WO2023143608A1 - Composition, method for preparing same, and use thereof - Google Patents

Composition, method for preparing same, and use thereof Download PDF

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WO2023143608A1
WO2023143608A1 PCT/CN2023/073842 CN2023073842W WO2023143608A1 WO 2023143608 A1 WO2023143608 A1 WO 2023143608A1 CN 2023073842 W CN2023073842 W CN 2023073842W WO 2023143608 A1 WO2023143608 A1 WO 2023143608A1
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antibody
immune checkpoint
pharmaceutically acceptable
mrna
parts
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PCT/CN2023/073842
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French (fr)
Chinese (zh)
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曹勇斌
李陈子
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上海复东生物医药有限责任公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • RIG-I/MDA5 and TLR3 agonists of the present invention are, for example, Poly-ICLC and/or BO112.
  • the blocking agent of the present invention is for example one or more of animal fat, beeswax, carnauba wax, hydrogenated vegetable oil, stearic acid, stearyl alcohol and glyceryl monostearate.
  • the epigenetic drug is chidamide, tequelstat, evonib, seridelin or apatalone
  • the glutamine metabolism regulator is L-asparaginase CB -839, V-9302, 2-allyl-1-hydroxy-9,10-anthraquinone or sulfasalazine;
  • the target antigen in the hematological malignancies of the present invention is one or more of CD30, CD22, CD79b, CD19, CD138, CD74, CD37, CD33, CD19 and CD98.
  • the dosage form of the therapeutic agent is injection, gel, in-situ gelling system, ointment, suppository, spray, solution, suspension, emulsion, implant, penetrant, etc. Skin agent, microneedle or oral preparation.
  • Group 7 Orthotopic intratumoral injection of lyophilized powder injection of a combination of tequelstat and L-asparaginase;
  • Group 14 Orthotopic intratumoral injection of apatalone freeze-dried powder injection
  • Group 3 Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine freeze-dried powder injection;
  • Group 9 Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, and resimod combination freeze-dried powder injection;
  • Group 18 Orthotopic intratumoral injection of interleukin-15mRNA freeze-dried powder injection
  • Group 19 Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and interleukin-15mRNA composition freeze-dried powder injection;
  • Group 20 Orthotopic intratumoral injection of MK-1454 freeze-dried powder injection
  • the final dose of decitabine is 2.5 mg/kg
  • the final dose of 6-diazo-5-oxo-L-norleucine is 1 mg/kg
  • anti-PD - The final dose of L1 antibody is 0.5mg/kg
  • the final dose of anti-4-1BB antibody is 0.5mg/kg
  • the final dose of anti-CD40 antibody is 0.5mg/kg
  • anti-PD-L1/4-1BB double The final dose of anti-PD-L1/CD47 double antibody is 1mg/kg
  • the final dose of anti-PD-1/LAG-3 double antibody is 1mg/kg
  • anti-PD-1 The final dose of anti-PD-1/TIGIT-3 double antibody is 1mg/kg
  • the final dose of anti-PD-L1 antibody mRNA is 0.5mg/kg and anti -
  • the final dose of 4-1BB antibody mRNA was 0.5 mg/kg.
  • Group 7 orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-4-1BB antibody combination Freeze-dried powder injection;
  • Group 11 Intratumoral injection of anti-PD-L1/4-1BB dual-antibody freeze-dried powder injection;
  • Group 16 Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-1/LAG-3 double antibody composition lyophilized powder injection;
  • Group 17 Orthotopic intratumoral injection of anti-PD-1/TIM-3 dual-antibody freeze-dried powder injection;
  • Group 2 Orthotopic intratumoral injection of decitabine freeze-dried powder injection
  • Group 9 Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-L1/4-1BB double antibody composition lyophilized powder injection;
  • Group 3 Intravenous injection of JHU-083 freeze-dried powder injection
  • the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine
  • the acid is a solid powder; the slow-release material is gelatin microspheres (same as Example 8) and sodium alginate (same as Example 8).

