOs, siRNAs), aptamers, small molecule compounds, etc. However, the specific disclosures are those of anti-IL-11 antibodies and IL-11 target siRNA sequences, while the specific sequence of IL-11 ASOs is not disclosed.

[0012] International Publication No. 02 / 085308 (Patent Document 8), International Publication No. 02 / 085309 (Patent Document 9), and International Publication No. 00 / 062736 (Patent Document 10) mention IL-11 nucleic acid and antisense oligonucleotide fragments, but the specific sequence of IL-11ASO is not disclosed.

[0013] Korean Published Patent No. 2013-0121235 (Patent Document 11) discloses antisense DNA complementary to human IL-11 mRNA, but does not disclose the degree to which this antisense inhibits IL-11 expression. Furthermore, the sugar portion, phosphate-binding portion, and nucleic acid base portion of the nucleoside of the antisense oligonucleotide are not modified.

[0014] Blood, Vol 81, No 4, 1993: pp 889-893 (Non-Patent Literature 1) discloses a 15-nucleotide IL-11 antisense oligonucleotide (DNA), but the sugar portion, phosphate bond portion, and nucleotide base portion of the oligonucleotide nucleoside are not modified.

[0015] Am J Physiol Gastrointest Liver Physiol 289: G274-G284, 2005 (Non-Patent Literature 2) discloses 15 nucleic acid base IL-11 antisense oligonucleotides, but does not disclose whether or not they are modified.

[0016] Sci Adv. 2022 Jun 24;8(25):eabn7162. (Non-patent document 3) discloses that damaged lung tissue can be repaired in a mouse model of bleomycin-induced pulmonary fibrosis by administering an siRNA (siIL11) that blocks IL-11 signaling. [Prior art documents] [Patent Documents]

[0017] [Patent Document 1] International Publication No. 2010 / 115868 Pamphlet [Patent Document 2] International Publication No. 2019 / 207122 Brochure [Patent Document 3] International Publication No. 2020 / 152122 Brochure [Patent Document 4] International Publication No. 2020 / 225147 Brochure [Patent Document 5] International Publication No. 2021 / 255182 brochure [Patent Document 6] International Publication No. 2022 / 090509 Brochure [Patent Document 7] International Publication No. 2023 / 006765 Brochure [Patent Document 8] International Publication No. 02 / 085308 Pamphlet [Patent Document 9] International Publication No. 02 / 085309 Pamphlet [Patent Document 10] International Publication No. 00 / 062736 Pamphlet [Patent Document 11] Korean Published Patent No. 2013-0121235 Brochure [Non-patent literature]

[0018] [Non-Patent Document 1] Blood, Vol 81, No 4, 1993: pp 889-893. [Non-Patent Document 2] AJP-Gastrointest Liver Physiol vol 289, G274-G284, 2005. [Non-Patent Document 3] Sci Adv. 2022 Jun 24;8(25):eabn7162. [Overview of the project] [Problems that the invention aims to solve]

[0019] In the circumstances described above, the main objective of the present invention is to provide IL-11 antisense oligonucleotides, or pharmaceutically acceptable salts thereof, or solvates thereof, that can inhibit the expression of IL-11 or IL-11 mRNA, as well as pharmaceutical compositions characterized by containing them as active ingredients, and their pharmaceutical uses, particularly as preventive and / or therapeutic agents for diseases involving IL-11 (e.g., fibrotic diseases, gastrointestinal polyposis, etc.). Furthermore, an objective of the present invention is also to provide a method for producing the IL-11 antisense oligonucleotides, or pharmaceutically acceptable salts thereof, or solvates thereof.

[0020] Several challenges may exist in the development of nucleic acid drugs, including antisense oligonucleotides. Specifically, these include issues related to activity level, stability, toxicity, enzymatic degradation resistance, target tissue targeting, intracellular distribution, cytoplasmic distribution, pharmacokinetics, and administration methods. The goal is to resolve these challenges as much as possible and to discover highly effective compounds.

[0021] Under these circumstances, there was a need to provide drugs that can inhibit IL-11 expression in cells, tissues, organs, etc. within the body, particularly nucleic acid drugs that can inhibit IL-11 mRNA expression at the gene level, such as IL-11 antisense oligonucleotides, pharmaceutically acceptable salts thereof, or solvates thereof. [Means for solving the problem]

[0022] To solve the above problems, the present inventors have diligently conducted research to obtain an IL-11 antisense oligonucleotide that is excellent at inhibiting the expression of IL-11 or IL-11 mRNA and has high safety. As a result, they have found, for example, an IL-11 antisense oligonucleotide having the characteristics described below, or a pharmaceutically acceptable salt thereof or solvate thereof. That is, the IL-11 antisense oligonucleotide of the present invention is, for example, an antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is complementary to the isolength portion of the IL-11 nucleic acid, and the oligonucleotide is characterized by including at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0023] The IL-11 antisense oligonucleotide of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, can inhibit the expression of IL-11 or IL-11 mRNA, and therefore may have an ameliorative effect on diseases involving IL-11 (e.g., fibrotic diseases, gastrointestinal polyposis, etc.). Based on this finding, the inventors have completed the present invention.

[0024] The present invention relates to IL-11 antisense oligonucleotides as shown in the following embodiments, or pharmaceutically acceptable salts thereof, or solvates thereof, and pharmaceutical compositions characterized by containing them as active ingredients, and pharmaceutical uses thereof, which may be more specifically as follows [1] to [44-2].

[0025] [1] An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is complementary to the isolength portion of the IL-11 nucleic acid, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. [1-1] An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isolength portion of the IL-11 nucleic acid, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0026] [2] The antisense oligonucleotide according to embodiment [1] or [1-1], wherein the IL-11 nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0027] [3] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within nucleic acid bases 1-2378, 1-753, 1-153, 154-2378, 154-753, or 754-2378 of SEQ ID NO: 1. [3-1] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within nucleic acid bases 1 to 153 of SEQ ID NO: 1. [3-2] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within nucleic acid bases 154 to 753 of SEQ ID NO: 1. [3-3] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within nucleic acid bases 754 to 2378 of SEQ ID NO: 1.

[0028] [4] The nucleic acid base sequence of oligonucleotides is as follows: nucleic acid bases 27-42, 82-97, 94-109, 148-163, 152-167, 170-185, 198-213, 240-255, 322-337, 331-346, 337-352, 340-355, 357-372, 363-378, 368-383, 379-394, 407-422, 418-433, 422-437, 427-442 ,428~443,431~446,451~466,454~469,455~470,456~471,456~473,457~472,458~473,472~487,473~488,490~505,492~507,493~508,494~509,495~510,496~511,497~512,499~514,500~515,501~516,502~517,503~518, 504~519, 505~520, 506~521, 507~522, 508~523, 509~524, 510~525, 510~527, 511~526, 512~527, 527~542, 574~589, 577~592, 683~700, 691~706, 696~711, 701~716, 717~732, 774~789, 776~791, 777~792, 778~793, 780~795, 7 An antisense oligonucleotide according to any one of the embodiments [1] to [2], which is at least 80% complementary to the equal-length portions within 83-798, 784-799, 785-800, 786-801, 787-802, 899-914, 904-919, 1115-1130, 1127-1142, 1138-1153, 1158-1173, 1766-1781, 2266-2281, or 2324-2339.

[0029] [4-1] The nucleic acid base sequence of oligonucleotides is as follows: nucleic acid bases 27-42, 198-213, 331-346, 357-372, 363-378, 379-394, 422-437, 431-446, 451-466, 454-469, 456-471, 456-473, 457-472, 458-473, 472-487, 473-488, 492-507, 493-508, 494-509, 495-510, 502-517, 503-518, 504-519, 505-520, 506-521, 507-522, 508-523, 509-524, 510-52 An antisense oligonucleotide according to any one of the embodiments [1]-[2], which is at least 80% complementary to the equal-length portions in 5, 510-527, 511-526, 512-527, 527-542, 574-589, 577-592, 683-700, 691-706, 696-711, 701-716, 717-732, 774-789, 776-791, 777-792, 778-793, 780-795, 786-801, 787-802, 899-914, 904-919, 1115-1130, 1127-1142, 1766-1781, or 2324-2339.

[0030] [4-2] The nucleic acid base sequence of oligonucleotides is as follows: nucleic acid bases 198-213, 331-346, 422-437, 431-446, 451-466, 454-469, 456-473, 457-472, 458-473, 472-487, 493-508, 502-517, 503-518, 504-519, 505-520, 506-521, 507-522, 508-523, 509-524, 510 An antisense oligonucleotide according to any one of the embodiments [1]-[2], which is at least 80% complementary to an equal-length portion in ~525, 510~527, 511~526, 512~527, 574~589, 683~700, 691~706, 696~711, 701~716, 776~791, 777~792, 778~793, 786~801, 904~919, 1766~1781, or 2324~2339.

[0031] [4-3] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within the nucleic acid bases 198-213, 331-346, 422-437, 431-446, 451-466, 454-469, 457-472, 458-473, 472-487, 502-517, 503-518, 504-519, 506-521, 507-522, 508-523, 511-526, 574-589, 683-700, 691-706, 696-711, 701-716, 777-792, 904-919 or 2324-2339 of SEQ ID NO: 1.

[0032] [4-4] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion among the nucleic acid bases 456-473, 457-472, 493-508, 503-518, 504-519, 505-520, 509-524, 510-525, 510-527, 511-526, 512-527, 776-791, 777-792, 778-793, 786-801 or 1766-1781 of SEQ ID NO: 1.

[0033] [4-5] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within the nucleic acid bases 456-477, 457-478, 493-514, 503-524, 504-525, 505-526, 509-530, 510-531, 511-532, 512-533, 776-797, 777-798, 778-799, 786-807 or 1766-1787 of SEQ ID NO: 1.

[0034] [4-6] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within the nucleic acid bases 451-472, 452-473, 487-508, 497-518, 498-519, 499-520, 503-524, 504-525, 505-526, 506-527, 770-791, 771-792, 772-793, 780-801 or 1760-1781 of SEQ ID NO: 1.

[0035] [5] The nucleic acid base sequence of oligonucleotides is the nucleic acid bases 601-6682, 601-753, 601-760, 601-2122, 601-2295, 601-2494, 601-2581, 601-2692, 601-2854, 601-4886, 601-5057, 601-6682, 754-760, 754-2122, 754-2295, 754-2494, 754-2581, 754~2692, 754~2854, 754~4886, 754~5057, 754~6682, 761~2122, 761~2295, 761~2494, 761~2581, 761~2692, 761~2854, 761~4886, 761~5057, 761~6682, 2123~2295, 2123~2494, 2123~2581, 2123~2692, 2123~2854, 2123~4 886, 2123~5057, 2123~6682, 2296~2494, 2296~2581, 2296~2692, 2296~2854, 2296~4886, 2296~5057, 2296~6682, 2495~2581, 2495~2692, 2495~2854, 2495~4886, 2495~5057, 2495~6682, 2582~2692, 2582~2854, 2582~488 6, an antisense oligonucleotide according to any one of the embodiments [1] to [2], which is at least 80% complementary to the equal-length portions in 2582-5057, 2582-6682, 2693-2854, 2693-4886, 2693-5057, 2693-6682, 2855-4886, 2855-5057, 2855-6682, 4887-5057, 4887-6682, or 5058-6682. [5-1] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within nucleic acid bases 601 to 753 of SEQ ID NO: 2. [5-2] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portions within nucleic acid bases 754-760, 2123-2295, 2495-2581, 2693-2854 or 4887-5057 of Sequence ID No. 2. [5-3] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portion within nucleic acid bases 5058 to 6682 of SEQ ID NO: 2. [5-4] The antisense oligonucleotide according to any one of the embodiments [1] to [2], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isochromatic portions within nucleic acid bases 761-2122, 2296-2494, 2582-2692, or 2855-4886 of Sequence ID No. 2.

[0036] [6] The nucleic acid base sequence of oligonucleotides is as follows: nucleic acid bases 627-642, 682-697, 694-709, 766-781, 930-945, 956-971, 1343-1358, 1558-1573, 1607-1622, 2132-2147, 2160-2175, 2202-2217, 2290-2305, 2348-2363, 2363-2378, 2372-2387, 2383-2398, 2412-2427, 2477-2492, 2498-2513, 2501-2516, 2518-2533, 2524-2539, 2529~2544, 2540~2555, 2690~2705, 2694~2709, 2699~2714, 2700~2715, 2703~2718, 2723~2738, 2726~2741, 2727~2742, 2728~2743, 2728~2745, 2729~ 2744, 2730~2745, 2744~2759, 2745~2760, 2762~2777, 2764~2779, 2765~2780, 2766~2781, 2767~2782, 2768~2783, 2769~2784, 2771~2786, 2772~2787, 2773~2788, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~ 2799, 2799~2814, 2852~2867, 2865~2880, 2915~2930, 2946~2961, 2978~2993, 2999~3014, 3037~3052, 3073~3088, 3111~3126, 3124~3139, 3134~3149, 3145~3160, 3163~3178, 3184~3199, 3199~3214, 3226~3241, 3245~3260, 3258~3273, 3278~3293, 3290~3305, 3626~3641, 3664~3679, 3690~3705, 3705~ 3720, 3749~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877, 3902~3917, 3926~3941, 3940~3955, 3963~3978, 3984~3999, 3999~4014,4018~4033, 4032~4047, 4051~4066, 4068~4083, 4086~4101, 4161~4176, 4180~4195, 4290~4305, 4373~4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4601~ 4616, 4622~4637, 4646~4661, 4653~4668, 4676~4691, 4698~4713, 4751~4766, 4780~4795, 4799~4814, 4852~4867, 4879~4894, 4987~5004, 4995~5010, 5000~5015, An antisense oligonucleotide according to any one of the embodiments [1]-[2], which is at least 80% complementary to the equal-length portions within 5005-5020, 5021-5036, 5078-5093, 5080-5095, 5081-5096, 5082-5097, 5084-5099, 5087-5102, 5088-5103, 5089-5104, 5090-5105, 5091-5106, 5203-5218, 5208-5223, 5419-5434, 5431-5446, 5442-5457, 5462-5477, 6070-6085, 6570-6585, or 6628-6643.

[0037] [6-1] The nucleic acid base sequence of oligonucleotides is 627~642, 930~945, 956~971, 1343~1358, 1558~1573, 1607~1622, 2160~2175, 2363~2378, 2372~2387, 2383~2398, 2412~2427, 2477~2492, 2518~2533, 2524~2539, 2540~2555, 2694~2709, 2703~2718, 2723~2738, 2726~2741, 2728~2743, 2728~2745, 2729~2744, 27 30-2745, 2744-2759, 2745-2760, 2764-2779, 2765-2780, 2766-2781, 2767-2782, 2774-2789, 2775-2790, 2776-2791, 2777-2792, 2778-2793, 2779-2 794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~2799, 2799~2814, 2865~2880, 2915~2930, 2946~2961, 2999~3014, 3037~3052, 3 111~3126, 3124~3139, 3145~3160, 3163~3178, 3226~3241, 3258~3273, 3290~3305, 3626~3641, 3664~3679, 3690~3705, 3705~3720, 3749~3764, 3764~ 3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877, 3902~3917, 3926~3941, 3940~3955, 3963~3978, 3984~3999, 3999~4014, 4018~4033, 4032~4047, 4051~4066, 4068~4083, 4086~4101, 4161~4176, 4180~4195, 4290~4305, 4373~4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4601~4616, 4622~ 4637, 4646~4661, 4653~4668, 4698~4713, 4751~4766, 4780~4795, 4799~4814, 4852~4867, 4987~5004, 4995~5010, 5000~5015, 5005~5020, 5021~5036,An antisense oligonucleotide according to any one of the embodiments [1]-[2], which is at least 80% complementary to the equal-length portions within 5078-5093, 5080-5095, 5081-5096, 5082-5097, 5084-5099, 5090-5105, 5091-5106, 5203-5218, 5208-5223, 5419-5434, 5431-5446, 6070-6085, or 6628-6643.

[0038] [6-2] The nucleic acid base sequence of oligonucleotides is as follows: nucleic acid bases 1343~1358, 1607~1622, 2160~2175, 2363~2378, 2383~2398, 2412~2427, 2477~2492, 2694~2709, 2703~2718, 2723~2738, 2726~2741, 2728~2745, 2729~2744, 2730~2745, 2744~2759, 2765~2780, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~2799, 2915~2930, 2946~2961, 2999~3014, 3037~3052, 3124~3139, 3145~3160, 3163~3178, 3226~3241, 3258~3273, 3290~3305, 3626~3641, 3690~3705, 3705~3720, 374 9~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877, 3902~3917, 3926~3941, 3940~3955, 3963~3978, 3984~3999, 3999~4014, 4018~4033, 4032~4047, 4051~4066, 4068~4083, 4180~4195, 4290~4305, 4373~4388, 4500~4515, 4528~4543, 4543~4558, 4578~4 An antisense oligonucleotide according to any one of the embodiments [1] to [2], which is at least 80% complementary to the equal-length portions in 593, 4601 to 4616, 4646 to 4661, 4698 to 4713, 4751 to 4766, 4852 to 4867, 4987 to 5004, 4995 to 5010, 5000 to 5015, 5005 to 5020, 5080 to 5095, 5081 to 5096, 5082 to 5097, 5090 to 5105, 5208 to 5223, 6070 to 6085, or 6628 to 6643.

[0039] [6-3] The nucleic acid base sequence of oligonucleotides is 2160~2175, 2363~2378, 2383~2398, 2412~2427, 2477~2492, 2694~2709, 2703~2718, 2723~2738, 2726~2741, 2729~2744, 2730~2745, 2744~2759, 2774~2789, 2775~2790, 2776~2791, 2778~2793, 2779~2794, 2780~2795, 2783~2798, 2915~2930, 3145~3160, 3163~3178, 322 An antisense oligonucleotide according to any one of the embodiments [1]-[2], which is at least 80% complementary to the equal-length portions in 6-3241, 3290-3305, 3705-3720, 3787-3802, 3820-3835, 3850-3865, 3926-3941, 3963-3978, 3999-4014, 4068-4083, 4290-4305, 4601-4616, 4751-4766, 4987-5004, 4995-5010, 5000-5015, 5005-5020, 5081-5096, 5208-5223, or 6628-6643.

[0040] [6-4] The nucleic acid base sequence of oligonucleotides is as follows: nucleic acid bases 1343-1358, 1607-1622, 2728-2745, 2729-2744, 2765-2780, 2775-2790, 2776-2791, 2777-2792, 2781-2796, 2782-2797, 2782-2799, 2783-2798, 2784-2799, 2946-2961, 2999-3014, 3037-3052, 3124-3139, 3258-3273, 3626-3641, 3690-3705, 3749-3764, 3764-3779, 3862-387 7, an antisense oligonucleotide according to any one of the embodiments [1]-[2], which is at least 80% complementary to the equal-length portions in 3902-3917, 3940-3955, 3984-3999, 4018-4033, 4032-4047, 4051-4066, 4180-4195, 4373-4388, 4500-4515, 4528-4543, 4543-4558, 4578-4593, 4646-4661, 4698-4713, 4852-4867, 5080-5095, 5081-5096, 5082-5097, 5090-5105 or 6070-6085.

[0041] [6-5] The nucleic acid base sequence of oligonucleotides is as follows: nucleic acid bases 1343-1364, 1607-1628, 2728-2749, 2729-2750, 2765-2786, 2775-2796, 2776-2797, 2777-2798, 2781-2802, 2782-2803, 2783-2804, 2784-2805, 2946-2967, 2999-3020, 3037-3058, 3124-3145, 3258-3279, 3626-3647, 3690-3711, 3749-3770, 3764-3785, 3862-3883, 390 An antisense oligonucleotide according to any one of the embodiments [1]-[2], which is at least 80% complementary to the equal-length portions in 2-3923, 3940-3961, 3984-4005, 4018-4039, 4032-4053, 4051-4072, 4180-4201, 4373-4394, 4500-4521, 4528-4549, 4543-4564, 4578-4599, 4646-4667, 4698-4719, 4852-4873, 5080-5101, 5081-5102, 5082-5103, 5090-5111, or 6070-6091.

[0042] [6-6] The nucleic acid base sequence of oligonucleotides is as follows: nucleic acid bases 1337~1358, 1601~1622, 2723~2744, 2724~2745, 2759~2780, 2769~2790, 2770~2791, 2771~2792, 2775~2796, 2776~2797, 2777~2798, 2778~2799, 2940~2961, 2993~3014, 3031~3052, 3118~3139, 3252~3273, 3620~3641, 3684~3705, 3743~3764, 3758~3779, 3856~3877, An antisense oligonucleotide according to any one of the embodiments [1]-[2], which is at least 80% complementary to the equal-length portions in 3896-3917, 3934-3955, 3978-3999, 4012-4033, 4026-4047, 4045-4066, 4174-4195, 4367-4388, 4494-4515, 4522-4543, 4537-4558, 4572-4593, 4640-4661, 4692-4713, 4846-4867, 5074-5095, 5075-5096, 5076-5097, 5084-5105 or 6064-6085.

[0043] [7] In any one of the embodiments [1] to [6-6], the number of linked nucleosides is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0044] [8] In any one of the embodiments [1] to [7], the complementarity of the nucleic acid base sequence of the oligonucleotide to the isolength portion of the IL-11 nucleic acid is, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the isolength portion within nucleic acid bases 683 to 700 of SEQ ID NO: 1 and the isolength portion within nucleic acid bases 4987 to 5004 of SEQ ID NO: 2 are excluded.

[0045] [9]Antisense oligonucleotide according to any one of the embodiments [1] to [8], having inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[0046] [9-1]An antisense oligonucleotide according to any one of the embodiments [1] to [8], wherein the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, about 5% or more, and is about 5-100%, about 30-100%, about 70-100%, about 80-100%, or about 90-100%. [9-2] IC due to inhibition of IL-11 or IL-11 mRNA expression 50 An antisense oligonucleotide according to any one of the embodiments [1] to [8], wherein the value is, for example, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, or about 10 nM or less.

[0047]

[10] Antisense oligonucleotides according to any one of the embodiments [1] to [9-2], or pharmaceutically acceptable salts thereof, or solvates thereof.

[0048]

[11] An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5 consecutive nucleic acid bases from any of the nucleic acid bases included in the nucleic acid base sequence selected from SEQ ID NOs. 4 to 156, and the oligonucleotide comprises at least one modification selected from a modified sugar, a modified nucleoside bond, and a modified nucleic acid base.

[0049] [11A]An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5 consecutive nucleic acid bases from any of the nucleic acid base sequences selected from SEQ ID NOs. 4 to 156, the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, is at least 80% complementary to the isolength portion of IL-11 nucleic acid, and has inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[0050] [11-1] In the embodiments

[11] or [11A] described above, the number of linked nucleosides is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0051] [11-2] In any one of the embodiments

[11] to [11-1] described above, the number of consecutive nucleic acid bases among the nucleic acid bases included in the nucleic acid base sequence is, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18; for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0052] [11-3] The antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs. 4 to 156. [11-4] Oligonucleotides are sequence numbers 4, 10, 13, 16, 17, 19, 22, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 74, 75, 76, 77, 80, 82, 84, 85, 86, 87, 88, 91, 92, 93, 94, 95, 97, 98, 99, 101, 102, 104, 105, 1 An antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], comprising a nucleic acid base sequence selected from 07, 108, 111, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 156.

[0053] [11-5] Oligonucleotides with SEQ ID NOs: 10, 13, 22, 25, 26, 27, 30, 31, 32, 33, 37, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 60, 61, 62, 65, 66, 67, 72, 75, 80, 82, 86, 88, 91, 93, 94, 95, 98, 99, 101, 102, 105, 107, 108, 111, 113, 115, 116 An antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], comprising a nucleic acid base sequence selected from 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 138, 139, 140, 141, 142, 143, 144, 145, 147, 150, 151, 154, 156. [11-6] An antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 30, 31, 37, 46, 47, 48, 52, 53, 54, 55, 56, 65, 66, 67, 72, 80, 86, 88, 99, 101, 102, 105, 113, 116, 118, 120, 121, 125, 126, 128, 130, 132, 133, 134, 138, 140, 141, 142, 143, 144, 147, 150, 154. [11-7] Antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 46, 47, 48, 65, 66, 67, 72, 88, 105, 116, 118, 120, 128, 134, 140, 141, 142, 143, 147, 154, 156.

[0054] [11-8] The antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of a nucleic acid base sequence selected from sequence numbers 4 to 156. [11-9] Oligonucleotides are sequence numbers 4, 10, 13, 16, 17, 19, 22, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 74, 75, 76, 77, 80, 82, 84, 85, 86, 87, 88, 91, 92, 93, 94, 95, 97, 98, 99, 101, 102, 104, 105, 107, 108 An antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], having a nucleic acid base sequence consisting of nucleic acid base sequences selected from 111, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 156. [11-10] Oligonucleotides are sequence numbers 10, 13, 22, 25, 26, 27, 30, 31, 32, 33, 37, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 60, 61, 62, 65, 66, 67, 72, 75, 80, 82, 86, 88, 91, 93, 94, 95, 98, 99, 101, 102, 105, 107, 108, 111, 113, 115, 116, 118, An antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], having a nucleic acid base sequence consisting of nucleic acid base sequences selected from 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 138, 139, 140, 141, 142, 143, 144, 145, 147, 150, 151, 154, 156. [11-11] The antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of nucleic acid base sequences selected from SEQ ID NOs: 30, 31, 37, 46, 47, 48, 52, 53, 54, 55, 56, 65, 66, 67, 72, 80, 86, 88, 99, 101, 102, 105, 113, 116, 118, 120, 121, 125, 126, 128, 130, 132, 133, 134, 138, 140, 141, 142, 143, 144, 147, 150, 154. [11-12] The antisense oligonucleotide according to any one of the embodiments

[11] to [11-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of a nucleic acid base sequence selected from SEQ ID NOs: 46, 47, 48, 65, 66, 67, 72, 88, 105, 116, 118, 120, 128, 134, 140, 141, 142, 143, 147, 154, 156.

[0055] [11-13] In the embodiments

[11] to [11-12] described above, the nucleic acid base sequence of the oligonucleotide has complementarity to the isolength portion of the IL-11 nucleic acid of, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the nucleic acid base of SEQ ID NO: 156 is excluded. [11-14] In the above embodiment [11-13], the IL-11 nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0056] [11-15]Antisense oligonucleotide according to any one of the embodiments

[11] to [11-14], having inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[0057] [11-16]An antisense oligonucleotide according to any one of the embodiments

[11] to [11-15], wherein the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, about 5% or more, and is one of about 5-100%, about 30-100%, about 70-100%, about 80-100%, or about 90-100%. [11-17] IC of inhibition of IL-11 or IL-11 mRNA expression 50 An antisense oligonucleotide according to any one of the embodiments

[11] to [11-15], wherein the value is, for example, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, or about 10 nM or less.

[0058] [11-18] Antisense oligonucleotides or pharmaceutically acceptable salts thereof or solvates thereof according to any one of the embodiments

[11] to [11-17] described above.

[0059]

[12] An antisense oligonucleotide comprising an oligonucleotide consisting of 15 to 22 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases from any of the nucleic acid bases included in the nucleic acid base sequence selected from SEQ ID NOs: 4 to 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0060] [12-1] In the above embodiment

[12] , the number of linked nucleosides is, for example, 15 to 22, 16 to 22, or 16 to 18; preferably 16 to 18 or 16 to 22; and more preferably 16 or 18.

[0061] [12-2] In the embodiments

[12] or [12-1] described above, the number of consecutive nucleic acid bases among the nucleic acid bases included in the nucleic acid base sequence is, for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0062] [12-3] The antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs. 4 to 156. [12-4] Oligonucleotides are sequence numbers 4, 10, 13, 16, 17, 19, 22, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 74, 75, 76, 77, 80, 82, 84, 85, 86, 87, 88, 91, 92, 93, 94, 95, 97, 98, 99, 101, 102, 104, 105, 1 An antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], comprising a nucleic acid base sequence selected from 07, 108, 111, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 156. [12-5] Oligonucleotides with SEQ ID NOs: 10, 13, 22, 25, 26, 27, 30, 31, 32, 33, 37, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 60, 61, 62, 65, 66, 67, 72, 75, 80, 82, 86, 88, 91, 93, 94, 95, 98, 99, 101, 102, 105, 107, 108, 111, 113, 115, 116 An antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], comprising a nucleic acid base sequence selected from 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 138, 139, 140, 141, 142, 143, 144, 145, 147, 150, 151, 154, 156. [12-6] An antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 30, 31, 37, 46, 47, 48, 52, 53, 54, 55, 56, 65, 66, 67, 72, 80, 86, 88, 99, 101, 102, 105, 113, 116, 118, 120, 121, 125, 126, 128, 130, 132, 133, 134, 138, 140, 141, 142, 143, 144, 147, 150, 154. [12-7] Antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 46, 47, 48, 65, 66, 67, 72, 88, 105, 116, 118, 120, 128, 134, 140, 141, 142, 143, 147, 154, 156.

[0063] [12-8] The antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of a nucleic acid base sequence selected from sequence numbers 4 to 156. [12-9] Oligonucleotides with SEQ ID NOs: 4, 10, 13, 16, 17, 19, 22, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 74, 75, 76, 77, 80, 82, 84, 85, 86, 87, 88, 91, 92, 93, 94, 95, 97, 98, 99, 101, 102, 104, 105, 107, 108 An antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], having a nucleic acid base sequence consisting of a nucleic acid base sequence selected from 111, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 156. [12-10] Oligonucleotides are sequence numbers 10, 13, 22, 25, 26, 27, 30, 31, 32, 33, 37, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 60, 61, 62, 65, 66, 67, 72, 75, 80, 82, 86, 88, 91, 93, 94, 95, 98, 99, 101, 102, 105, 107, 108, 111, 113, 115, 116, 118, An antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], having a nucleic acid base sequence consisting of nucleic acid base sequences selected from 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 138, 139, 140, 141, 142, 143, 144, 145, 147, 150, 151, 154, 156. [12-11] The antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of nucleic acid base sequences selected from SEQ ID NOs: 30, 31, 37, 46, 47, 48, 52, 53, 54, 55, 56, 65, 66, 67, 72, 80, 86, 88, 99, 101, 102, 105, 113, 116, 118, 120, 121, 125, 126, 128, 130, 132, 133, 134, 138, 140, 141, 142, 143, 144, 147, 150, 154. [12-12]An antisense oligonucleotide according to any one of the embodiments

[12] to [12-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of a nucleic acid base sequence selected from SEQ ID NOs: 46, 47, 48, 65, 66, 67, 72, 88, 105, 116, 118, 120, 128, 134, 140, 141, 142, 143, 147, 154, 156.

