TGFB2-IRF5 therapeutic agent for cancer

Abstract

This invention relates to agents, uses, and methods for treating cancer using agents to suppress IRF5 expression. Synergistic therapies include agents, uses, and methods for treating cancer using agents to suppress IRF5 expression in combination with agents to suppress TGF-β2 expression. One or more biomarkers may be used to select subjects who will benefit from the methods, agents, or uses, including IFNGR2, JAK1, and STAT1; as well as TGF-β2 and one or more of IRF5, TLR9, FOXP3, CCL22, CREB5, CD8a, CD86, CC14, CD163, ITGAX, and CD11c. The agents and compositions may be used in combination with chemotherapy or other standard therapeutic therapies. TIFF2026519789000031.tif100168

Description

Technical Field

[0001] Sequence Listing This application includes a sequence listing that was created on May 15, 2024, and electronically submitted as a ST.26 file named 018988-015WO1_SL.xml, with a size of 904,128 bytes.

[0002] Technical Field The present invention relates to an agent, use, and method for treating cancer using an agent for suppressing the expression of IRF5. The synergistic therapy further includes an agent, use, and method for treating cancer using an agent for suppressing the expression of IRF5 in combination with an agent for suppressing the expression of TGF-β2. One or more biomarkers can be used to select a subject who benefits from the method, agent, or use, including IFNGR2, JAK1, and STAT1; and one or more of TGF-β2 and IRF5, TLR9, FOXP3, CCL22, CREB5, CD8a, CD86, CC14, CD163, ITGAX, and CD11c. The agents and compositions can be used in combination with chemotherapy or other standard therapeutic treatments.

Background Art

[0003] Background Cancer is a complex pathological condition involving multiple diverse cellular pathways. Due to this complexity, many anticancer drugs have limited or partial therapeutic efficacy.

[0004] Disadvantages of conventional therapies include insufficient effectiveness, determined by overall survival.

[0005] Further disadvantages of conventional therapies include serious unwanted side effects such as killing healthy cells in addition to cancer cells.

[0006] Additional disadvantages of anticancer agents include high toxicity at the required therapeutic dosage levels.

[0007] There is a need for methods, agents, and uses for cancer that increase efficacy and reduce toxicity and undesirable side effects.

[0008] To deliver significant antitumor and cancer immunotherapy effects, therapeutic compositions from different agents are required, which can reduce side effects and adverse health effects. There is an urgent need for improved guidance on the use of such compositions, including the use of appropriate biomarkers to select the synergistic effects of those compositions. [Overview of the Initiative]

[0009] overview The present invention relates to agents, uses, and methods for treating cancer using agents for inhibiting or suppressing IRF5 expression, either alone or in combination with other agents.

[0010] Aspects of the present invention provide synergistic therapies comprising agents, uses, and methods for treating cancer using an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression.

[0011] This disclosure further encompasses the use of biomarkers for selecting subjects who will benefit from the methods, agents, or uses disclosed herein, the biomarkers of which include IFNGR2, JAK1, and STAT1; as well as TGF-β2 and one or more of IRF5, TLR9, FOXP3, CCL22, CREB5, CD8a, CD86, CC14, CD163, ITGAX, and CD11c.

[0012] The anticancer agents and compositions of this disclosure can also be used in combination with chemotherapy and other standard treatments for cancer.

[0013] In some embodiments, the methods and therapeutic strategies of the present invention can increase efficacy and reduce toxic side effects and adverse health effects in the treatment of cancer.

[0014] In a further embodiment, the methods and therapeutic strategies of the present invention can improve therapeutic guidance by using appropriate biomarkers to select synergistic effects of compositions.

[0015] The embodiments of the present invention include the following:

[0016] Agents for inhibiting or suppressing IRF5 expression to treat or induce remission of cancer symptoms in a target population.

[0017] Use of a composition containing an agent for inhibiting or suppressing IRF5 expression in the preparation of a pharmacopoeia for treating or relieving cancer symptoms in a subject.

[0018] A method for treating or relieving the symptoms of cancer in a person in need, A step of preparing a pharmaceutical composition containing an agent for inhibiting or suppressing IRF5 expression; and The step of administering a therapeutically sufficient amount of the composition to the subject. Methods that include...

[0019] The above-mentioned agents, uses, or methods, wherein the cancer is a glioma, low-grade glioma, glioblastoma, diffuse endogenous pontine glioma (DIPG), diffuse median glioma (DMG), metastases to the leptomeninges or brain, cancer of the brain or spinal cord, or CNS tumor.

[0020] The above-mentioned drug, use, or method, wherein the cancer is pancreatic cancer.

[0021] Comprising using one or more biomarkers to select a subject who will benefit from said agent, use, or method, said biomarkers being elevated levels of TGF-β2 and elevated levels of one or more of IFNGR2, JAK1, and STAT1, said agent, use, or method.

[0022] Comprising using one or more biomarkers to select a subject who will benefit from said agent, use, or method, said biomarkers being levels of TGF-β2 and levels of one or more of IRF5, TLR9, FOXP3, CCL22, CREB5, CD8a, CD86, CC14, CD163, ITGAX, and CD11c, said agent, use, or method.

[0023] Said agent, medicament, or administration One or more IRF5-specific antisense oligonucleotides that are complementary to the IRF5 transcript and 15 to 30 nucleotides in length Comprising, said agent, use, or method.

[0024] Said agent, medicament, or administration One or more IRF5-specific antisense oligonucleotides that are complementary to the pre-RNA, pre-mRNA, or mRNA of IRF5 and 18 to 21 nucleotides in length Comprising, said agent, use, or method.

[0025] Said agent, medicament, or administration One or more IRF5-specific antisense oligonucleotides that are complementary to the IRF5 transcript in any of Table 1, Table 2, and Table 3 Comprising, said agent, use, or method.

[0026] Said agent, medicament, or administration being an IRF5-specific antisense oligonucleotide: TIFF2026519789000002.tif12147, said agent, use, or method.

[0027] The above-mentioned agent, use, or method comprising an IRF5-specific antisense oligonucleotide from any of Tables 1, 2, and 3, having one or more nucleotides chemically modified as a phosphorothioate nucleoside linkage, methoxypropylphosphonate nucleoside linkage, aminophosphoric linkage to a morpholino group, 2'-OMe ribose group, 2'-MOE methoxyethyl ribose group, 2'-4'-restricted methoxyethyl bicyclic ribose group, 2'-4'-restricted ethyl bicyclic ribose group, LNA ribose group, 2'-F ribose group, or 5-methylcytodine base.

[0028] The above-mentioned agent, use, or method, wherein the agent is conjugated with polyethylene glycol, a lipid, or a tribranched N-acetylgalactosamine.

[0029] The above-mentioned agent, use, or method comprising a carrier which is sterile water for injection, physiological saline, isotonic physiological saline, phosphate-buffered physiological saline, or a combination thereof.

[0030] The above-mentioned agent, pharmaceutical, or administration is substantially free of excipients.

[0031] The above-mentioned agent, pharmaceutical, or administration is stable in a carrier at 37°C for at least 14 days.

[0032] The above-mentioned agent, drug, or administration is combined with a standard treatment procedure for cancer, the above-mentioned agent, use, or method.

[0033] The above-mentioned agent, use, or method, wherein the agent is administered by infusion, injection, or continuous intracranial infusion.

[0034] The above-mentioned agents, uses, or methods, including any one or more additional pharmaceuticals, such as targeted cancer drugs, cancer growth blockers, or EGFR inhibitors, erlotinib, gefitinib, afatinib, osimertinib, dacomitinib, and combinations thereof.

[0035] The above-mentioned agent, use, or method, including any one or more additional pharmaceuticals that are targeted cancer drugs selected from bevacizumab, everolimus, verzutifan, dabrafenib, trametinib, and combinations thereof.

[0036] The above-mentioned agent, use, or method, comprising any one or more additional pharmaceuticals which are cancer growth blockers selected from angiogenesis inhibitors, histone deacetylase inhibitors, hedgehog blockers, mTOR inhibitors, p53 inhibitors, PARP inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and combinations thereof.

[0037] This includes any one or more additional pharmaceuticals for the treatment of gliomas, selected from TMZ, radiation, and bevacizumab, or Includes any one or more additional pharmaceuticals for the treatment of pancreatic cancer, selected from paclitaxel, gemcitabine, 5FU, leucovrin, nal-irinotecan, FOLFOX, FOLFIRI, FOLFIRINOX, and nal-FIRINOX. The above-mentioned agents, uses, or methods.

[0038] The agent, drug, or administration described above reduces the mortality rate of a subject at 6, 12, 18, 24, 30, or 36 months.

[0039] The agent, drug, or administration described above increases the survival rate of the subject at 6, 12, 18, 24, 30, or 36 months.

[0040] The above agents; and Carrier A kit that includes this.

[0041] An agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression to treat or induce remission of cancer symptoms in a subject.

[0042] Use of a composition comprising an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression in the preparation of a pharmacopoeia for treating or relieving cancer symptoms in a subject.

[0043] A method for treating or relieving the symptoms of cancer in a person in need, A step of preparing a pharmaceutical composition comprising an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression; and The step of administering a therapeutically sufficient amount of the composition to the subject. Methods that include...