Abstract

Disclosed is a composition, comprising an epigenetic drug and a glutamine metabolism regulator. The composition enables metabolic and epigenetic reprogramming in a tumor microenvironment, activates an immune response of a body to a tumor, generates a synergistic therapeutic effect against the tumor, and is a tumor-specific immunotherapy. The composition can kill in-situ tumors, and at the same time, by means of the immune response, inhibit the growth of distant metastatic tumors and reduce the probability of tumor recurrence.

Description

一种组合物、其制备方法及应用A kind of composition, its preparation method and application
本申请要求申请日为2022/1/30的中国专利申请202210114707X的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 202210114707X with a filing date of 2022/1/30. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明属于癌症治疗领域，具体涉及一种组合物、其制备方法及应用。The invention belongs to the field of cancer treatment, and specifically relates to a composition, its preparation method and application.
背景技术Background technique
表观遗传学药物治疗肿瘤是最有前景的肿瘤治疗方向之一，该法通过靶向肿瘤细胞及其所处微环境中各类细胞的表观遗传调控关键节点干预表观基因组水平，可整体上控制肿瘤的发生和进展(Ghoneim H E,Fan Y,Moustaki A,et al.De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation.[J].Cell,2017,170(1):142-157.)。与此同时，越来越多的研究发现，调控肿瘤微环境(Tumor Micro-environment，TME)中的谷氨酰胺代谢重编程，能够搅乱肿瘤的代谢，让肿瘤的“Warburg效应”瘫痪，逆转肿瘤微环境的缺氧、多酸和缺营养状态，解除肿瘤微环境的免疫抑制能力，同时直接或间接地激活T细胞等免疫细胞，提升机体对肿瘤的免疫杀伤效果(Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion[J].Science,366.)。Epigenetic drug treatment of tumors is one of the most promising directions for tumor treatment. This method intervenes at the epigenome level by targeting tumor cells and the key nodes of epigenetic regulation of various types of cells in the microenvironment, which can be used as a whole. Control tumor occurrence and progression (Ghoneim H E, Fan Y, Moustaki A, et al. De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation.[J].Cell,2017,170(1):142 -157.). At the same time, more and more studies have found that regulating the reprogramming of glutamine metabolism in the tumor microenvironment (Tumor Micro-environment, TME) can disrupt the metabolism of tumors, paralyze the "Warburg effect" of tumors, and reverse tumors. Hypoxia, acidity and nutrient deficiency in the microenvironment relieve the immunosuppressive ability of the tumor microenvironment, and at the same time directly or indirectly activate T cells and other immune cells to enhance the immune killing effect of the body against tumors (Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion [J]. Science, 366.).
发明内容Contents of the invention
本发明为了解决现有技术对肿瘤浸润T细胞的耗竭状态逆转能力不足，免疫应答率和抗肿瘤疗效仍然不足的缺陷，提供了一种组合物，其包括表观遗传药物和谷氨酰胺代谢调节剂。本发明所述组合物能够对肿瘤微环境进行代谢与表观遗传重编程，极大程度地协同激活机体对肿瘤的免疫反应，对肿瘤产生超出预料的协同治疗效果，是一种高效的肿瘤特异性免疫治疗方案，可以在有效杀灭原位肿瘤的同时通过免疫反应抑制、降低远端转移瘤的生长和肿瘤复发的概率。In order to solve the deficiencies of the prior art in reversing the exhausted state of tumor-infiltrating T cells, the immune response rate and anti-tumor efficacy are still insufficient, the present invention provides a composition, which includes epigenetic drugs and glutamine metabolism regulation agent. The composition of the present invention can carry out metabolic and epigenetic reprogramming on the tumor microenvironment, synergistically activate the body's immune response to the tumor to a great extent, and produce an unexpected synergistic therapeutic effect on the tumor. It is an efficient tumor-specific The anti-immunotherapy program can effectively kill the tumor in situ while suppressing the immune response, reducing the growth of distant metastatic tumors and the probability of tumor recurrence.