[0064] [12-13] In the embodiments

[12] to [12-12] described above, the nucleic acid base sequence of the oligonucleotide has complementarity to the isolength portion of the IL-11 nucleic acid of, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the nucleic acid base of SEQ ID NO: 156 is excluded. [12-14] In the above embodiment [12-13], the IL-11 nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0065] [12-15]Antisense oligonucleotide according to any one of the embodiments

[12] to [12-14], having inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[0066] [12-16]An antisense oligonucleotide according to any one of the embodiments

[12] to [12-15], wherein the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, about 5% or more, and is about 5-100%, about 30-100%, about 70-100%, about 80-100%, or about 90-100%. [12-17] IC of inhibition of IL-11 or IL-11 mRNA expression 50 An antisense oligonucleotide according to any one of the embodiments

[12] to [12-15], wherein the value is, for example, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, or about 10 nM or less.

[0067] [12-18] Antisense oligonucleotides or pharmaceutically acceptable salts thereof or solvates thereof according to any one of the embodiments

[12] to [12-17].

[0068] [12A] An antisense oligonucleotide comprising an oligonucleotide consisting of 16 to 22 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases from any of the nucleic acid bases included in the nucleic acid base sequence selected from SEQ ID NOs: 4 to 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0069] [12A-1] In the above embodiment [12A], the number of linked nucleosides is, for example, 16 to 22, 16 to 18; preferably 16 to 18; more preferably 16 or 18.

[0070] [12A-2] In the embodiments [12A] or [12A-1] described above, the number of consecutive nucleic acid bases among the nucleic acid bases included in the nucleic acid base sequence is, for example, 5 to 18, 10 to 18, 15 to 18, or 16 to 18; preferably, at least 16, 17, or 18; more preferably, at least 16 or 18.

[0071] [12A-3]Antisense oligonucleotide according to any one of embodiments [12A] to [12A-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from sequence numbers 4 to 156. [12A-4] oligonucleotides are numbered 4, 10, 13, 16, 17, 19, 22, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 74, 75, 76, 77, 80, 82, 84, 85, 86, 87, 88, 91, 92, 93, 94, 95, 97, 98, 99, 101, 102, 104, 105, 10 An antisense oligonucleotide according to any one of the embodiments [12A] to [12A-2], comprising a nucleic acid base sequence selected from 7, 108, 111, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 156.

[0072] [12A-5] oligonucleotides are available in SEQ ID NOs: 10, 13, 22, 25, 26, 27, 30, 31, 32, 33, 37, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 60, 61, 62, 65, 66, 67, 72, 75, 80, 82, 86, 88, 91, 93, 94, 95, 98, 99, 101, 102, 105, 107, 108, 111, 113, 115, 116, 118, 119, 120, 1 An antisense oligonucleotide according to any one of the embodiments [12A] to [12A-2], or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising a nucleic acid base sequence selected from 21, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 138, 139, 140, 141, 142, 143, 144, 145, 147, 150, 151, 154, 156.

[0073] [12A-6]Antisense oligonucleotide according to any one of the embodiments [12A] to [12A-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 30, 31, 37, 46, 47, 48, 52, 53, 54, 55, 56, 65, 66, 67, 72, 80, 86, 88, 99, 101, 102, 105, 113, 116, 118, 120, 121, 125, 126, 128, 130, 132, 133, 134, 138, 140, 141, 142, 143, 144, 147, 150, 154.

[0074] [12A-7]Antisense oligonucleotide according to any one of the embodiments [12A] to [12A-2], wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 46, 47, 48, 65, 66, 67, 72, 88, 105, 116, 118, 120, 128, 134, 140, 141, 142, 143, 147, 154, 156.

[0075] [12A-8]Antisense oligonucleotide according to any one of embodiments [12A] to [12A-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of a nucleic acid base sequence selected from sequence numbers 4 to 156. [12A-9] oligonucleotides are numbered 4, 10, 13, 16, 17, 19, 22, 25, 26, 27, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 74, 75, 76, 77, 80, 82, 84, 85, 86, 87, 88, 91, 92, 93, 94, 95, 97, 98, 99, 101, 102, 104, 105, 107, 108 An antisense oligonucleotide according to any one of the embodiments [12A] to [12A-2], having a nucleic acid base sequence consisting of a nucleic acid base sequence selected from 111, 113, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, 152, 153, 154, 156.

[0076] [12A-10] oligonucleotides are available in SEQ ID NOs: 10, 13, 22, 25, 26, 27, 30, 31, 32, 33, 37, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 60, 61, 62, 65, 66, 67, 72, 75, 80, 82, 86, 88, 91, 93, 94, 95, 98, 99, 101, 102, 105, 107, 108, 111, 113, 115, 116, 118, 1 An antisense oligonucleotide according to any one of the embodiments [12A] to [12A-2], having a nucleic acid base sequence consisting of nucleic acid base sequences selected from 19, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 138, 139, 140, 141, 142, 143, 144, 145, 147, 150, 151, 154, 156.

[0077] [12-11] The antisense oligonucleotide according to any one of the embodiments [12A] to [12A-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of nucleic acid base sequences selected from SEQ ID NOs: 30, 31, 37, 46, 47, 48, 52, 53, 54, 55, 56, 65, 66, 67, 72, 80, 86, 88, 99, 101, 102, 105, 113, 116, 118, 120, 121, 125, 126, 128, 130, 132, 133, 134, 138, 140, 141, 142, 143, 144, 147, 150, 154.

[0078] [12A-12]Antisense oligonucleotide according to any one of the embodiments [12A] to [12A-2], wherein the oligonucleotide has a nucleic acid base sequence consisting of a nucleic acid base sequence selected from SEQ ID NOs: 46, 47, 48, 65, 66, 67, 72, 88, 105, 116, 118, 120, 128, 134, 140, 141, 142, 143, 147, 154, 156.

[0079] [12A-13] In the embodiments [12A] to [12A-12] described above, the nucleic acid base sequence of the oligonucleotide has complementarity to the isolength portion of the IL-11 nucleic acid of, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the nucleic acid base of SEQ ID NO: 156 is excluded. [12A-14] In the above embodiment [12A-13], the IL-11 nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0080] [12A-15]Antisense oligonucleotide according to any one of embodiments [12A] to [12A-14], having inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[0081] [12A-16]An antisense oligonucleotide according to any one of embodiments [12A] to [12A-15], wherein the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, about 5% or more, and is about 5-100%, about 30-100%, about 70-100%, about 80-100%, or about 90-100%. [12A-17] IC of inhibition of IL-11 or IL-11 mRNA expression 50 An antisense oligonucleotide according to any one of the embodiments [12A] to [12A-15], wherein the value is, for example, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, or about 10 nM or less.

[0082] [12A-18] Antisense oligonucleotides or pharmaceutically acceptable salts thereof or solvates thereof as described in any one of the embodiments [12A] to [12A-17].

[0083]

[13] The modified sugar is a bicyclic sugar, and the antisense oligonucleotide or a pharmaceutically acceptable salt thereof or solvate thereof according to any one of the embodiments [1] to [12A-18] described above.

[0084] [13-1] In the above embodiment

[13] , the bicyclic sugar is a bicyclic sugar that bridges at the 4'-2' position, for example, the bridge at the 4'-2' position is 4'-CH2-O-2':(LNA nucleoside), 4'-(CH2)2-O-2':(ENA nucleoside), 4'-CH(CH3)-O-2':(cEt nucleoside), 4'-C(=O)-N(CH3)-2':(AmNA nucleoside), 4'-CH2-N(C(=NH)(NH2))-2':(GuN A nucleoside), 4'-CH2-N(C(=NH)(NHtBu)-2':(GuNA(t-Bu) nucleoside), 4'-C(CH3)2-O-2', 4'-CH(OCH2CH3)-O-2', 4'-CH2-CH(CH3)-2', 4'-CH2-C(=CH2)-2', 4'-CH2-CH2-CH2-2', 4'-CH2-NH-O-2', 4'-CH2-N(CH3)-O-2', 4'-CH2-NH-2', 4'-CH2-N( Examples include CH3)-2', 4'-CH2-N(OCH3)-2', 4'-CH2-O-NH-2', 4'-CH2-ON(CH3)-2', 4'-CH2-S-2', 4'-C(-CH2CH2-)-O-2':(scpBNA nucleoside), etc. Preferably, selected from the group consisting of LNA nucleoside, ENA nucleoside, cEt nucleoside, AmNA nucleoside, GuNA nucleoside, and GuNA(t-Bu) nucleoside. At least one; more preferably at least one selected from the group consisting of LNA nucleoside, ENA nucleoside, cEt nucleoside, GuNA nucleoside, and GuNA(t-Bu) nucleoside; even more preferably at least one selected from the group consisting of LNA nucleoside, ENA nucleoside, cEt nucleoside, and GuNA(t-Bu) nucleoside; particularly preferably LNA nucleoside.

[0085]

[14] The antisense oligonucleotide according to any one of the above aspects [1] to [12A - 18], wherein the modified sugar is a non-bicyclic modified sugar.

[0086] [14 - 1] In the above aspect

[14] , examples of the non-bicyclic modified sugar include a sugar modified at the 2'-position, a sugar modified at the 5'-position, and the like.

[0087] [14 - 2] In the above aspect [14 - 1], the group at the 2'-position of the sugar modified at the 2'-position is, for example, 2'-OR 1 , 2'-R 1 [[ID=1十二]], 2'-R 2 OR 1 , 2'-SH, 2'-SR 1 , 得2'-NH2, 2'-NHR 1 , 2'-NR 1 2, 2'-N3, 2'-CN, 2'-F, 2'-Cl, 2'-Br, 2'-I, 2'-R 2 C(O)XR 3 (In each group, R 1 is alkyl or aryl; R 2 is alkylene; X is an oxygen atom, NH or NR 1 ; R 3 is alkyl), and the like; preferably, the group at the 2'-position is at least one group selected from the group consisting of 2'-OCH3, 2'-F, 2'-O-CH2CH2OCH3: (2'-O-MOE nucleoside), 2'-NH2, 2'-O-CH2CH2C(O)OCH3, 2'-O-CH2CH2C(O)OCH2CF3, 2'-O-CH2CH2C(O)NHCH3: (2'-O-MCE nucleoside), and 2'-O-CH2CH2C(O)N(CH3)2; more preferably, the group at the 2'-position is at least one group selected from the group consisting of 2'-O-CH2CH2C(O)OCH3, 2'-O-CH2CH2C(O)OCH2CF3, 2'-O-CH2CH2C(O)NHCH3: (2'-O-MCE nucleoside), and 2'-O-CH2CH2C(O)N(CH; even more preferably, the group at the 2'-position is 2'-O-CH2CH2C(O)NHCH3: (2'-O-MCE nucleoside).

[0088] [14-3] In the above embodiment [14-1], the group at the 5' position of the sugar modified at the 5' position is, for example, 5'-CP, etc.

[0089]

[15] In any one of the embodiments [1] to [12A-18] described above, the modified internucleoside bond is, for example, a phosphorothioate bond, a phosphorodithioate bond, a phosphotriester bond, an alkylphosphonate bond, an aminoalkylphosphotriester bond, an alkylenephosphonate bond, a phosphine bond, a phosphoramidate bond, an aminoalkylphosphorimidate bond, a thiophosphorimidate bond, a thionoalkylphosphonate bond, a thionoalkylphosphotriester bond, a thiophosphate bond, a selenophosphate bond, a boranophosphate bond, a mesylphosphorimidate bond, a phosphoryl(1,3-dimethylimidazolidined-2-imine)amide bond, and the like.

[0090] [15-1] In the above embodiment

[15] , the modified internucleoside bond is, for example, at least one bond selected from the group consisting of phosphorothioate bonds, phosphorodithioate bonds, alkylphosphonate bonds, phosphoramidate bonds, and boranophosphate bonds; preferably, a phosphorothioate bond.

[0091] [15-2] An antisense oligonucleotide according to any one of the embodiments [1] to [12A-18], or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of the internucleoside bonds is a phosphorothioate bond. [15-3] Antisense oligonucleotides according to any one of the embodiments [1] to [12A-18], wherein each nucleoside bond is a phosphorothioate bond, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0092]

[16] In any one of the embodiments [1] to [12A-18], the modified nucleic acid base is, for example, pseudouracil, 3-methyluracil, dihydrouracil, 5-alkylcytosine (e.g., 5-methylcytosine), 5-alkyluracil (e.g., 5-ethyluracil), 5-halouracil (5-bromouracil), 6-azapyrimidine, 6-alkylpyrimidine (6-methyluracil), 2-thiouracil, 4-thiouracil, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5'-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluracil, 1-methyladenine, 1-methylhypoxanthine, 2,2-dimethylguanine, 3-methylcytosine, 2-methyladenine, 2-methylguanine, N 6 -Methyladenine, 7-methylguanine, 5-methoxyaminomethyl-2-thiouracil, 5-methylaminomethyluracil, 5-methylcarbonylmethyluracil, 5-methyloxyuracil, 5-methyl-2-thiouracil, 2-methylthio-N 6 These are nucleic acid bases such as isopentenyl adenine, uracil-5-oxyacetic acid, 2-thiocytosine, purine, 2,6-diaminopurine, 2-aminopurine, isoguanine, indole, imidazole, and xanthine.

[0093] [16-1] In the above embodiment

[16] , the modified nucleic acid base is preferably 5-methylcytosine.

[0094]

[17] Antisense oligonucleotides according to any one of embodiments [1] to [16-1], or pharmaceutically acceptable salts thereof, or solvates thereof, wherein the oligonucleotide comprises a deoxy region consisting of 5 to 20 linked deoxyribonucleosides. [17-1] In the above embodiment

[17] , at least one of the nucleosides in the deoxy region is a 2'-β-D-deoxyribonucleoside. [17-2] In the embodiments

[17] or [17-1] described above, the number of linked nucleosides included in the deoxy region is, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; for example, 5 to 15, 7 to 12 or 9 to 10; preferably 9 to 10. [17-3] In any one of the embodiments

[17] to [17-2], the nucleoside adjacent to the deoxy region contains at least one modified sugar.

[0095]

[18] Oligonucleotides, The central region (G) consists of 5 to 20 linked nucleosides. A 5' region (W) consisting of 1 to 5 linked nucleosides 5 ), and A 3' region (W) consisting of 1 to 5 linked nucleosides 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, the antisense oligonucleotide or a pharmaceutically acceptable salt thereof or solvate thereof as described in any one of embodiments [1] to [17-3] above.

[0096] [18-1] Oligonucleotides, The central region (G) consists of 5 to 15 linked nucleosides. The 5' region (W) consists of 3 to 5 linked nucleosides. 5 ), and The 3' region (W) consists of 3 to 5 linked nucleosides. 3 An antisense oligonucleotide according to the above embodiment

[18] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising )

[0097] [18-2] Oligonucleotides, A central region (G) consisting of 7 to 12 linked nucleosides, The 5' region (W) consists of 3 to 5 linked nucleosides. 5 ), and The 3' region (W) consists of 3 to 5 linked nucleosides. 3 Antisense oligonucleotides according to the above embodiment

[18] or [18-1], or pharmaceutically acceptable salts thereof, or solvates thereof, comprising )

[0098] [18-3] Oligonucleotides A central region (G) consisting of 9-10 linked nucleosides, The 5' region (W) consists of 3 to 5 linked nucleosides. 5 ), and The 3' region (W) consists of 3 to 5 linked nucleosides. 3 An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or solvate thereof according to any one of the embodiments

[18] to [18-2], comprising )

[0099] [18-4] Oligonucleotides, The central region (G) consists of nine linked nucleosides. 5' region (W 5 ) is a nucleoside consisting of three linked molecules. 3' region (W 3 ) is a nucleoside consisting of four linked nucleosides. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of the embodiments

[18] to [18-3] described above.

[0100] [18-5] Oligonucleotides, The central region (G) consists of nine linked nucleosides. 5' region (W 5 ) is a nucleoside consisting of four linked molecules. 3' region (W 3 ) is a nucleoside consisting of three linked nucleosides. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of the embodiments

[18] to [18-3] described above.

[0101] [18-6] of oligonucleotides, The central region (G) consists of 10 linked nucleosides. 5' region (W 5 ) is a nucleoside consisting of three linked molecules. 3' region (W 3 ) is a nucleoside consisting of three linked nucleosides. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of the embodiments

[18] to [18-3] described above.

[0102] [18-7] Oligonucleotides, The central region (G) consists of nine linked nucleosides. 5' region (W 5 ) is a nucleoside consisting of 5 linked molecules. 3' region (W 3 ) is a nucleoside consisting of four linked nucleosides. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of the embodiments

[18] to [18-3] described above.

[0103] [18-8] oligonucleotides, The central region (G) consists of nine linked nucleosides. 5' region (W 5 ) is a nucleoside consisting of four linked molecules. 3' region (W 3 ) is a nucleoside consisting of five linked nucleosides. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of the embodiments

[18] to [18-3] described above.

[0104] [18-9] Oligonucleotides, The central region (G) consists of 10 linked nucleosides. 5' region (W 5 ) is a nucleoside consisting of four linked molecules. 3' region (W 3 ) is a nucleoside consisting of four linked nucleosides. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof according to any one of the embodiments

[18] to [18-3] described above.

[0105] [18-10]5' region (W 5 ) and 3' region (W 3 An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or solvate thereof according to any one of the embodiments

[18] to [18-9], wherein each nucleoside of the above is a modified sugar.

[0106] [18-11] An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or solvate thereof according to any one of the embodiments

[18] to [18-10], wherein one of the nucleosides at the 3' and / or 5' end of the nucleoside of the central region (G) is a deoxyribonucleoside.

[0107] [18-12] In any one of the embodiments

[18] to [18-11] described above, the nucleoside of the central region (G) may be selected from deoxyribonucleosides.

[0108] [18-13] In any one of the embodiments

[18] to [18-12] described above, 5' region (W 5 ) and 3' region (W 3 The nucleoside-modified sugar of ) may be selected from LNA or 2'-O-MCE.

[0109] [18-14] In any one of the embodiments

[18] to [18-13] described above, the nucleoside in the central region (G) may contain 5-methylcytosine as a modified nucleic acid base.

[0110] [18-15] In any one of aspects

[18] to [18-14], at least one of the internucleoside linkages is a phosphorothioate linkage. [18-16] In any one of aspects

[18] to [18-15], each internucleoside linkage is a phosphorothioate linkage.

[0111]

[19] An antisense oligonucleotide comprising an oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence selected from SEQ ID NOs: 46, 47, 48, 66, 72, wherein the oligonucleotide has a central region (G) consisting of 9 linked nucleosides, a 5' region (W 5 ) consisting of 3 linked nucleosides, and a 3' region (W 3 ) consisting of 4 linked nucleosides, the central region (G) is located between the 5' region (W 5 ) and the 3' region (W 3 ), and the nucleosides of the 5' region (W 5 ) and the 3' region (W 3 ) each contain at least one modified sugar, and the nucleosides of the central region (G) optionally contain deoxyribonucleosides, an antisense oligonucleotide. [19-A] In aspect

[19] , the oligonucleotides consisting of nucleosides having the nucleobase sequences of SEQ ID NOs: 46, 47, 48, 66, 72 each contain a compound having a chemical structure represented by SEQ ID NOs: 209, 214, 220, 224, 251, 254, 264.

[0112] [19-1] An antisense oligonucleotide comprising an oligonucleotide consisting of 16 linked nucleosides having a nucleobase sequence selected from SEQ ID NOs: 32, 46, 47, 48, 66, 72, wherein the oligonucleotide has a central region (G) consisting of 9 linked nucleosides, The 5' region (W) consists of four linked nucleosides. 5 ), and The 3' region (W) consists of three linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 The nucleosides of each antisense oligonucleotide contain at least one modified sugar, and the nucleoside in the central region (G) optionally contains a deoxyribonucleoside. [19-1-A] In the above embodiment [19-1], oligonucleotides comprising nucleosides having the nucleic acid base sequences of SEQ ID NOs. 32, 46, 47, 48, 66, and 72 each include compounds having the chemical structure represented by SEQ ID NOs. 191, 208, 213, 219, 223, 250, 253, and 263.

[0113] [19-2] Sequence IDs 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 ,,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,10 An antisense oligonucleotide comprising an oligonucleotide consisting of 16 linked nucleosides having a nucleic acid base sequence selected from 2, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, wherein the oligonucleotide is The central region (G) consists of 10 linked nucleosides. The 5' region (W) consists of three linked nucleosides. 5 ), and The 3' region (W) consists of three linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 The nucleosides of each antisense oligonucleotide contain at least one modified sugar, and the nucleoside in the central region (G) optionally contains a deoxyribonucleoside.

[0114] [19-2-A] In the above embodiment [19-2], Sequence IDs 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 8 2, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 1 Oligonucleotides consisting of nucleosides having nucleic acid base sequences 49, 150, 151, 152, 153, 154, and 155 are respectively 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 185, 186, 187, 188, 189, 190, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 2 06, 207, 210, 211, 212, 215, 216, 217, 218, 221, 222, 225, 226, 227, 228, 229, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 24 7, 248, 249, 252, 255, 256, 257, 258, 259, 260, 261, 262, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 3 It contains compounds having the chemical structure represented by 19, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, and 348.

[0115] [19-3] An antisense oligonucleotide comprising an oligonucleotide consisting of 18 linked nucleosides having the nucleic acid base sequence of Sequence ID No. 156, wherein the oligonucleotide is The central region (G) consists of nine linked nucleosides. The 5' region (W) consists of five linked nucleosides. 5 ), and The 3' region (W) consists of four linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 The nucleosides of each antisense oligonucleotide contain at least one modified sugar, and the nucleoside in the central region (G) optionally contains a deoxyribonucleoside. [19-3-A] In the above embodiment [19-3], the oligonucleotide comprising a nucleoside having the nucleic acid base sequence of SEQ ID NO: 156 includes a compound having the chemical structure represented by SEQ ID NO: 349.

[0116] [19-4] An antisense oligonucleotide comprising an oligonucleotide consisting of 18 linked nucleosides having a nucleic acid base sequence selected from Sequence ID Nos. 30 and 54, wherein the oligonucleotide is The central region (G) consists of 10 linked nucleosides. The 5' region (W) consists of four linked nucleosides. 5 ), and The 3' region (W) consists of four linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 The nucleosides of each antisense oligonucleotide contain at least one modified sugar, and the nucleoside in the central region (G) optionally contains a deoxyribonucleoside. [19-4-A] In the above embodiment [19-4], the oligonucleotides comprising nucleosides having the nucleic acid base sequences of SEQ ID NOs. 30 and 54 include compounds having the chemical structures represented by SEQ ID NOs. 183, 184, 230, and 231.

[0117] [19-5]5' region (W 5 ) and 3' region (W 3 The antisense oligonucleotide according to any one of the embodiments

[19] to [19-4-A], wherein each nucleoside of ) is a modified sugar.

[0118] [19-6] In any one of the above embodiments

[19] to [19-5], the 5' region (W 5 ) and 3' region (W 3 The nucleoside-modified sugar of ) may be selected from the modified sugars described in any one of the above embodiments

[13] to [14-3].

[0119] [19-7] In any one of the above embodiments

[19] to [19-6], the 5' region (W 5 ) and 3' region (W 3 The nucleoside-modified sugar of ) may be selected from LNA or 2'-O-MCE.

[0120] [19-8] An antisense oligonucleotide according to any one of the embodiments

[19] to [19-7], wherein one of the nucleosides at the 3' end and / or 5' end of the nucleoside of the central region (G) is a deoxyribonucleoside.

[0121] [19-9] In any one of the embodiments

[19] to [19-8] described above, the nucleoside of the central region (G) may be selected from deoxyribonucleosides.

[0122] [19-10] In any one of the embodiments

[19] to [19-9] described above, the nucleoside in the central region (G) may contain 5-methylcytosine as a modified nucleic acid base.

[0123] [19-11] In any one of the embodiments

[19] to [19-10], the nucleoside bond may be a modified nucleoside bond as described in embodiment

[15] or [15-1].

[0124] [19-12] In any one of the embodiments

[19] to [19-11] described above, at least one of the nucleoside bonds is a phosphorothioate bond. [19-13] In any one of the embodiments

[19] to [19-12] described above, each nucleoside bond is a phosphorothioate bond.

[0125] [19-14] In any one of the above aspects

[19] to [19-13], the nucleobase sequence of the oligonucleotide has a complementarity to the co-length portion of the IL-11 nucleic acid of, for example, at least 80%, at least 85%, at least 90%, at least 95% or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95% or 100%; more preferably at least 85%, at least 90%, at least 95% or 100%; still more preferably at least 90%, at least 95% or 100%; particularly still more preferably at least 95% or 100%. However, when the complementarity is at least 90% to 100%, the nucleobases of SEQ ID NO: 156 are excluded. [19-15] In the above aspect [19-14], the IL-11 nucleic acid has the nucleobase sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0126] [19-16] An antisense oligonucleotide according to any one of the above aspects

[19] to [19-15], which has an inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[0127] [19-17] An antisense oligonucleotide according to any one of the above aspects

[19] to [19-16], wherein the inhibition rate of the expression of IL-11 or IL-11 mRNA is, for example, about 5% or more, about 5 to 100%, about 30 to 100%, about 70 to 100%, about 80 to 100% or about 90 to 100%. [19-18] The IC 50 value of the inhibition of the expression of IL-11 or IL-11 mRNA is, for example, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, or about 10 nM or less, for an antisense oligonucleotide according to any one of the above aspects

[19] to [19-16].

[0128] [19-19] An antisense oligonucleotide according to any one of the above aspects

[19] to [19-18], or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0129]

[20] An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the oligonucleotide has an oligonucleotide consisting of at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleosides from any of the nucleosides contained in sequences selected from SEQ ID NOs. 157 to 349, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0130] [20-1] In the above embodiment

[20] , the number of linked nucleosides is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0131] [20-2] In any one of the embodiments

[20] to [20-1], the number of consecutive nucleosides is, for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0132] [20-3] Oligonucleotides with sequence numbers 157, 163, 166, 169, 170, 172, 175, 178, 179, 180, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 195, 196, 197, 198, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 21 5, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 260, 26 1, 262, 263, 264, 265, 266, 267, 268, 269, 270, 273, 275, 277, 278, 279, 280, 281, 284, 285, 286, 287, 288, 290, 291, 292, 294, 295, 297, 298, 300, 301, 304, 306, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 31 An antisense oligonucleotide according to any one of the embodiments

[20] to [20-2], comprising a sequence selected from 8, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 343, 344, 345, 346, 347, 349. [20-4] Oligonucleotides are sequence numbers 163, 166, 175, 178, 179, 180, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 196, 204, 205, 206, 207, 208, 209, 210, 211, 213, 214, 215, 216 ,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,237,238,240,242,243,244,247,248,249,250,251,252,253,254,255,260,261, 262, 263, 264, 265, 268, 273, 275, 279, 281, 284, 286, 287, 288, 291, 292, 294, 295, 298, 300, 301, 304, 306, 308, 309, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 3 An antisense oligonucleotide according to any one of the embodiments

[20] to [20-2], comprising a sequence selected from 21, 322, 323, 324, 325, 326, 327, 328, 331, 332, 333, 334, 335, 336, 337, 338, 340, 343, 344, 347, 349. [20-5] Oligonucleotides with sequence numbers 183, 184, 185, 187, 189, 190, 196, 205, 207, 208, 209, 210, 211, 213, 214, 216, 218, 219, 220, 221, 222, 223, 224, 228, 229, 230, 231, 232, 233, 234, 238, 247, 249, 250, 251, 253, 254, 255, 260, 261, An antisense oligonucleotide according to any one of the embodiments

[20] to [20-2], comprising a sequence selected from 262, 263, 264, 265, 273, 279, 281, 292, 294, 295, 298, 306, 309, 311, 313, 314, 318, 319, 321, 323, 325, 326, 327, 331, 333, 334, 335, 336, 337, 340, 343, 347. [20-6]Antisense oligonucleotide according to any one of the embodiments

[20] to [20-2], wherein the oligonucleotide comprises a sequence selected from sequence numbers 205, 207, 208, 209, 210, 211, 213, 214, 216, 218, 219, 220, 247, 249, 250, 251, 252, 253, 254, 255, 260, 261, 262, 263, 264, 265, 281, 298, 309, 311, 313, 321, 327, 333, 334, 335, 336, 340, 347, 349.

[0133] [20-7] In any one of the embodiments

[20] to [20-6] described above, the nucleic acid base sequence of the oligonucleotide has complementarity to the isolength portion of the IL-11 nucleic acid of, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the oligonucleotide of SEQ ID NO: 349 is excluded. [20-16] In the above embodiment [20-15], the IL-11 nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0134] [20-8]Antisense oligonucleotide according to any one of the embodiments

[20] to [20-7], having inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[0135] [20-9]Antisense oligonucleotide according to any one of the embodiments

[20] to [20-8], wherein the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, about 5% or more, and is about 5-100%, about 30-100%, about 70-100%, about 80-100%, or about 90-100%. [20-10] IC of inhibition of IL-11 or IL-11 mRNA expression 50 An antisense oligonucleotide according to any one of the embodiments

[20] to [20-8], wherein the value is, for example, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, or about 10 nM or less.

[0136] [20-11] Antisense oligonucleotides or pharmaceutically acceptable salts thereof or solvates thereof as described in any one of the embodiments

[20] to [20-10].

[0137]

[21] Antisense oligonucleotides, pharmaceutically acceptable salts thereof, or solvates thereof, including modified oligonucleotides having the chemical structures described in the table below. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0138] In the table, "(L)" represents an LNA nucleoside, "(V)" represents a 2'-O-MCE nucleoside, lowercase letters represent deoxyribonucleosides, uppercase letters (except for "L" in (L) and "V" in (V)) represent ribonucleosides, "^" represents a phosphorothioate bond, "5(x)" indicates that the nucleic acid base of the deoxyribonucleoside is 5-methylcytosine, and "5" in "5(V)" and "5(L)" indicates that the nucleic acid base of the nucleoside is 5-methylcytosine. In the notation of chemical structures, when "^" is not indicated between two adjacent nucleosides, the internucleoside bond between those two nucleosides is a phosphodiester bond.

[0139]

[22] Antisense oligonucleotides, pharmaceutically acceptable salts thereof, or solvates thereof, including modified oligonucleotides having the chemical structures described in the table below. [Table 8] [Table 9] [Table 10]

[0140] In the table, "(L)" represents an LNA nucleoside, "(V)" represents a 2'-O-MCE nucleoside, lowercase letters represent deoxyribonucleosides, uppercase letters (except for "L" in (L) and "V" in (V)) represent ribonucleosides, "^" represents a phosphorothioate bond, "5(x)" indicates that the nucleic acid base of the deoxyribonucleoside is 5-methylcytosine, and "5" in "5(V)" and "5(L)" indicates that the nucleic acid base of the nucleoside is 5-methylcytosine. In the notation of chemical structures, when "^" is not indicated between two adjacent nucleosides, the internucleoside bond between those two nucleosides is a phosphodiester bond.