[0044] The above-mentioned agents, uses, or methods, wherein the cancer is a glioma, low-grade glioma, glioblastoma, diffuse endogenous pontine glioma (DIPG), diffuse median glioma (DMG), metastases to the leptomeninges or brain, cancer of the brain or spinal cord, or CNS tumor.

[0045] The above-mentioned drug, use, or method, wherein the cancer is pancreatic cancer.

[0046] The above-mentioned agent, use, or method comprises using one or more biomarkers to select subjects who will benefit from the agent, use, or method, wherein the biomarkers are levels of TGF-β2, and levels of one or more of IFNGR2, STAT1, IRF1, IRF5, CD276, and CD204.

[0047] The above-mentioned agent, use, or method, wherein the cancer is a low-grade glioma having tumor cells exhibiting wild-type IDH1 or IDH2, as well as one or more of the following: upregulated IFNGR2, upregulated STAT1, upregulated IRF1, upregulated IRF5, upregulated CD276, and upregulated CD204.

[0048] The aforementioned IRF5 agent, pharmaceutical, or administration One or more IRF5-specific antisense oligonucleotides, complementary to the IRF5 transcript and 15-30 nucleotides in length. The above-mentioned agents, uses, or methods, including the above-mentioned.

[0049] The aforementioned IRF5 agent, pharmaceutical, or administration IRF5-specific antisense oligonucleotides, one or more types of IRF5-specific antisense oligonucleotides that are complementary to IRF5 pre-RNA, pre-mRNA, or mRNA and are 18-21 nucleotides in length. The above-mentioned agents, uses, or methods, including the above-mentioned.

[0050] The aforementioned IRF5 agent, pharmaceutical, or administration One or more IRF5-specific antisense oligonucleotides complementary to the IRF5 transcripts in any of Tables 1, 2, and 3. The above-mentioned agents, uses, or methods, including the above-mentioned.

[0051] The agent for inhibiting or suppressing IRF5 expression is YE6144(S,E)-N1-(6-fluoro-3-(2-(6-morpholinopyridazine-3-yl)vinyl)-1H-indazole-5-yl)butan-1,2-diamine hydrochloride, an IRF5 dimerization cell-invasive peptide inhibitor, an NLS peptide mimetic, or a decoy peptide, as described above, its use, or method.

[0052] The aforementioned TGF-β2 agent, pharmaceutical, or administration One or more TGF-β2-specific antisense oligonucleotides, complementary to the TGF-β2 transcript and 15-30 nucleotides in length. The above-mentioned agents, uses, or methods, including the above-mentioned.

[0053] The aforementioned TGF-β2 agent, pharmaceutical, or administration One or more TGF-β2-specific antisense oligonucleotides that are complementary to TGF-β2 pre-RNA, pre-mRNA, or mRNA, and are 18-21 nucleotides in length. The above-mentioned agents, uses, or methods, including the above-mentioned.

[0054] The aforementioned TGF-β2 agent, pharmaceutical, or administration One or more TGF-β2-specific antisense oligonucleotides complementary to the TGF-β2 transcript, as listed in either Table 4 or Table 5. The above-mentioned agents, uses, or methods, including the above-mentioned.

[0055] The aforementioned agents, pharmaceuticals, or administrations are in the following combinations: The above-mentioned agents, uses, or methods, including TIFF2026519789000003.tif26142.

[0056] The above-mentioned agent, use, or method, wherein the antisense oligonucleotide is one of those listed in Tables 1, 2, 3, 4, and 5, and comprises one or more nucleotides that are chemically modified as a phosphorothioate nucleoside linkage, a methoxypropylphosphonate nucleoside linkage, an aminophosphoric linkage to a morpholino group, a 2'-OMe ribose group, a 2'-MOE methoxyethyl ribose group, a 2'-4'-restricted methoxyethyl bicyclic ribose group, a 2'-4'-restricted ethyl bicyclic ribose group, an LNA ribose group, a 2'-F ribose group, or a 5-methylcytodine base.

[0057] The above-mentioned agent, use, or method, wherein the agent is conjugated with polyethylene glycol, a lipid, or a tribranched N-acetylgalactosamine.

[0058] The above-mentioned agent, use, or method comprising a carrier which is sterile water for injection, physiological saline, isotonic physiological saline, phosphate-buffered physiological saline, or a combination thereof.

[0059] The above-mentioned agent, pharmaceutical, or administration is substantially free of excipients.

[0060] The above-mentioned agent, pharmaceutical, or administration is stable in a carrier at 37°C for at least 14 days.

[0061] The above-mentioned agent, drug, or administration is combined with a standard treatment procedure for cancer, the above-mentioned agent, use, or method.

[0062] The above-mentioned agent, use, or method, wherein the agent for inhibiting or suppressing IRF5 expression and the agent for inhibiting or suppressing TGF-β2 expression are administered together, simultaneously, sequentially, or at separate times.

[0063] The above-mentioned agent, use, or method, wherein the agent is administered by infusion, injection, or continuous intracranial infusion.

[0064] The above-mentioned agents, uses, or methods, including any one or more additional pharmaceuticals, such as targeted cancer drugs, cancer growth blockers, or EGFR inhibitors, erlotinib, gefitinib, afatinib, osimertinib, dacomitinib, and combinations thereof.

[0065] The above-mentioned agent, use, or method, including any one or more additional pharmaceuticals that are targeted cancer drugs selected from bevacizumab, everolimus, verzutifan, dabrafenib, trametinib, and combinations thereof.

[0066] The above-mentioned agent, use, or method, comprising any one or more additional pharmaceuticals which are cancer growth blockers selected from angiogenesis inhibitors, histone deacetylase inhibitors, hedgehog blockers, mTOR inhibitors, p53 inhibitors, PARP inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and combinations thereof.

[0067] This includes any one or more additional pharmaceuticals for the treatment of gliomas, selected from TMZ, radiation, and bevacizumab, or Includes any one or more additional pharmaceuticals for the treatment of pancreatic cancer, selected from paclitaxel, gemcitabine, 5FU, leucobrin, nal-irinotecan, FOLFOX, FOLFIRI, FOLFIRINOX, and nal-FIRINOX. The above-mentioned agents, uses, or methods.

[0068] The agent, drug, or administration described above reduces the mortality rate of a subject at 6, 12, 18, 24, 30, or 36 months.

[0069] The agent, drug, or administration described above increases the survival rate of the subject at 6, 12, 18, 24, 30, or 36 months.

[0070] The above agents; and Carrier A kit that includes this. [Brief explanation of the drawing]

[0071] [Figure 1]This study presents the results of a clinical outcome study in pancreatic cancer patients (PDAC) and demonstrates the beneficial impact of the therapeutic use of IRF5-specific antisense agents in combination with TGF-β2-specific antisense agents on overall survival in pancreatic cancer patients. The Kaplan-Meier chart (KM plotter) in Figure 1 shows a significant improvement in overall survival in patients with median IRF5 and low TGF-β2. This study established the basis for the therapeutic use of IRF5-specific antisense agents in combination with TGF-β2-specific antisense agents for treating pancreatic cancer. The median overall survival for patients from the IRF5 (low)-TGFβ2 (low) group was 38 months (log-rank P = 0.00059), a significant and remarkable increase compared to the 16 months observed in patients from the IRF5 (low)-TGFβ2 (high) group. [Figure 2] This study presents the results of a clinical outcome study of 513 patients with low-grade glioma (cBioPortal) and demonstrates the beneficial impact of therapeutic use of IRF5-specific antisense agents on overall survival in patients with low-grade glioma. The Kaplan-Meier chart in Figure 2 shows a significant improvement in overall survival for patients with a median IRF5 of less than 5. This study establishes the basis for the therapeutic use of IRF5-specific antisense agents for treating low-grade glioma. The median overall survival for patients from the IRF5 (low) group was 95 months (log-rank P<0.0001), a significant and remarkable increase compared to the 64 months observed for patients in the IRF5 (high) group. [Figure 3]This study presents the results of a clinical outcome study of 513 patients with low-grade glioma (cBioPortal) and demonstrates the beneficial impact of therapeutic use of IRF5-specific antisense agents in combination with TGF-β2-specific antisense agents on overall survival in patients with low-grade glioma. The Kaplan-Meier chart in Figure 3 shows a significant improvement in overall survival in patients with low TGF-β2 and median IRF5. This study establishes the basis for the therapeutic use of IRF5-specific antisense agents in combination with TGF-β2-specific antisense agents for treating low-grade glioma. The median overall survival for patients from the IRF5(low)-TGFβ2(low) group was 105 months (log-rank P<0.0001), a significant and remarkable increase compared to the 27 months observed for patients in the IRF5(high)-TGFβ2(high) group. [Figure 4] The results of a study of pediatric DIPG tumor samples are presented. mRNA expression levels were obtained for IFNGR2 (N=45), JAK1 (N=45), and STAT1 (N=45), and for primary tumor samples, they were expressed as log2-converted transcripts per million (TPM). IFNGR2 mRNA levels were significantly upregulated in DIPG samples compared to normal pontine tissue (1.58-fold increase, P=0.0006). Pediatric DIPG patients with brain tumors localized in the pons / brainstem included the following molecular subtype classifications: DMG, H3K27M (N=23); DMG, H3K27M, TP53 (N=8); HGG, H3 wild-type (N=2); HGG, H3 wild-type, TP53 (N=1); HGG, unclassified (N=10), and undetermined. mRNA expression levels in DIPG samples were compared to those in normal pontine samples from 29 pontine regions (21 subjects). The bar graph illustrates the mean mRNA expression levels in tumor samples (dark gray bars) compared to normal pontine samples (light gray bars). Statistically significant differences in mRNA expression levels were evaluated using two-way ANOVA. [Figure 5]The results of a study of pediatric DIPG tumor samples are presented. mRNA expression levels of antigen-presenting cells in pediatric DIPG tumors were downregulated compared to normal brainstem tissue. mRNA expression levels of CD14 (N=45), CD163 (N=45), CD86 (N=45), and ITGAX (N=45) were obtained (log2 TPM) from pediatric DIPG samples and compared to expression in normal pontine samples. The bar graph illustrates the mean mRNA expression levels in tumor samples from pediatric DIPG patients (dark gray bars) compared to normal pontine samples (light gray bars). Compared to normal brainstem / pontine tissue, mRNA expression of CD14, CD163, and ITGAX in pediatric DIPG patients was significantly reduced by 1.64-fold (P=0.037), 1.75-fold (P=0.019), and 3.33-fold (P<0.0001), respectively. Differences in mRNA expression levels were evaluated using two-way ANOVA. [Modes for carrying out the invention]