为解决上述技术问题，本发明提供以下技术方案：In order to solve the above technical problems, the present invention provides the following technical solutions:
技术方案之一：一种组合物，其包括表观遗传药物和谷氨酰胺代谢调节剂。One of the technical proposals: a composition comprising epigenetic drugs and glutamine metabolism regulators.
本发明所述表观遗传药物能够通过靶向肿瘤细胞及其所处微环境中免疫细胞、血管内皮细胞、成纤维细胞、脂肪细胞和周细胞中的一种或多种细胞的表观遗传调控关键节点干预表观基因组水平，从整体上控制肿瘤的发生和进展。 The epigenetic drug of the present invention can regulate the epigenetics of one or more cells in tumor cells and immune cells, vascular endothelial cells, fibroblasts, adipocytes and pericytes in their microenvironment Key nodes intervene at the epigenome level to control the occurrence and progression of tumors as a whole.
在本发明一较佳实施方案中，所述表观遗传药物包括DNA甲基转移酶(DNA methyl transferase，DNMT)抑制剂、组蛋白去乙酰化酶(Histone deacetylase，HDAC)抑制剂、组蛋白甲基转移酶(Histone methyltransferases，HMT)抑制剂、异柠檬酸脱氢酶(Isocitrate dehydrogenase，IDH)抑制剂、组蛋白去甲基化酶(Histone demethylase，HDM)抑制剂和Bromodomain and Extra-Terminal(BET)抑制剂中的一种或多种。In a preferred embodiment of the present invention, the epigenetic drugs include DNA methyltransferase (DNA methyl transferase, DNMT) inhibitors, histone deacetylase (Histone deacetylase, HDAC) inhibitors, histone alpha Base transferase (Histone methyltransferases, HMT) inhibitors, isocitrate dehydrogenase (Isocitrate dehydrogenase, IDH) inhibitors, histone demethylase (Histone demethylase, HDM) inhibitors and Bromodomain and Extra-Terminal (BET ) one or more of the inhibitors.
本发明所述DNA甲基转移酶抑制剂例如阿扎胞苷(Vidaza，5-azacytidine，CC-486，AZA)、地西他滨(Dacogen，decitabine，DAC)、6-巯基嘌呤(Mercaptopurine，6-mp)、SGI-1027、γ-谷维素、CM-272、EML741、NSC232003、DS-437、Guadecitabine(SGI-110)及其药学上可接受的盐、DC_517、DC-05、CM-579及其药学上可接受的盐、GSK-3484862、七尾霉素A(Nanaomycin A)、GSK-3685032、5-氟脱氧胞苷、N-邻苯二酰-L-色氨酸(N-Phthalyl-L-tryptophan，RG108)、Isofistularin-3、硫鸟嘌呤(Thioguanine，NSC 752)、Zebularine(NSC 309132)、盐酸普鲁卡因胺和(-)-表没食子儿茶素没食子酸酯中的一种或多种。DNA methyltransferase inhibitors of the present invention such as azacitidine (Vidaza, 5-azacytidine, CC-486, AZA), decitabine (Dacogen, decitabine, DAC), 6-mercaptopurine (Mercaptopurine, 6 -mp), SGI-1027, γ-oryzanol, CM-272, EML741, NSC232003, DS-437, Guadecitabine (SGI-110) and its pharmaceutically acceptable salts, DC_517, DC-05, CM-579 and its Pharmaceutically acceptable salts, GSK-3484862, Nanaomycin A (Nanaomycin A), GSK-3685032, 5-fluorodeoxycytidine, N-phthalyl-L-tryptophan (N-Phthalyl-L- One or more of tryptophan, RG108), Isofistularin-3, Thioguanine (Thioguanine, NSC 752), Zebularine (NSC 309132), procainamide hydrochloride and (-)-epigallocatechin gallate kind.