[0141]

[23] Antisense oligonucleotides, pharmaceutically acceptable salts thereof, or solvates thereof, including modified oligonucleotides having the chemical structures described in the table below. [Table 11]

[0142] In the table, "(L)" represents an LNA nucleoside, "(V)" represents a 2'-O-MCE nucleoside, lowercase letters represent deoxyribonucleosides, uppercase letters (except for "L" in (L) and "V" in (V)) represent ribonucleosides, "^" represents a phosphorothioate bond, "5(x)" indicates that the nucleic acid base of the deoxyribonucleoside is 5-methylcytosine, and "5" in "5(V)" and "5(L)" indicates that the nucleic acid base of the nucleoside is 5-methylcytosine. In the notation of chemical structures, when "^" is not indicated between two adjacent nucleosides, the internucleoside bond between those two nucleosides is a phosphodiester bond.

[0143]

[24] The following formula: [ka] The antisense oligonucleotide of Sequence ID No. 260, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0144]

[25] The following formula: [ka] The antisense oligonucleotide of Sequence ID No. 263, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0145]

[26] The following formula: [ka] The antisense oligonucleotide of sequence number 264 represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0146]

[27] The following formula: [ka] The antisense oligonucleotide of Sequence ID No. 210, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0147]

[28] The following formula: [ka] The antisense oligonucleotide of Sequence ID No. 211, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0148]

[29] The following formula: [ka] The antisense oligonucleotide of Sequence ID No. 213, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0149]

[30] The following formula: [ka] The antisense oligonucleotide of sequence number 349, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0150]

[31] An antisense oligonucleotide according to any one of the embodiments [1] to

[30] , to which a functional molecule is bound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [31-1] In the above embodiment

[31] , the binding site of the functional molecule is, for example, the oxygen atom at the 3' position of the nucleotide at the 3' end of the antisense oligonucleotide, or the oxygen atom at the 5' position of the nucleotide at the 5' end; for example, the oxygen atom at the 3' position of the nucleotide at the 3' end of the antisense oligonucleotide; for example, the oxygen atom at the 5' position of the nucleotide at the 5' end of the antisense oligonucleotide.

[0151] [31-2] In the embodiments

[31] or [31-1] described above, the functional molecule is, for example, directly bonded to the 3' oxygen atom of the 3' terminal nucleotide of the antisense oligonucleotide, or to the 5' oxygen atom of the 5' terminal nucleotide, or bonded via a binding group (e.g., a degradable group, an indegradable group, etc.), or bonded via a binding group and an optional linker. [31-3] In any one of the embodiments

[31] to [31-2] described above, the functional molecule is, for example, a lipid (e.g., tocopherol, cholesterol), a protein, a peptide, an antibody, a sugar chain (e.g., glucose, sucrose), etc. [31-4] In the above embodiment [31-3], the functional molecule is, for example, α-tocopherol (vitamin E), cholesterol, and a GalNAc cluster containing 1 to 3 GalNAc ligands.

[0152]

[32] A pharmaceutical composition characterized by containing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, according to any one of the embodiments [1] to [31-4] described above.

[0153]

[33] A pharmaceutical composition for preventing, improving and / or treating IL-11-related diseases, comprising an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, according to any one of the embodiments [1] to [31-4] described above.

[0154]

[34] Use of a pharmaceutical composition containing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, for the manufacture of a drug for preventing, improving and / or treating a disease involving IL-11.

[0155]

[35] The pharmaceutical composition according to any one of the embodiments

[32] to

[34] further comprising a pharmaceutically acceptable carrier.

[0156]

[36] A preventive, ameliorative and / or therapeutic agent for diseases involving IL-11, characterized by containing as an active ingredient an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as described in any one of the embodiments [1] to [31-4] above. [36-1] Antisense oligonucleotides according to any one of the embodiments [1] to [31-4], or pharmaceutically acceptable salts thereof, or solvates thereof, for the prevention, improvement and / or treatment of diseases involving IL-11.

[0157]

[37] A preventive and / or therapeutic agent for diseases involving IL-11, characterized by containing as an active ingredient an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as described in any one of the embodiments [1] to [31-4] above. [37-1] Antisense oligonucleotides according to any one of the embodiments [1] to [31-4], or pharmaceutically acceptable salts thereof, or solvates thereof, for the prevention and / or treatment of diseases involving IL-11.

[0158]

[38] In the above embodiment, the diseases involving IL-11 include fibrotic diseases (idiopathic pulmonary fibrosis, interstitial lung disease with progressive fibrosis (PF-ILD), pulmonary arterial hypertension, Alport syndrome, tubulointerstitial nephritis, glomerulostenosis, hepatic fibrosis (non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)), systemic sclerosis, chronic The diseases selected from pancreatitis, cardiovascular fibrosis, gastrointestinal polyposis (Peutz-Jeggers syndrome, familial adenomatous polyposis), inflammatory diseases (asthma, chronic obstructive pulmonary disease, pulmonary arterial hypertension, ulcerative colitis, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), cancer (liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, breast cancer), abnormal uterine bleeding, and preeclampsia.

[0159] [38-1] In the above embodiment

[38] , preferably, the disease involving IL-11 is selected from fibrotic diseases (idiopathic pulmonary fibrosis, interstitial lung disease with progressive fibrosis (PF-ILD), pulmonary arterial hypertension, Alport syndrome, tubulointerstitial nephritis, glomerulostenosis, hepatic fibrosis (non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)), systemic sclerosis, chronic pancreatitis, cardiovascular fibrosis), and gastrointestinal polyposis (Peutz-Jeggers syndrome, familial adenomatous polyposis); more preferably, it is selected from idiopathic pulmonary fibrosis, interstitial lung disease with progressive fibrosis (PF-ILD), and Peutz-Jeggers syndrome.

[0160]

[39] An IL-11 and / or IL-11 mRNA expression inhibitor comprising at least one antisense oligonucleotide or a pharmaceutically acceptable salt thereof according to any one of the embodiments [1] to [31-4] described above, or a solvate thereof. [39-1] Antisense oligonucleotides according to any one of the embodiments [1] to [31-4], or pharmaceutically acceptable salts thereof, or solvates thereof, for the inhibition of IL-11 and / or IL-11 mRNA expression.

[0161]

[40] Use of an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to any one of the embodiments [1] to [31-4] above, for the manufacture of an agent for preventing, improving and / or treating a disease involving IL-11. [40-1] Use of an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as a pharmaceutical composition according to any one of the embodiments [1] to [31-4] above.

[0162]

[41] Use of antisense oligonucleotides or pharmaceutically acceptable salts thereof, or solvates thereof, according to any one of the embodiments [1] to [31-4], for the manufacture of pharmaceutical compositions for the treatment of diseases involving IL-11.

[0163]

[42] Use of an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an expression inhibitor of IL-11 and / or IL-11 mRNA, as described in any one of the embodiments [1] to [31-4] above. [42-1] Use of an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to any one of the embodiments [1] to [31-4] above, for the production of an IL-11 and / or IL-11 mRNA expression inhibitor.

[0164]

[43] A method for preventing, improving and / or treating a disease involving IL-11, comprising administering a pharmaceutical composition containing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient to a subject in need of prevention, improvement and / or treatment of the disease. [43-1] A method for preventing and / or treating a disease involving IL-11, comprising administering a pharmaceutical composition containing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient to a subject in need of prevention and / or treatment of the disease.

[0165] [43-2] In the above embodiment, the diseases involving IL-11 include fibrotic diseases (idiopathic pulmonary fibrosis, interstitial lung disease with progressive fibrosis (PF-ILD), pulmonary arterial hypertension, Alport syndrome, tubulointerstitial nephritis, glomerulostenosis, hepatic fibrosis (non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)), systemic sclerosis, chronic The diseases selected from among (pancreatitis, cardiovascular fibrosis), gastrointestinal polyposis (Peutz-Jeghers syndrome, familial adenomatous polyposis), inflammatory diseases (asthma, chronic obstructive pulmonary disease, pulmonary arterial hypertension, ulcerative colitis, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), cancer (liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, endometrial cancer, ovarian cancer, testicular cancer, breast cancer), abnormal uterine bleeding, and preeclampsia.

[0166] [43-3] In the above embodiment [43-2], preferably, the disease involving IL-11 is selected from fibrotic diseases (idiopathic pulmonary fibrosis, interstitial lung disease with progressive fibrosis (PF-ILD), pulmonary arterial hypertension, Alport syndrome, tubulointerstitial nephritis, glomerulostenosis, hepatic fibrosis (non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)), systemic sclerosis, chronic pancreatitis, cardiovascular fibrosis), and gastrointestinal polyposis (Peutz-Jeggers syndrome, familial adenomatous polyposis); more preferably, it is selected from idiopathic pulmonary fibrosis, interstitial lung disease with progressive fibrosis (PF-ILD), and Peutz-Jeggers syndrome.

[0167] [43-4] In the embodiments described above

[43] to [43-3], the subject is humans, non-human mammals, birds, etc.

[0168]

[44] A pharmaceutical composition characterized by containing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof as described in any one of the embodiments [1] to [31-4], and at least one agent for the prevention and / or treatment of a disease involving IL-11. [44-1] A pharmaceutical composition containing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, used in combination with an agent for the prevention and / or treatment of a disease involving IL-11. [44-2] In the embodiments

[44] or [44-1] described above, agents for the prevention and / or treatment of diseases involving IL-11 include, for example, (1-1) antifibrotic agents, (1-2) CTGF inhibitors, (1-3) pentraxin 2, (1-4) PDE4 inhibitors, (1-5) Galectin-3 inhibitors, (1-6) GPR40 agonists / GPR80 inhibitors, (1-7) GPR84 inhibitors, (1-8) FXIIa inhibitors, (1-9) PDE3 / 4 inhibitors, (1-10) HSP47 inhibitors, (1-11) BAFF receptor inhibitors, (1-12) TGFβ1 inhibitors, (1-13) Superoxide(1-14) dismutase (SOD) modulators, (1-15) LPA1 inhibitors, (2-1) MET / VEGF receptor inhibitors, (2-1) angiotensin II receptor antagonists, (2-2) angiotensin-converting enzyme inhibitors, (2-3) bardoxolone methyl, (2-4) SGLT2 inhibitors, (2-5) antihyperphosphatemia agents, (2-6) selective mineralocorticoid receptor antagonists, (2-7) endothelin receptor antagonists, (2-8) CFTR gene inducers, (2-9) miR-21 inhibitors, (3-1) GHRH receptor agonists, (3-2) FX (3-3) R agonists, (3-5) THR-β agonists, (3-6) GLP-1 receptor agonists, (3-7) PPARα / δ / γ agonists, (3-8) Dual GIP / GLP-1 receptor agonists, (3-9) FGF21 receptor activators, (3-11) PPARα agonists, (3-12) Bile acid transporter inhibitors, (3-13) Acetyl-CoA carboxylase (ACC) inhibitors, (3-14) Dual GLP-1 / glucagon coreceptor agonists, (3-15) CCR2 chemokine inhibitors, (3-16) DGAT2 inhibitors, (4-1) Ursodeoxycholic acid Oxycholic acid, (4-6) PPARα / δ agonists, (4-7) CCR2 / CCR5 chemokine inhibitors, (4-8) FGF-19 ligands, (5-3) Synthetic corticosteroids, (5-4) Immunosuppressants, (5-5) Anti-CD20 monoclonal antibodies, (5-6) 5-HT2 receptor inhibitors, (5-7) IL-17 inhibitors, (5-8) IL-1 ligand inhibitors, (5-9) IL-31 receptor inhibitors, (5-10) Melanocortin 1 receptor agonists, (5-11) Neuropilin 2 modulators, (6-1) Protease inhibitors, (6-2) (7-1) Geopoietin-like protein 3 inhibitors, (7-2) Fluoropyrimidine-based anticancer drugs, (7-3) Platinum-based anticancer drugs, (7-4) Topoisomerase I inhibitors, (7-5) Anti-VEGF antibodies, (7-6) VEGF inhibitors, (7-7) Anti-EGFR antibodies, (7-7) Immune checkpoint inhibitors, (7-8) Taxane-based anticancer drugs, (7-9) Anti-HER2 antibodies, (8-1) 5-ASA preparations, (8-2) Steroids, (8-4) Anti-TNF antibodies, (8-5) JAK inhibitors, (8-6) Anti-human α4β7 integrin antibodies, (8-7) Anti-IL-12 / 23These include p40 antibodies, (8-8) anti-IL-23 antibodies, (8-9) S1PR agonists, (9-1) long-acting β2 agonists, (9-2) long-acting anticholinergics, (9-3) inhaled corticosteroids, (10-1) prostacyclin or prostacyclin derivatives, (10-3) PDE5 inhibitors, (10-4) guanylate cyclase stimulants, (11-1) iron preparations, (11-3) COX-2 selective inhibitors, (11-2) mTOR inhibitors, (11-4) nonsteroidal anti-inflammatory drugs, (12-2) MEK1 / MEK2 inhibitors, (12-3) CTNNB1 inhibitors, etc.

[0169] The present invention may also include assay methods for IL-11 antisense oligonucleotides as shown in the following embodiments

[45] .

[45] A method for screening IL-11 antisense oligonucleotides by measuring the expression level of IL-11 mRNA in cells, These cells are, for example, IL-11 expressing cells such as HEK293, U-251 MG, NIH-3T3, and primary cultured lung fibroblasts. A screening method for IL-11 antisense oligonucleotides, comprising the following steps (1) to (3). (1) A step of contacting the cells with IL-11 antisense oligonucleotide and incubating them. (2) The step of increasing the expression of IL-11 mRNA by treating the cells with PMA (Phorbol 12-myristate 13-acetate) or TGF-β Transforming growth factor-beta) and incubating them. (3) A step of measuring the expression level of IL-11 mRNA transcript in the cells. [Effects of the Invention]

[0170] The IL-11 antisense oligonucleotides of the present invention, or pharmaceutically acceptable salts thereof, or solvates thereof, have the effect of preventing and / or treating IL-11-related diseases by inhibiting the expression of IL-11 or IL-11 mRNA. [Modes for carrying out the invention]

[0171] The present invention relates to IL-11 antisense oligonucleotides that can inhibit the expression of IL-11 or IL-11 mRNA, and to pharmaceutical compositions characterized by containing them as active ingredients.

[0172] The embodiments of the present invention will be described in detail below. However, the present invention is not limited to the embodiments described below, and can be implemented in any form without departing from the spirit of the invention. Furthermore, preferred embodiments and more preferred embodiments exemplified below can be used in combination with each other as appropriate, regardless of expressions such as "for example," "preferred," and "more preferred." In addition, the numerical ranges are described as examples, and ranges obtained by appropriately combining the upper or lower limits of each range with the numerical values ​​described in the examples can also be used.

[0173] 1. IL-11 (Interleukin-11) IL-11 is a multifaceted cytokine and is a member of the IL-6 family of cytokines, which also includes IL-6, IL-27, IL-31, oncostatin, leukemia inhibitor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), and neuropoietin (NP-1).

[0174] The IL-11 genome sequence is mapped to the centromere region of chromosome 19 in humans and chromosome 7 in mice, and is transcribed and translated along with classical signal peptides that ensure efficient secretion from cells. The IL-11 activator protein complex, and cJun / AP-1 located within its promoter sequence, are crucial for the fundamental transcriptional regulation of IL-11. (Du, X. & Williams, DA Interleukin-11: review of molecular, cell biology, and clinical use. Blood 89, 3897-3908 (1997).)

[0175] Genes encoding IL-11 from species such as humans, mice, and rats have been cloned and sequenced and are available from GenBank. For example, the nucleic acid sequence of human IL-11 cDNA is available with accession number: BC012506.1, GI: 15341754, NM_000641.4 (incorporated herein as SEQ ID NO: 1), etc. The genome DNA sequence of human IL-11 is available with accession number: NC_000019.10, REGION: complement(55364382..55371063) (incorporated herein as SEQ ID NO: 2), etc. The nucleic acid sequence of mouse IL-11 cDNA is available with accession number: NM_008350.4 (incorporated herein as SEQ ID NO: 3), etc. The nucleic acid sequence of rat IL-11 cDNA is available with accession number: AF347935.1, GI: 13549072, etc. Furthermore, human IL-11 genomic DNA sequences such as ENSG00000095752 Chromosome 19: 55,364,382-55,370,463 are available from the Ensembl database, and mouse IL-11 cDNA such as ENSMUST00000094892.12 is also available from the Ensembl database.

[0176] In the nucleic acid of Sequence ID No. 1, nucleic acid bases 1-153 are represented as the 5'-UTR region, nucleic acid bases 154-753 as the CDS region, and nucleic acid bases 754-2378 as the 3'-UTR. In addition, in the nucleic acid of Sequence ID No. 1, nucleic acid bases 1-160 are sometimes referred to as Exon-1, nucleic acid bases 161-333 as Exon-2, nucleic acid bases 334-420 as Exon-3, nucleic acid bases 421-582 as Exon-4, and nucleic acid bases 583-2378 as Exon-5.

[0177] In the nucleic acid of Sequence ID No. 2, nucleic acid bases 601-753 are represented as the 5'-UTR region, nucleic acid bases 754-760, 2123-2295, 2495-2581, 2693-2854, and 4887-6682 as the CDS region, and nucleic acid bases 5058-6682 as the 3'-UTR. In addition, in the nucleic acid of Sequence ID No. 2, nucleic acid bases 601-760 are sometimes referred to as Exon-1, nucleic acid bases 2123-2295 as Exon-2, nucleic acid bases 2495-2581 as Exon-3, nucleic acid bases 2693-2854 as Exon-4, and nucleic acid bases 4887-6682 as Exon-5.

[0178] "IL-11" may include IL-11 derived from any species. It may also include isoforms, fragments, variants, homologs, etc. of IL-11 derived from any species. Examples of species include humans or non-human mammals (dogs, cats, rats, mice, monkeys, cattle, horses, pigs, sheep, etc.), preferably humans or non-human mammals (rats or mice), and more preferably humans.

[0179] 2. IL-11 antisense oligonucleotides In this specification, "antisense oligonucleotide" (hereinafter sometimes referred to as "ASO") means an oligonucleotide having a nucleic acid base sequence capable of hybridizing to the corresponding segment of a target nucleic acid encoding a target protein. Antisense oligonucleotides can be single-stranded or double-stranded.

[0180] The IL-11 antisense oligonucleotide of the present invention (hereinafter sometimes referred to as "the antisense oligonucleotide of the present invention" or "the IL-11 ASO of the present invention") is an oligonucleotide having a nucleic acid base sequence capable of hybridization with the corresponding region of the target nucleic acid, human IL-11 nucleic acid.

[0181] "Nucleic acid" refers to a molecule composed of monomeric nucleotides. Nucleic acids may include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acid, double-stranded nucleic acid, small interfering ribonucleic acid (siRNA), and microRNA (miRNA). A "target protein" refers to a protein whose regulation is desired. "Target nucleic acid" refers to a nucleic acid that can be targeted by an antisense oligonucleotide, and "targeting" refers to the design of an antisense oligonucleotide that specifically hybridizes with the target nucleic acid and induces the desired effect. "Hybrid formation" refers to the annealing of complementary nucleic acid molecules. In one embodiment, the complementary nucleic acid molecules include, but are not limited to, antisense oligonucleotides and target nucleic acids.

[0182] A "nucleic acid base" refers to a heterocyclic region that can form a pair with a base of another nucleic acid. Purine bases or pyrimidine bases are preferred as nucleic acid bases. "Nucleic acid base sequence" refers to a sequence of nucleic acid bases that is independent of any sugar site, binding site, or nucleic acid base modification. "Nucleoside" refers to a compound in which a nucleic acid base and a sugar portion are bonded together. "Ribonucleoside" refers to a nucleoside whose sugar portion is ribose. "Deoxyribonucleoside" refers to a nucleoside in which the sugar portion is D-2-deoxyribose. A "nucleotide" is a compound in which a phosphate group is attached to the sugar portion of a nucleoside. An "oligonucleotide" refers to a compound having a structure in which nucleosides are polymerized by phosphodiester bonds or modified phosphodiester bonds. Examples of naturally occurring oligonucleotides include 2'-deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). There are also oligonucleotides in which the sugar moiety, phosphate moiety, or nucleic acid base moiety are modified independently of each other.

[0183] Antisense oligonucleotides can act on target sequences through various mechanisms, including ribonuclease H (RNase H) degradation of mRNA, steric hindrance of ribosomal subunit binding, alteration of mRNA maturity, splicing activation, inhibition of 5'-cap formation, translation arrest, and double-stranded RNase activation. In some cases, antisense oligonucleotides targeting regions near polyadenylation sites are known to enhance mRNA stability.

[0184] The antisense oligonucleotide of the present invention is a compound that, when administered to a target, can inhibit the expression of IL-11 in the target cells, tissues, organs, etc. Furthermore, the antisense oligonucleotide of the present invention is a compound that, when administered to a target, can inhibit the expression of IL-11 mRNA in the target cells, and as a result, the expression of IL-11 in the target cells, tissues, organs, etc., can be inhibited, thereby inhibiting the action of IL-11.

[0185] "Expression" may refer to gene expression or target protein expression. These can be measured by the methods described in the examples herein, or by methods known to those skilled in the art. Expression encompasses all functions by which the information encoded by a gene is converted into structures that exist and function within the cell. These structures may include, but are not limited to, the products of transcription and translation.

[0186] "Inhibition" means a decrease compared to the control condition. For example, inhibition of IL-11 expression means that in the presence of IL-11ASO, the level of IL-11 expression decreases compared to the control condition. Similarly, inhibition of IL-11 mRNA expression means that in the presence of IL-11ASO, the level of IL-11 mRNA expression decreases compared to the control condition.

[0187] The antisense oligonucleotides of the present invention may inhibit IL-11 expression by, for example, repressing the transcription of the gene encoding IL-11, repressing post-transcriptional processing of the mRNA encoding IL-11, reducing the stability of the mRNA encoding IL-11, or promoting the degradation of the mRNA encoding IL-11.

[0188] When describing a drug as "inhibiting IL-11 expression," it may also include "inhibiting IL-11 mRNA expression." Similarly, when describing a drug as "inhibiting IL-11 mRNA expression," it may also include "inhibiting IL-11 expression."

[0189] The antisense oligonucleotides of the present invention are compounds capable of regulating the expression of IL-11 or IL-11 mRNA. "Regulation of expression" refers to the ability of the oligonucleotide to alter the amount of IL-11 protein or IL-11 mRNA compared to the amount of IL-11 or IL-11 mRNA before administration of IL-11ASO. The regulation of expression is determined by comparison with a control study.

[0190] One aspect of "regulation" is understood to be the ability of an oligonucleotide to inhibit, downregulate, reduce, suppress, remove, stop, block, prevent, decrease, reduce, avoid, or terminate IL-11 expression, for example, by degrading or blocking the translation of IL-11 mRNA.

[0191] The "subject" may include, but is not limited to, humans, non-human mammals (e.g., dogs, cats, rats, mice, rabbits, monkeys, chimpanzees, cows, horses, pigs, sheep, goats, etc.), birds (e.g., chickens), etc. Preferably, the "subject" is humans.

[0192] The antisense oligonucleotide of the present invention is preferably capable of reducing or suppressing the expression level of IL-11 or IL-11 mRNA in target cells, tissues, organs, etc. For example, when the antisense oligonucleotide of the present invention is administered to any cell, it is preferable that the amount of IL-11 or IL-11 mRNA expressed in that cell is reduced or suppressed compared to the amount of IL-11 or IL-11 mRNA expressed in cells that are not administered the antisense oligonucleotide. In this case, it means that the antisense oligonucleotide is capable of inhibiting the expression of IL-11 or IL-11 mRNA.

[0193] The degree of inhibition of IL-11 or IL-11 mRNA expression may be partial, for example, approximately 5% or more, approximately 10% or more, approximately 20% or more, approximately 30% or more, approximately 40% or more, approximately 50% or more, approximately 60% or more, approximately 70% or more, approximately 80% or more, and approximately 90% or more. The degree of inhibition of IL-11 or IL-11 mRNA expression may be approximately 5-100%, approximately 30%-100%, approximately 70%-100%, approximately 80%-100%, and approximately 90%-100%. In the examples described later, the degree of inhibition of IL-11 mRNA expression (the degree of inhibition of IL-11 expression) is confirmed by measuring the expression level of IL-11 mRNA.

[0194] The antisense oligonucleotide of the present invention targets nucleic acids encoding IL-11 (e.g., hIL-11 mRNA, pre-mRNA) as target nucleic acids and binds to them via hydrogen bonds between bases. Binding of the antisense oligonucleotide to the target nucleic acid results in inhibition of translation from mRNA, inhibition of gene product expression, and the like.

[0195] The antisense oligonucleotides of the present invention can be designed to bind complementarily to pre-mRNA or mRNA transcribed from genomic nucleic acids to suppress the expression of a target nucleic acid sequence. Examples of IL-11 nucleic acid sequences include known sequences available from GenBank, such as the hIL-11 cDNA sequence (accession number: NM_000641.4) (incorporated herein as SEQ ID NO: 1) and the hIL-11 genomic DNA sequence (accession number: NC_000019.10, REGION: complement(55364382..55371063)) (incorporated herein as SEQ ID NO: 2).

[0196] The antisense oligonucleotides of the present invention can be designed based on the sequence of the IL-11 nucleic acid. The ASO can also be designed to be complementary to the coding region, untranslated transcription region, etc., as the target region of the target nucleic acid. The "target region" refers to a part of the target nucleic acid that one or more antisense oligonucleotides target.

[0197] When an antisense oligonucleotide is written in the 5' to 3' direction, it has a nucleic acid base sequence that includes the reverse complementary strand of the target segment within the target nucleic acid. "Target segment" refers to the nucleotide sequence of the target nucleic acid that the antisense oligonucleotide targets. "5'" refers to the 5' end of the nucleotide, and "3'" refers to the 3' end of the nucleotide.

[0198] Oligonucleotides contain a sequence of nucleotides complementary to the target nucleic acid sequence present in the target nucleic acid molecule. The sequence of nucleotides is not particularly limited, but examples include 7 to 100, 7 to 50, 7 to 40, 7 to 30, or 7 to 25 consecutive nucleotides. Oligonucleotides of the present invention may contain, for example, 7 to 30, 7 to 25, 10 to 25, 15 to 22, 16 to 22, 16 to 20, 16 to 18, or 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 consecutive nucleotides.

[0199] In one embodiment, the present invention provides an IL-11 antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides. The antisense oligonucleotide of the present invention comprises an oligonucleotide sequence complementary to an isolength portion of the sequence of the IL-11 nucleic acid (SEQ ID NO: 1 or 2) and has at least 80% complementarity. "Linked nucleosides" means adjacent nucleosides linked to each other by internucleoside bonds.

[0200] Antisense oligonucleotides can increase or decrease the length of consecutive nucleotides, and can also introduce mismatched bases (non-complementary nucleic acid bases) while maintaining activity. A "mismatched base (non-complementary nucleic acid base)" refers to a nucleic acid base of the first nucleic acid that cannot pair with the corresponding nucleic acid base of the second or target nucleic acid. The introduction of mismatched bases includes (i) the substitution of some nucleic acid bases of the antisense oligonucleotide with nucleic acid bases that cannot pair with the target nucleic acid, (ii) the inclusion of nucleic acid bases that cannot pair with the target nucleic acid in some nucleic acid bases of the antisense oligonucleotide, resulting in an increase in the length of consecutive nucleotides by that amount (insertion), and (iii) the deletion of nucleic acid bases that can pair with the target nucleic acid in the complementary portion of the antisense oligonucleotide and the target nucleic acid, resulting in a decrease in the length of consecutive nucleotides by that amount (deletion).

[0201] The isolength portion refers to the portion formed by the hybridization of the antisense oligonucleotide and the IL-11 nucleic acid. If the mismatch base is not introduced into the antisense oligonucleotide, the length (number of nucleosides) of the antisense oligonucleotide and the target segment are the same. If the mismatch (i) is introduced into the antisense oligonucleotide, the length (number of nucleosides) of the antisense oligonucleotide and the target segment are the same. If the mismatch (ii) insertion is introduced into the antisense oligonucleotide, the isolength portion of the target nucleic acid is shorter than that of the antisense oligonucleotide by the amount of the insertion base (also referred to as having a reduced number of nucleosides). If the mismatch (iii) deletion is introduced into the antisense oligonucleotide, the isolength portion of the target nucleic acid is longer than that of the antisense oligonucleotide by the amount of the deletion base (also referred to as having an increased number of nucleosides).

[0202] The antisense oligonucleotides of the present invention may contain nucleotide sequences in the isolength portion of the target nucleic acid, IL-11 nucleic acid, that have complete complementarity (100%) or substantial complementarity (e.g., at least 80% to 100%, at least 85% to 100%, at least 90% to 100%, or at least 95% to 100%) with consecutive nucleic acid bases in the nucleotide sequence. "Consecutive nucleic acid bases" means nucleic acid bases that are directly adjacent to each other.

[0203] "Complementarity" refers to the ability of an antisense oligonucleotide to form base pairs (hybrid formation) with the corresponding nucleic acid bases in the target nucleic acid. Base pairing (hybrid formation) is formed by Watson-Crick, Hoogsteen, or reverse Hoogsteen hydrogen bonds between the corresponding nucleic acid bases. "Complementarity" is sometimes also called "base complementarity."

[0204] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is complementary to the isolength portion of the IL-11 nucleic acid, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0205] In one embodiment, the number of linked nucleosides in the antisense oligonucleotide of the present invention is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0206] In one embodiment, the number of consecutive nucleic acid bases complementary to the isolength portion of the nucleic acid bases of the IL-11 nucleic acid of the antisense oligonucleotide of the present invention is, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18; for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0207] In one embodiment, the complementarity of the nucleic acid base sequence of the antisense oligonucleotide of the present invention to the isolength portion of the IL-11 nucleic acid is, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%.

[0208] In one embodiment, the antisense oligonucleotide of the present invention can inhibit the expression of IL-11 or IL-11 mRNA, and the degree of inhibition of expression (also referred to as the "expression inhibition rate" in the examples described below) is, for example, about 5% or more, about 5-100%, about 30-100%, about 50-100%, and about 70-100%. 50 The values ​​are, for example, approximately 50 nM or less, approximately 40 nM or less, approximately 30 nM or less, approximately 20 nM or less, approximately 10 nM or less, etc. The method for measuring the degree of inhibition of the expression is not particularly limited, but for example, it can be measured and calculated by the method described in the examples below.