[0072] Detailed explanation of this disclosure This invention relates to methods, compositions, and their use for treating or relieving cancer symptoms in human or animal subjects using pharmaceutical compositions designed to enhance antitumor effects.

[0073] One aspect of the present invention aims to suppress IRF5 mRNA expression using, for example, an antisense oligonucleotide.

[0074] This invention relates to agents, compositions, uses, drug products, and methods for treating cancer using agents for inhibiting or suppressing IRF5 expression, agents for inhibiting or suppressing TGF-β2 expression, and combinations thereof. These agents may be used in combination with checkpoint inhibitors.

[0075] Synergistic therapies include combinations of agents that inhibit or suppress IRF5, either alone or in conjunction with agents that suppress TGF-β2 expression.

[0076] In certain embodiments, agents for suppressing IRF5 expression can be used alone or in combination with agents for suppressing TGF-β2 expression to treat or induce remission of cancer symptoms in a subject.

[0077] A further embodiment involves the use of a composition comprising an agent for suppressing IRF5 expression, either alone or in combination with an agent for suppressing TGF-β2 expression, in the preparation of a pharmacopoeia for treating or relieving cancer symptoms in a subject.

[0078] Additional embodiments include methods for treating or relieving cancer symptoms in a subject requiring such treatment, the methods comprising: preparing a pharmaceutical composition comprising an agent for suppressing IRF5 expression, either alone or in combination with an agent for suppressing TGF-β2 expression; and administering the composition to the subject.

[0079] While not wishing to be constrained by theory, the applicants have found that of the three isoforms of TGF-β, only TGF-β2 has been found to be associated with the pathogenesis of cancer. Accordingly, aspects of the present invention provide agents and methods for inhibiting or suppressing the expression of TGF-β2 in combination with other agents, which result in remarkable improvements in overall survival in cancer patients.

[0080] In some embodiments, one or more biomarkers, including IRF5 and / or ITGAM, may be used to select subjects who will benefit from the method, agent, or use. Additional biomarkers include IFNGR2, JAK1, and STAT1; as well as IRF5, TLR9, FOXP3, CCL22, CREB5, CD8a, CD86, IFNGR2, CC14, CD163, ITGAX, and CD11c.

[0081] As used herein, the term "agent" can refer to one or more active compounds; a combination of active compounds; or a composition comprising one or more active compounds with a carrier and / or solvent and / or any number of excipients. In some embodiments, a composition may be a pharmaceutical composition. In certain embodiments, a composition may be a pharmaceutical composition containing a therapeutically effective amount of one or more active compounds. Some examples of excipients are shown in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975, and Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980. Methods for determining the therapeutically effective amount of a compound are known in the art.

[0082] In some embodiments, the methods and therapeutic strategies of the present invention can increase efficacy and reduce toxic side effects and adverse health effects in the treatment of cancer.

[0083] In a further embodiment, the methods and therapeutic strategies of the present invention can improve therapeutic guidance by using appropriate biomarkers to select synergistic effects of compositions.

[0084] Human IRF5-specific antisense oligodeoxynucleotides Aspects of the present invention further include pharmaceutical compositions for inhibiting or suppressing IRF5 expression, or for treating or relieving cancer symptoms in humans or animals. The pharmaceutical compositions may include pharmaceutically acceptable salt forms, ester forms, or polymorphs or stereoisomers of any active agent of the present disclosure, as well as a carrier. IRF5 inhibitors may be selected from IRF5-specific antisense oligonucleotides. The carrier may be sterile water for injection, saline, isotonic saline, or a combination thereof.

[0085] IRF5 antisense can be chemically modified in the same manner as described below for TGF-β2 antisense.

[0086] Examples of agents of this disclosure for inhibiting or suppressing IRF5 expression include IRF5-specific antisense oligonucleotides, as shown in Table 1.

[0087] (Table 1) IRF5-specific antisense oligonucleotides TIFF2026519789000004.tif123147

[0088] In some embodiments, the following criteria can be used for antisense oligonucleotides: A) 40% <= GC % <= 60%; B) The target sequence does not contain GGGG; C) Mean unpairing probability >= 0.5 for target site nucleotides; D) For each peak in the accessibility profile that may have a threshold probability above 0.5, all sites targeting the same peak can be ranked by their average unpairing probability (higher is better), and a maximum of n sites can be selected for each peak, where n is determined by max([peak width / site length], 2); E) Among the sites that satisfy criteria A to D, the top 20 unique sites with the highest average probability of non-pairing can be listed.

[0089] In certain embodiments, the number of reported sites can be reduced by using the mean unpaired probability with filter criteria C, D, and E to make the fracture energy calculation easier to manage.

[0090] As is well known in the art, IRF5 antisense sequences can be chemically modified to provide active variants, LNA variants, and gap mar variants thereof. These sequences can be used as active agents in any combination, for example, a pooled combination.

[0091] In some embodiments, the IRF5 antisense sequence can be an nMn RNA(2'-OMe)*-DNA*-RNA(2'-OMe)* gapmer, where n is 3 to 7 and M is 6 to 12. In certain embodiments, the IRF5 antisense sequence can be a 3-10-3 or 5-10-5 LNA*-DNA*-LNA* or cEt*-DNA*-cEt* gapmer.

[0092] It is understood that various forms of additional antisense oligonucleotides can be constructed based on the IRF5 gene sequence.

[0093] Additional examples of the agents of this disclosure for inhibiting or suppressing IRF5 expression include IRF5-specific antisense oligonucleotides, shown in Table 2.

[0094] (Table 2) IRF5-specific antisense oligonucleotides TIFF2026519789000005.tif213147TIFF2026519789000006.tif235147TIFF2026519789000007.tif235147TIFF2026519789000008.tif235147 TIFF2026519789000009.tif235147TIFF2026519789000010.tif235147TIFF2026519789000011.tif235147TIFF2026519789000012.tif235147 TIFF2026519789000013.tif235147TIFF2026519789000014.tif235147TIFF2026519789000015.tif235147TIFF2026519789000016.tif235147 TIFF2026519789000017.tif235147TIFF2026519789000018.tif235147TIFF2026519789000019.tif235147TIFF2026519789000020.tif235147

[0095] Any unmodified antisense oligonucleotide in this specification may have any number and order of nucleotides modified by phosphorothioate linkage. In some embodiments, all nucleotides can be modified by phosphorothioate linkage.

[0096] Additional examples of agents of this disclosure for inhibiting or suppressing IRF5 expression include the IRF5-specific phosphorothioate antisense oligonucleotides shown in Table 3. Phosphothioate linkages are represented by an asterisk (*).

[0097] (Table 3) IRF5-specific phosphorothioate antisense oligonucleotides TIFF2026519789000021.tif68163

[0098] In some embodiments, as described herein, the IRF5 antisense sequence may be a gapmer formed by adding 1 to 5 protected ribonucleotides to each flanking portion of the phosphorothioate deoxynucleotide sequence in Table 3. For example, the ribonucleotides may be protected with 2'-OMe, 2'-OEt, or 2'-O-MOE substituents, or with LNA, cMOE, or cEt bridges, as well as phosphorothioate linkages.

[0099] Anti-cancer methods and compositions The present invention includes agents for inhibiting or suppressing IRF5 expression to treat or induce remission of cancer symptoms in a subject.

[0100] In a further embodiment, the present invention includes the use of a composition comprising an agent for inhibiting or suppressing IRF5 expression in the preparation of a pharmacopoeia for treating or relieving symptoms of cancer in a subject.

[0101] In certain embodiments, the present invention includes a method for treating or relieving cancer symptoms in a subject of interest, the method comprising: preparing a pharmaceutical composition comprising an agent for inhibiting or suppressing IRF5 expression; and administering a therapeutically sufficient amount of the composition to the subject.