[0209] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is, for example, at least 80% complementary to the isolength portion within nucleic acid bases 1-2378, 1-753, 1-153, 154-2378, 154-753, or 754-2378 of the IL-11 nucleic acid of SEQ ID NO: 1, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0210] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the same as that of the IL-11 nucleic acid of SEQ ID NO: 1, specifically the nucleic acid bases 27-42, 82-97, 94-109, 148-163, 152-167, 170-185, 198-213, 240-255, 322-337, 331-346, 337-352, 340-355, 357-372, 363-378, 368-383, 379-394 , 407~422, 418~433, 422~437, 427~442, 428~443, 431~446, 451~466, 454~469, 455~470, 456~471, 456~473, 457~472, 458~473, 472~487, 473~488, 490~505, 492~507, 493~508, 494~509, 495~510, 496~511, 497~512, 499~514, 500~515, 501~516, 502~517, 503~5 18, 504~519, 505~520, 506~521, 507~522, 508~523, 509~524, 510~525, 510~527, 511~526, 512~527, 527~542, 574~589, 577~592, 683~700, 691~706, 696~711, 701~716, 717~732, 774~789, 776~791, 777~792, 778~793, 780~795, 783~798, 784~799, 785~800, 786 The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within ~801, 787~802, 899~914, 904~919, 1115~1130, 1127~1142, 1138~1153, 1158~1173, 1766~1781, 2266~2281, or 2324~2339, and wherein the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0211] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 27-42, 198-213, 331-346, 357-372, 363-378, 379-394, 422-437, 431-446, 451-4 of the IL-11 nucleic acid of SEQ ID NO: 1. 66, 454~469, 456~471, 456~473, 457~472, 458~473, 472~487, 473~488, 492~507, 493~508, 494~509, 495~510, 502~517, 503~518, 504~519, 505~520, 506~521, 507~522, 508~523, 509~524, 510~ 525, 510-527, 511-526, 512-527, 527-542, 574-589, 577-592, 683-700, 691-706, 696-711, 701-716, 717-732, 774-789, 776-791, 777-792, 778-793, 780-795, 786-801, 787-802, 899-914, 904 The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within ~919, 1115~1130, 1127~1142, 1766~1781, or 2324~2339, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0212] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 198-213, 331-346, 422-437, 431-446, 451-466, 454-469, 456-473, 457-472, 458-473, 472-487, 493-508, 502-517, 503-518, 504-519, 505-520, 506-521, 507-522, 508-523, 509-524, 5 The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 10-525, 510-527, 511-526, 512-527, 574-589, 683-700, 691-706, 696-711, 701-716, 776-791, 777-792, 778-793, 786-801, 904-919, 1766-1781, or 2324-2339, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0213] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 198-213, 331-346, 422-437, 431-446, 451-466, 454-469, 457-472, 458-473, 472-487, 502-517, 503-518, 504-519, 506-521, 507- The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 522, 508-523, 511-526, 574-589, 683-700, 691-706, 696-711, 701-716, 777-792, 904-919, or 2324-2339, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0214] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is, for example, at least 80% complementary to an isolength portion within the nucleic acid bases 456-473, 457-472, 493-508, 503-518, 504-519, 505-520, 509-524, 510-525, 510-527, 511-526, 512-527, 776-791, 777-792, 778-793, 786-801, or 1766-1781 of the IL-11 nucleic acid of SEQ ID NO: 1, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0215] In the above embodiment, the complementarity of the nucleic acid base sequence of the oligonucleotide contained in the antisense oligonucleotide of the present invention to the nucleic acid base of the IL-11 nucleic acid of SEQ ID NO: 1 is, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the equal-length portion within nucleic acid bases 683 to 700 of the IL-11 nucleic acid of SEQ ID NO: 1 is excluded.

[0216] In the above embodiment, the number of linked nucleosides forming the oligonucleotide in the antisense oligonucleotide of the present invention is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0217] In one embodiment, the antisense oligonucleotide of the present invention has, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases that are complementary to the nucleic acid bases of the IL-11 nucleic acid of SEQ ID NO: 1; for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0218] In one embodiment, the present invention provides an antisense oligonucleotide having inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[0219] In one embodiment, the present invention provides IL-11 antisense oligonucleotides or pharmaceutically acceptable salts thereof or solvates thereof.

[0220] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases of IL-11 nucleic acid of SEQ ID NO: 601-6682, 601-753, 601-760, 601-2122, 601-2295, 601-2494, 601-2581, 601-2692, 601-2854, 601-4886, 601-5057, 601-6682, 754-760, 754-2122, 754-2295, 754-2494, 754-2581, 754-2692, 754-2854, 754-4886, 754-5057, 754-6682, 76 1-2122, 761-2295, 761-2494, 761-2581, 761-2692, 761-2854, 761-4886, 761-5057, 761-6682, 2123-2295, 2123-2494, 2123-2581, 2123-2692, 2123-2854, 2123-4886, 2123- 5057, 2123~6682, 2296~2494, 2296~2581, 2296~2692, 2296~2854, 2296~4886, 2296~5057, 2296~6682, 2495~2581, 2495~2692, 2495~2854, 2495~4886, 2495~5057, 2495~6682, The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 2582-2692, 2582-2854, 2582-4886, 2582-5057, 2582-6682, 2693-2854, 2693-4886, 2693-5057, 2693-6682, 2855-4886, 2855-5057, 2855-6682, 4887-5057, 4887-6682, or 5058-6682, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0221] In one embodiment, the number of linked nucleosides forming the oligonucleotide in the antisense oligonucleotide of the present invention, which is complementary to the nucleic acid base of the IL-11 nucleic acid of SEQ ID NO: 2, is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0222] In one embodiment, the antisense oligonucleotide of the present invention has a number of consecutive nucleic acid bases complementary to the nucleic acid base portion of the IL-11 nucleic acid of SEQ ID NO: 2, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18; for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0223] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 627-642, 682-697, 694-709, 766-781, 930-945, 956-971, 1343-1358, 1558-1573, 1607-1622, 2132-2147, 2160-2175, 2202-2217, 2290-2305, 2348-2363, 2363-2378, 2372-2387, 2383-2398, 2412~2427, 2477~2492, 2498~2513, 2501~2516, 2518~2533, 2524~2539, 2529~2544, 2540~2555, 2690~2705, 2694~2709, 2699~2714, 2700~2715, 2703~ 2718, 2723~2738, 2726~2741, 2727~2742, 2728~2743, 2728~2745, 2729~2744, 2730~2745, 2744~2759, 2745~2760, 2762~2777, 2764~2779, 2765~2780, 2766~2781, 2767~2782, 2768~2783, 2769~2784, 2771~2786, 2772~2787, 2773~2788, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~ 2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~2799, 2799~2814, 2852~2867, 2865~2880, 2915~2930, 2946~2961, 2978~2993, 2999~3014, 3037~3052, 3073~3088, 3111~3126, 3124~3139, 3134~3149, 3145~3160, 3163~3178, 3184~3199, 3199~3214, 3226~3241, 3245~3260, 3258~ 3273, 3278~3293, 3290~3305, 3626~3641, 3664~3679, 3690~3705, 3705~3720, 3749~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877,3902~3917, 3926~3941, 3940~3955, 3963~3978, 3984~3999, 3999~4014, 4018~4033, 4032~4047, 4051~4066, 4068~4083, 4086~4101, 4161~4176, 4180~4195, 4290~4305, 4373~4388, 4500~4515, 452 8~4543, 4543~4558, 4578~4593, 4601~4616, 4622~4637, 4646~4661, 4653~4668, 4676~4691, 4698~4713, 4751~4766, 4780~4795, 4799~4814, 4852~4867, 4879~4894, 4987~5004, 4995~5010, 5000~50 15, 5005~5020, 5021~5036, 5078~5093, 5080~5095, 5081~5096, 5082~5097, 5084~5099, 5087~5102, 5088~5103, 5089~5104, 5090~5105, 5091~5106, 5203~5218, 5208~5223, 5419~5434, 5431~5446, The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 5442-5457, 5462-5477, 6070-6085, 6570-6585, or 6628-6643, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0224] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 627-642, 930-945, 956-971, 1343-1358, 1558-1573, 1607-1622, 2160-2175, 2363-2378, 2372-2387, 2383-2398, 2412-2427, 2477-2492, 2518-2533, 2524-2539, 2540-2555, 2694-2709, 270 3-2718, 2723-2738, 2726-2741, 2728-2743, 2728-2745, 2729-2744, 2730-2745, 2744-2759, 2745-2760, 2764-2779, 2765-2780, 2766-2781, 2767-27 82, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~2799, 27 99~2814, 2865~2880, 2915~2930, 2946~2961, 2999~3014, 3037~3052, 3111~3126, 3124~3139, 3145~3160, 3163~3178, 3226~3241, 3258~3273, 3290~3 305, 3626~3641, 3664~3679, 3690~3705, 3705~3720, 3749~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877, 3902~3917, 3926~3941, 3 940~3955, 3963~3978, 3984~3999, 3999~4014, 4018~4033, 4032~4047, 4051~4066, 4068~4083, 4086~4101, 4161~4176, 4180~4195, 4290~4305, 4373~ 4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4601~4616, 4622~4637, 4646~4661, 4653~4668, 4698~4713, 4751~4766, 4780~4795, 4799~4814,The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 4852-4867, 4987-5004, 4995-5010, 5000-5015, 5005-5020, 5021-5036, 5078-5093, 5080-5095, 5081-5096, 5082-5097, 5084-5099, 5090-5105, 5091-5106, 5203-5218, 5208-5223, 5419-5434, 5431-5446, 6070-6085, or 6628-6643, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0225] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases of IL-11 nucleic acid of SEQ ID NO: 1343-1358, 1607-1622, 2160-2175, 2363-2378, 2383-2398, 2412-2427, 2477-2492, 2694-2709, 2703-2718, 2723-2738, 2726-2741, 2728-2745, 2729-2744, 2730-2745, 2744-2759, 2765- 2780, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~279 9, 2915~2930, 2946~2961, 2999~3014, 3037~3052, 3124~3139, 3145~3160, 3163~3178, 3226~3241, 3258~3273, 3290~3305, 3626~3641, 3690~3705, 3 705~3720, 3749~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877, 3902~3917, 3926~3941, 3940~3955, 3963~3978, 3984~3999, 3999 ~4014, 4018~4033, 4032~4047, 4051~4066, 4068~4083, 4180~4195, 4290~4305, 4373~4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4601~46 16, in the isolength portions within 4646~4661, 4698~4713, 4751~4766, 4852~4867, 4987~5004, 4995~5010, 5000~5015, 5005~5020, 5080~5095, 5081~5096, 5082~5097, 5090~5105, 5208~5223, 6070~6085 or 6628~6643, for example, at least 80% complementary, wherein the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds and modified nucleic acid bases,We provide antisense oligonucleotides.

[0226] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the same as the nucleic acid bases 2160 to 2175, 2363 to 2378, 2383 to 2398, 2412 to 2427, 2477 to 2492, 2694 to 2709, 2703 to 2492 of the IL-11 nucleic acid of SEQ ID NO: 2. 2718, 2723~2738, 2726~2741, 2729~2744, 2730~2745, 2744~2759, 2774~2789, 2775~2790, 2776~2791, 2778~2793, 2779~2794, 2780~2795, 2783~2798, 2915~2930, 3145~3160, 3163~3178, 3 226~3241, 3290~3305, 3705~3720, 3787~3802, 3820~3835, 3850~3865, 3926~3941, 3963~3978, 3999~4014, 4068~4083, 4290~4305, 4601~4616, 4751~4766, 4987~5004, 4995~5010, 5000~50 The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 15, 5005-5020, 5081-5096, 5208-5223, or 6628-6643, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0227] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 1343-1358, 1607-1622, 2728-2745, 2729-2744, 2765-2780, 2775-2790, 2776-27 91, 2777~2792, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~2799, 2946~2961, 2999~3014, 3037~3052, 3124~3139, 3258~3273, 3626~3641, 3690~3705, 3749~3764, 3764~3779, 3862~3 877, 3902~3917, 3940~3955, 3984~3999, 4018~4033, 4032~4047, 4051~4066, 4180~4195, 4373~4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4646~4661, 4698~4713, 4852~4867, 5080~ The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 5095, 5081-5096, 5082-5097, 5090-5105, or 6070-6085, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0228] In the above embodiment, the complementarity of the nucleic acid base sequence of the oligonucleotide contained in the antisense oligonucleotide of the present invention to the nucleic acid base of the IL-11 nucleic acid of SEQ ID NO: 2 is, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 85%, at least 90%, at least 95%, or 100%; particularly preferably at least 90%, at least 95%, or 100%; and even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the equal-length portion within nucleic acid bases 4987 to 5004 of the IL-11 nucleic acid of SEQ ID NO: 2 is excluded.

[0229] In the above embodiment, the number of linked nucleosides forming the oligonucleotide in the antisense oligonucleotide of the present invention is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0230] In one embodiment, the antisense oligonucleotide of the present invention has, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases that are complementary to the nucleic acid bases of the IL-11 nucleic acid of SEQ ID NO: 2; for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0231] In one embodiment, the present invention provides a pharmaceutically acceptable salt of the antisense oligonucleotide of the present invention, a solvate of the antisense oligonucleotide of the present invention, or a solvate of a pharmaceutically acceptable salt of the antisense oligonucleotide of the present invention.

[0232] In one embodiment, the inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide of the present invention, which is complementary to the nucleic acid base of the IL-11 nucleic acid of SEQ ID NO: 1 or 2, is, for example, about 5% or more, about 5-100%, about 30-100%, about 50-100%, and about 70-100%. 50 The values ​​are, for example, approximately 50 nM or less, approximately 40 nM or less, approximately 30 nM or less, approximately 20 nM or less, approximately 10 nM or less, etc. The method for measuring the expression inhibition rate is not particularly limited, but for example, it can be measured and calculated by the method described in the examples below.

[0233] The antisense oligonucleotides of the present invention include those existing via tautomerism and geometric isomerism, as well as mixtures thereof or mixtures of their respective isomers. Furthermore, if a chiral center is present, or if a chiral center is formed as a result of isomerization, the invention includes the existence of each optical isomer and mixtures in any ratio. In the case of compounds having two or more chiral centers, diastereomers based on each optical isomer also exist. The present invention encompasses all of these types in any proportion. Furthermore, optically active compounds can be obtained for this purpose by methods well known to those skilled in the art.

[0234] For example, if the antisense oligonucleotide of the present invention contains a modified phosphodiester bond (e.g., a phosphorothioate bond) and the phosphorus atom is a chiral atom, then both forms of oligonucleotides with controlled phosphorus atom stereochemistry and oligonucleotides with uncontrolled phosphorus atom stereochemistry are included within the scope of the present invention.

[0235] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 27-42, 82-97, 94-109, 148-163, 152-167, 170-185, 198-213, 240-255, 322-337, 331-346, 337-352, 340-355, 357-372, 363-378, 368-383, 379-394, 407-422, 4 18~433, 422~437, 427~442, 428~443, 431~446, 451~466, 454~469, 455~470, 456~471, 456~473, 457~472, 458~473, 472~487, 473~488, 490~505, 492~507, 493~508, 494~509, 495~510, 496~511, 497~512, 499~514, 500~515, 501~516, 502~517, 503~518, 504~519, 505~520, 506~521, 507~522, 508~523, 509~524, 510~525, 510~527, 511~526, 512~527, 527~542, 574~589, 577~592, 683~700, 691~706, 696~711, 701~716, 717~732, 774~789, 776~791, 777~792, 778~793, 780~795, 783~798, 784~799, 785~800, 786~801, 787~802, 899~914, 904~919 The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 1115-1130, 1127-1142, 1138-1153, 1158-1173, 1766-1781, 2266-2281, or 2324-2339, and that the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, and that the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, 5%-100%.

[0236] In this specification, the inhibition rate of IL-11 or IL-11 mRNA expression refers to the inhibition rate when the concentration of the antisense oligonucleotide of one embodiment of the present invention used when evaluating IL-11 protein expression or IL-11 mRNA expression is 30 nM.

[0237] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the same as that of the IL-11 nucleic acid of SEQ ID NO: 1, specifically the nucleic acid bases 27-42, 198-213, 331-346, 357-372, 363-378, 379-394, 422-437, 431-446, 451-466, and 454-469. ,456~471,456~473,457~472,458~473,472~487,473~488,492~507,493~508,494~509,495~510,502~517,503~518,504~519,505~520,506~521,507~522,508~523,509~524,510~525,510~527,511~526, 512~527, 527~542, 574~589, 577~592, 683~700, 691~706, 696~711, 701~716, 717~732, 774~789, 776~791, 777~792, 778~793, 780~795, 786~801, 787~802, 899~914, 904~919, 1115~1130, 1127~1142, 1766~ The present invention provides an antisense oligonucleotide that is, for example, at least 80% complementary to an isolength portion within 1781 or 2324-2339, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, and the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, 30%-100%.

[0238] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 198-213, 331-346, 422-437, 431-446, 451-466, 454-469, 456-473, 457-472, 458-473, 472-487, 493-508, 502-517, 503-518, 504-519, 505-520, 506-521, 507-522, 508-523, 509-524, 510-525, 510-527, 511-5 The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 26, 512-527, 574-589, 683-700, 691-706, 696-711, 701-716, 776-791, 777-792, 778-793, 786-801, 904-919, 1766-1781, or 2324-2339, and each oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, and the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, 50%-100%.

[0239] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 456-473, 457-472, 493-508, 503-518, 504-519, 505-520, 509-524, 510-525, 510-527, 511-526, 512-527, 776-791 of the IL-11 nucleic acid of SEQ ID NO. 1. The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portions within 777-792, 778-793, 786-801, or 1766-1781, and that the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, and that inhibit the expression of IL-11 or IL-11 mRNA is, for example, 70%-100%.

[0240] In one embodiment, the present invention comprises, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is, for example, at least 80% complementary to an isolength portion within nucleic acid bases 503-518, 504-519, 505-520, 683-700, 776-791, 777-792, 778-793, or 786-801 of the IL-11 nucleic acid of SEQ ID NO: 1, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, wherein the inhibition of IL-11 or IL-11 mRNA expression is, for example, IC 50 We provide antisense oligonucleotides with a value of approximately 50 nM or less.

[0241] In the above embodiment, the complementarity of the nucleic acid base sequence of the oligonucleotide contained in the antisense oligonucleotide of the present invention to the nucleic acid base of the IL-11 nucleic acid of SEQ ID NO: 1 is, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the equal-length portion within nucleic acid bases 683 to 700 of the IL-11 nucleic acid of SEQ ID NO: 1 is excluded.

[0242] In the above embodiment, the number of linked nucleosides forming the oligonucleotide in the antisense oligonucleotide of the present invention is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0243] In the embodiments described above, the antisense oligonucleotide of the present invention has, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases that are complementary to the nucleic acid bases of the IL-11 nucleic acid of SEQ ID NO: 1; for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0244] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 627-642, 682-697, 694-709, 766-781, 930-945, 956-971, 1343-1358, 1558-1573, 1607-1622, 2132-2147, 2160-2175, 2202-2217, 2290-2305, 2348-2363, 2363-2378, 2372-2387, 2383-2398, 2412~2427, 2477~2492, 2498~2513, 2501~2516, 2518~2533, 2524~2539, 2529~2544, 2540~2555, 2690~2705, 2694~2709, 2699~2714, 2700~2715, 2703~ 2718, 2723~2738, 2726~2741, 2727~2742, 2728~2743, 2728~2745, 2729~2744, 2730~2745, 2744~2759, 2745~2760, 2762~2777, 2764~2779, 2765~2780, 2766~2781, 2767~2782, 2768~2783, 2769~2784, 2771~2786, 2772~2787, 2773~2788, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~ 2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2783~2798, 2784~2799, 2799~2814, 2852~2867, 2865~2880, 2915~2930, 2946~2961, 2978~2993, 2999~3014, 3037~3052, 3073~3088, 3111~3126, 3124~3139, 3134~3149, 3145~3160, 3163~3178, 3184~3199, 3199~3214, 3226~3241, 3245~ 3260, 3258~3273, 3278~3293, 3290~3305, 3626~3641, 3664~3679, 3690~3705, 3705~3720, 3749~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865,3862~3877, 3902~3917, 3926~3941, 3940~3955, 3963~3978, 3984~3999, 3999~4014, 4018~4033, 4032~4047, 4051~4066, 4068~4083, 4086~4101, 4161~4176, 4180~4195, 4290~4305, 4373~4388, 4500~4515, 452 8~4543, 4543~4558, 4578~4593, 4601~4616, 4622~4637, 4646~4661, 4653~4668, 4676~4691, 4698~4713, 4751~4766, 4780~4795, 4799~4814, 4852~4867, 4879~4894, 4987~5004, 4995~5010, 5000~5015, 5005~5 020, 5021~5036, 5078~5093, 5080~5095, 5081~5096, 5082~5097, 5084~5099, 5087~5102, 5088~5103, 5089~5104, 5090~5105, 5091~5106, 5203~5218, 5208~5223, 5419~5434, 5431~5446, 5442~5457, 5462~5477 The present invention provides antisense oligonucleotides that are, for example, at least 80% complementary to the isolength portion within 6070-6085 or 6628-6643, and that the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, and that inhibit the expression of IL-11 or IL-11 mRNA to, for example, 5%-100%.

[0245] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 627-642, 930-945, 956-971, 1343-1358, 1558-1573, 1607-1622, 2160-2175, 2363-2378, 2372-2387, 2383-2398, 2412-2427, 2477-2492, 2518-2533, 2524-2539, 2540-2555, 2694-2709, 270 3-2718, 2723-2738, 2726-2741, 2728-2743, 2728-2745, 2729-2744, 2730-2745, 2744-2759, 2745-2760, 2764-2779, 2765-2780, 2766-2781, 2767-27 82, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~2799, 27 99~2814, 2865~2880, 2915~2930, 2946~2961, 2999~3014, 3037~3052, 3111~3126, 3124~3139, 3145~3160, 3163~3178, 3226~3241, 3258~3273, 3290~3 305, 3626~3641, 3664~3679, 3690~3705, 3705~3720, 3749~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877, 3902~3917, 3926~3941, 3 940~3955, 3963~3978, 3984~3999, 3999~4014, 4018~4033, 4032~4047, 4051~4066, 4068~4083, 4086~4101, 4161~4176, 4180~4195, 4290~4305, 4373~ 4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4601~4616, 4622~4637, 4646~4661, 4653~4668, 4698~4713, 4751~4766, 4780~4795, 4799~4814,4852~4867, 4987~5004, 4995~5010, 5000~5015, 5005~5020, 5021~5036, 5078~5093, 5080~5095, 5081~5096, 5082~5097, 5084~5099, 5090~5105, 5091~5106, 5203~5218, 5208~5223, 5419~5434, 5431~5446, 60 The present invention provides an antisense oligonucleotide that is, for example, at least 80% complementary to an isolength portion within 70-6085 or 6628-6643, and comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, and exhibits an IL-11 or IL-11 mRNA expression inhibition rate of, for example, 30%-100%.

[0246] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases of IL-11 nucleic acid of SEQ ID NO: 1343-1358, 1607-1622, 2160-2175, 2363-2378, 2383-2398, 2412-2427, 2477-2492, 2694-2709, 2703-2718, 2723-2738, 2726-2741, 2728-2745, 2729-2744, 2730-2745, 2744-2759, 2765- 2780, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~279 9, 2915~2930, 2946~2961, 2999~3014, 3037~3052, 3124~3139, 3145~3160, 3163~3178, 3226~3241, 3258~3273, 3290~3305, 3626~3641, 3690~3705, 3 705~3720, 3749~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877, 3902~3917, 3926~3941, 3940~3955, 3963~3978, 3984~3999, 3999 ~4014, 4018~4033, 4032~4047, 4051~4066, 4068~4083, 4180~4195, 4290~4305, 4373~4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4601~46 16, 4646~4661, 4698~4713, 4751~4766, 4852~4867, 4987~5004, 4995~5010, 5000~5015, 5005~5020, 5080~5095, 5081~5096, 5082~5097, 5090~5105, 5208~5223, 6070~6085 or 6628~6643, for example, at least 80% complementary, wherein the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds and modified nucleic acid bases,The present invention provides an antisense oligonucleotide that inhibits the expression of IL-11 or IL-11 mRNA by, for example, 50% to 100%.

[0247] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 1343-1358, 1607-1622, 2728-2745, 2729-2744, 2765-2780, 2775-2790, 2776-2791, 2777-27 92, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784~2799, 2946~2961, 2999~3014, 3037~3052, 3124~3139, 3258~3273, 3626~3641, 3690~3705, 3749~3764, 3764~3779, 3862~3877, 3902~3917, 3940~3 955, 3984~3999, 4018~4033, 4032~4047, 4051~4066, 4180~4195, 4373~4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4646~4661, 4698~4713, 4852~4867, 5080~5095, 5081~5096, 5082~5097, 5090~ The present invention provides an antisense oligonucleotide that is, for example, at least 80% complementary to an isolength portion within 5105 or 6070-6085, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, and the inhibition rate of IL-11 or IL-11 mRNA expression is, for example, 70%-100%.

[0248] In one embodiment, the present invention includes, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid bases of IL-11 nucleic acid of SEQ ID NO: 1607-1622, 2775-2790, 2776-2791, 2777-2792, 3124-3139, 3626-3641, 3690-3705, 3749-3764, 3940-3955, 4051-4066, 4373-4388, 4500-4515, 4528- For example, at least 80% complementary oligonucleotides are present in the isolength portions within 4543, 4543-4558, 4646-4661, 4852-4867, 4987-5004, 5080-5095, 5081-5096, 5082-5097, 5090-5105, or 5090-5105, and the oligonucleotides include at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases, thereby inhibiting the expression of IL-11 or IL-11 mRNA, for example, IC 50 We provide antisense oligonucleotides with a value of approximately 50 nM or less.

[0249] In the above embodiment, the complementarity of the nucleic acid base sequence of the oligonucleotide contained in the antisense oligonucleotide of the present invention to the nucleic acid base of the IL-11 nucleic acid of SEQ ID NO: 2 is, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the equal-length portion within nucleic acid bases 4987 to 5004 of the IL-11 nucleic acid of SEQ ID NO: 2 is excluded.

[0250] In the above embodiment, the number of linked nucleosides forming the oligonucleotide in the antisense oligonucleotide of the present invention is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0251] In one embodiment, the antisense oligonucleotide of the present invention has, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases that are complementary to the nucleic acid bases of the IL-11 nucleic acid of SEQ ID NO: 2; for example, 5 to 18, 10 to 18, or 15 to 18; preferably at least 16, 17, or 18; more preferably at least 16 or 18.

[0252] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5 consecutive nucleic acid bases from any of the nucleic acid bases included in the nucleic acid base sequence selected from SEQ ID NOs. 4 to 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0253] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 of the nucleic acid bases included in a nucleic acid base sequence selected from SEQ ID NOs: 4 to 156; preferably at least 16, 17, or 18; more preferably at least 16 or 18 consecutive nucleic acid bases, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0254] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs. 4 to 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0255] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide in which 7 to 30 nucleosides are linked, wherein the nucleic acid base sequence of the oligonucleotide consists of a nucleic acid base sequence selected from SEQ ID NOs. 4 to 156, and the oligonucleotide includes at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0256] In the above embodiment, the number of linked nucleosides forming the oligonucleotide in the antisense oligonucleotide of the present invention is, for example, 7 to 30, 7 to 25, 10 to 25, 10 to 22, 15 to 22, 16 to 22, or 16 to 18; preferably 15 to 22 or 16 to 22; more preferably 16 to 18; and even more preferably 16 or 18.

[0257] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 15 to 22 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least five consecutive nucleic acid bases from any of the nucleic acid base sequences selected from SEQ ID NOs. 4 to 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0258] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 15 to 22 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 of the nucleic acid bases included in a nucleic acid base sequence selected from SEQ ID NOs: 4 to 156; preferably at least 16, 17, or 18; more preferably at least 16 or 18 consecutive nucleic acid bases, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0259] In one embodiment, the present invention provides an antisense oligonucleotide comprising an oligonucleotide consisting of, for example, 15 to 22 linked nucleosides, wherein the oligonucleotide comprises a nucleobase sequence selected from SEQ ID NOs: 4 to 156, and the oligonucleotide comprises at least one modification selected from a modified sugar, a modified internucleoside linkage, and a modified nucleobase.

[0260] In one embodiment, the present invention provides an antisense oligonucleotide comprising an oligonucleotide in which, for example, 15 to 22 nucleosides are linked, wherein the nucleobase sequence of the oligonucleotide consists of a nucleobase sequence selected from SEQ ID NOs: 4 to 156, and the oligonucleotide comprises at least one modification selected from a modified sugar, a modified internucleoside linkage, and a modified nucleobase.

[0261] In the above embodiment, the number of linked nucleosides forming the oligonucleotide comprised in the antisense oligonucleotide of the present invention is, for example, 15 to 22, 16 to 22, or 16 to 18; preferably 16 to 18 or 16 to 22; more preferably 16 or18.

[0262] In the above embodiment, the inhibition rate of the expression of IL-11 or IL-11 mRNA by the antisense oligonucleotide of the present invention is, for example, about 5% or more, about 5 to 100%, about 30% to 100%, about 70% to 100%, about 80% to 100%, or about 90% to 100%. Also, the IC 50 value is, for example, about 5 nm or less, about 40 nm or less, about 30 nm or less, about 20 nm or less, about 10 nm or less, etc.

[0263] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5 consecutive nucleic acid bases from any of the nucleic acid base sequences selected from SEQ ID NOs. 4-29, 31-53, and 55-155, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0264] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or at least 16 nucleic acid bases from any nucleic acid base sequence selected from SEQ ID NOs. 4-29, 31-53, 55-155; preferably, at least 16 consecutive nucleic acid bases, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0265] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs. 4-29, 31-53, and 55-155, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 5% to 100%.

[0266] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 4, 10, 13, 16, 17, 19, 22, 25-27, 29, 31-34, 36-39, 45-53, 55-68, 72-77, 80, 82, 84-88, 91-95, 97-99, 101, 102, 104, 105, 107, 108, 111, 113, 115-148, and 150-154, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 30% to 100%.

[0267] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 10, 13, 22, 25-27, 31-33, 37, 45-53, 55, 56, 58, 60-62, 65-67, 72, 75, 80, 82, 86, 88, 91, 93-95, 98, 99, 101, 102, 105, 107, 108, 111, 113, 115, 116, 118-135, 138-145, 147, 150, 151, 154, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the aforementioned antisense oligonucleotide is 50% to 100%.

[0268] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 31, 37, 46-48, 52-53, 55, 56, 65-67, 72, 80, 86, 88, 99, 101, 102, 105, 113, 116, 118, 120, 121, 125, 126, 128, 130, 132-134, 138, 140-144, 147, 150, 154, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 70%-100%.

[0269] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs. 46-48, 65-67, 72, 88, 105, 116, 118, 120, 128, 134, 140-143, 147, 154, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. Inhibition of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is IC 50 The value is, for example, approximately 50 nM or less.

[0270] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is selected from SEQ ID NOs: 4-29, 31-53, and 55-155, and the oligonucleotide includes at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 5% to 100%.