[0102] The present invention includes an agent for inhibiting or suppressing IRF5 expression, used in combination with an agent for inhibiting or suppressing TGF-β2 expression, to treat or induce remission of cancer symptoms in a subject.

[0103] In a further embodiment, the present invention includes the use of a composition comprising an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression in the preparation of a pharmacopoeia for treating or relieving cancer symptoms in a subject.

[0104] In certain embodiments, the present invention includes a method for treating or relieving cancer symptoms in a subject of interest, the method comprising: preparing a pharmaceutical composition comprising an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression; and administering a therapeutically sufficient amount of the composition to the subject.

[0105] The present invention also includes agents for inhibiting or suppressing IRF5 expression, used in combination with agents for inhibiting or suppressing TGF-β2 expression and immune checkpoint inhibitors, to treat or induce remission of cancer symptoms in a subject.

[0106] In a further embodiment, the present invention includes the use of a composition comprising an agent for inhibiting or suppressing the expression of TGF-β2 and an agent for inhibiting or suppressing the expression of IRF5 in combination with an immune checkpoint inhibitor, in the preparation of a pharmacopoeia for treating or relieving the symptoms of cancer in a subject.

[0107] In certain embodiments, the present invention includes a method for treating or relieving cancer symptoms in a subject of interest, the method comprising: preparing a pharmaceutical composition comprising an agent for inhibiting or suppressing the expression of TGF-β2 and an agent for inhibiting or suppressing the expression of IRF5 in combination with an immune checkpoint inhibitor; and administering a therapeutically sufficient amount of the composition to the subject.

[0108] The present invention includes methods for treating or relieving cancer symptoms in a human or animal subject as needed by administering to the subject a pharmaceutical composition comprising a therapeutically sufficient amount of an agent for inhibiting or suppressing the expression of TGF-β2; and by administering to the subject a therapeutically sufficient amount of a pharmaceutical composition comprising a checkpoint inhibitor.

[0109] In certain embodiments, the present invention includes agents for inhibiting or suppressing TGF-β2 expression in combination with immune checkpoint inhibitors for use in the treatment or remission of cancer symptoms in human subjects or animals.

[0110] In an additional aspect, the present invention includes the use of a composition comprising an agent for inhibiting or suppressing TGF-β2 expression in the preparation of a pharmacopoeia for treating or relieving cancer symptoms in human subjects or animals, in combination with an immune checkpoint inhibitor.

[0111] Any of the aforementioned therapeutic agents can be combined with an immune checkpoint inhibitor.

[0112] Any of the aforementioned therapeutic agents may be combined with standard treatment procedures for cancer. Anticancer agents and drugs can be administered by infusion, injection, or continuous intracranial infusion.

[0113] Any of the aforementioned therapeutic agents may be combined with one or more additional pharmaceuticals, including targeted cancer drugs, cancer growth blockers, or EGFR inhibitors, erlotinib, gefitinib, afatinib, osimertinib, dacomitinib, and combinations thereof.

[0114] In some embodiments, any of the aforementioned therapeutic agents may be combined with one or more additional pharmaceuticals that are targeted cancer drugs selected from bevacizumab, everolimus, verzutifan, dabrafenib, trametinib, and combinations thereof.

[0115] In a further embodiment, any of the aforementioned therapeutic agents may be combined with one or more additional pharmaceuticals, which are cancer growth blockers selected from angiogenesis inhibitors, histone deacetylase inhibitors, hedgehog blockers, mTOR inhibitors, p53 inhibitors, PARP inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and combinations thereof.

[0116] In certain embodiments, any of the aforementioned therapeutic agents may be combined with one or more additional pharmaceuticals for the treatment of gliomas selected from TMZ, radiation, and bevacizumab, or with one or more additional pharmaceuticals for the treatment of pancreatic cancer selected from paclitaxel, gemcitabine, 5FU, leucobrin, nal-irinotecan, FOLFOX, FOLFIRI, FOLFIRINOX, and nal-FIRINOX.

[0117] Human TGF-β2-specific phosphorothioate antisense oligodeoxynucleotide Antisense oligonucleotides (ASOs) can be single-stranded deoxyribonucleotides and may be complementary to mRNA targets. Antisense therapy can downregulate molecular targets, which can be achieved by inducing RNase H endonuclease activity that cleaves RNA-DNA heteroduplexes and significantly reduces translation of target genes. Other ASO mechanisms include inhibition of 5' cap formation, alteration of splicing processes such as splice switching, and steric hindrance of ribosome activity.

[0118] Antisense therapeutic strategies can utilize single-stranded DNA oligonucleotides that inhibit protein synthesis by mediating catalytic degradation of target mRNA or by binding to sites on mRNA required for translation. Antisense oligonucleotides can be designed to target viral RNA genomes or viral transcripts. Antisense oligonucleotides can provide an approach for identifying potential targets and therefore may correspond to potential therapeutic agents.

[0119] Antisense oligonucleotides can be small synthetic fragments of single-stranded DNA, possibly 15–30 nucleotides in length. ASOs can specifically bind to complementary DNA / RNA sequences via Watson-Crick hybridization, and once bound to the target RNA, they inhibit the translation process either by inducing cleavage mechanisms or by inhibiting mRNA maturation. ASOs can selectively inhibit gene expression with specificity. Chemical modifications to the DNA or RNA can be used to increase stability.

[0120] For example, modifications can be introduced into phosphodiester bonds, sugar rings, and the backbone. ASO antivirals can block the translation process by either (i) cleavage of mRNA mediated by ribonuclease H (RNAse H) or RNase P, or (ii) steric (non-binding) blockage of enzymes involved in the translation of the target gene. Human TGF-β2-specific phosphorothioate antisense oligodeoxynucleotide (OT-101; AP12009; Travedersen) (hereinafter referred to as OT-101 or AP12009) aims to reduce the level of TGF-β2 protein in malignant gliomas, thereby slowing disease progression.

[0121] Antisense oligodeoxynucleotides are short strings of DNA designed to downregulate gene expression by interfering with the translation of specific encoded proteins at the mRNA level. OT-101 is a synthetic 18-mer phosphorothioate oligodeoxynucleotide (S-ODN) in which all 3'-5' links are modified to phosphorothioate. The molecular formula is C 177 H 208 N 60 Na 17 O 94 P 17 S 17 Its molecular weight is 6,143 g / mol. OT-101 was designed to be complementary to a specific sequence of human TGF-β2 mRNA after gene expression.

[0122] OT-101 may be supplied as a lyophilized powder in 50 mL glass vials in three different quantities. Each vial is identified by the clinical trial drug name, trial number, dosing group, administration method, OT-101 content (mg), total volume after dissolution (mL) and resulting concentration (μM), sponsor name, manufacturer name, batch number, vial number, storage temperature, and expiration date. The investigational drug may be supplied in sealed units, separately packaged for each concentration. The packaging may include the appropriate vial and all necessary components of the administration system (i.e., syringe, tubing, and filter). Before use, the lyophilized powder of OT-101 is dissolved in an isotonic (0.9%) aqueous sodium chloride solution. A leaflet describing the preparation of the product for administration at the desired concentration may be included in the packaging.

[0123] Examples of agents of this disclosure for inhibiting or suppressing TGF-β expression include antisense oligonucleotides specific to TGF-β1, TGF-β2, or TGF-β3.

[0124] Examples of agents of this disclosure for inhibiting or suppressing TGF-β2 expression include TGF-β2-specific antisense oligonucleotides shown in Table 4, SEQ ID NO: 667-802.

[0125] (Table 4) TGF-β2-specific antisense oligonucleotides TIFF2026519789000022.tif62147TIFF2026519789000023.tif235147TIFF20265197890 00024.tif235147TIFF2026519789000025.tif235147TIFF2026519789000026.tif51147

[0126] As is well known in the art, the sequences in Table 4 can be chemically modified to provide their active variants, their LNA variants, and their gap mar variants. The sequences in Table 4 can be used as active agents in any combination, for example, a pooled combination.

[0127] It will be understood that additional antisense oligonucleotides can be constructed based on the gene sequence of TGF-β2 in this disclosure.

[0128] In some embodiments, the antisense sequence agent can be a gapmer formed by adding 1 to 5 protected ribonucleotides to each adjacent region of the phosphorothioate deoxynucleotide sequence in Table 4. For example, the ribonucleotides can be protected with 2'-OMe, 2'-OEt, or 2'-O-MOE substituents, or with LNA, cMOE, or cEt bridges, as well as phosphorothioate linkages.

[0129] In some embodiments, the agent, which is an antisense sequence, can be an nMn RNA(2'-OMe)*-DNA*-RNA(2'-OMe)* gapmer, where n is 3 to 7 and M is 6 to 12. In certain embodiments, the gapmer can be a 3-10-3 or 5-10-5 LNA*-DNA*-LNA* or cEt*-DNA*-cEt* gapmer (* represents phosphorothioate linkage).

[0130] Examples of agents of this disclosure for inhibiting or suppressing TGF-β2 expression include TGF-β2-specific antisense oligonucleotides, shown in SEQ ID NO: 803-810 in Table 5.

[0131] (Table 5) TGF-β2-specific phosphorothioate antisense oligonucleotides TIFF2026519789000027.tif55170

[0132] Aspects of the present invention further include pharmaceutical compositions for inhibiting or suppressing TGF-β expression in humans or animals, or for treating or relieving cancer symptoms. The pharmaceutical compositions may include a TGF-β inhibitor, artemisinin, its pharmaceutically acceptable salt forms, esters, polymorphs, or stereoisomers, and any combination thereof, as well as a carrier. The TGF-β inhibitor may be selected from TGF-β2-specific antisense oligonucleotides. The carrier may be sterile water for injection, saline, isotonic saline, or a combination thereof.

[0133] Importantly, the compositions of this disclosure may be substantially free of excipients. Compositions of the present invention that are substantially free of excipients have been found to be remarkably stable in a carrier. In some embodiments, the compositions may be stable at 37°C in a carrier for at least 14 days, or at least 21 days, or at least 28 days.

[0134] In additional embodiments, the pharmaceutical composition for injection may contain less than 1% by weight of an excipient, or less than 0.5% by weight of an excipient, or less than 0.1% by weight of an excipient.

[0135] OT-101 Antisense Oligonucleotide Drug Product API Travedersen / OT-101 is a synthetic 18-mer S-ODN consisting of the bases adenine (A), thymine (T), guanine (G), and cytosine (C), with all 3'-5' links modified to phosphorothioates. The sulfur modification makes the drug more resistant to degradation, resulting in increased stability in vitro and in vivo. Its molecular structure (nucleotide sequence) was designed to be complementary to a specific sequence of human transforming growth factor-beta-2 (TGF-β2) mRNA. To achieve the best antisense effect in vitro and in vivo, this sequence was selected from among relevant molecules due to its superior chemical and structural properties, bioactivity, and specificity.

[0136] Table 6 shows the chemical structure, exemplary phosphorothioate moiety (CAG), and physical characteristics of trabedersene.

[0137] (Table 6) Chemical and physical characteristics of Travedelsene TIFF2026519789000028.tif104163

[0138] The IMPs are supplied as sterile lyophilized products for injection solutions in 50H glass vials (primary containers) containing 7.37 mg of travedersen (intratumoral treatment) and 20R glass vials (primary containers) containing 250 mg of travedersen (intravenous treatment). Excipients may be absent from the finished drug product. These glass vials are commonly used for parenteral administration. The glass vials are sealed with sterile rubber stoppers suitable for lyophilization. The stoppers are sealed with crimping caps, including colored flip-off caps. For clinical use, each vial is provided in a white collapsible box to protect it from light exposure and damage during transport. Both the glass vials and collapsible boxes are labeled according to local requirements. The primary and secondary containers of the closure system meet international quality standards for packaging sterile solid drug products for injection.

[0139] Checkpoint inhibitors As referred to herein, checkpoint inhibitors, which are known in the art, are immune checkpoint inhibitors. Checkpoint inhibitors are immunotherapeutic drugs that block checkpoint proteins from binding to their partner proteins. This prevents the "off" signal from being sent, thereby allowing T cells to kill cancer cells. More specifically, checkpoint proteins such as PD-1 on T cells suppress the immune response. The binding of PD-L1 to PD-1 prevents T cells from killing tumor cells. Therefore, by blocking the binding of PD-L1 to PD-1 with immune checkpoint inhibitors, T cells may be allowed to kill tumor cells. The immune system is essentially reactivated, and as a result, T cells can attack cancer cells.

[0140] In some embodiments, the checkpoint inhibitors of the present disclosure may be inhibitors of CTLA-4, PD-1, or PD-L1.

[0141] In certain embodiments, the checkpoint inhibitors of this disclosure may be inhibitors of PD-1.

[0142] In certain embodiments, the checkpoint inhibitor of this disclosure may be pembrolizumab.

[0143] In certain embodiments, the checkpoint inhibitors of this disclosure may be pembrolizumab, nivolumab, semiprimab, spartalizumab, atezolizumab, avelumab, or durvalumab.

[0144] While we do not wish to be constrained by theory, PD-1 receptor-ligand interactions could be a major pathway for tumor hijacking and suppression of immune regulation. Under healthy conditions, the normal function of PD-1 expressed on the surface of activated T cells is to downmodulate unwanted or excessive immune responses, including autoimmune reactions. Following T cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to an immune receptor tyrosine-based switch motif in its cytoplasmic tail, which results in the dephosphorylation of effector molecules involved in the CD3 T cell signaling cascade, such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta chain-associated protein kinase (ZAP70).