[0271] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is selected from SEQ ID NOs: 4, 10, 13, 16, 17, 19, 22, 25-27, 29, 31-34, 36-39, 45-53, 55-68, 72-77, 80, 82, 84-88, 91-95, 97-99, 101, 102, 104, 105, 107, 108, 111, 113, 115-148, 150-154, and the oligonucleotide includes at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 30% to 100%.

[0272] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is selected from SEQ ID NOs: 10, 13, 22, 25-27, 31-33, 37, 45-53, 55, 56, 58, 60-62, 65-67, 72, 75, 80, 82, 86, 88, 91, 93-95, 98, 99, 101, 102, 105, 107, 108, 111, 113, 115, 116, 118-135, 138-145, 147, 150, 151, 154, and the oligonucleotide includes at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the aforementioned antisense oligonucleotide is 50% to 100%.

[0273] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is selected from SEQ ID NOs: 31, 37, 46-48, 52-53, 55, 56, 65-67, 72, 80, 86, 88, 99, 101, 102, 105, 113, 116, 118, 120, 121, 125, 126, 128, 130, 132-134, 138, 140-144, 147, 150, 154, and the oligonucleotide includes at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 70%-100%.

[0274] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 16 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is selected from SEQ ID NOs. 46-48, 65-67, 72, 88, 105, 116, 118, 120, 128, 134, 140-143, 147, 154, and the oligonucleotide includes at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is IC 50 The value is, for example, approximately 50 nM or less.

[0275] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising at least five consecutive nucleic acid bases from any of the nucleic acid base sequences selected from SEQ ID NOs. 30, 54, and 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0276] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide contains at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 nucleic acid bases from a nucleic acid base sequence selected from SEQ ID NOs. 30, 54, and 156; preferably at least 16, 17, or 18; more preferably having a nucleic acid base sequence containing at least 16 or 18 consecutive nucleic acid bases, wherein the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0277] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 30, 54, and 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 50% to 100%.

[0278] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 30 or 54, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 70% to 100%.

[0279] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide comprises the nucleic acid base sequence of SEQ ID NO: 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. Inhibition of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is IC 50 The value is, for example, approximately 50 nM or less.

[0280] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is a nucleic acid base sequence selected from SEQ ID NOs: 30, 54, and 156, and the oligonucleotide includes at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 50% to 100%.

[0281] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide consists of the nucleic acid base sequence of SEQ ID NO: 30 or 54, and the oligonucleotide includes at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. The inhibition rate of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is 70% to 100%.

[0282] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is the nucleic acid base sequence of SEQ ID NO: 156, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. Inhibition of IL-11 or IL-11 mRNA expression by the antisense oligonucleotide is IC 50 The value is, for example, approximately 50 nM or less.

[0283] The complementarity of the nucleic acid base sequence of the antisense oligonucleotide of the above embodiment to the nucleic acid base portion of the IL-11 nucleic acid of SEQ ID NO: 1 or 2 is, for example, at least 80%, at least 85%, at least 90%, at least 95%, or 100%; preferably at least 80%, at least 85%, at least 90%, at least 95%, or 100%; more preferably at least 85%, at least 90%, at least 95%, or 100%; even more preferably at least 90%, at least 95%, or 100%; and particularly even more preferably at least 95%, or 100%. However, if the complementarity is at least 90% to 100%, the nucleic acid base sequence of SEQ ID NO: 156 is excluded.

[0284] In one embodiment, the present invention provides an antisense oligonucleotide comprising, for example, an oligonucleotide consisting of 18 linked nucleosides, wherein the oligonucleotide has a nucleic acid base sequence comprising, for example, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases from the nucleic acid base sequence of Sequence ID No. 156, the antisense oligonucleotide is 100% complementary to the isolength portion within nucleic acid bases 685-702 of the IL-11 nucleic acid of Sequence ID No. 3, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

[0285] In one embodiment, the present invention provides a pharmaceutically acceptable salt of an antisense oligonucleotide according to any of the above embodiments, a solvate of the antisense oligonucleotide, or a solvate of a pharmaceutically acceptable salt of the antisense oligonucleotide.

[0286] The antisense oligonucleotides of the present invention, or sequences thereof, may be gapmers. A “gapmer” refers to an oligonucleotide having a “central region” located between the 5' and 3' regions and containing multiple nucleosides that facilitate cleavage by RNaseH. Antisense oligonucleotide gapmers are typically used to inhibit target nucleic acids via RNaseH-mediated degradation. The “central region” may also be referred to as the “gap” or “gap segment”; the “5' region” and “3' region” may also be referred to as the “wing,” “5' wing segment,” or “3' wing segment.”

[0287] The gapmer has at least three distinct structural regions, the "5' region (W 5 )", "Gap (Central Region (G))" and "3' Region (W3 ) contains. The gapmer is of the formula W 5 -G-W 3 and can be represented by, in the 5'→3' orientation (where W 5 is on the 5' side and W 3 represents the 3' side).

[0288] The central region (G) is a region containing an extension of consecutive nucleotides (which may include deoxyribonucleosides) capable of recruiting an oligonucleotide to RNaseH (e.g., human RNaseH1, etc.). RNaseH is a cellular enzyme that recognizes double-stranded DNA-RNA and enzymatically cleaves RNA molecules. The central region (G) is adjacent to a 5' region (W 5 ) containing nucleosides with one or more modified sugar sites and a 3' region (W 3 ) containing nucleosides with one or more modified sugar sites. The nucleosides with one or more modified sugar sites located in the 5' region (W 5 ) and the 3' region (W 3 ) enhance the affinity of the oligonucleotide for the target nucleic acid.

[0289] In certain embodiments, the nucleosides with one or more modified sugar sites located in the 5' region (W 5 ) and the 3' region (W 3 ) include, for example, nucleosides modified at the 2' position, nucleosides cross-linked between the 2'-4' positions (nucleosides having bicyclic sugars), etc., and can be independently selected from, for example, 2'-O-MCE nucleosides, LNA nucleosides, etc. The 5' region (W 5 ) and the 3' region (W 3 ) are regions that may contain one or more nucleotides chemically different from the nucleotides of the central region (G), or one or more nucleotides chemically the same.

[0290] In one embodiment, the 3'-most and 5'-most nucleosides of the central region (G) each contain a 2'-deoxyfuranosyl sugar moiety (DNA nucleoside). The position of a nucleoside in the "central region (G)" is counted from the 5' end of the central region. That is, the 5'-most nucleoside of the central region is located at position 1 of the central region (G).

[0291] The antisense oligonucleotide of the present invention, or a sequence of nucleotides thereof, is of formula W 5 -GW 3 It may include a gapmer region represented by W. 5 -GW 3 The total number of nucleosides may be, for example, 7-30, 7-25, 10-25, 15-22, 16-22, 16-20, 16-18, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, etc.

[0292] formula W 5 -GW 3 The central region (G) is the 5' region (W 5 ) and 3' region (W 3 Since each of them is directly adjacent to the other, the 5' region (W 5 ) and the central region (G), or the central region (G) and the 3' region (W 3 No intervening nucleotides are present between them.

[0293] In one embodiment, the antisense oligonucleotide of the present invention is, for example, a nucleoside with 5 to 20 linked nucleosides in the central region (G), and a 5' region (W 5 ) and 3' region (W 3 Each of these may contain 1 to 5 linked nucleosides.

[0294] The gapmer oligonucleotide of the present invention is, for example, of the following formula: [W 5 a ]-[G b]-[W 3 c ] (In the formula, a, b, and c represent the number of nucleotides in each region, where a = 1 to 5, b = 5 to 20, and c = an integer between 1 and 5.)

[0295] Also, although not limited to the following, for example, the following formula: [W 5 1-4 ]-[G 5-20 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 6-20 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 7-20 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 8-20 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 9-20 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 9-19 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 9-18 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 9-17 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 9-16 ]-[W 3 1-4 ] [W 51-4 ]-[G 9-15 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 9-14 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 9-13 ]-[W 3 1-4 ] [W 5 1-4 ]-[G 9-12 ]-[W 3 1-4 ] [W 5 3-5 ]-[G 9-12 ]-[W 3 3-5 ] [W 5 5]-[G 9-12 ]-[W 3 4] [W 5 4]-[G 9-12 ]-[W 3 4] [W 5 4]-[G 9-12 ]-[W 3 3] [W 5 3]-[G 9-12 ]-[W 3 4] [W 5 3]-[G 9-12 ]-[W 3 3], [W 5 3]-[G 10-12 ]-[W 3 3], etc. (In each formula, W 5 G and W 3 The number in the lower right corner represents the number of linked nucleotides in each region.

[0296] In the above formula, the gapmer region W 5 -GW 3The total length is, for example, the length of at least 7, for example, 7-30, 7-25, 10-25, 10-22, 15-22, 16-22, 16-20, 16-18, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked nucleotides.

[0297] <Central area (G)> The central region (G) may include, but is not limited to, a central region (G) with a length of at least 5 consecutive nucleosides, for example, 7 to 20 consecutive nucleosides, 8 to 19 consecutive nucleosides, 9 to 18 consecutive nucleosides, 10 to 17 consecutive nucleotides, 11 to 16 consecutive nucleotides, 12 to 15 consecutive nucleotides, or 13 to 14 consecutive nucleotides. Furthermore, the nucleosides in the central region (G) may include consecutive deoxyribonucleosides.

[0298] The central region (G) may, in one embodiment, be, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive deoxyribonucleosides. At least one cytosine residue within the central region (G) may be methylated at position 5, and such residues may be denoted herein as 5(x). All cytosine residues within the central region (G) may be methylated at position 5.

[0299] In one embodiment, the consecutive nucleosides in the central region (G) may have at least one phosphorothioate bond between each nucleoside. For example, it may consist of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive deoxyribonucleosides with phosphorothioate bonds. In one embodiment, all of the nucleoside bonds within the central region (G) may be phosphorothioate bonds. In one embodiment, 1 to 5 (preferably 1 to 3, 1 to 2, and 1) of the nucleoside bonds within the central region (G) may be phosphodiester bonds, and all of the remaining nucleoside bonds within the central region (G) may be phosphorothioate bonds.

[0300] Gapmers have a deoxyribonucleoside in their central region (G), but sometimes a modified nucleoside capable of recruiting RNaseH is used within the central region (G).

[0301] <5' area (W 5 )·3' region (W 3 )> 5' region (W 5 ) is located immediately next to the 5' deoxyribonucleoside in the central region (G). 5' region (W 5 The most 3' nucleoside of the ) may be a nucleoside with a modified sugar moiety, such as an LNA nucleoside or a 2'-O-MCE nucleoside.

[0302] 3' region (W 3 ) is located immediately next to the 3' deoxyribonucleoside in the central region (G). 3' region (W 3 The 5' nucleoside of the ) may be a nucleoside with a modified sugar moiety, such as an LNA nucleoside or a 2'-O-MCE nucleoside.

[0303] 5' region (W 5 ) and 3' region (W 3) One or more cytosine residues within the region may have at least one methylated at position 5. 5' region (W 5 ) and 3' region (W 3 The 5th position of all cytosine residues within the parentheses may be methylated.

[0304] In one embodiment, the 5' region (W 5 In one embodiment, the consecutive nucleosides may have at least one phosphorothioate bond between each nucleoside. 5 In some embodiments, all of the nucleoside bonds within the ) can become phosphorothioate bonds. 5 ) 1 to 3 (preferably 1 to 2, 1) nucleoside-internucleoside bonds are phosphodiester bonds, and the 5' region (W 5 In some cases, all remaining internucleoside bonds within the ) may be phosphorothioate bonds. In this case, the phosphodiester bond is located on the central region (G) side, and the phosphorothioate bond is located on the 5' region (W). 5 It is preferable to position it on the 5' side within the )

[0305] In one embodiment, the 3' region (W 3 In one embodiment, the consecutive nucleosides may have at least one phosphorothioate bond between each nucleoside. 3 In some embodiments, all of the nucleoside bonds within the ) can become phosphorothioate bonds. 3 ) 1 to 3 (preferably 1 to 2 or 1) nucleoside interbonds are phosphodiester bonds, and the 3' region (W 3 In some cases, all of the remaining internucleoside bonds within the ) may be phosphorothioate bonds. In this case, the phosphodiester bond is located on the central region (G) side, and the phosphorothioate bond is located on the 3' region (W). 3 It is preferable to position it on the 3' side within the )

[0306] In one embodiment, the present invention provides a oligonucleotide, The central region (G) consists of 5 to 20 linked nucleosides. A 5' region (W) consisting of 1 to 5 linked nucleosides 5 ), and A 3' region (W) consisting of 1 to 5 linked nucleosides 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0307] In one embodiment, the present invention provides a oligonucleotide, The central region (G) consists of 5 to 15 linked nucleosides. The 5' region (W) consists of 3 to 5 linked nucleosides. 5 ), and The 3' region (W) consists of 3 to 5 linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0308] In one embodiment, the present invention provides a oligonucleotide, A central region (G) consisting of 7 to 12 linked nucleosides, The 5' region (W) consists of 3 to 5 linked nucleosides. 5 ), and The 3' region (W) consists of 3 to 5 linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0309] In one embodiment, the present invention provides a oligonucleotide, A central region (G) consisting of 9-10 linked nucleosides, The 5' region (W) consists of 3 to 5 linked nucleosides. 5 ), and The 3' region (W) consists of 3 to 5 linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0310] In one embodiment, the 5' region (W 5 ) and 3' region (W 3 The nucleoside-modified sugars may be selected from LNA nucleosides, 2'-O-MCE nucleosides, and nucleosides listed below as bicyclic sugars.

[0311] In one embodiment, the present invention provides a oligonucleotide, A central region (G) consisting of 9-10 linked nucleosides, The 5' region (W) consists of 3 to 5 linked nucleosides. 5 ), and The 3' region (W) consists of 3 to 5 linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 The nucleosides in each region (G) comprise LNA or 2'-O-MCE, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing antisense oligonucleotides or pharmaceutically acceptable salts thereof or solvates thereof.

[0312] In one embodiment, the present invention provides a oligonucleotide, The central region (G) consists of nine linked nucleosides. The 5' region (W) consists of three linked nucleosides. 5 ), and The 3' region (W) consists of four linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0313] In one embodiment, the present invention provides a oligonucleotide, The central region (G) consists of nine linked nucleosides. The 5' region (W) consists of four linked nucleosides.5 ), and The 3' region (W) consists of three linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0314] In one embodiment, the present invention provides a oligonucleotide, The central region (G) consists of 10 linked nucleosides. The 5' region (W) consists of three linked nucleosides. 5 ), and The 3' region (W) consists of three linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0315] In one embodiment, the present invention provides a oligonucleotide, The central region (G) consists of nine linked nucleosides. The 5' region (W) consists of five linked nucleosides. 5 ), and The 3' region (W) consists of four linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0316] In one embodiment, the present invention provides a oligonucleotide, The central region (G) consists of nine linked nucleosides. The 5' region (W) consists of four linked nucleosides. 5 ), and The 3' region (W) consists of 5 linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0317] In one embodiment, the present invention provides a oligonucleotide, The central region (G) consists of 10 linked nucleosides. The 5' region (W) consists of four linked nucleosides. 5 ), and The 3' region (W) consists of four linked nucleosides. 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3Each nucleoside comprises at least one modified sugar, and the nucleoside in the central region (G) optionally comprises a deoxyribonucleoside, providing an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0318] In one embodiment, the 5' region (W 5 ) and 3' region (W 3 Antisense oligonucleotides, pharmaceutically acceptable salts thereof, or solvates thereof are provided, in which each nucleoside of the given nucleotide is a modified sugar.

[0319] In one embodiment, the 5' region (W 5 ) and 3' region (W 3 Examples of modified sugars of the nucleoside include LNA, 2'-O-MCE, and other modified sugars.

[0320] In one embodiment, the 5' region (W 5 The modified sugar at the 5' end of ) is 2'-O-MCE, and the 3' region (W 5 The modified sugar at the 3' end of ) is 2'-O-MCE.

[0321] In one embodiment, the 5' region (W 5 The arrangement of the modified sugar in the ) (5'→3' orientation) is selected from the group consisting of VLL, VVL, VLV, LLL, LVL, LLV, VLLV, VLVL, VLLL, VVLL and VVLLV, and the 3' region (W 3 The arrangement of the modified sugar in (5'→3' orientation) is selected from the group consisting of LLV, LVV, VLV, LLL, LVL, VLL, VLLV, LVLV, LLLV, LLVV, and VLLVV, where the left side is the 5' side and the right side is the 3' side, V is a non-bicyclic modified sugar (preferably 2'-O-MCE), and L is a bicyclic sugar (preferably LNA).

[0322] In one embodiment, the 5' region (W 5The arrangement of the modified sugar in (5'→3' orientation) is selected from the group consisting of VLL, LLL and VLLV, and the 3' region (W 3 The arrangement of the modified sugar in (5'→3' orientation) is LLV, where the left side is the 5' side and the right side is the 3' side, V is a non-bicyclic modified sugar (preferably 2'-O-MCE), and L is a bicyclic sugar (preferably LNA).

[0323] In one embodiment, one of the nucleosides at the 3' end and / or 5' end of the nucleoside in the central region (G) may be a deoxyribonucleoside.

[0324] In one embodiment, each nucleoside in the central region (G) may be selected from deoxyribonucleosides.

[0325] In one embodiment, the nucleoside in the central region (G) may contain at least one modified nucleic acid base (e.g., 5-methylcytosine, etc.).

[0326] In one embodiment, the central region (G) and the 5' region (W 5 The bond between the two is selected from a phosphodiester bond or a modified phosphodiester bond, for example, a phosphodiester bond or a phosphorothioate bond, preferably a phosphorothioate bond. In one embodiment, the central region (G) and the 3' region (W 3 The bond between the two is selected from a phosphodiester bond or a modified phosphodiester bond, for example, a phosphodiester bond or a phosphorothioate bond, preferably a phosphorothioate bond.

[0327] The complementarity of the nucleic acid bases of the IL-11 nucleic acid of sequence number 1 or 2 of the antisense oligonucleotide in the above embodiment, the nucleic acid base sequence and the number of nucleic acid bases it may contain, the modified nucleoside, or the inhibition rate of IL-11 or IL-11 mRNA expression may be the same as described above.

[0328] <Area W 5A and region W 3A > The oligonucleotide of the present invention is a sequence of oligonucleotides complementary to the target nucleic acid, for example, the above formula W 5 -GW 3 Contains oligonucleotides represented by . Also, the 5' region (W 5 ) and / or 3' region (W 3 ) may further contain additional 5' and / or 3' nucleosides. The additional 5' and / or 3' nucleosides are in "region W 5A ”, “Area W 3A This is expressed as follows: The additional 5' and / or 3' nucleosides may or may not be perfectly complementary to the target nucleic acid.

[0329] Area W 5A and / or region W 3A It can be used to link functional molecules to a continuous nucleotide sequence, such as a gapmer. When used to link a continuous nucleotide sequence to a functional molecule, the region W 5A and / or region W 3A It plays the role of a linker that can be decomposed under physiological conditions.

[0330] Area W 5A and region W 3A These are, respectively, the 5' region (W 5 ) the 5' end, or the 3' region (W 3 It can be attached to the 3' end of ) for example, W 5A -W 5 -GW 3 , W 5 -GW 3 -W 3A , or W 5A -W 5 -GW 3 -W 3A It can be expressed by the following equation. In the above equation, W 5 -GW 3 This is the gapmer portion of the oligonucleotide, region W.5A or region W 3A These constitute separate parts of the oligonucleotide.

[0331] Area W 5A and region W 3A Each of these may independently contain, for example, 1 to 5 consecutive nucleotides, and may be complementary or non-complementary to the target nucleic acid. 5' region (W 5 ) or 3' region (W 3 The nucleotides adjacent to ) may be, for example, DNA, RNA, their nucleic acid bases, sugars, and / or nucleotides with modified nucleoside bonds.

[0332] The oligonucleotide of the present invention is a sequence of oligonucleotides complementary to the target nucleic acid, for example, the above formula W 5 -GW 3 It contains oligonucleotides represented by the 5' region (W 5 ) and / or 3' region (W 3 ) in which a further 5' nucleoside (region W) is added via a linker (L) [see "5. Addition of Functional Molecules" for details on the linker]. 5B ) and / or 3' nucleoside (region W 3B ) can include. Region W 5B and / or region W 3B The nucleoside may be perfectly complementary to the target nucleic acid, or it may not be perfectly complementary, and also W 5 -GW 3 It can also be complementary to that.

[0333] Area W 5B and region W 3B These are, respectively, the 5' region (W 5 ) the 5' end, or the 3' region (W 3 ) can be joined via a linker at the 3' end, for example, W 5 -GW 3 -LW 3B , W 5B -LW 5 -GW 3 , or W5B -LW 5 -GW 3 -LW 3B It can be expressed by the following equation (where L may be the same or different):

[0334] In one embodiment, region W 5B or region W 3B Each of these can independently contain, for example, 1 to 30 consecutive nucleotides, and also region W 5 -GW 3 It is possible to design it to be completely or substantially complementary to it, and in designing it, one can refer to International Publication No. 2017 / 131124, International Publication No. 2018 / 143475, International Publication No. 2019 / 022196, etc. In one embodiment, region W 5B or region W 3B is region W 5 -GW 3 It can contain the same or a similar number of nucleosides; for example, the number of nucleosides may be 7-30, 15-22, or 16-18. Region W 5B or region W 3B Each nucleoside can be independently selected from ribonucleosides, deoxyribonucleosides, bicyclic nucleosides, and nucleosides having a non-bicyclic modified sugar, for example, independently selected from ribonucleosides. As for nucleoside modifications, modifications used for the gapmer portion mentioned above, or modifications described later, can be appropriately selected and used. Region W 5B or region W 3B The nucleoside bond is independently selected from a phosphodiester bond or a modified phosphodiester bond, for example, independently selected from a phosphodiester bond and a phosphorothioate bond.

[0335] In one embodiment, region W 5 -GW 3 Completely complementary to or The region W is designed to be substantially complementary. 5B or region W 3BThis is done without a linker in region W 5 -GW 3 It may form a double-stranded complex with it.

[0336] In one embodiment of the present invention, an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, is provided, comprising a modified oligonucleotide having the chemical structure shown in the table below. [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18]

[0337] In the table, "(L)" represents an LNA nucleoside, "(V)" represents a 2'-O-MCE nucleoside, lowercase letters represent deoxyribonucleosides, uppercase letters (except for "L" in (L) and "V" in (V)) represent ribonucleosides, "^" represents a phosphorothioate bond, "5(x)" indicates that the nucleic acid base of the deoxyribonucleoside is 5-methylcytosine, and "5" in "5(V)" and "5(L)" indicates that the nucleic acid base of the nucleoside is 5-methylcytosine. In the notation of chemical structures, when "^" is not indicated between two adjacent nucleosides, the internucleoside bond between those two nucleosides is a phosphodiester bond.

[0338] One embodiment of the present invention, the following formula: [ka] The compound represented by Sequence ID No. 260, a pharmaceutically acceptable salt thereof, or a solvate thereof is provided.

[0339] One embodiment of the present invention, the following formula: [ka] The compound represented by Sequence ID No. 263, a pharmaceutically acceptable salt thereof, or a solvate thereof is provided.

[0340] One embodiment of the present invention, the following formula: [ka] The compound represented by Sequence ID No. 264, a pharmaceutically acceptable salt thereof, or a solvate thereof is provided.

[0341] One embodiment of the present invention, the following formula: [ka] The compound represented by Sequence ID No. 210, a pharmaceutically acceptable salt thereof, or a solvate thereof is provided.

[0342] One embodiment of the present invention, the following formula: [ka] The compound represented by Sequence ID No. 211, a pharmaceutically acceptable salt thereof, or a solvate thereof is provided.

[0343] One embodiment of the present invention, the following formula: [ka] The compound represented by Sequence ID No. 213, a pharmaceutically acceptable salt thereof, or a solvate thereof is provided.

[0344] One embodiment of the present invention, the following formula: [ka] The compound represented by Sequence ID No. 349, a pharmaceutically acceptable salt thereof, or a solvate thereof is provided.

[0345] 3. Qualification In one embodiment, the antisense oligonucleotide of the present invention can be chemically modified to have inhibitory activity against the expression of IL-11 or IL-11 mRNA, high binding affinity to IL-11 nucleic acid, resistance to degradation by nucleases in vivo, etc.

[0346] A "modified nucleotide" refers to a nucleotide having a modified sugar moiety, a modified nucleoside bond, and / or a modified nucleic acid base. A "modified oligonucleotide" refers to an oligonucleotide containing at least one modified nucleoside bond, a modified sugar, and / or a modified nucleic acid base. A "modified sugar" refers to substitution, conversion, etc., from the natural sugar moiety. By modifying the sugar moiety into a modified nucleoside, it may be possible to obtain, for example, high stability against nucleases, high binding affinity to target nucleic acids, and other biologically beneficial properties.

[0347] The nucleic acid base portion of a nucleoside is usually a heterocyclic base portion. A nucleotide is a nucleoside that further contains a phosphate group covalently bonded to the sugar portion of the nucleoside. In such nucleosides containing pentofuranosyl sugars, the phosphate group can be bonded to the 2', 3', or 5' hydroxyl portion of the sugar. Oligonucleotides are formed through the covalent bonds of adjacent nucleosides, forming linear polymer oligonucleotides. Within the oligonucleotide structure, the phosphate group usually forms internucleoside bonds of the oligonucleotide. "Internucleoside bond" refers to a chemical bond between nucleosides.

[0348] In one embodiment, the antisense oligonucleotide of the present invention may be a single-stranded oligonucleotide comprising a modified oligonucleotide, for example, an oligonucleotide in which at least one of the phosphate bond moieties between each nucleoside, the sugar moiety of each nucleoside, or the nucleic acid base moiety is modified. The modified oligonucleotide may have desirable properties compared to the natural form of oligonucleotide, such as high intracellular uptake, high affinity for nucleic acid targets, high stability in the presence of nucleases, or high inhibitory activity.

[0349] The natural nucleoside bond between RNA and DNA is a 3' to 5' phosphodiester bond. Antisense oligonucleotides having one or more modified nucleoside bonds (non-natural nucleoside bonds) may be used to obtain desirable properties such as high intracellular uptake, high affinity for target nucleic acids, and high stability in the presence of nucleases.

[0350] The antisense oligonucleotides of the present invention may have at least one phosphate bond between each nucleoside of the nucleotide constituting the oligonucleotide being a modified internucleoside bond. "Modified internucleoside bond" means substitution or conversion from a natural internucleoside bond (i.e., a phosphodiester internucleoside bond).

[0351] Modified nucleoside bonds are not particularly limited, but can be selected from modified bonds such as phosphorothioate bonds, phosphorodithioate bonds, phosphotriester bonds, alkylphosphonate bonds, aminoalkylphosphotriester bonds, alkylenephosphonate bonds, phosphine bonds, phosphoramidate bonds, aminoalkylphosphorimidate bonds, thiophosphorimidate bonds, thionoalkylphosphonate bonds, thionoalkylphosphotriester bonds, thiophosphate bonds, selenophosphate bonds, boranophosphate bonds, etc.; for example, phosphorothioate bonds, phosphorodithioate bonds, alkylphosphonate bonds, phosphoramidate bonds, boranophosphate bonds, mesylphosphorimidate bonds (e.g., Nucleic Acids Modified bonds can be selected from, for example, Research, 49(16), pp. 9026-9041, phosphoryl(1,3-dimethylimidazolidined-2-imine) amide bonds (see, for example, Nucleic Acids Research, 50(10), pp. 5443-5466).

[0352] In one embodiment, the internucleoside bonds of the antisense oligonucleotide of the present invention may consist of, for example, one, more, or all phosphorothioate bonds. In another embodiment, the internucleoside bonds of the antisense oligonucleotide of the present invention may consist of, for example, all phosphorothioate bonds. In yet another embodiment, the oligonucleotide having modified internucleoside bonds may include, for example, internucleoside bonds that do not contain a phosphorus atom. Methods for forming phosphorus-containing or phosphorus-free bonds are well known from known literature and other sources.

[0353] In one embodiment, the antisense oligonucleotide of the present invention may contain one or more nucleosides with modified sugar moieties.

[0354] In one embodiment, the antisense oligonucleotide of the present invention may contain at least one chemically modified ribofuranose ring in the sugar portion of the nucleoside constituting the oligonucleotide. The chemically modified ribofuranose ring is not particularly limited, but examples include a ribofuranose ring modified at the 5', 2', etc. (also called a non-bicyclic modified sugar), a ribofuranose ring bridged with a non-geminal ring atom (also called a bicyclic sugar), a ring in which the oxygen atom of the ribofuranose ring is substituted with a sulfur atom, N-(protecting group), NH, N-alkyl, CH2, CH(alkyl), C(alkyl)2, etc., and combinations thereof. For example, "modified at the 2' position" means that the 2' position of the ribofuranose ring is substituted with a substituent other than a hydrogen atom or a hydroxyl group. "Modified at the 5' position" means that the hydrogen atom at the 5' position of the ribofuranose ring is substituted with a substituent other than a hydrogen atom. A "bicyclic sugar" (also called a "bicyclic bridged sugar") refers to a furanose ring modified by a bridge of two or three atoms (for example, the ring structure described below). A bicyclic sugar means a sugar having at least two rings, and may have two or more rings, or even three or more rings.

[0355] The protecting group for the aforementioned N-(protecting group) can be appropriately selected from the nitrogen atom protecting groups listed in textbooks such as Greene et al.'s "Protective Groups in Organic Synthesis, 5th Edition, 2014, John Wiley & Sons."

[0356] The bicyclic sugars are not particularly limited, but examples include nucleosides (also called bicyclic nucleosides) that are crosslinked between the 4' and 2' positions of the ribofuranose ring. In one embodiment, the antisense oligonucleotide of the present invention contains at least one bicyclic sugar including a crosslink from the 4' to 2' position of the ribofuranose ring. The aforementioned bicyclic sugars are not particularly limited, but examples include 4'-CH2-O-2':(LNA nucleoside, formula (MF-1) below), 4'-(CH2)2-O-2':(ENA nucleoside, formula (MF-2) below), 4'-CH(CH3)-O-2':(cEt nucleoside, formula (MF-3) below), and 4'-C(=O)-N(CH3)-2':(AmNA nucleoside, formula (MF-1) below). Notation (MF-4), 4'-CH2-N(C(=NH)(NH2))-2':(GuNA nucleoside, formula below (MF-5)), 4'-CH2-N(C(=NH)(NHtBu)-2':(GuNA(t-Bu) nucleoside, formula below (MF-6)), 4'-C(CH3)2-O-2':(formula below (MF-7)), 4'-CH(OH2CH3)-O-2':(formula below (MF -8)), 4'-CH2-CH(CH3)-2': (Equation below (MF-9)), 4'-CH2-C(=CH2)-2': (Equation below (MF-10)), 4'-CH2-CH2-CH2-2': (Equation below (MF-11)), 4'-CH2-NH-O-2': (Equation below (MF-12a)), 4'-CH2-N(CH3)-O-2': (Equation below (MF-12b)), 4'-CH2-N Examples of bicyclic sugars include H-2' (see formula (MF-13a) below), 4'-CH2-N(CH3)-2' (see formula (MF-13b) below), 4'-CH2-N(OCH3)-2' (see formula (MF-13c) below), 4'-CH2-O-NH-2' (see formula (MF-14a) below), 4'-CH2-ON(CH3)-2' (see formula (MF-14b) below), 4'-CH2-S-2' (see formula (MF-15) below), and 4'-C(-CH2CH2-)-O-2' (scpBNA nucleoside, see formula (MF-16) below). [ka] [ka]

[0357] In one embodiment, the bicyclic nucleoside is at least one selected from the group consisting of LNA nucleoside, ENA nucleoside, cEt nucleoside, GuNA nucleoside, GuNA(t-Bu) nucleoside, and scpBNA nucleoside. In one embodiment, the bicyclic nucleoside is at least one selected from the group consisting of LNA nucleoside, ENA nucleoside, cEt nucleoside, GuNA(t-Bu) nucleoside, and scpBNA nucleoside. In one embodiment, the bicyclic nucleoside is preferably an LNA nucleoside.

[0358] In one embodiment, the bicyclic sugar is at least one selected from the group consisting of LNA, ENA, cEt, GuNA, GuNA(t-Bu), and scpBNA. In one embodiment, the bicyclic sugar is at least one selected from the group consisting of LNA, ENA, cEt, GuNA(t-Bu), and scpBNA. In one embodiment, the bicyclic sugar is preferably LNA.

[0359] In one embodiment, the antisense oligonucleotide of the present invention may include, for example, a non-bicyclic modified sugar such as a nucleoside modified at the 2' position or a nucleoside modified at the 5' position. A "non-bicyclic modified sugar" (also called a "non-crosslinked modified sugar") means a modified ribofuranose ring that does not fall under the category of a "bicyclic sugar." Therefore, a "non-bicyclic modified sugar" may also be a sugar having two rings, and thus also includes the 5'-CP described later.

[0360] The group at the 2' position of a nucleoside modified at the 2' position is not particularly limited, but for example, 2'-OR 1 , 2'-R 1 , 2'-R 2 Ure 1 , 2'-SH, 2'-SR 1 , 2'-NH2, 2'-NHR 1 , 2'-NR 12, 2'-N3, 2'-CN, 2'-F, 2'-Cl, 2'-Br, 2'-I, 2'-R 2 C(O)XR 3 (In each group, R 1 R is alkyl or aryl; 2 is an alkylene; X is an oxygen atom, NH or NR 1 And; R 3 Examples include (where is alkyl).

[0361] In one embodiment, the group at the 2' position is at least one group selected from the group consisting of 2'-CH2CH2C(O)OCH3, 2'-CH2CH2C(O)OCH2CF3, 2'-CH2CH2C(O)NHCH3:(2'-O-MCE nucleoside), and 2'-CH2CH2C(O)N(CH3)2. In one embodiment, the group at the 2' position is preferably 2'-CH2CH2C(O)NHCH3:(2'-O-MCE nucleoside).

[0362] In this specification, "alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms ("C 1-6 This means "alkyl." Specifically, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. The alkyl group may be substituted with 1 to 3 atoms, such as halogen atoms, alkoxy, cyano, or nitro.

[0363] In this specification, "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0364] In this specification, "alkoxy" means a linear or branched alkyl group having 1 to 6 carbon atoms substituted with one oxygen atom, and "(C 1-6It is represented as "alkyl)-O-". Specifically, examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, and isohexyloxy, and preferably an alkoxy ((C) having 1 to 3 carbon atoms. 1-3 It is alkyl)-O-).

[0365] In this specification, "alkoxy" means an aryl compound having 6 to 10 carbon atoms. Specifically, examples include phenyl, α-naphthyl, and β-naphthyl, preferably phenyl. The aryl compound may be substituted with 1 to 3 atoms, such as halogen atoms, alkyl, alkoxy, cyano, or nitro.

[0366] In this specification, "alkylene" refers to linear or branched alkylene (-(CH2)) with 1 to 6 carbon atoms. n - (means n=1~6). -(CH2) n -The hydrogen atom is, for example, C 1-3 It may be substituted with 1 to 3 alkyl groups, etc. Specifically, examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 2-(ethyl)trimethylene, and 1-(methyl)tetramethylene.

[0367] The group at the 5' position of the nucleoside modified at the 5' position is not particularly limited, but for example, the two hydrogen atoms of the methylene (-CH2-) at the 5' position are substituted, as shown in the formula 5'-CP(where the substituent at the 2' position (R CP Examples of modifications include (see above for the description of "nucleosides with modified 2' position"), etc. [ka]

[0368] The nucleic acid bases of the nucleotides that make up oligonucleotides are not particularly limited, but for example, adenine (A), guanine (G), thymine (T), cytosine (C), uracil (U), hypoxanthine, and modified nucleic acid bases thereof can be used. The aforementioned "modified nucleic acid bases" are not particularly limited, but examples include pseudouracil, 3-methyluracil, dihydrouracil, 5-alkylcytosine (e.g., 5-methylcytosine), 5-alkyluracil (e.g., 5-ethyluracil), 5-halouracil (5-bromouracil), 6-azapyrimidine, 6-alkylpyrimidine (6-methyluracil), 2-thiouracil, 4-thiouracil, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5'-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluracil, 1-methyladenine, 1-methylhypoxanthine, 2,2-dimethylguanine, 3-methylcytosine, 2-methyladenine, 2-methylguanine, N 6 -Methyladenine, 7-methylguanine, 5-methoxyaminomethyl-2-thiouracil, 5-methylaminomethyluracil, 5-methylcarbonylmethyluracil, 5-methyloxyuracil, 5-methyl-2-thiouracil, 2-methylthio-N 6 Examples include isopentenyl adenine, uracil-5-oxyacetic acid, 2-thiocytosine, purine, 2,6-diaminopurine, 2-aminopurine, isoguanine, indole, imidazole, xanthine, etc.; preferably 5-methylcytosine. The nucleic acid base is preferably selected from adenine (A), guanine (G), thymine (T), cytosine (C), uracil (U), and 5-methylcytosine.

[0369] By using modified nucleic acid bases in oligonucleotides, it may be possible to improve the stability of antisense oligonucleotides, for example.

[0370] 4. Salts and solvates The antisense oligonucleotides of the present invention may form salts. Such salts are not particularly limited as long as they are pharmaceutically acceptable, but include, for example, alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, and N,N' Examples include organic amine salts such as dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt; hydrohalides such as hydrofluoric acid, hydrochloride, hydrobromide, and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates, and phosphates; lower alkanesulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; arylsulfonates such as benzenesulfonates and p-toluenesulfonates; organic salts such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, and maleates; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, and aspartates. These salts can be produced by known methods.

[0371] The antisense oligonucleotides of the present invention, or salts thereof, may exist in non-solvated or solvated forms. In this specification, “solvate” means a molecular complex comprising the compound of the present invention and one or more pharmaceutically acceptable solvent molecules (e.g., water, ethanol, etc.). When the solvent molecule is water, it is specifically referred to as “hydrate.” These solvates can be prepared by known methods.

[0372] The description of the present invention relating to antisense oligonucleotides may include descriptions relating to salts of antisense oligonucleotides, solvates of antisense oligonucleotides, and solvates of salts of antisense oligonucleotides.

[0373] 5. Addition of functional molecules Antisense oligonucleotides can also be bound with any functional molecule to enhance their activity, intracellular distribution, intracellular uptake, delivery to specific organs (target sites), etc. The functional molecule may be directly bound to the 3' oxygen atom of the 3' terminal nucleotide of the antisense oligonucleotide, or to the 5' oxygen atom of the 5' terminal nucleotide, or it may be bound to the aforementioned site of the antisense oligonucleotide via a binding group (e.g., a degradable group, a non-degradable group, etc.), or via a binding group and an optional linker.

[0374] Functional molecules are not particularly limited, but their binding imparts a desired function to the antisense oligonucleotide. Desired functions include delivery to target sites (various organs, tissues, cells, etc.), labeling, and purification.

[0375] Functional molecules are not particularly limited, but include a wide variety of molecules such as lipids (e.g., tocopherol, cholesterol), proteins, peptides, antibodies, and glycans (e.g., glucose, sucrose). Molecules that confer labeling functions are not particularly limited, but include fluorescent proteins and luciferases. Molecules that confer purification functions are not particularly limited, but include biotin, avidin, His-tagged peptides, GST-tagged peptides, and FLAG-tagged peptides.

[0376] Oligonucleotides can be linked to a linker via a physiologically degradable group (e.g., phosphate, phosphorothioate, amide, etc.) or an indegradable group (e.g., ether, carbamate, or CC (e.g., -CH2-CH2-)). Functional molecules can also be linked to a linker via a physiologically degradable group or an indegradable group.

[0377] For example, an oligonucleotide may be linked to a linker at its 3' end via a phosphate and / or at its 5' end via a phosphorothioate. A degradable group is a group that exists sufficiently stably outside the cell but, upon being taken up into a target cell, is degraded, releasing the two parts to which it is bound (oligonucleotide, linker + functional molecule). Degradable groups are affected by degradation factors under physiological conditions, such as pH, redox potential, or the presence of degradation molecules.

[0378] For example, a functional molecule can be bound to a linker via a degradable / indegradable group, and the linker to which the functional molecule is bound can further be bound to an oligonucleotide via a degradable / indegradable group at its 3' and / or 5' ends.

[0379] The linker that connects the functional molecule to the oligonucleotide only needs to be able to perform the function of the functional molecule as an oligonucleotide molecule. Therefore, any linker that stably connects the functional molecule and the oligonucleotide is acceptable and is not limited. Examples of such linkers include groups derived from oligonucleotides with 2 to 20 nucleotides, groups derived from polypeptides with 2 to 20 amino acids, alkylene groups with 2 to 20 carbon atoms, and alkenylene groups with 2 to 20 carbon atoms.

[0380] For example, if the linker is an alkylene group having 2 to 20 carbon atoms or an alkenylene group having 2 to 20 carbon atoms, the hydrogen atoms of the methylene group (-CH2-) contained in the alkylene group or alkenylene group may be independently substituted with groups such as halogen atoms, hydroxyl groups, protected hydroxyl groups, amino groups, protected amino groups, oxo groups, thioxo groups, etc. Also, the methylene groups contained in the alkylene group or alkenylene group may be independently substituted with -O-, -NH-, -N(R)-(R is C 1-6 Alkyl alkyl groups, halogenated C 1-6 Alkyl alkyl group, C 2-7 They may be substituted with alkanoyl groups, protecting groups for amino and imino groups, etc., -S-, -S(O)-, or -S(O)2-.

[0381] The protecting groups for the protected hydroxyl, amino, and imino groups can be appropriately selected from the nitrogen atom protecting groups listed in textbooks such as Greene et al.'s "Protective Groups in Organic Synthesis, 5th Edition, 2014, John Wiley & Sons."

[0382] Methods for conjugating functional molecules with oligonucleotides can refer to methods well known in the field. For example, after conjugating a functional molecule with a linker by a known method, it is possible to convert it to an amidite using an amiditation reagent or to an H-phosphonate using an H-phosphonate reagent, and then conjugate it with an oligonucleotide.

[0383] 6.IL-11 nucleic acid / target region / sequence Nucleotide sequences encoding human IL-11 include, but are not limited to, the human IL-11 cDNA sequence (Genebank accession number: BC012506.1, GI: 15341754, NM_000641.4) (sequence number 1 in this specification) and the human IL-11 genomic DNA sequence (Genebank accession number: NC_000019.10, REGION: complement(55364382..55371063)) (sequence number 2 in this specification), etc.

[0384] The nucleotide sequences encoding mouse IL-11 include, but are not limited to, the mouse IL-11 cDNA sequence (Genebank accession number: NM_008350.4) (referred to as Sequence ID No. 3 in this specification), etc.

[0385] In one embodiment, for example, the target region may be a region of the IL-11 nucleic acid such as the 3'-UTR, 5'-UTR, exons, introns, exon / intron junctions, coding regions, translation initiation regions, and translation termination regions. Structurally defined regions of the IL-11 nucleic acid can be obtained from sequence databases such as NCBI by accession number. This information is incorporated herein by reference. In one embodiment, the target region may encompass the sequence from the 5' target site of one target segment within the target region to the 3' target site of another target segment within the same target region.

[0386] The antisense oligonucleotide of the present invention is sequenced such that it can hybridize with at least one target region of the target nucleic acid, IL-11 nucleic acid, to obtain a desired effect. In one embodiment, the desired effect is, for example, a decrease in the expression level of IL-11, a decrease in the expression level of IL-11 mRNA, or a decrease in the amount of protein encoded by IL-11 nucleic acid, but is not limited to these.

[0387] The target region may contain one or more target segments. The antisense oligonucleotide hybridizes with at least one target segment within the target region. In some embodiments, the antisense oligonucleotide may or may not hybridize with multiple target segments. In some embodiments, the target segment within the target region may be separated by, for example, about 300 or fewer nucleotides. In some embodiments, the target segment within the target region may consist of, for example, 250-200, 200-150, 150-100, 100-90, 90-80, 80-70, 70-60, 60-50, 50-40, 40-30, 30-20, 20-10, 10 or fewer nucleotides on the target nucleic acid. Alternatively, it may be separated by a number of nucleotides within a range defined by a combination of the upper or lower limits of the above numerical ranges (e.g., 100-10, 50-10, etc.).

[0388] In one embodiment, the target segment preferably consists of 7 to 30 nucleotides, more preferably 10 to 25, 15 to 22, or 16 to 18 nucleotides.

[0389] Appropriate target segments of IL-11 nucleic acid are identified within the 5'-UTR, coding region, 3'-UTR, intron, exon, or exon / intron junction. Target segments containing start or stop codons are also appropriate target segments. Appropriate target segments of IL-11 nucleic acid may specifically exclude certain structurally defined regions, such as start or stop codons.

[0390] Determining the appropriate target segment of IL-11 nucleic acid can be done by comparing the IL-11 nucleic acid sequence with other sequences in the genome. For example, the BLAST algorithm may be used to identify regions of similarity between different nucleic acids. This comparison may also prevent the selection of antisense oligonucleotides that could hybridize nonspecifically with sequences other than the selected IL-11 nucleic acid (i.e., non-target or off-target sequences).

[0391] There may be a change in the activity of the antisense oligonucleotide within the active target region (for example, activity defined by a decrease in IL-11 mRNA expression). In one embodiment, a decrease in IL-11 mRNA expression indicates inhibition or suppression of IL-11 expression. A decrease in IL-11 protein expression indicates inhibition or suppression of IL-11 mRNA expression. For example, improvement, prevention, or treatment of the pathogenesis of diseases involving IL-11 can indicate inhibition or suppression of IL-11 expression.

[0392] 7. Hybrid Formation and Complementarity In one embodiment, the antisense oligonucleotide of the present invention can specifically hybridize with the target nucleic acid, IL-11. The mechanism of hybridization is based on hydrogen bonds between complementary nucleic acid bases of the nucleic acid molecule (e.g., Watson-Crick, Hoogsteen, or reverse Hoogsteen hydrogen bonds). Methods for determining whether a sequence is specifically hybridizable with a target nucleic acid are well known in the art.

[0393] The antisense oligonucleotide and IL-11 nucleic acid of the present invention are complementary to each other if a sufficient number of nucleic acid bases of the antisense oligonucleotide can form hydrogen bonds with the corresponding nucleic acid bases of the IL-11 nucleic acid. As a result, the desired effect is obtained.

[0394] The non-complementary nucleic acid bases between the antisense oligonucleotide of the present invention and the IL-11 nucleic acid are tolerable, provided that the antisense oligonucleotide can specifically hybridize with the IL-11 nucleic acid, and that the antisense oligonucleotide can exert the desired effect. The antisense oligonucleotide of the present invention can hybridize across one or more segments of the IL-11 nucleic acid such that intervening segments or adjacent segments do not participate in the hybridization event (e.g., loop structure, mismatch, or hairpin structure).

[0395] In one embodiment, the antisense oligonucleotide or a particular portion thereof of the present invention is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the IL-11 nucleic acid, its target region, target segment, or particular portion.

[0396] The complementarity (%) between an antisense oligonucleotide and a target nucleic acid region can be calculated using known methods in the art. For example, if 18 of the 20 nucleic acid bases in an antisense oligonucleotide are complementary to the target region of the target nucleic acid and can specifically form a hybrid, then the antisense oligonucleotide will have 90% complementarity. In this example, the remaining non-complementary nucleic acid bases may cluster with complementary nucleic acid bases or be scattered, and do not need to be contiguous with each other or with complementary nucleic acid bases.

[0397] In one embodiment, the antisense oligonucleotide or a specific portion thereof of the present invention may be perfectly complementary (i.e., 100% complementary) to the IL-11 nucleic acid or a specific portion thereof. "Perfectly complementary (100% complementary)" means that each nucleic acid base of the antisense oligonucleotide can form a complete base pair with the corresponding nucleic acid base of the target nucleic acid.

[0398] It is possible that each nucleic acid base of the first nucleic acid has a complementary nucleic acid base in the second nucleic acid. If the first nucleic acid is an antisense oligonucleotide and the target nucleic acid is the second nucleic acid, for example, an antisense oligonucleotide having 20 nucleic acid bases will be perfectly complementary to a target sequence of any length of 20 or more nucleic acid bases (e.g., 200 bases), as long as there is a corresponding 20 nucleic acid base portion in the target nucleic acid that is perfectly complementary to the antisense oligonucleotide.

[0399] Non-complementary nucleic acid bases may be located at the 5' or 3' end of an antisense oligonucleotide, or they may be located within the antisense oligonucleotide. If two or more non-complementary nucleic acid bases are present, they may be contiguous or discontinuous. In some embodiments, non-complementary nucleic acid bases may be located within gap segments or wing segments of the antisense oligonucleotide.

[0400] In one embodiment, the antisense oligonucleotide of the present invention, to which 7 to 30 nucleosides are bound, may also contain, for example, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer non-complementary nucleic acid bases (mismatch bases) relative to the target nucleic acid or a specific portion thereof.

[0401] "Nucleic acid base complementarity" refers to nucleic acid bases that can form base pairs with other nucleic acid bases. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In some embodiments, complementary nucleic acid bases refer to nucleic acid bases of an antisense compound that can form base pairs with the nucleic acid bases of the target nucleic acid. For example, if a nucleic acid base at a certain position in an antisense compound can form a hydrogen bond with a nucleic acid base at a certain position in the target nucleic acid, the positions of the hydrogen bonds between the oligonucleotide and the target nucleic acid are considered complementary in terms of the nucleic acid base pair.

[0402] 8. Method for producing antisense oligonucleotides The antisense oligonucleotides of the present invention can be prepared by those skilled in the art by appropriately selecting known methods. For example, those skilled in the art can use the phosphoramidite method or the H-phosphonate method and synthesize them using commercially available automated nucleic acid synthesizers (such as those manufactured by Applied Biosystems, Beckman, Gene Design, and Nippon Techno Service). Those skilled in the art can refer to known literature such as, for example, Nucleic Acids Research, vol 12, number 11, pp 4539-4557, 1984; Tetrahedron Letters, Vol 1.22, No.20, pp 1859-1862, 1981; International Publication Nos. 88 / 00201, 91 / 10671, 99 / 14226, 00 / 47599, 03 / 095467, 2005 / 021570, 2007 / 102581; U.S. Patent No. 5214135, U.S. Patent No. 6770748; Japanese Patent No. 3420984, Japanese Patent No. 4012579. Furthermore, synthesis can also be carried out by enzymatic reactions. Examples of the enzymes mentioned above include, but are not limited to, polymerases, ligases, and restriction enzymes. The method for producing antisense oligonucleotides according to this embodiment may include a step of extending the nucleoside chain at the 3' or 5' end.

[0403] Many methods for linking functional molecules with antisense oligonucleotides are well known in this field, and can be found, for example, in European Journal of Pharmaceutics and Biopharmaceutics, 2016, 107, pp 321-340, Advanced Drug Delivery Reviews, 2016, 104, pp 78-92, Expert Opinion on Drug Delivery, 2014, 11, pp 791-822. For example, after linking a functional molecule with a linker by a known method, it can be converted to an amidite using an amiditation reagent, or to an H-phosphonate using an H-phosphonate reagent, and then linked to an oligonucleotide.

[0404] The crude antisense oligonucleotide product obtained can be purified by reverse-phase column chromatography or the like to obtain the antisense oligonucleotide.

[0405] 9. Diseases involving IL-11 IL-11 is expressed in cells, tissues, organs, etc., in the body, and a variety of diseases can develop due to its physiological effects. Therefore, if the expression of IL-11 or IL-11 mRNA can be inhibited at target sites such as cells, tissues, organs, etc. in the body by administering the IL-11 antisense oligonucleotide of the present invention, it may be possible to prevent, improve, and / or treat diseases involving IL-11.

[0406] Diseases involving IL-11 are not limited to those mentioned above, but include, for example, fibrotic diseases (e.g., idiopathic pulmonary fibrosis, interstitial lung disease with progressive fibrosis (PF-ILD), pulmonary arterial hypertension, Alport syndrome, tubulointerstitial nephritis, glomerulostenosis, hepatic fibrosis (e.g., non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), etc.), systemic scleroderma, chronic pancreatitis, and cardiovascular fibrosis. Diseases that may be contributing to the condition include gastrointestinal polyposis (e.g., Peutz-Jeghers syndrome, familial adenomatous polyposis, etc.), inflammatory diseases (e.g., asthma, chronic obstructive pulmonary disease, pulmonary arterial hypertension, ulcerative colitis, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, etc.), cancer (e.g., liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, breast cancer, etc.), and other diseases (e.g., abnormal uterine bleeding, preeclampsia, etc.) (see Tables 19-21). [Table 19] [Table 20] [Table 21]

[0407] "Fibrotic diseases" are diseases that involve tissue fibrosis occurring in various tissues, in which connective tissue components are excessively deposited in organs such as the skin, lungs, liver, and kidneys, affecting their function and leading to organ dysfunction. Examples include idiopathic pulmonary fibrosis (IPF), interstitial lung disease with progressive fibrosis (PF-ILD), pulmonary arterial hypertension, Alport syndrome, glomerulofibrosis, tubulointerstitial nephritis, hepatic fibrosis (NASH, NAFLD, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), etc.), systemic scleroderma, chronic pancreatitis, and diseases involving cardiovascular fibrosis.

[0408] IL-11 is a cytokine belonging to the IL-6 family and is produced in fibrotic and epithelial cells. It is known to be secreted by fibroblasts in response to fibrosis-promoting stimuli such as transforming growth factor-β (TGF-β) and to influence fibrosis.

[0409] Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease that causes progressive pulmonary fibrosis of unknown origin and is designated as a rare disease in Japan. Most cases develop after the age of 50, leading to irreversible fibrosis of the lungs, a decline in respiratory function, and ultimately death. The disease generally progresses progressively, with a median survival time of approximately three years from diagnosis. The incidence is estimated at around 10 cases per 100,000 people, and the number of patients in Japan is estimated to be around 10,000-something. Currently, there are few effective treatments for IPF, and treatment primarily involves drug therapy (e.g., anti-inflammatory drugs, immunosuppressants, antioxidants, antifibrotic agents (e.g., pirfenidone and nintedanib)) to suppress progression. If respiratory function declines significantly and hypoxia develops, home oxygen therapy is used. It has been reported that IL-11 expression is elevated in the lungs of patients with this disease, and that pulmonary fibrosis occurs in mice due to IL-11 overexpression. Furthermore, it has been reported that fibrosis is improved in a mouse model of pulmonary fibrosis induced by bleomycin administration by suppressing IL-11 signaling or expression.

[0410] "Interstitial lung disease with progressive fibrosis (PF-ILD)" is a group of interstitial lung diseases characterized by pulmonary fibrosis, respiratory symptoms, and respiratory function that worsen over time, and IPF, mentioned above, is included in PF-ILD.

[0411] Pulmonary arterial hypertension (IPF) is a disease characterized by severe pulmonary hypertension without any apparent underlying cause. While IL-11 expression is elevated in IPF patients, it is even more elevated in IPF patients with pulmonary hypertension, and it has been reported that pulmonary hypertension can be induced in mice by administering IL-11.

[0412] Alport syndrome is a progressive chronic glomerulonephritis caused by a gene mutation in type IV collagen, and generally has a poor prognosis. It has been reported that administering anti-IL-11Rα antibodies to Alport syndrome model mice lacking type IV collagen improves proteinuria and renal function.

[0413] "Tubulointerstitial nephritis" is a disease in which inflammation occurs in the renal tubules and interstitial tissue, and the lesion progresses chronically, leading to interstitial fibrosis. "Chronic kidney disease" is a disease characterized by persistent kidney damage, and as it progresses, fibrosis occurs in the renal glomeruli and interstitium. It has been reported that administering IL-11 to mice causes fibrosis in the kidneys, and knockout mice for IL-11 or IL11RA have been reported to exhibit milder fibrosis in renal injury models.

[0414] Examples of "liver fibrosis" include NASH, NAFLD, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).

[0415] NAFLD stands for nonalcoholic fatty liver disease, a condition characterized by fatty liver disease detected on imaging tests, without the presence of alcoholic liver disease or other liver damage. Among NAFLDs, nonalcoholic steatohepatitis (NASH) is a progressive disease that develops into cirrhosis and liver cancer. Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease that causes destruction and fibrosis of hepatocytes, ultimately leading to cirrhosis and liver failure. Primary sclerosing cholangitis (PSC) is a progressive chronic inflammatory disease that causes fibrous stenosis of the bile ducts inside and outside the liver, ultimately leading to cirrhosis. IL-11 has been reported to induce fibrosis of hepatic stellate cells, and high expression of IL-11 in the livers of NASH, PBC, and PSC patients suggests that it contributes to hepatic fibrosis. Furthermore, it has been reported that in NASH model mice, the disease state improves with the administration of anti-IL-11Rα antibodies.

[0416] Systemic sclerosis (SSC) is a chronic autoimmune disease characterized by hardening of the skin and internal organs, with symptoms including Raynaud's phenomenon, skin sclerosis, other skin symptoms, pulmonary fibrosis, scleroderma renal crisis, and reflux esophagitis. It is known that serum IL-11 levels are elevated in patients with SSC, and high expression of IL-11 has also been reported in skin-derived fibroblasts from patients, suggesting that IL-11 contributes to the fibrosis of SSC.

[0417] Chronic pancreatitis is a progressive inflammatory disease characterized by impaired pancreatic function due to inflammation of the pancreas, and is associated with fibrosis of the pancreas. Anti-IL-11Rα antibodies have been reported to suppress fibrosis in a mouse model of pancreatitis.

[0418] Cardiovascular fibrosis includes, for example, hypertrophic cardiomyopathy, dilated cardiomyopathy, and non-atherosclerosis. Hypertrophic cardiomyopathy is a myocardial disease that causes primary ventricular hypertrophy, while dilated cardiomyopathy is a disease characterized by decreased ventricular contractility and ventricular enlargement, accompanied by myocardial fibrosis. Non-atherosclerosis is a disease in which fibrosis occurs in the aorta and its major branches with age. In mice, administration of IL-11 induces cardiac fibrosis, and it has been reported that administration of anti-IL-11Rα antibodies suppresses fibrosis in a mouse cardiac fibrosis model.

[0419] "Gastrointestinal polyposis" refers to a condition characterized by the presence of numerous polyp lesions in the gastrointestinal tract. Examples include Peutz-Jeghers syndrome and familial adenomatous polyposis.

[0420] Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder characterized by hamartomatous polyps throughout the entire digestive tract except the esophagus, and pigmented lesions on the skin and mucous membranes of the lips, oral cavity, fingertips, etc. It is classified as a rare disease (a designated chronic childhood disease). The incidence is estimated to be approximately 1 in 50,000 to 200,000 births, and the number of patients in Japan is estimated to be around 600 to 2,400. Currently, polyps that develop in the digestive tract are treated with endoscopic therapy, but because patients are at high risk of developing malignant tumors, including in the digestive tract, lifelong care is necessary for disease management. It is a genetic disorder in which mutations in STK11 (serine / threonine kinase 11) are found in most cases.

[0421] Familial adenomatous polyposis (FAP) is a disease characterized by the development of multiple adenomas in the large intestine, and if left untreated, almost all patients develop colorectal cancer. It is a genetic disorder caused by germ cell mutations in the APC (Adenomatous Polyposis Coli) gene.

[0422] STK11 knockout mice, the causative gene for Peutz-Jeghers syndrome; APC mutant mice, the causative gene for familial adenomatous polyposis (Apc Min / + It has been reported that IL-11 expression is elevated in polyps that develop in mice, and also in APC Min / + Since it has been reported that knocking out IL11RA in mice results in fewer polyps, it is thought that IL-11 contributes to the development and proliferation of polyps.

[0423] "Inflammatory diseases" are diseases caused by inflammation, and examples include asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (ulcerative colitis, Crohn's disease), rheumatoid arthritis, and multiple sclerosis.

[0424] Asthma is primarily caused by chronic inflammation of the bronchi, which can be triggered by allergens, viral infections, smoking, and other factors. Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease caused by long-term inhalation exposure to harmful substances, primarily tobacco smoke.

[0425] Inflammatory bowel disease (IBD) is a general term for diseases of unknown cause characterized by erosions and ulcers in the mucous membranes of the large and small intestines. Major IBDs include ulcerative colitis and Crohn's disease. High levels of IL-11 are reported in patients with ulcerative colitis, and overexpression of IL-11 in mice has been shown to produce IBD-like symptoms. Therefore, IL-11 is thought to be involved in the onset and exacerbation of IBD.

[0426] Rheumatoid arthritis is a disease in which inflammation occurs in the joints due to an immune system abnormality, resulting in joint pain and swelling. Since arthritis is induced when IL-11 is administered into the joints of mice, and arthritis induced by BSA / IL-1 is reduced in IL11RA knockout mice, it is thought that IL-11 contributes to inflammation in the joints.

[0427] Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease characterized by demyelination and neurodegeneration. Many MSC patients exhibit central nervous system symptoms known as Clinically Isolated Syndrome (CIS). It has been reported that IL-11 expression is elevated in the blood and cerebrospinal fluid of MSC patients, and that IL-11RA knockout mice are resistant to the exacerbation of symptoms in experimental autoimmune encephalosporinitis models used as models for multiple sclerosis.