[0145] Numbered embodiments of the present invention include: (1) Agents for inhibiting or suppressing IRF5 expression to treat or induce remission of cancer symptoms in a subject. (2) Use of a composition comprising an agent for inhibiting or suppressing IRF5 expression in the preparation of a medicine for treating or relieving cancer symptoms in a subject. (3) Methods for treating or relieving cancer symptoms in persons in need, A step of preparing a pharmaceutical composition containing an agent for inhibiting or suppressing IRF5 expression; and The step of administering a therapeutically sufficient amount of the composition to the subject. Methods that include... (4) Any agent, use, or method according to any of embodiments 1 to 3, wherein the cancer is a glioma, a low-grade glioma, a glioblastoma, a diffuse endogenous pontine glioma (DIPG), a diffuse median glioma (DMG), a metastasis to the leptomeninges or brain, a cancer of the brain or spinal cord, or a CNS tumor. (5) Any agent, use, or method according to any of embodiments 1 to 4, wherein the cancer is pancreatic cancer. (6) Any of embodiments 1 to 5 of an agent, use, or method, comprising using one or more biomarkers to select subjects who will benefit from the agent, use, or method, wherein the biomarkers are elevated levels of TGF-β2, and elevated levels of one or more of IFNGR2, JAK1, and STAT1. (7) Any of embodiments 1 to 6, an agent, use, or method, comprising using one or more biomarkers to select subjects who will benefit from the agent, use, or method, wherein the biomarkers are levels of TGF-β2 and levels of one or more of IRF5, TLR9, FOXP3, CCL22, CREB5, CD8a, CD86, CC14, CD163, ITGAX, and CD11c. (8) The agent, pharmaceutical, or administration is One or more IRF5-specific antisense oligonucleotides, complementary to the IRF5 transcript and 15-30 nucleotides in length. A drug, use, or method of any of embodiments 1 to 7, including the above. (9) The agent, pharmaceutical, or administration is IRF5-specific antisense oligonucleotides, one or more types of IRF5-specific antisense oligonucleotides that are complementary to IRF5 pre-RNA, pre-mRNA, or mRNA and are 18-21 nucleotides in length. A drug, use, or method of any of embodiments 1 to 8, including the above. (10) The agent, pharmaceutical, or administration is One or more IRF5-specific antisense oligonucleotides complementary to the IRF5 transcript, as listed in Table 1, Table 2, or Table 3. A drug, use, or method of any of embodiments 1 to 9, including the above. (11) A drug, use, or method according to any of embodiments 1 to 10, wherein the agent, pharmaceutical, or administration comprises an IRF5-specific antisense oligonucleotide having SEQ ID NO:1 or SEQ ID NO:657. (12) An agent, use, or method according to any of embodiments 1 to 11, comprising an IRF5-specific antisense oligonucleotide in any of Tables 1, 2, and 3, having one or more nucleotides chemically modified as a phosphorothioate nucleoside linkage, a methoxypropylphosphonate nucleoside linkage, an aminophosphoric linkage to a morpholino group, a 2'-OMe ribose group, a 2'-MOE methoxyethyl ribose group, a 2'-4'-restricted methoxyethyl bicyclic ribose group, a 2'-4'-restricted ethyl bicyclic ribose group, an LNA ribose group, a 2'-F ribose group, or a 5-methylcytodine base. (13) An agent, use, or method according to any of embodiments 1 to 12, wherein the agent is conjugated with polyethylene glycol, a lipid, or a tribranched N-acetylgalactosamine. (14) A drug, use, or method according to any of embodiments 1 to 13, comprising a carrier which is sterile water for injection, physiological saline, isotonic physiological saline, phosphate-buffered physiological saline, or a combination thereof. (15) Any agent, use, or method of administration according to any of embodiments 1 to 14, wherein the agent, pharmaceutical, or administration is substantially free of excipients. (16) A drug, use, or method according to any of embodiments 1 to 15, wherein the agent, pharmaceutical, or administration is stable in a carrier at 37°C for at least 14 days. (17) Any agent, use, or method according to any of embodiments 1 to 16, wherein the agent, pharmaceutical, or administration is combined with a standard treatment for cancer. (18) A drug, use, or method of administration of the drug by infusion, injection, or continuous intracranial infusion, as described in any of embodiments 1 to 17. (19) Any one or more additional pharmaceuticals, including targeted cancer drugs, cancer growth blockers, or EGFR inhibitors, erlotinib, gefitinib, afatinib, osimertinib, dacomitinib, and combinations thereof. A drug, use, or method of any of embodiments 1 to 18, including the above. (20) Any one or more additional pharmaceuticals that are targeted cancer drugs selected from bevacizumab, everolimus, verzutifan, dabrafenib, trametinib, and combinations thereof. A drug, use, or method of any of embodiments 1 to 19, including the above. (21) Any one or more additional drugs that are cancer growth blockers selected from angiogenesis inhibitors, histone deacetylase inhibitors, hedgehog blockers, mTOR inhibitors, p53 inhibitors, PARP inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and combinations thereof. A drug, use, or method of any of embodiments 1 to 20, including the above. (22) Any one or more additional pharmacologics for the treatment of glioma, selected from TMZ, radiation, and bevacizumab, or Includes any one or more additional pharmaceuticals for the treatment of pancreatic cancer, selected from paclitaxel, gemcitabine, 5FU, leucovrin, nal-irinotecan, FOLFOX, FOLFIRI, FOLFIRINOX, and nal-FIRINOX. An agent, use, or method according to any of embodiments 1 to 21. (23) Any agent, drug, or method of administration according to any of embodiments 1 to 22, wherein the agent, drug, or administration reduces the mortality rate of a subject at 6, 12, 18, 24, 30, or 36 months. (24) Any agent, drug, or method of administration according to any of embodiments 1 to 23, which increases the survival rate of a subject at 6, 12, 18, 24, 30, or 36 months. (25) Any agent of embodiment 1 to 24; and Carrier A kit that includes this. (26) An agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression to treat or induce remission of cancer symptoms in a subject. (27) Use of a composition comprising an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression in the preparation of a pharmacopoeia for treating or relieving cancer symptoms in a subject. (28) A method for treating or relieving the symptoms of cancer in a person in need, A step of preparing a pharmaceutical composition comprising an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression; and The step of administering a therapeutically sufficient amount of the composition to the subject. Methods that include... (29) Any agent, use, or method according to any of embodiments 26 to 28, wherein the cancer is a glioma, a low-grade glioma, a glioblastoma, a diffuse endogenous pontine glioma (DIPG), a diffuse median glioma (DMG), a metastasis to the leptomeninges or brain, a cancer of the brain or spinal cord, or a CNS tumor. (30) Any agent, use, or method according to any of embodiments 26 to 29, wherein the cancer is pancreatic cancer. (31) Any agent, use, or method of any aspect 26 to 30, comprising using one or more biomarkers to select subjects who will benefit from the agent, use, or method, wherein the biomarkers are levels of TGF-β2 and levels of one or more of IFNGR2, STAT1, IRF1, IRF5, CD276, and CD204. (32) Any agent, use, or method according to any of embodiments 26 to 31, wherein the cancer is a low-grade glioma having tumor cells exhibiting wild-type IDH1 or IDH2, as well as one or more of the following: upregulated IFNGR2, upregulated STAT1, upregulated IRF1, upregulated IRF5, upregulated CD276, and upregulated CD204. (33) The IRF5 agent, pharmaceutical, or administration is One or more IRF5-specific antisense oligonucleotides, complementary to the IRF5 transcript and 15-30 nucleotides in length. A drug, use, or method of any of embodiments 26 to 32, including the above. (34) The IRF5 agent, pharmaceutical, or administration is IRF5-specific antisense oligonucleotides, one or more types of IRF5-specific antisense oligonucleotides that are complementary to IRF5 pre-RNA, pre-mRNA, or mRNA and are 18-21 nucleotides in length. A drug, use, or method of any of embodiments 26 to 33, including the above. (35) The IRF5 agent, pharmaceutical, or administration is One or more IRF5-specific antisense oligonucleotides complementary to the IRF5 transcript, as listed in Table 1, Table 2, or Table 3. A drug, use, or method of any of embodiments 26 to 34, including the above. (36) An agent, use, or method according to any of embodiments 26 to 35, wherein the agent for inhibiting or suppressing IRF5 expression is YE6144(S,E)-N1-(6-fluoro-3-(2-(6-morpholinopyridazine-3-yl)vinyl)-1H-indazole-5-yl)butan-1,2-diamine hydrochloride, an IRF5 dimerization cell-invasive peptide inhibitor, an NLS peptide mimetic, or a decoy peptide. (37) The TGF-β2 agent, pharmaceutical, or administration described above One or more TGF-β2-specific antisense oligonucleotides, complementary to the TGF-β2 transcript and 15-30 nucleotides in length. A drug, use, or method of any of embodiments 26 to 36, including the above. (38) The TGF-β2 agent, pharmaceutical, or administration described above One or more TGF-β2-specific antisense oligonucleotides that are complementary to TGF-β2 pre-RNA, pre-mRNA, or mRNA, and are 18-21 nucleotides in length. A drug, use, or method of any of embodiments 26 to 37, including the above. (39) The TGF-β2 agent, pharmaceutical, or administration described above One or more TGF-β2-specific antisense oligonucleotides complementary to the TGF-β2 transcript, as listed in either Table 4 or Table 5. A drug, use, or method of any of embodiments 26 to 38, including the above. (40) The agent, pharmaceutical, or administration is in any of the following combinations: SEQ ID NO:1 and SEQ ID NO:667, or SEQ ID NO:657 and SEQ ID NO:803 A drug, use, or method of any of embodiments 26 to 39, including the above. (41) Any agent, use, or method according to any of embodiments 26 to 40, wherein the antisense oligonucleotide is from any of Tables 1, 2, 3, 4, and 5 and comprises one or more nucleotides that are chemically modified as a phosphorothioate nucleoside linkage, a methoxypropylphosphonate nucleoside linkage, an aminophosphoric linkage to a morpholino group, a 2'-OMe ribose group, a 2'-MOE methoxyethyl ribose group, a 2'-4'-restricted methoxyethyl bicyclic ribose group, a 2'-4'-restricted ethyl bicyclic ribose group, an LNA ribose group, a 2'-F ribose group, or a 5-methylcytodine base. (42) An agent, use, or method according to any of embodiments 26 to 41, wherein the agent is conjugated with polyethylene glycol, a lipid, or a tribranched N-acetylgalactosamine. (43) A drug, use, or method according to any of embodiments 26 to 42, comprising a carrier which is sterile water for injection, physiological saline, isotonic physiological saline, phosphate-buffered physiological saline, or a combination thereof. (44) Any agent, use, or method of administration according to any of embodiments 26 to 43, wherein the agent, pharmaceutical, or administration is substantially free of excipients. (45) A drug, use, or method according to any of embodiments 26 to 44, wherein the agent, pharmaceutical, or administration is stable in a carrier at 37°C for at least 14 days. (46) Any agent, use, or method of administration according to any of embodiments 26 to 45, wherein the agent, pharmaceutical, or administration is combined with a standard treatment procedure for cancer. (47) Any agent, use, or method according to any of embodiments 26 to 46, wherein an agent for inhibiting or suppressing the expression of IRF5 and an agent for inhibiting or suppressing the expression of TGF-β2 are administered together, simultaneously, sequentially, or at separate times. (48) A drug, use, or method of administration of the drug by infusion, injection, or continuous intracranial infusion, as described in any of embodiments 26 to 47. (49) Any one or more additional pharmaceuticals, including targeted cancer drugs, cancer growth blockers, or EGFR inhibitors, erlotinib, gefitinib, afatinib, osimertinib, dacomitinib, and combinations thereof. A drug, use, or method of any of embodiments 26 to 48, including the above. (50) Any one or more additional drugs that are targeted cancer drugs selected from bevacizumab, everolimus, verzutifan, dabrafenib, trametinib, and combinations thereof. A drug, use, or method of any of embodiments 26 to 49, including the above. (51) Any one or more additional drugs that are cancer growth blockers selected from angiogenesis inhibitors, histone deacetylase inhibitors, hedgehog blockers, mTOR inhibitors, p53 inhibitors, PARP inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and combinations thereof. A drug, use, or method of any of embodiments 26 to 50, including the above. (52) Any one or more additional pharmacologics for the treatment of glioma, selected from TMZ, radiation, and bevacizumab, or Includes any one or more additional pharmaceuticals for the treatment of pancreatic cancer, selected from paclitaxel, gemcitabine, 5FU, leucobrin, nal-irinotecan, FOLFOX, FOLFIRI, FOLFIRINOX, and nal-FIRINOX. An agent, use, or method according to any of embodiments 26 to 51. (53) Any agent, drug, or method of administration according to any of embodiments 26 to 52, which reduces the mortality rate of a subject at 6, 12, 18, 24, 30, or 36 months. (54) Any agent, drug, or method of administration according to any of embodiments 26 to 53, which increases the survival rate of a subject at 6, 12, 18, 24, 30, or 36 months. (55) Any agent of embodiment 26 to 54; and Carrier A kit that includes this.

[0146] All publications, including patents, patent application publications, and non-patent publications, as well as sequence listings, referred to herein are expressly incorporated herein by reference in their entirety for any purpose.

[0147] While the aforementioned disclosures have been described in detail as examples for the purpose of clarifying understanding, it will be apparent to those skilled in the art that certain changes and modifications are included in this disclosure and that they can be implemented within the scope of the appended claims, which are presented as examples rather than limitations, without excessive experimentation. The present invention includes all such additional embodiments, equivalents, and modifications. The present invention includes any combination or mixture of various exemplary components, examples, and features, materials, elements, or limitations in the claimed embodiments.

[0148] The designations of agents, compositions, and structures in this disclosure encompass all possible isomers, stereoisomers, diastereomers, enantiomers, and / or optical isomers understood to exist for any given structure, including racemics or any other mixtures thereof. [Examples]

[0149] Example 1: This example shows the clinical outcomes of pancreatic cancer patients who benefit from suppressing IRF5 in combination with suppressing TGF-β2.

[0150] Figure 1 shows the results of a study on clinical outcomes in pancreatic cancer patients (PDAC) and the beneficial impact of the therapeutic use of IRF5-specific antisense agents in combination with TGF-β2-specific antisense agents on overall survival in pancreatic cancer patients. The Kaplan-Meier chart (KM plotter) in Figure 1 shows a significant improvement in overall survival in patients with IRF5 < median and low TGF-β2. This study established the basis for the therapeutic use of IRF5-specific antisense agents in combination with TGF-β2-specific antisense agents for treating pancreatic cancer.

[0151] The median overall survival for patients in the IRF5 (low)-TGFβ2 (low) group was 38 months (log-rank P = 0.00059), which was a significant and remarkable increase compared to the 16 months observed in patients in the IRF5 (low)-TGFβ2 (high) group.

[0152] Example 2: This example demonstrates the clinical outcomes of patients with low-grade glioma who benefit from suppressing IRF5.

[0153] Figure 2 shows the results of a clinical outcome study of 513 patients with low-grade glioma (cBioPortal) and the beneficial impact of therapeutic use of IRF5-specific antisense agents on overall survival in patients with low-grade glioma. The Kaplan-Meier chart in Figure 2 shows a significant improvement in overall survival in patients with a median IRF5 of less than 5. This study established the basis for the therapeutic use of IRF5-specific antisense agents for treating low-grade glioma.

[0154] The median overall survival for patients in the IRF5 (low) group was 95 months (log-rank P < 0.0001), which was a significant and remarkable increase compared to the 64 months observed in patients in the IRF5 (high) group.

[0155] Example 3: This example demonstrates the clinical outcomes of patients with low-grade glioma who benefit from suppressing IRF5 in combination with suppressing TGF-β2.

[0156] Figure 3 shows the results of a clinical outcome study of 513 patients with low-grade glioma (cBioPortal) and the beneficial impact of therapeutic use of IRF5-specific antisense agents in combination with TGF-β2-specific antisense agents on overall survival in patients with low-grade glioma. The Kaplan-Meier chart in Figure 3 shows a significant improvement in overall survival in patients with low TGF-β2 and IRF5 <median. This study established the basis for the therapeutic use of IRF5-specific antisense agents in combination with TGF-β2-specific antisense agents for the treatment of low-grade glioma.

[0157] The median overall survival for patients in the IRF5 (low)-TGFβ2 (low) group was 105 months (log-rank P < 0.0001), which was a significant and remarkable increase compared to the 27 months observed in patients in the IRF5 (high)-TGFβ2 (high) group.

[0158] Example 4: This example demonstrates that IFNGR2, JAK1, and STAT1 were biomarkers for selecting pediatric DIPG patients. mRNA levels of IFNGR2, JAK1, and STAT1 can be used individually, in combination with each other, or in any combination with other biomarkers and patient inclusion criteria for selecting pediatric DIPG patients.

[0159] Figure 4 shows the results of a study of pediatric DIPG tumor samples. mRNA expression levels were obtained for IFNGR2 (N=45), JAK1 (N=45), and STAT1 (N=45), and for primary tumor samples, they were expressed as log2-converted transcripts per million (TPM). IFNGR2 mRNA levels were significantly upregulated in DIPG samples compared to normal pontine tissue (1.58-fold increase, P=0.0006). Pediatric DIPG patients with brain tumors localized in the pons / brainstem included the following molecular subtype classifications: DMG, H3K27M (N=23); DMG, H3K27M, TP53 (N=8); HGG, H3 wild-type (N=2); HGG, H3 wild-type, TP53 (N=1); HGG, unclassified (N=10), undetermined 1. mRNA expression levels in DIPG samples were compared to those in normal pontine samples from 29 pontine regions (21 subjects). The bar graph illustrates the mean mRNA expression levels in tumor samples (dark gray bars) compared to normal pontine samples (light gray bars). Statistically significant differences in mRNA expression levels were evaluated using two-way ANOVA.

[0160] Example 5: This example demonstrates that CD14, CD163, and ITGAX were biomarkers for selecting pediatric DIPG patients. The mRNA levels of CD14, CD163, and ITGAX can be used individually, in combination with each other, or in any combination with other biomarkers and patient inclusion criteria to select pediatric DIPG patients.

[0161] Figure 5 shows the results of a study of pediatric DIPG tumor samples. mRNA expression levels of antigen-presenting cells in pediatric DIPG tumors were downregulated compared to normal brainstem tissue. mRNA expression levels of CD14 (N=45), CD163 (N=45), CD86 (N=45), and ITGAX (N=45) were obtained (log2 TPM) from pediatric DIPG samples and compared to expression in normal pontine samples. The bar graph illustrates the mean mRNA expression levels in tumor samples from pediatric DIPG patients (dark gray bars) compared to normal pontine samples (light gray bars). Compared to normal brainstem / pontine tissue, mRNA expression of CD14, CD163, and ITGAX in pediatric DIPG patients was significantly reduced by 1.64-fold (P=0.037), 1.75-fold (P=0.019), and 3.33-fold (P<0.0001), respectively. Differences in mRNA expression levels were evaluated using two-way ANOVA.

Claims

1. Agents for inhibiting or suppressing IRF5 expression to treat or induce remission of cancer symptoms in a target population.

2. Use of a composition containing an agent for inhibiting or suppressing IRF5 expression in the preparation of a pharmacopoeia for treating or relieving cancer symptoms in a subject.

3. A method for treating or relieving the symptoms of cancer in a person in need, A step of preparing a pharmaceutical composition containing an agent for inhibiting or suppressing IRF5 expression; and The step of administering a therapeutically sufficient amount of the composition to the subject. Methods that include...

4. The agent, use, or method according to any one of claims 1 to 3, wherein the cancer is a glioma, a low-grade glioma, a glioblastoma, a diffuse endogenous pontine glioma (DIPG), a diffuse median glioma (DMG), a metastasis to the leptomeninges or brain, a cancer of the brain or spinal cord, or a CNS tumor.

5. The agent, use, or method according to any one of claims 1 to 3, wherein the cancer is pancreatic cancer.

6. An agent, use, or method according to any one of claims 1 to 3, comprising using one or more biomarkers to select subjects who will benefit from the agent, use, or method, wherein the biomarkers are elevated levels of TGF-β2, and elevated levels of one or more of IFNGR2, JAK1, and STAT1.

7. An agent, use, or method according to any one of claims 1 to 3, comprising using one or more biomarkers to select subjects who will benefit from the agent, use, or method, wherein the biomarkers are levels of TGF-β2 and levels of one or more of IRF5, TLR9, FOXP3, CCL22, CREB5, CD8a, CD86, CC14, CD163, ITGAX, and CD11c.

8. The aforementioned agent, pharmaceutical, or administration One or more IRF5-specific antisense oligonucleotides, complementary to the IRF5 transcript and 15–30 nucleotides in length. An agent, use, or method according to any one of claims 1 to 3, including the following:

9. The aforementioned agent, pharmaceutical, or administration IRF5-specific antisense oligonucleotides, one or more types of IRF5-specific antisense oligonucleotides that are complementary to IRF5 pre-RNA, pre-mRNA, or mRNA and are 18-21 nucleotides in length. An agent, use, or method according to any one of claims 1 to 3, including the following:

10. The aforementioned agent, pharmaceutical, or administration One or more IRF5-specific antisense oligonucleotides complementary to the IRF5 transcript, as listed in Table 1, Table 2, or Table 3. An agent, use, or method according to any one of claims 1 to 3, including the following:

11. The aforementioned agent, pharmaceutical, or administration is an IRF5-specific antisense oligonucleotide: An agent, use, or method according to any one of claims 1 to 3, including the following:

12. An agent, use, or method according to any one of claims 1 to 3, comprising an IRF5-specific antisense oligonucleotide in any of Tables 1, 2, and 3, having one or more nucleotides chemically modified as a phosphorothioate nucleoside linkage, a methoxypropylphosphonate nucleoside linkage, an aminophosphoric linkage to a morpholino group, a 2'-OMe ribose group, a 2'-MOE methoxyethyl ribose group, a 2'-4'-restricted methoxyethyl bicyclic ribose group, a 2'-4'-restricted ethyl bicyclic ribose group, an LNA ribose group, a 2'-F ribose group, or a 5-methylcytodine base.

13. The agent, use, or method according to any one of claims 1 to 3, wherein the agent is conjugated with polyethylene glycol, a lipid, or a tribranched N-acetylgalactosamine.

14. A drug, use, or method according to any one of claims 1 to 3, comprising a carrier which is sterile water for injection, physiological saline, isotonic physiological saline, phosphate-buffered physiological saline, or a combination thereof.

15. The agent, pharmacopoeia, or administration according to any one of claims 1 to 3, wherein the agent, pharmacopoeia, or administration is substantially free of excipients.

16. The agent, pharmacopoeia, or administration according to any one of claims 1 to 3, wherein the agent, pharmacopoeia, or administration is stable in a carrier at 37°C for at least 14 days.

17. The agent, drug, or method according to any one of claims 1 to 3, wherein the agent, drug, or administration is combined with a standard treatment for cancer.