[0428] Cancer is a disease in which abnormal cells proliferate uncontrollably, invading and metastasizing to surrounding tissues. Examples of cancers that occur in different tissues include liver cancer, pancreatic cancer, colorectal cancer, stomach cancer, uterine cancer, ovarian cancer, testicular cancer, and breast cancer. IL-11 or IL-11Rα is highly expressed in various malignant tumor tissues, and in gastrointestinal cancers (stomach cancer, colorectal cancer), it has been reported that suppressing IL-11 signaling or knocking out IL-11RA in animal models suppresses tumor development and proliferation, suggesting that IL-11 may be involved in tumor inflammation and proliferation.

[0429] "Liver cancer" is a general term for cancers that occur in the liver, and includes primary liver cancer and metastatic liver cancer. IL-11 has been reported to be involved in the recurrence of liver cancer. Pancreatic cancer is a malignant tumor that develops in the pancreas, and pancreatic ductal carcinoma, which originates in the epithelium (pancreatic duct cells), accounts for the vast majority of cases. IL-11 is highly expressed in the blood of patients with pancreatic cancer.

[0430] Colorectal cancer is a malignant tumor that originates from the surface mucosa of the colon or rectum, and the majority of cases are adenocarcinomas. IL-11 is highly expressed in colorectal cancer patients, and tumor suppression by inhibiting IL-11 has been shown in mouse adenoma models. Gastric cancer is a malignant tumor that develops in the stomach, and the majority of cases are adenocarcinomas that originate from mucosal epithelial cells. In a mouse model of gastric cancer, IL11RA knockout mice suppress tumor development.

[0431] Endometrial cancer is a malignant tumor that originates from the endometrium in the body of the uterus. IL-11 is highly expressed in the cancerous tissue of patients. Ovarian cancer is a malignant tumor that develops in the ovaries. IL-11Rα is highly expressed in patient tissue. Testicular cancer is a germ cell tumor that originates from germ cells in the testes. IL-11Rα is highly expressed in patient tissue. Breast cancer is a malignant tumor that develops in the tissue of the mammary glands. IL-11 is highly expressed in breast cancer tissue.

[0432] Other diseases involving IL-11 include abnormal uterine bleeding, preeclampsia, and other conditions.

[0433] "Abnormal uterine bleeding" is vaginal bleeding that is frequent, irregular, lasts longer than a normal menstrual period, or is heavy. It is known that ovulation disorders, endometrial polyps, and leiomyomas can be causes. IL-11 is expressed in endometrial stromal and epithelial cells, and it is known that IL-11 expression in stromal cells increases during decidualization. Furthermore, it has been reported that administration of anti-IL-11 antibodies or anti-IL-11Rα antibodies can suppress the amount of bleeding in a mouse model of abnormal uterine bleeding.

[0434] "Preeclampsia" is a disease characterized by the first onset of hypertension at 20 weeks of gestation, accompanied by proteinuria. It has been reported that IL-11 expression is elevated in the blood and placenta of women who develop preeclampsia even before the onset of symptoms, and it has been reported that administering IL-11 to pregnant mice induces preeclampsia-like symptoms in the mice.

[0435] 10. Compositions, preventive / therapeutic agents The antisense oligonucleotide of the present invention is an antisense oligonucleotide that targets the IL-11 nucleic acid (the sequence of SEQ ID NO: 1 or SEQ ID NO: 2), and can inhibit the expression of IL-11 mRNA and also inhibit the expression of IL-11. The antisense oligonucleotide of the present invention can effectively control the expression of the IL-11 gene, and its administration can provide high therapeutic efficacy.

[0436] In one embodiment, a composition is provided for controlling, for example, the expression of the IL-11 gene by an antisense effect, which contains the antisense oligonucleotide of the present invention as an active ingredient.

[0437] In one embodiment, a pharmaceutical composition is provided that contains at least one of the antisense oligonucleotides of the present invention, a pharmaceutically acceptable salt thereof, and a solvate thereof as an active ingredient.

[0438] In one embodiment, a pharmaceutical composition for preventing, improving and / or treating IL-11-related diseases is provided, comprising at least one of the antisense oligonucleotides of the present invention, pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient.

[0439] In this specification, "diseases involving IL-11" refers, for example, to the diseases described in "9. Diseases involving IL-11" above.

[0440] In one embodiment, the use of the antisense oligonucleotides of the present invention, pharmaceutically acceptable salts thereof, or solvates thereof is provided for the manufacture of agents for preventing, improving and / or treating diseases involving IL-11.

[0441] In one embodiment, an agent for the prevention, improvement, and / or treatment of IL-11-related diseases is provided, characterized by containing at least one of the antisense oligonucleotides of the present invention, a pharmaceutically acceptable salt thereof, and a solvate thereof as an active ingredient.

[0442] In one embodiment, the present invention provides antisense oligonucleotides, pharmaceutically acceptable salts thereof, or solvates thereof for the prevention, improvement and / or treatment of diseases involving IL-11.

[0443] In one embodiment, an IL-11 and / or IL-11 mRNA expression inhibitor is provided, comprising / at least one of the antisense oligonucleotides of the present invention, pharmaceutically acceptable salts thereof, and solvates thereof.

[0444] In one embodiment, the present invention provides antisense oligonucleotides, pharmaceutically acceptable salts thereof, or solvates thereof for inhibiting the expression of IL-11 and / or IL-11 mRNA.

[0445] In one embodiment, the use of a pharmaceutical composition containing at least one of the antisense oligonucleotides, pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient is provided for the manufacture of a drug for preventing, improving and / or treating diseases involving IL-11.

[0446] In one embodiment, the use of the antisense oligonucleotide of the present invention, a pharmaceutically acceptable salt thereof, and at least one solvate thereof as a pharmaceutical composition is provided.

[0447] In one embodiment, the use of the antisense oligonucleotide of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof is provided for the preparation of a pharmaceutical composition.

[0448] In one embodiment, the use of at least one of the antisense oligonucleotides of the present invention, pharmaceutically acceptable salts thereof, and solvates thereof as an inhibitor of IL-11 and / or IL-11 mRNA expression is provided.

[0449] In one embodiment, the use of the antisense oligonucleotides of the present invention, pharmaceutically acceptable salts thereof, or solvates thereof is provided for the production of IL-11 and / or IL-11 mRNA expression inhibitors.

[0450] In one embodiment, a method is provided for preventing, improving and / or treating an IL-11-related disease, comprising administering a pharmaceutical composition containing at least one of the antisense oligonucleotides of the present invention, pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient to a subject in need of prevention, improvement and / or treatment of the disease.

[0451] In one embodiment, a method is provided for preventing and / or treating an IL-11-related disease, comprising administering a pharmaceutical composition containing at least one of the antisense oligonucleotides of the present invention, pharmaceutically acceptable salts thereof, and solvates thereof as an active ingredient to a subject in need of prevention and / or treatment of the disease.

[0452] In this specification, "subjects" include, but are not limited to, humans, non-human mammals (e.g., dogs, cats, rats, mice, rabbits, monkeys, chimpanzees, cattle, horses, pigs, sheep, goats, etc.), birds (e.g., chickens), etc.

[0453] In this specification, unless otherwise specified, "improvement" means an improvement in the symptoms or condition of a disease, prevention or delay of the worsening of the symptoms or condition of a disease, reversal, prevention or delay of the progression of the symptoms of a disease, or treatment of the disease.

[0454] In this specification, unless otherwise specified, “prevention” means preventing or delaying the onset of a disease, or reducing the risk of developing a disease in the subject.

[0455] In this specification, "treatment" means any treatment of the disease in the subject (e.g., improvement of the disease, reduction of the disease, recovery from the disease, alleviation of the disease, suppression of the disease progression, etc.), unless otherwise specified. It may also include preventing the onset and / or progression of the disease in the subject.

[0456] The administration method of the composition containing the antisense oligonucleotide of the present invention is not particularly limited as long as it is a pharmaceutically acceptable administration method, and examples include oral administration, intravenous administration, intra-arterial administration, intramuscular administration, intraperitoneal administration, subcutaneous administration, intradermal administration, intratissue administration, transdermal administration, intra-airway administration, transpulmonary administration, rectal administration, administration by intravenous fluid, and transnasal administration, which can be selected according to the treatment method.

[0457] The composition containing the antisense oligonucleotide of the present invention can be formulated by known pharmaceutical methods. The dosage form is not particularly limited, but examples include tablets, capsules, granules, fine granules, powders, pills, aerosols, inhalants, ointments, patches, topical applications, transdermal formulations, lotions, suppositories, injections, lozenges, liquids, alcoholic formulations, suspensions, extracts, elixirs, lyophilized formulations, and the like.

[0458] In these formulations, there are no particular restrictions as long as the carrier is pharmaceutically acceptable. For example, sterile water or physiological saline, vegetable oil, solvent, base, emulsifier, suspending agent, surfactant, pH adjuster, stabilizer, flavoring agent, fragrance agent, excipient, vehicle, preservative, binder, diluent, isotonic agent, analgesic agent, bulking agent, disintegrant, buffer, coating agent, lubricant, coloring agent, sweetener, viscosity agent, flavoring agent, solubilizer, and other additives can be appropriately combined. Furthermore, the carrier may include, for example, an inert solid diluent or filler, a sterile aqueous solution, and various organic solvents.

[0459] The composition comprising the antisense oligonucleotide of the present invention may also include, for example, a carrier capable of promoting the delivery of the ASO to a target site (target tissue). The carrier is not particularly limited as long as it is a pharmaceutically acceptable carrier, and examples include cationic carriers such as cationic liposomes and cationic polymers.

[0460] The aqueous solvent that can be used to dissolve the antisense oligonucleotide of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples of aqueous solvents include water for injection, distilled water for injection, electrolyte solutions such as physiological saline, glucose solution, and maltose solution.

[0461] The dosage of the composition of the present invention should preferably be adjusted considering the type of antisense oligonucleotide contained in the present invention, the dosage form, the age, weight, and condition of the recipient, the route of administration, and the nature and severity of the disease. For adults, for example, the amount of antisense oligonucleotide of the present invention administered is approximately 0.0001 mg / kg to approximately 100 mg / kg per day. This dosage may vary depending on the type of disease being targeted, the form of administration, and the target molecule, and it may be sufficient to administer less than this amount, or it may be necessary to administer more than this amount. In addition, the number of administrations may be selected from, for example, once a day to several times a day, or at intervals of one day to several days.

[0462] In this invention, "approximately" may include values ​​up to ±20% of the given numerical value, preferably up to ±10%. For example, when stating "IL-11 mRNA expression was inhibited by approximately 70%", the level of inhibition may include inhibition within the range of 56% to 84%, preferably within the range of 63% to 77%.

[0463] 11. Combined use / combination The antisense oligonucleotide of the present invention, or a pharmaceutical composition containing said antisense oligonucleotide, can be used in combination with other drugs or agents in a manner common in medical practice. Examples of drugs that can be used in combination with or formulated with the antisense oligonucleotide of the present invention include drugs used for the prevention, improvement, or treatment of diseases involving IL-11.

[0464] In one embodiment, a pharmaceutical composition is provided comprising at least one of the antisense oligonucleotides of the present invention, or pharmaceutically acceptable salts thereof, and solvates thereof, as well as at least one other drug or agent, such as an agent for improving, preventing, or treating a disease involving IL-11.

[0465] In one embodiment, a pharmaceutical composition is provided containing at least one of the antisense oligonucleotides of the present invention, a pharmaceutically acceptable salt thereof, and a solvate thereof as an active ingredient, which is used in combination with other drugs or agents such as drugs for improving, preventing, or treating diseases involving IL-11.

[0466] There are no particular limitations on the types of drugs that can be used to treat, prevent, or cure diseases involving IL-11 (including those that are expected to be effective, preventive, or therapeutic agents), but examples include the following: [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27]

[0467] For diseases involving IL-11, it may be possible to reduce the dosage of existing medications and mitigate side effects by using the aforementioned concomitant drugs or medications. This concomitant method is not limited to diseases involving IL-11, and the drugs used in concomitant use are not limited to the drugs and compounds exemplified above.

[0468] When using the antisense oligonucleotide of the present invention in combination with a drug that can be used in combination with it, the drugs may be used in separate formulations (or kits containing each of them) or as a combination drug. In the case of separate formulations, the drugs may be taken simultaneously or at different times.

[0469] The administration method of the antisense oligonucleotide and the co-administered drug of the present invention is not particularly limited, and it is sufficient that the antisense oligonucleotide and the co-administered drug are combined at the time of administration. Examples of such administration methods include (1) to (5). (1) Administration of a single formulation obtained by simultaneously formulating the antisense oligonucleotide of the present invention and a co-agent, (2) Simultaneous administration of two formulations obtained by separately formulating the antisense oligonucleotide of the present invention and the co-administered drug via the same route of administration. (3) Administration of two formulations obtained by separately formulating the antisense oligonucleotide of the present invention and a co-administered drug, with a time difference between them, via the same administration route. (4) Simultaneous administration of two formulations obtained by separately formulating the antisense oligonucleotide and the co-administered drug of the present invention via different routes of administration. (5) Administration of two formulations obtained by separately formulating the antisense oligonucleotide of the present invention and the co-administered drug, with a time difference between them, via different administration routes (for example, administration in the order of antisense oligonucleotide of the present invention → co-administered drug, or in the reverse order). Hereinafter, these administration methods will be collectively referred to as the "combination agents of the present invention."

[0470] When administering the combination agent of the present invention, for example, the combination drug and the antisense oligonucleotide of the present invention may be administered at the same time, the antisense oligonucleotide of the present invention may be administered after the administration of the combination drug, or the combination drug may be administered after the administration of the antisense oligonucleotide of the present invention. When administering with a time difference, the time difference will vary depending on the active ingredient, dosage form, and method of administration. For example, when administering a concomitant drug first, the antisense oligonucleotide of the present invention can be administered after the concomitant drug has been administered, for example, within approximately 1 minute to 3 days, approximately 10 minutes to 1 day, approximately 15 minutes to 12 hours, approximately 30 minutes to 6 hours, or approximately 60 minutes to 3 hours. When administering the antisense oligonucleotide of the present invention first, a method of administering the concomitant drug after administering the antisense oligonucleotide of the present invention can be described as administering the concomitant drug within approximately 1 minute to 3 days, approximately 10 minutes to 1 day, approximately 15 minutes to 12 hours, approximately 30 minutes to 6 hours, approximately 60 minutes to 3 hours, etc.

[0471] The dosage of concomitant drugs can be set to any amount as long as side effects are not a problem, and can be appropriately selected based on clinically used dosages. Furthermore, the mixing ratio of the antisense oligonucleotide of the present invention and the concomitant drug can be appropriately selected depending on the target patient, route of administration, target disease, symptoms, combination, etc. When the antisense oligonucleotide of the present invention is used in combination with a concomitant drug, the amounts of each agent can be reduced within a safe range considering the opposing effects of those agents. For example, when the target patient is a human, approximately 0.01 to approximately 100 parts by mass of the concomitant agent can be used for every 1 part by mass of the antisense oligonucleotide of the present invention.

[0472] The combined agent of the present invention can be formulated into a pharmaceutical composition, for example, a dosage form similar to that described above for the antisense oligonucleotide of the present invention, by mixing the antisense oligonucleotide of the present invention and / or the combined agent with a low-toxicity, pharmacologically acceptable carrier according to known methods, and administered orally or parenterally.

[0473] As a carrier that can be used in the manufacture of the combination agent of the present invention, the same type as that used in the pharmaceutical composition of the antisense oligonucleotide of the present invention described above can be used. The mixing ratio of the antisense oligonucleotide of the present invention and the combination drug in the combination agent of the present invention can be appropriately selected depending on the target of administration, route of administration, disease, etc.

[0474] The above-mentioned concomitant drugs may be used in combination of two or more in appropriate proportions. The dosage of the concomitant drugs can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the antisense oligonucleotide of the present invention and the concomitant drug can be appropriately selected depending on the target of administration, route of administration, target disease, symptoms, combination, etc. For example, when the target of administration is a human, approximately 0.01 to approximately 100 parts by mass of the concomitant drug can be used for 1 part by mass of the antisense oligonucleotide of the present invention.

[0475] For example, the content of the antisense oligonucleotide of the present invention in the combination agent of the present invention varies depending on the form of the formulation, but is usually in the range of about 0.01 to about 99.9% by mass, about 0.1 to about 50% by mass, about 0.5 to about 20% by mass, etc., relative to the entire formulation.

[0476] The content of the concomitant drug in the concomitant formulation of the present invention varies depending on the form of the formulation, but is usually in the range of about 0.01 to about 99.9% by mass, about 0.1 to about 50% by mass, or about 0.5 to about 20% by mass relative to the entire formulation.

[0477] The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the formulation, but is usually in the range of about 1 to about 99.99% by mass, about 10 to about 90% by mass, etc., relative to the entire formulation.

[0478] The same content may be used when the antisense oligonucleotide and the concomitant drug of the present invention are formulated separately. As mentioned above, the dosage varies depending on various conditions, so it may be sufficient to use a smaller amount than the above dosage, or it may be necessary to administer a dose exceeding the range.

[0479] 12. Assay method for IL-11 mRNA expression level According to one embodiment, the present invention provides a method for assaying the expression level of IL-11 mRNA. The assay method is not particularly limited, but for example, the method described in the examples below can be used.

[0480] Specifically, this is a screening method for IL-11 antisense oligonucleotides by measuring the expression level of IL-11 mRNA in cells, wherein the cells are IL-11 expressing cells such as HEK293, U-251 MG, NIH-3T3, and primary cultured lung fibroblasts, and the screening includes the following steps (1) to (3). (1) A step of contacting the cells with IL-11 antisense oligonucleotide and incubating them. (2) The step of increasing the expression of IL-11 mRNA by treating the cells with PMA (Phorbol 12-myristate 13-acetate) or TGF-β (Transforming growth factor-beta) and incubating them. (3) A step of measuring the expression level of IL-11 mRNA transcript in the cells.

[0481] Cells expressing IL-11 used in the aforementioned screening method can be obtained, for example, by means of cell banks, purchase from cell distributors, or cell isolation from tissues.

[0482] The method for contacting the IL-11 antisense oligonucleotide with the cells in step (1) above is not particularly limited, but one example is to add the IL-11 antisense oligonucleotide to a culture medium containing cells and then contact the cells. As the culture medium, for example, a cell culture medium such as MEM medium can be used, and the medium may contain components other than the medium components (for example, inactivated FBS, antibiotics (for example, penicillin, streptomycin, etc.), amino acids (for example, L-glutamine, etc.)).

[0483] Alternatively, the IL-11 antisense oligonucleotide may be added in the form of a mixture after mixing the IL-11 antisense oligonucleotide and a transfection reagent (e.g., Lipofectamine 3000, etc.) in a medium such as Reduced Serum Medium. The container used to hold the culture medium when bringing IL-11 antisense oligonucleotides into contact with cells is not particularly limited, but commercially available containers such as 96-well plates can be used.

[0484] In step (2) above, commercially available PMA (Phorbol 12-myristate 13-acetate) or TGF-β (Transforming growth factor-beta) can be used as the added product.

[0485] The incubation time in step (1) is not particularly limited, but examples include about 4 to about 72 hours, about 16 to about 48 hours, about 40 hours, etc., and is preferably about 40 hours. Similarly, the incubation time in step (2) is not particularly limited, but examples include about 4 to about 72 hours, about 5 to about 30 hours, about 10 to about 20 hours, about 16 hours, etc., and is preferably about 16 hours. In steps (1) and (2), the incubation temperature is not particularly limited, but may be, for example, 20 to 45°C, 25 to 40°C, 30 to 40°C, and is preferably 35 to 40°C.

[0486] The method for measuring the expression level of the IL-11 mRNA transcript in step (3) above is not particularly limited, but it can be measured by, for example, real-time PCR. [Examples]

[0487] The present invention will be described more specifically below with reference to examples, but the embodiments of the present invention are not limited to the following examples. In the examples, the sequence indicated by "SEQ No. of BASE SEQ" is expressed independently of any modification of the sugar moiety, nucleoside bond, or nucleic acid base moiety. The chemical structure shows the modified form of the sugar moiety, nucleoside bond, or nucleic acid base moiety of the oligonucleotide, and a unique sequence number (SEQ No. of compd.) for that compound is indicated.

[0488] In the chemical structure notation in the examples, unless otherwise specified, "(L)" represents LNA (β-D-methyleneoxyBNA) nucleoside, "(V)" represents 2'-O-MCE nucleoside, "(m)" represents 2'-O-MOE nucleoside, lowercase letters (except "m" in (m)) represent deoxyribonucleosides, uppercase letters (except "L" in (L) and "V" in (V)) represent ribonucleosides, "^" represents a phosphorothioate bond, "5(x)" indicates that the nucleic acid base of the deoxyribonucleoside is 5-methylcytosine, and "5" in "5(m)", "5(V)", and "5(L)" indicates that the nucleic acid base of the nucleoside is 5-methylcytosine.

[0489] In the chemical structure notation in the examples, if there is no "^" between two adjacent nucleosides, the nucleoside bond between those two nucleosides is a phosphodiester bond. For example, in the notation "5(L)A(L)", the nucleoside bond between 5-methylcytosine and A is a phosphodiester bond, and in the notation "5(L)g", the nucleoside bond between 5-methylcytosine and g is a phosphodiester bond.

[0490] (Manufacturing Example 1) The antisense oligonucleotides listed in Tables 28-34 (compounds represented by chemical structures corresponding to compound numbers) were prepared using the nucleic acid automated synthesizer nS-8II (Gene Design Co., Ltd.) or NTS M-8-SE (Nippon Techno Service Co., Ltd.).

[0491] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34]

[0492] Tables 28-34 show the target location of each antisense oligonucleotide within the sequence of SEQ ID NO: 1 (hIL-11 cDNA sequence) or SEQ ID NO: 2 (hIL-11 genomic DNA sequence) of the IL-11 nucleic acid, and Tables 35-38 show the SEQ ID NOs corresponding to each antisense oligonucleotide.

[0493] In Tables 35-38, "Compd. No." refers to the compound number. "SEQ1 START" refers to the "SEQ ID NO: 1 start site" and indicates the position number of the 5' nucleoside targeted by the antisense oligonucleotide in SEQ ID NO: 1. "SEQ1 END" refers to the "SEQ ID NO: 1 stop site" and indicates the position number of the 3' nucleoside targeted by the antisense oligonucleotide in SEQ ID NO: 1. "SEQ2 START" means "SEQ ID NO: 2 Start Site" and indicates the position number of the 5' nucleoside targeted by the antisense oligonucleotide in SEQ ID NO: 2. "SEQ2 END" means "SEQ ID NO: 2 Stop Site" and indicates the position number of the 3' nucleoside targeted by the antisense oligonucleotide in SEQ ID NO: 2.

[0494] Each antisense oligonucleotide targets either the hIL-11 cDNA sequence designated herein as Sequence ID No. 1, or / or the hIL-11 genomic DNA sequence designated herein as Sequence ID No. 2.

[0495] In the table, a hyphen ("-") indicates that the antisense oligonucleotide does not target its hIL-11 cDNA sequence or the hIL-11 genomic DNA sequence with 100% complementarity. "BASE SEQUENCE" shows the nucleic acid base sequence of the antisense oligonucleotide. "SEQ No. of BASE SEQ" shows the sequence number corresponding to the nucleic acid base sequence of the antisense oligonucleotide. "SEQ No. of compd." shows the sequence number unique to each antisense oligonucleotide. In the "region" column, "CDS," "3'-UTR," "5'-UTR," and "intron" indicate that the antisense oligonucleotide is complementary to the CDS region, 3'-UTR region, 5'-UTR region, and intron, respectively.

[0496] [Table 35] [Table 36] [Table 37] [Table 38]

[0497] The nucleic acid sequence of Compd193 (sequence number 156) is complementary to sequences 685-702 of mouse IL-11 mRNA represented by sequence number 3.

[0498] In vitro activity evaluation a) Construction of human IL-11 stably expressing cells Human IL-11 (NM_000641) and a neomycin resistance gene-expressing vector (ORIGENE) were introduced into HEK293 cells (ECACC) using FuGENE® HD Transfection Reagent (Promega). Cells were cultured in DMEM (high-glucose) medium containing 10% inactivated FBS, 100 U / mL penicillin, 0.1 mg / mL streptomycin, and 1 mg / mL Geneticin® to obtain drug-resistant clones. Human IL-11 mRNA expression in the obtained clones was evaluated using real-time PCR. RNA was extracted from the cells using RNeasy® Mini Kit (QIAGEN) or RNeasy® 96 Kit (QIAGEN), and cDNA was obtained by reverse transcription using SuperScript IV VILO master mix (Invitrogen). The obtained cDNA was used to perform real-time PCR on a 7500 Fast real-time PCR system or a QuantStudio 3 real-time PCR system (Applied Biosystems) using TaqMan® Fast Universal PCR Master Mix as the real-time PCR reagent. TaqMan® Gene Expression Assays (Applied Biosystems, Assay ID Hs01055414_m1 or Hs01055413_g1) were used as the probe and primer.

[0499] b) Construction of mouse cells that stably express IL-11 Vectors expressing mouse IL-11 (NM_008350) and a neomycin resistance gene were constructed and introduced into HEK293 cells (ECACC) using FuGENE® HD Transfection Reagent (Promega). Cells were cultured in DMEM (high-glucose) medium containing 10% inactivated FBS, 100 U / mL penicillin, 0.1 mg / mL streptomycin, and 1 mg / mL Geneticin® to obtain drug-resistant clones. Mouse IL-11 mRNA expression in the obtained clones was evaluated using real-time PCR. RNA was extracted from the cells using RNeasy® Mini Kit (QIAGEN) or RNeasy® 96 Kit (QIAGEN), and cDNA was obtained by reverse transcription using SuperScript IV VILO master mix (Invitrogen). The obtained cDNA was used for real-time PCR using TaqMan® Fast Universal PCR Master Mix as the real-time PCR reagent, performed on a 7500 Fast real-time PCR system or a QuantStudio 3 real-time PCR system (Applied Biosystems). The probe and primer used were TaqMan® Gene Expression Assays (Applied Biosystems, Assay ID Mm00434162_m1).

[0500] c) Evaluation of human IL-11 mRNA expression suppression (1) Human IL-11 stable expression cells (cells obtained in the construction of human IL-11 stable expression cells described above a) were suspended in DMEM (high-glucose) medium containing 10% inactivated FBS, 100 U / mL penicillin, and 0.1 mg / mL streptomycin the day before transfection, and 3.0 x 10⁻¹⁴⁻¹ 4Cells were seeded in 96-well plates to a concentration of cells per well. The following day, the test compound and the transfection reagent Lipofectamine 3000 (Thermo Fisher Scientific) were mixed in Opti-MEM® (Thermo Fisher Scientific) as the medium, incubated at room temperature for 10 minutes, and then added to the culture medium to a concentration of 30 nM. The cells were then cultured at 37°C under 5% CO2 conditions. After approximately 24 hours of processing, RNA was isolated from the cells, and the human IL-11 mRNA expression level was measured by real-time PCR. RNA was extracted from the cells using RNeasy® Mini Kit (QIAGEN), and cDNA was obtained by reverse transcription using SuperScript IV VILO master mix (Invitrogen). Using the obtained cDNA, real-time PCR was performed on a 7500 Fast real-time PCR system or a QuantStudio 3 real-time PCR system (Applied Biosystems) using TaqMan® Fast Advanced Master Mix (Applied Biosystems) as the real-time PCR reagent. TaqMan® Gene Expression Assays (Applied Biosystems) were used as the primer-probe set to measure human IL-11 (Assay ID Hs01055413_g1) and human B2M (Assay ID Hs99999907_m1). The measurement results were analyzed using the ΔΔCt method with human B2M as the reference gene. The expression level (%) (ii) and inhibition rate (%) (100%-ii) in cells treated with the test compound were calculated, with the expression level (i) of human IL-11 mRNA in untreated control cells with only the transfection reagent added set to 100%. The expression levels (%) (inhibition rate (%)) of human IL-11 mRNA at 30 nM of the test substance obtained by this method are shown in Tables 39-42.

[0501] d) Evaluation of human IL-11 mRNA expression suppression (2) U-251 MG cells (ECACC) were suspended the day before transfection in MEM medium containing 10% inactivated FBS, 100 U / mL penicillin, 0.1 mg / mL streptomycin, and 2 mM L-Glutamine solution, and then 1.0 x 10⁻¹⁴ cells were prepared. 4Cells were seeded in 96-well plates to a concentration of cells per well. The following day, the test compound and the transfection reagent Lipofectamine 3000 (Thermo Fisher Scientific) were mixed using Opti-MEM® (Thermo Fisher Scientific) as the medium, incubated at room temperature for 10 minutes, and then added to the culture medium to a concentration of 0.03–100 nM. After approximately 24 hours, PMA (Phorbol-12-myristate-13-acetate, Sigma-Aldrich) dissolved in DMSO was added to the wells at a concentration of 10 ng / mL, and the cells were cultured at 37°C under 5% CO2 conditions. After approximately 16 hours, RNA was isolated from the cells, and the human IL-11 mRNA expression level was measured by real-time PCR. RNA was extracted from the cells using RNeasy® Mini Kit (QIAGEN), and cDNA was obtained by reverse transcription using SuperScript IV VILO master mix (Invitrogen). Using the obtained cDNA, real-time PCR was performed on a 7500 Fast real-time PCR system or a QuantStudio 3 real-time PCR system (Applied Biosystems) using TaqMan® Fast Advanced Master Mix (Applied Biosystems) as the real-time PCR reagent. Human IL-11 (Assay ID Hs01055413_g1) and human B2M (Assay ID Hs99999907_m1) were measured using TaqMan® Gene Expression Assays (Applied Biosystems) as the primer-probe set. The measurement results were analyzed using the ΔΔCt method with human B2M as the reference gene, and the expression level (%) (ii) in cells treated with the test compound and the expression inhibition rate (%) (100%-ii) were calculated, with the expression level (i) of human IL-11 mRNA in untreated control cells set to 100%. Tables 43-46 show the expression level (%) (expression inhibition rate (%)) of human IL-11 mRNA at 30 nM using the example compounds obtained by this method, and IC.50 The values ​​are listed in Tables 47 and 48.

[0502] e) Evaluation of suppression of human IL-11 protein expression U-251 MG cells (ECACC) were suspended the day before transfection in MEM medium containing 10% inactivated FBS, 100 U / mL penicillin, 0.1 mg / mL streptomycin, and 2 mM L-Glutamine solution, and then 1.0 x 10⁻¹⁴ cells were prepared. 4 Seeds are seeded into 96-well plates to a cell / well ratio. The following day, the test compound and the transfection reagent Lipofectamine 3000 (Thermo Fisher Scientific) are mixed using Opti-MEM® (Thermo Fisher Scientific) as the medium, incubated at room temperature for 10 minutes, and then added to the culture medium to a concentration of 0.03–100 nM. After approximately 24 hours, PMA (Phorbol-12-myristate-13-acetate, Sigma-Aldrich) dissolved in DMSO is added to the wells to a concentration of 10 ng / mL, and the cells are cultured at 37°C under 5% CO2 conditions. DMSO is added to the wells that were not treated with PMA. Approximately 16 hours later, the culture supernatant was collected, and the human IL-11 concentration in the supernatant was measured using the IL-11 ELISA Kit (abcam). The inhibitory activity (IC) of each test substance was determined by setting the IL-11 expression in the supernatant of untreated and untreated cells to 0% and the IL-11 expression in the supernatant of PMA-treated cells to 100%. 50 Calculate the value.