18. The agent, use, or method according to any one of claims 1 to 3, wherein the agent is administered by infusion, injection, or continuous intracranial infusion.

19. Any one or more additional pharmaceuticals, including targeted cancer drugs, cancer growth blockers, or EGFR inhibitors, erlotinib, gefitinib, afatinib, osimertinib, dacomitinib, and combinations thereof. An agent, use, or method according to any one of claims 1 to 3, including the following:

20. Any one or more additional targeted cancer drugs selected from bevacizumab, everolimus, verzutifan, dabrafenib, trametinib, and combinations thereof. An agent, use, or method according to any one of claims 1 to 3, including the following:

21. Any one or more additional drugs that are cancer growth blockers selected from angiogenesis inhibitors, histone deacetylase inhibitors, hedgehog blockers, mTOR inhibitors, p53 inhibitors, PARP inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and combinations thereof. An agent, use, or method according to any one of claims 1 to 3, including the following:

22. This includes any one or more additional pharmaceuticals for the treatment of gliomas, selected from TMZ, radiation, and bevacizumab, or Includes any one or more additional pharmaceuticals for the treatment of pancreatic cancer, selected from paclitaxel, gemcitabine, 5FU, leucovrin, nal-irinotecan, FOLFOX, FOLFIRI, FOLFIRINOX, and nal-FIRINOX. The agent, use, or method according to any one of claims 1 to 3.

23. The agent, pharmacopoeia, or administration described in any one of claims 1 to 3, which reduces the mortality rate of a subject at 6, 12, 18, 24, 30, or 36 months.

24. The agent, drug, or administration according to any one of claims 1 to 3, wherein the agent, drug, or administration increases the survival rate of the subject at 6, 12, 18, 24, 30, or 36 months.

25. The agent according to any one of claims 1 to 3; and Carrier A kit that includes this.

26. An agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression to treat or induce remission of cancer symptoms in a subject.

27. Use of a composition comprising an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression in the preparation of a pharmacopoeia for treating or relieving cancer symptoms in a subject.

28. A method for treating or relieving the symptoms of cancer in a person in need, A step of preparing a pharmaceutical composition comprising an agent for inhibiting or suppressing IRF5 expression in combination with an agent for inhibiting or suppressing TGF-β2 expression; and The step of administering a therapeutically sufficient amount of the composition to the subject. Methods that include...

29. The agent, use, or method according to any one of claims 26 to 28, wherein the cancer is a glioma, a low-grade glioma, a glioblastoma, a diffuse endogenous pontine glioma (DIPG), a diffuse median glioma (DMG), a metastasis to the leptomeninges or brain, a cancer of the brain or spinal cord, or a CNS tumor.

30. The agent, use, or method according to any one of claims 26 to 28, wherein the cancer is pancreatic cancer.

31. An agent, use, or method according to any one of claims 26 to 28, comprising using one or more biomarkers to select subjects who will benefit from the agent, use, or method, wherein the biomarkers are levels of TGF-β2 and levels of one or more of IFNGR2, STAT1, IRF1, IRF5, CD276, and CD204.

32. The agent, use, or method according to any one of claims 26 to 28, wherein the cancer is a low-grade glioma having tumor cells exhibiting wild-type IDH1 or IDH2, as well as one or more of the following: upregulated IFNGR2, upregulated STAT1, upregulated IRF1, upregulated IRF5, upregulated CD276, and upregulated CD204.

33. The aforementioned IRF5 agent, pharmaceutical, or administration One or more IRF5-specific antisense oligonucleotides, complementary to the IRF5 transcript and 15–30 nucleotides in length. An agent, use, or method according to any one of claims 26 to 28, including the following:

34. The aforementioned IRF5 agent, pharmaceutical, or administration IRF5-specific antisense oligonucleotides, one or more types of IRF5-specific antisense oligonucleotides that are complementary to IRF5 pre-RNA, pre-mRNA, or mRNA and are 18-21 nucleotides in length. An agent, use, or method according to any one of claims 26 to 28, including the following:

35. The aforementioned IRF5 agent, pharmaceutical, or administration One or more IRF5-specific antisense oligonucleotides complementary to the IRF5 transcript, as listed in Table 1, Table 2, or Table 3. An agent, use, or method according to any one of claims 26 to 28, including the following:

36. The agent, use, or method according to any one of claims 26 to 28, wherein the agent for inhibiting or suppressing IRF5 expression is YE6144(S,E)-N1-(6-fluoro-3-(2-(6-morpholinopyridazine-3-yl)vinyl)-1H-indazole-5-yl)butan-1,2-diamine hydrochloride, an IRF5 dimerization cell-invasive peptide inhibitor, an NLS peptide mimetic, or a decoy peptide.

37. The aforementioned TGF-β2 agent, pharmaceutical, or administration One or more TGF-β2-specific antisense oligonucleotides, complementary to the TGF-β2 transcript and 15–30 nucleotides in length. An agent, use, or method according to any one of claims 26 to 28, including the following:

38. The aforementioned TGF-β2 agent, pharmaceutical, or administration One or more TGF-β2-specific antisense oligonucleotides that are complementary to TGF-β2 pre-RNA, pre-mRNA, or mRNA, and are 18-21 nucleotides in length. An agent, use, or method according to any one of claims 26 to 28, including the following:

39. The aforementioned TGF-β2 agent, pharmaceutical, or administration One or more TGF-β2-specific antisense oligonucleotides complementary to the TGF-β2 transcript, as listed in either Table 4 or Table 5. An agent, use, or method according to any one of claims 26 to 28, including the following:

40. The aforementioned agents, pharmaceuticals, or administrations are in the following combinations: An agent, use, or method according to any one of claims 26 to 28, including the following:

41. The agent, use, or method according to any one of claims 26 to 28, wherein the antisense oligonucleotide is from any of Tables 1, 2, 3, 4, and 5, and comprises one or more nucleotides that are chemically modified as a phosphorothioate nucleoside linkage, a methoxypropylphosphonate nucleoside linkage, an aminophosphoric linkage to a morpholino group, a 2'-OMe ribose group, a 2'-MOE methoxyethyl ribose group, a 2'-4'-restricted methoxyethyl bicyclic ribose group, a 2'-4'-restricted ethyl bicyclic ribose group, an LNA ribose group, a 2'-F ribose group, or a 5-methylcytodine base.

42. The agent, use, or method according to any one of claims 26 to 28, wherein the agent is conjugated with polyethylene glycol, a lipid, or a tribranched N-acetylgalactosamine.

43. A drug, use, or method according to any one of claims 26 to 28, comprising a carrier which is sterile water for injection, physiological saline, isotonic physiological saline, phosphate-buffered physiological saline, or a combination thereof.

44. The agent, pharmacopoeia, or administration according to any one of claims 26 to 28, wherein the agent, pharmacopoeia, or administration is substantially free of excipients.

45. The agent, pharmacopoeia, or administration according to any one of claims 26 to 28, wherein the agent, pharmacopoeia, or administration is stable in a carrier at 37°C for at least 14 days.

46. The agent, pharmacopoeia, or administration according to any one of claims 26 to 28, wherein the agent, pharmacopoeia, or administration is combined with a standard treatment for cancer.

47. An agent, use, or method according to any one of claims 26 to 28, wherein an agent for inhibiting or suppressing the expression of IRF5 and an agent for inhibiting or suppressing the expression of TGF-β2 are administered together, simultaneously, sequentially, or at separate times.

48. The agent, use, or method according to any one of claims 26 to 28, wherein the agent is administered by infusion, injection, or continuous intracranial infusion.

49. Any one or more additional pharmaceuticals, including targeted cancer drugs, cancer growth blockers, or EGFR inhibitors, erlotinib, gefitinib, afatinib, osimertinib, dacomitinib, and combinations thereof. An agent, use, or method according to any one of claims 26 to 28, including the following:

50. Any one or more additional targeted cancer drugs selected from bevacizumab, everolimus, verzutifan, dabrafenib, trametinib, and combinations thereof. An agent, use, or method according to any one of claims 26 to 28, including the following:

51. Any one or more additional drugs that are cancer growth blockers selected from angiogenesis inhibitors, histone deacetylase inhibitors, hedgehog blockers, mTOR inhibitors, p53 inhibitors, PARP inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and combinations thereof. An agent, use, or method according to any one of claims 26 to 28, including the following:

52. This includes any one or more additional pharmaceuticals for the treatment of gliomas, selected from TMZ, radiation, and bevacizumab, or Includes any one or more additional pharmaceuticals for the treatment of pancreatic cancer, selected from paclitaxel, gemcitabine, 5FU, leucobrin, nal-irinotecan, FOLFOX, FOLFIRI, FOLFIRINOX, and nal-FIRINOX. The agent, use, or method according to any one of claims 26 to 28.

53. The agent, pharmacopoeia, or administration described in any one of claims 26 to 28, which reduces the mortality rate of a subject at 6, 12, 18, 24, 30, or 36 months.

54. The agent, pharmacopoeia, or administration according to any one of claims 26 to 28, wherein the agent, pharmacopoeia, or administration increases the survival rate of a subject at 6, 12, 18, 24, 30, or 36 months.

55. The agent according to any one of claims 26 to 28; and Carrier A kit that includes this.

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