[0503] f) Evaluation of mouse IL-11 mRNA expression suppression Mouse IL-11 stable-expressing cells (as described in b above, cells obtained from the construction of mouse IL-11 stable-expressing cells) were suspended in DMEM (high-glucose) medium containing 10% inactivated FBS, 100 U / mL penicillin, and 0.1 mg / mL streptomycin the day before transfection, and 2.5 x 10⁻¹⁴⁻¹ 4Cells were seeded in 96-well plates to a concentration of cells per well. The following day, the test compound and the transfection reagent Lipofectamine 3000 (Thermo Fisher Scientific) were mixed using Opti-MEM® (Thermo Fisher Scientific) as the medium, incubated at room temperature for 10 minutes, and then added to the culture medium to a concentration of 0.03-100 nM. The mixture was then cultured at 37°C under 5% CO2 conditions. After approximately 24 hours of processing, RNA was isolated from the cells, and the mouse IL-11 mRNA expression level was measured by real-time PCR. RNA was extracted from the cells using RNeasy® Mini Kit (QIAGEN), and cDNA was obtained by reverse transcription using SuperScript IV VILO master mix (Invitrogen). Using the obtained cDNA, real-time PCR was performed on a QuantStudio 3 real-time PCR system (Applied Biosystems) with TaqMan® Fast Advanced Master Mix (Applied Biosystems) as the real-time PCR reagent. Using TaqMan® Gene Expression Assays (Applied Biosystems) as a primer-probe set, mouse IL-11 (Assay ID Mm00434162_m1) and human B2M (Assay ID Hs99999907_m1) were measured. The measurement results were analyzed using the ΔΔCt method with human B2M as the reference gene, and the expression level (%) (ii) in cells treated with the test compound and the inhibition rate (%) (100%-ii) were calculated, with the expression level (i) of mouse IL-11 mRNA in untreated control cells with only the transfection reagent added set to 100%.

[0504] In vivo study (effects on pulmonary fibrosis) As a model of idiopathic pulmonary fibrosis, mice in which pulmonary fibrosis is induced by administration of bleomycin (BLM) are used. The example compounds of the present invention are administered intravenously or transpulmonaryly to mice in which pulmonary fibrosis has been induced by BLM once or twice a week, and body weight, lung weight, hydroxyproline content in lung tissue, Ashcroft score, and expression levels of fibrosis-related factors are evaluated.

[0505] In vivo study (effect on polyp proliferation) STK11 knockout mice are used as an animal model for Peutz-Jeggers syndrome. STK11+ / - mice are known to develop gastrointestinal hamartomatous polyps. STK11 knockout mice are created by deleting the gene region containing Exon 2 to Exon 7 of STK11 using the Crispr-Cas9 method. The example compounds of the present invention are administered subcutaneously to STK11+ / - mice once or twice a week, and body weight, polyp size, polyp number, etc., are evaluated.

[0506] In vivo study (effects on renal fibrosis) To evaluate the effects on renal fibrosis, a unilateral ureteral obstruction (UUO) model of the kidney is used. Mice that have undergone ureteral obstruction surgery on one ureter are subcutaneously administered the example compound of the present invention once or twice a week, and histopathological evaluation, biochemical tests, etc. are performed.

[0507] In vivo studies (evaluation of mRNA expression in tissues) Mouse IL-11 expression in mouse tissue (stomach, small intestine, large intestine, lung, testis, liver, kidney, or polyps from STK11 knockout mice) collected after administration of the example compounds will be evaluated using real-time PCR. RNA will be extracted from the tissue using TRIzol® Reagent (Thermo Fisher SCIENTIFIC) and RNeasy® Mini Kit (QIAGEN), and cDNA will be obtained by reverse transcription using SuperScript IV VILO master mix (Invitrogen). Real-time PCR will be performed using the obtained cDNA with TaqMan® Fast Advanced Master Mix (Applied Biosystems) as the real-time PCR reagent on a QuantStudio 3 real-time PCR system (Applied Biosystems). TaqMan® Gene Expression Assays (Applied Biosystems, Assay) will be used as the probe and primer. Using TaqMan® Gene Expression Assays (Applied Biosystems) as a primer-probe set, mouse IL-11 (Assay ID Mn00434162_m1), mouse HPRT (Mm03024075_m1), or mouse Gapdh (Mm99999915_g1) are measured. The measurement results are analyzed using the ΔΔCt method with HPRT as the reference gene, and the expression level of mouse IL-11 is shown compared to the control animal tissue untreated with the test compound.

[0508] Cytotoxicity evaluation test using Caspase 3 / 7 activity Caspase 3 / 7 activity was measured to evaluate cytotoxicity in HepG2 cells. Two days prior to the measurement of Caspase 3 / 7 activity, cells were suspended in DMEM (low-glucose) medium containing FBS and measured in 2.0 × 10⁶ units. 4Cells were seeded in 96-well clear-bottom plates. The following day, the test compound and the transfection reagent Lipofectamine 3000 (Thermo Fisher Scientific) were mixed in Opti-MEM® (Thermo Fisher Scientific) as the medium, incubated at room temperature for 15 minutes, and then added to the medium to concentrations of 30 and 100 nM. The mixture was incubated at 37°C and 5% CO2 for 24 hours. On the day of the assay, the Caspase-Glo® 3 / 7 Assay System (Promega) was added and incubated at room temperature for 1 hour. Caspase 3 / 7 activity was measured as a luciferase luminescence signal using a multi-label plate reader (Arvo x5, Perkin Elmer). The Caspase 3 / 7 activity of each test compound was calculated, with the luminescence signal of the well without the test compound set as 100%.

[0509] Pharmacokinetics (PK) trials (1) PK test After administering the example compounds to mice (using sterile water for injection for oral or duodenal administration, and physiological saline for intravenous or intratracheal administration), plasma, stomach, small intestine (duodenum, jejunum, and ileum), large intestine (colon, rectum), lungs, testes, liver, or kidneys were collected at a certain time after administration. Sample processing was performed using the liquid-liquid extraction method or solid-phase extraction method described below, and the concentration of the compounds in the tissues was measured by high-performance liquid chromatography / mass spectrometry (LC / MS: QTRAP5500·AB, Sciex). Similarly, standard solutions with known concentrations of the test compounds added were measured, and the tissue concentration (μg / mL or μg / g) was calculated from the prepared calibration curve.

[0510] (2) Liquid-liquid extraction method Add 50 mmol / L Tris buffer to each tissue except plasma, and prepare 5-20 (w / w)% tissue homogenate solutions using a bead homogenizer. Add the homogenate solution or plasma, internal standard solution, and ultrapure water to a tube to a total volume of 100 μL, and mix with an equal volume of 10 (v / v)% aqueous ammonia. Then, add 200 μL of phenol / chloroform / isoamyl alcohol (25:24:1) solution, mix with a Vortex mixer for about 30 seconds, centrifuge (micro-high-speed refrigerated centrifuge MX-305, manufactured by Tommy Seiko Co., Ltd., 20000 × g, 10 minutes, 20°C), and collect the supernatant. Add 50 (v / v)% aqueous acetic acid solution to 150 μL of the supernatant to prepare the LC / MS measurement sample.

[0511] (3) Solid phase extraction method Mix 50 mmol / L ammonium acetate (pH 5.5) with the LC / MS sample obtained by liquid-liquid extraction, add the entire volume to a solid-phase extraction plate (Oasis WAX 96-well μElution Plate), and aspirate. Wash the solid-phase extraction plate with the 50 mmol / L ammonium acetate solution and a 20 (v / v)% methanol aqueous solution, and aspirate. Add a 50 mmol / L triethylamine-containing 20% ​​methanol aqueous solution to the solid-phase extraction plate and elute the compound. Repeat this procedure twice, then dilute with a 0.05 (v / v)% triethylamine aqueous solution to prepare the LC / MS sample. [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48]

[0512] Sequence ID 1: Nucleic acid sequence of human IL-11 cDNA [ka]

[0513] Sequence ID 2: Human IL-11 genomic DNA sequence [ka] [ka] [ka]

[0514] Sequence ID 3: Nucleic acid sequence of mouse IL-11 cDNA [ka]

[0515] The present invention may include the following embodiments. [1] An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is complementary to the isolength portion of the IL-11 nucleic acid, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases. [2] The antisense oligonucleotide according to [1], wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isolength portion of the IL-11 nucleic acid. [3] The antisense oligonucleotide according to [1] or [2], wherein the IL-11 nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or 2.

[0516] [4] The nucleic acid base sequence of the oligonucleotide is such that the nucleic acid bases of SEQ ID NO: 27-42, 82-97, 94-109, 148-163, 152-167, 170-185, 198-213, 240-255, 322-337, 331-346, 337-352, 340-355, 357-372, 363-378, 368-383, 379-394, 407-422, 418-433, 422-437, 427-4 42, 428~443, 431~446, 451~466, 454~469, 455~470, 456~471, 456~473, 457~472, 458~473, 472~487, 473~488, 490~505, 492~507, 493~508, 494~509, 495~510, 496~511, 497~512, 499~514, 500~515, 501~516, 502~517, 503~51 8, 504~519, 505~520, 506~521, 507~522, 508~523, 509~524, 510~525, 510~527, 511~526, 512~527, 527~542, 574~589, 577~592, 683~700, 691~706, 696~711, 701~716, 717~732, 774~789, 776~791, 777~792, 778~793, 780~795 Antisense oligonucleotides according to any one of the above [1] to [3], which are at least 80% complementary to the equal-length portions within 783-798, 784-799, 785-800, 786-801, 787-802, 899-914, 904-919, 1115-1130, 1127-1142, 1138-1153, 1158-1173, 1766-1781, 2266-2281, or 2324-2339.

[0517] [5] The nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 627-642, 682-697, 694-709, 766-781, 930-945, 956-971, 1343-1358, 1558-1573, 1607-1622, 2132-2147, 2160-2175, 2202-2217, 2290-2305, 2348-2363, 2363-2378, 2372-2387, 2383-2398, 2412-2427, 2477-2492, 2498-2513, 2501-2516, 2518-2533, 2524-2539 of SEQ ID NO. 2 , 2529~2544, 2540~2555, 2690~2705, 2694~2709, 2699~2714, 2700~2715, 2703~2718, 2723~2738, 2726~2741, 2727~2742, 2728~2743, 2728~2745, 2729 ~2744, 2730~2745, 2744~2759, 2745~2760, 2762~2777, 2764~2779, 2765~2780, 2766~2781, 2767~2782, 2768~2783, 2769~2784, 2771~2786, 2772~2787 , 2773~2788, 2774~2789, 2775~2790, 2776~2791, 2777~2792, 2778~2793, 2779~2794, 2780~2795, 2781~2796, 2782~2797, 2782~2799, 2783~2798, 2784 ~2799, 2799~2814, 2852~2867, 2865~2880, 2915~2930, 2946~2961, 2978~2993, 2999~3014, 3037~3052, 3073~3088, 3111~3126, 3124~3139, 3134~3149 , 3145~3160, 3163~3178, 3184~3199, 3199~3214, 3226~3241, 3245~3260, 3258~3273, 3278~3293, 3290~3305, 3626~3641, 3664~3679, 3690~3705, 3705 ~3720, 3749~3764, 3764~3779, 3787~3802, 3820~3835, 3850~3865, 3862~3877, 3902~3917, 3926~3941, 3940~3955, 3963~3978, 3984~3999, 3999~4014,4018~4033, 4032~4047, 4051~4066, 4068~4083, 4086~4101, 4161~4176, 4180~4195, 4290~4305, 4373~4388, 4500~4515, 4528~4543, 4543~4558, 4578~4593, 4601 ~4616, 4622~4637, 4646~4661, 4653~4668, 4676~4691, 4698~4713, 4751~4766, 4780~4795, 4799~4814, 4852~4867, 4879~4894, 4987~5004, 4995~5010, 5000~5015 Antisense oligonucleotides according to any one of the above [1] to [3], which are at least 80% complementary to the equal-length portions within 5005-5020, 5021-5036, 5078-5093, 5080-5095, 5081-5096, 5082-5097, 5084-5099, 5087-5102, 5088-5103, 5089-5104, 5090-5105, 5091-5106, 5203-5218, 5208-5223, 5419-5434, 5431-5446, 5442-5457, 5462-5477, 6070-6085, 6570-6585, or 6628-6643.

[0518] [6] The antisense oligonucleotide according to any one of [1] to [5], wherein the nucleic acid base sequence of the oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to the isochromatic portion of the nucleic acid base of SEQ ID NO: 1 or 2. [7] An antisense oligonucleotide according to any one of the above items [1] to [6], wherein the number of linked nucleosides is 15 to 22, 16 to 22, or 16 to 18.

[0519] [8] An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide has a nucleic acid base sequence comprising at least 5 consecutive nucleic acid bases from among the nucleic acid base sequences selected from SEQ ID NOs. 4 to 156, and the oligonucleotide comprises at least one modification selected from a modified sugar, a modified nucleoside bond, and a modified nucleic acid base. [9] The antisense oligonucleotide according to [8], wherein the number of linked nucleosides is 15 to 22, 16 to 22, or 16 to 18.

[10] The antisense oligonucleotide according to [8] or [9], wherein the oligonucleotide has a nucleic acid base sequence containing at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases from the nucleic acid base sequence selected from SEQ ID NOs. 4 to 156.

[0520]

[11] The antisense oligonucleotide according to any one of the above [8] to

[10] , wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs. 4 to 156.

[12] The antisense oligonucleotide according to any one of the above [8] to

[10] , wherein the oligonucleotide has a nucleic acid base sequence consisting of a nucleic acid base sequence selected from sequence numbers 4 to 156.

[0521]

[13] The antisense oligonucleotide according to any one of the above [1] to

[12] , wherein at least one of the modified sugars contained in the oligonucleotide is a bicyclic sugar.

[14] The bicyclic sugar is a bicyclic sugar that bridges at the 4'-2' position, and the bridge at the 4'-2' position is 4'-CH2-O-2':(LNA nucleoside), 4'-(CH2)2-O-2':(ENA nucleoside), 4'-CH(CH3)-O-2':(cEt nucleoside), 4'-C(=O)-N(CH3)-2':(AmNA nucleoside), 4'-CH2-N(C(=NH)(NH2))-2':(GuNA nucleoside), 4'-CH2-N(C(=NH)(NHtBu)-2':(GuNA(t-Bu) nucleoside), 4'-C(CH3)2-O-2', 4'-CH(OCH2 An antisense oligonucleotide as described in

[13] above, selected from the group consisting of CH3)-O-2', 4'-CH2-CH(CH3)-2', 4'-CH2-C(=CH2)-2', 4'-CH2-CH2-CH2-2', 4'-CH2-NH-O-2', 4'-CH2-N(CH3)-O-2', 4'-CH2-NH-2', 4'-CH2-N(CH3)-2', 4'-CH2-N(OCH3)-2', 4'-CH2-O-NH-2', 4'-CH2-ON(CH3)-2', 4'-CH2-S-2', 4'-C(-CH2CH2-)-O-2':(scpBNA nucleoside).

[0522]

[15] The antisense oligonucleotide according to any one of the above [1] to

[12] , wherein at least one of the modified sugars contained in the oligonucleotide is a non-bicyclic modified sugar.

[16] The antisense oligonucleotide according to

[15] , wherein the non-bicyclic modified sugar is a sugar modified at the 2' position.

[17] The 2'-position group of the nucleoside modified at the 2' position is 2'-OR 1 , 2'-R 1 , 2'-R 2 Ure 1 , 2'-SH, 2'-SR 1 , 2'-NH2, 2'-NHR 1 , 2'-NR 1 2, 2'-N3, 2'-CN, 2'-F, 2'-Cl, 2'-Br, 2'-I, and 2'-R 2 C(O)XR 3 (In each group, R 1R is alkyl or aryl; 2 is an alkylene; X is an oxygen atom, NH or NR 1 And; R 3 The antisense oligonucleotide described in

[16] above, wherein the group is selected from the group consisting of (where is alkyl).

[0523]

[18] The antisense oligonucleotide according to any one of [1] to

[12] , wherein at least one of the modified internucleoside bonds contained in the oligonucleotide is a modified phosphate bond selected from the group consisting of a phosphorothioate bond, a phosphorodithioate bond, a phosphotriester bond, an alkylphosphonate bond, an aminoalkylphosphotriester bond, an alkylenephosphonate bond, a phosphine bond, a phosphoramidate bond, an aminoalkylphosphorimidate bond, a thiophosphorimidate bond, a thionoalkylphosphonate bond, a thionoalkylphosphotriester bond, a thiophosphate bond, a selenophosphate bond, a boranophosphate bond, a mesylphosphorimidate bond, and a phosphoryl(1,3-dimethylimidazolidined-2-imine)amide bond.

[0524]

[19] The antisense oligonucleotide according to any one of [1] to

[12] , wherein the nucleic acid base portion of the oligonucleotide comprises at least one modified nucleic acid base.

[20] The antisense oligonucleotide according to

[19] , wherein the modified nucleic acid base is 5-methylcytosine.

[0525]

[21] An antisense oligonucleotide comprising an oligonucleotide to which 7 to 30 nucleosides are attached, wherein the oligonucleotide is The central region (G) consists of 5 to 20 linked nucleosides. A 5' region (W) consisting of 1 to 5 linked nucleosides 5 ), and A 3' region (W) consisting of 1 to 5 linked nucleosides 3 ) including, The central region (G) is the 5' region (W 5 ) and 3' region (W 3 It is located between ) and the 5' region (W 5 ) and 3' region (W 3 An antisense oligonucleotide wherein each nucleoside comprises at least one modified sugar, the nucleoside of the central region (G) optionally comprises a deoxyribonucleoside, and the oligonucleotide is at least 80% complementary to the isolength portion of the IL-11 nucleic acid.

[0526]

[22] An antisense oligonucleotide according to any one of the above items [1] to

[21] , which has inhibitory activity on the expression of IL-11 or IL-11 mRNA.

[23] Antisense oligonucleotides as described in any one of items [1] to

[12] above, or pharmaceutically acceptable sal...

Claims

1. An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide is complementary to the isolength portion of the IL-11 nucleic acid, and the oligonucleotide comprises at least one modification selected from modified sugars, modified nucleoside bonds, and modified nucleic acid bases.

2. The antisense oligonucleotide according to claim 1, wherein the nucleic acid base sequence of the oligonucleotide is at least 80% complementary to the isolength portion of the IL-11 nucleic acid.

3. The antisense oligonucleotide according to claim 1 or 2, wherein the IL-11 nucleic acid has the nucleic acid base sequence of SEQ ID NO: 1 or 2.

4. The nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 27-42, 82-97, 94-109, 148-163, 152-167, 170-185, 198-213, 240-255, 322-337, 331-346, 337-352, 340-355, 357-372, 363-378, 368-383, 379-394, 407-422, 418-433, 422-437, 427-44 2, 428-443, 431-446, 451-466, 454-469, 455-470, 456-471, 456-473, 457-472, 458-473, 472-487, 473-488, 490-505, 492-507, 493-508, 494-509, 495-510, 496-511, 497-512, 499-514, 500-515, 501-516, 502-517, 503-51 8, 504-519, 505-520, 506-521, 507-522, 508-523, 509-524, 510-525, 510-527, 511-526, 512-527, 527-542, 574-589, 577-592, 683-700, 691-706, 696-711, 701-716, 717-732, 774-789, 776-791, 777-792, 778-793, 780-79 5. An antisense oligonucleotide according to any one of claims 1 to 3, which is at least 80% complementary to an equal-length portion within 783-798, 784-799, 785-800, 786-801, 787-802, 899-914, 904-919, 1115-1130, 1127-1142, 1138-1153, 1158-1173, 1766-1781, 2266-2281, or 2324-2339.

5. The nucleic acid base sequence of the oligonucleotide is the nucleic acid bases 627-642, 682-697, 694-709, 766-781, 930-945, 956-971, 1343-1358, 1558-1573, 1607-1622, 2132-2147, 2160-2175, 2202-2217, 2290-2305, 2348-2363, 2363-2378, 2372-2387, 2383-2398, 2412-2427, 2477-2492, 2498-2513, 2501-2516, 2518-2533, 2524-2539, 2 529-2544, 2540-2555, 2690-2705, 2694-2709, 2699-2714, 2700-2715, 2703-2718, 2723-2738, 2726-2741, 2727-2742, 2728-2743, 2728-2745, 2729-2 744, 2730-2745, 2744-2759, 2745-2760, 2762-2777, 2764-2779, 2765-2780, 2766-2781, 2767-2782, 2768-2783, 2769-2784, 2771-2786, 2772-2787, 2 773-2788, 2774-2789, 2775-2790, 2776-2791, 2777-2792, 2778-2793, 2779-2794, 2780-2795, 2781-2796, 2782-2797, 2782-2799, 2783-2798, 2784- 2799, 2799-2814, 2852-2867, 2865-2880, 2915-2930, 2946-2961, 2978-2993, 2999-3014, 3037-3052, 3073-3088, 3111-3126, 3124-3139, 3134-3149, 3145-3160, 3163-3178, 3184-3199, 3199-3214, 3226-3241, 3245-3260, 3258-3273, 3278-3293, 3290-3305, 3626-3641, 3664-3679, 3690-3705, 3705- 3720, 3749-3764, 3764-3779, 3787-3802, 3820-3835, 3850-3865, 3862-3877, 3902-3917, 3926-3941, 3940-3955, 3963-3978, 3984-3999, 3999-4014,4018-4033, 4032-4047, 4051-4066, 4068-4083, 4086-4101, 4161-4176, 4180-4195, 4290-4305, 4373-4388, 4500-4515, 4528-4543, 4543-4558, 4578-4593, 460 1-4616, 4622-4637, 4646-4661, 4653-4668, 4676-4691, 4698-4713, 4751-4766, 4780-4795, 4799-4814, 4852-4867, 4879-4894, 4987-5004, 4995-5010, 5000-50 15. An antisense oligonucleotide according to any one of claims 1 to 3, which is at least 80% complementary to an equal-length portion within 5005-5020, 5021-5036, 5078-5093, 5080-5095, 5081-5096, 5082-5097, 5084-5099, 5087-5102, 5088-5103, 5089-5104, 5090-5105, 5091-5106, 5203-5218, 5208-5223, 5419-5434, 5431-5446, 5442-5457, 5462-5477, 6070-6085, 6570-6585, or 6628-6643.

6. The antisense oligonucleotide according to any one of claims 1 to 5, wherein the nucleic acid base sequence of the oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to the isochromatic portion of the nucleic acid bases of SEQ ID NO: 1 or 2.

7. The antisense oligonucleotide according to any one of claims 1 to 6, wherein the number of linked nucleosides is 15 to 22, 16 to 22, or 16 to 18.

8. An antisense oligonucleotide comprising an oligonucleotide consisting of 7 to 30 linked nucleosides, wherein the nucleic acid base sequence of the oligonucleotide has a nucleic acid base sequence containing at least 5 consecutive nucleic acid bases from any of the nucleic acid bases included in the nucleic acid base sequence selected from SEQ ID NOs: 4 to 156, and the oligonucleotide comprises at least one modification selected from modified sugar, modified nucleoside bond, and modified nucleic acid base.

9. The antisense oligonucleotide according to claim 8, wherein the number of linked nucleosides is 15 to 22, 16 to 22, or 16 to 18.

10. The antisense oligonucleotide according to claim 8 or 9, wherein the oligonucleotide has a nucleic acid base sequence comprising at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 consecutive nucleic acid bases from any of the nucleic acid base sequences selected from SEQ ID NOs: 4 to 156.

11. The antisense oligonucleotide according to any one of claims 8 to 10, wherein the oligonucleotide comprises a nucleic acid base sequence selected from SEQ ID NOs: 4 to 156.

12. The antisense oligonucleotide according to any one of claims 8 to 10, wherein the oligonucleotide has a nucleic acid base sequence consisting of a nucleic acid base sequence selected from SEQ ID NOs: 4 to 156.

13. The antisense oligonucleotide according to any one of claims 1 to 12, wherein at least one of the modified sugars contained in the oligonucleotide is a bicyclic sugar.

14. The bicyclic sugar is a bicyclic sugar that crosslinks the 4'-2' positions, and the crosslinking at the 4'-2' positions is 4'-CH ２ -O-2'; (LNA nucleoside), 4'-(CH ２ ) ２ -O-2': (ENA nucleoside), 4'-CH(CH ３ )-O-2': (cEt nucleoside), 4'-C(=O)-N(CH ３ )-2': (AmNA nucleoside), 4'-CH ２ -N(C(=NH)(NH ２ ))-2': (GuNA nucleoside), 4'-CH ２ -N(C(=NH)(NHtBu)-2'; (GuNA(t-Bu) nucleoside), 4'-C(CH ３ )) ２ -O-2', 4'-CH(OCH ２ CH ３ )-O-2', 4'-CH ２ -CH(CH ３ )-2', 4'-CH ２ -C(=CH ２ )-2', 4'-CH ２ -CH ２ -CH ２ -2', 4'-CH ２ -NH-O-2', 4'-CH ２ -N(CH ３ )-O-2', 4'-CH ２ -NH-2', 4'-CH ２ -N(CH ３ )-2', 4'-CH ２ -N(OCH ３ )-2', 4'-CH ２ -O-NH-2', 4'-CH ２ -O-N(CH ３ )-2',, 4'-CH ２ -S-2', 4'-C(-CH ２ CH ２ -)-O-2': (scpBNA nucleoside), and is selected from the group consisting of, the antisense oligonucleotide according to claim 13.

15. The antisense oligonucleotide according to any one of claims 1 to 12, wherein at least one of the modified sugars contained in the oligonucleotide is a non-bicyclic modified sugar.

16. The antisense oligonucleotide according to claim 15, wherein the non-bicyclic modified sugar is a sugar modified at the 2' position.

17. The group at the 2' position of the nucleoside modified at the 2' position is 2'-OR １ , 2'-R １ , 2'-R ２ OR １ , 2'-SH, 2'-SR １ , 2'-NH ２ , 2'-NHR １ , 2'-NR １ ２ , 2'-N ３ , 2'-CN, 2'-F, 2'-Cl, 2'-Br, 2'-I, and 2'-R ２ C(O)XR ３ (In each group, R １ R is alkyl or aryl; ２ is an alkylene; X is an oxygen atom, NH or NR １ And; R ３ The antisense oligonucleotide according to claim 16, wherein the group is selected from the group consisting of (where is alkyl).

18. The antisense oligonucleotide according to any one of claims 1 to 12, wherein at least one of the modified internucleoside bonds contained in the oligonucleotide is a modified phosphate bond selected from the group consisting of a phosphorothioate bond, a phosphorodithioate bond, a phosphotriester bond, an alkylphosphonate bond, an aminoalkylphosphotriester bond, an alkylenephosphonate bond, a phosphine bond, a phosphoramidate bond, an aminoalkylphosphorimidate bond, a thiophosphorimidate bond, a thionoalkylphosphonate bond, a thionoalkylphosphotriester bond, a thiophosphate bond, a selenophosphate bond, a boranophosphate bond, a mesylphosphorimidate bond, and a phosphoryl(1,3-dimethylimidazolidined-2-imine)amide bond.

19. The antisense oligonucleotide according to any one of claims 1 to 12, wherein the nucleic acid base portion of the oligonucleotide comprises at least one modified nucleic acid base.

20. The antisense oligonucleotide according to claim 19, wherein the modified nucleic acid base is 5-methylcytosine.

21. An antisense oligonucleotide comprising an oligonucleotide to which 7 to 30 nucleosides are bonded, wherein the oligonucleotide is The central region (G) consists of 5 to 20 linked nucleosides. A 5' region (W) consisting of 1 to 5 linked nucleosides ５ ), and A 3' region (W) consisting of 1 to 5 linked nucleosides ３ ) including, The central region (G) is the 5' region (W ５ ) and 3' region (W ３ It is located between ) and the 5' region (W ５ ) and 3' region (W ３ An antisense oligonucleotide wherein each nucleoside comprises at least one modified sugar, the nucleoside of the central region (G) optionally comprises a deoxyribonucleoside, and the oligonucleotide is at least 80% complementary to the isolength portion of the IL-11 nucleic acid.

22. An antisense oligonucleotide according to any one of claims 1 to 21, having inhibitory activity on the expression of IL-11 or IL-11 mRNA.

23. An antisense oligonucleotide according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

24. Antisense oligonucleotides, including modified oligonucleotides having the chemical structures listed in the table below, or pharmaceutically acceptable salts thereof, or solvates thereof. Table 1 Table 2 Table 3 In the table, "(L)" represents LNA, "(V)" represents a 2'-O-MCE nucleoside, lowercase letters represent deoxyribonucleosides, uppercase letters (except for "L" in (L) and "V" in (V)) represent ribonucleosides, "^" represents a phosphorothioate bond, "5(x)" indicates that the nucleic acid base of the deoxyribonucleoside is 5-methylcytosine, and "5" in "5(V)" and "5(L)" indicates that the nucleic acid base of the nucleoside is 5-methylcytosine. In the notation of chemical structures, when "^" is not indicated between two adjacent nucleosides, the internucleoside bond between those two nucleosides is a phosphodiester bond.

25. The following formula: 【Chemistry 1】 The antisense oligonucleotide of Sequence ID No. 260, represented by [formula], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

26. The following formula: 【Chemistry 2】 The antisense oligonucleotide of Sequence ID No. 263, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

27. The following formula: 【Transformation 3】 The antisense oligonucleotide of sequence number 264, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

28. The following formula: 【Chemistry 4】 The antisense oligonucleotide of Sequence ID No. 210, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

29. The following formula: 【Transformation 5】 The antisense oligonucleotide of Sequence ID No. 211, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

30. The following formula: 【Transformation 6】 The antisense oligonucleotide of Sequence ID No. 213, represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

31. The following formula: 【Transformation 7】 The antisense oligonucleotide of sequence number 349 represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

32. A pharmaceutical composition characterized by containing at least one antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, according to any one of claims 1 to 31.

33. A method for preventing and / or treating a disease involving IL-11, comprising administering a pharmaceutical composition containing at least one antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient to a subject in need of prevention and / or treatment of the disease.

34. The method for prevention and / or treatment according to claim 33, wherein the disease involving IL-11 is selected from fibrotic diseases, gastrointestinal polyposis, inflammatory diseases, cancer, abnormal uterine bleeding, and pre-eclampsia.

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