本发明所述组蛋白去乙酰化酶抑制剂例如伏立诺他(Vorinostat，SAHA，MK0683，Zolinza)、罗来地辛(Romidepsin，FK 228)、贝利斯他(Belinostat，PXD101，PX105684)、帕比司他(Panobinostat，LBH589，NVP-LBH589)、西达本胺(Tucidinostat，Chidamide)、EOC103、HDAC-IN-4、Citarinostat(ACY-241,HDAC-IN-2)、HDAC8-IN-1、HDAC-IN-7(Chidamide impurity)、HDAC1/2-IN-3、HDAC-IN-5、GSK3117391(GSK3117391A,HDAC-IN-3)、HDAC/BET-IN-1、HDACs/mTOR Inhibitor 1、JAK/HDAC-IN-1、JAK/HDAC-IN-1、Quisinostat(JNJ-26481585)及其药学可接受的盐、BRD-6929、CDK/HDAC-IN-1、PI3K/HDAC-IN-1、IDO1and HDAC1Inhibitor(Compound 10)、NKL 22(化合物4b)、CRA-026440、Mocetinostat(MGCD0103)、LMK-235、RTS-V5、TMP195、SR-4370、TMP269、CHDI-390576、CAY10603(BML-281)、EDO-S101(Tinostamustine)、恩替诺特(Entinostat，MS-275，SNDX-275)、ACY-957、非美诺(Fimepinostat，CUDC-907)、AES-135、Citarinostat(ACY241)、Citarinostat(ACY241)、Citarinostat(ACY241)、Givinostat(ITF-2357)及其药学可接受的盐、Ricolinostat(ACY-1215)、伏立诺他-d5(Vorinostat-d5，SAHA-d5)、Droxinostat(NS41080)、FNDR-20123游离碱、ACY-738、RG2833(RGFP109)、BRD73954、Givinostat(ITF-2357)及其药学可接受的盐、MI-192、Resminostat及其药学可接受的盐、PTACH(NCH-51)、TH34、Domatinostat(4SC-202游离碱)及其药学可接受的盐、BG45、瑞诺司他(Resminostat，RAS2410，4SC-201)、西达本胺-d4(Tucidinostat D4，Chidamide D4)、曲古抑菌素A、吡美尔二苯胺106(Pimelic Diphenylamide 106，TC-H 106)、1- Naphthohydroxamic acid(Compound 2)、HPOB、HPOB、Nexturastat A、丁苯羟酸(Bufexamic acid)、ACY-1083、SKLB-23bb、QTX125、AES-350、Tubacin、SW-100、达诺司他(Dacinostat，LAQ824，NVP-LAQ824)、BRD 4354、QTX125TFA、BRD3308、BRD 4354ditrifluoroacetate、丙戊酸及其药学可接受的盐、Corin、Ac-Arg-Gly-Lys(Ac)-AMC、乙酰地那林(Tacedinaline，N-acetyldinaline)、RGFP966、小白菊内酯(Parthenolide)、Ac-Lys-AMC(AML)、Alteminostat(CKD-581)、Tubastatin A及其药学可接受的盐、斯普利特麻一辛(Splitomicin，Splitomycin)、PCI-34051、Pracinostat(SB939)、巴豆苷(Crotonoside，Isoguanosine)、MPT0G211及其药学可接受的盐、UF010、MPI_5a、CG347B、CG347B、Oxamflatin(Metacept-3)、WT-161、WT-161、WT-161、辛二酰双羟肟酸(Suberoyl bis-hydroxamic acid，Suberohydroxamic acid，SBHA)、MC1568、Psammaplin A、Dihydrochlamydocin、Dihydrochlamydocin、ACY-775、4-苯基丁酸(4-Phenylbutyric acid，4-PBA)及其药学可接受的盐、Apicidin(OSI 2040)、ITSA-1、ITSA-1、ITSA-1、Nanatinostat(CHR-3996)、Nanatinostat(CHR-3996)、Scriptaid(GCK1026)、CUDC-101、Remetinostat(SHP-141)、FCHFHS-ST7612AA1、正丁酸-d7(Butanoic acid-d7)、KA2507及其药学可接受的盐、MAC-VC-PABC-ST7612AA1、Chlamydocin、Pivanex(AN-9)、Tefinostat(CHR-2845)、Tasquinimod、Nampt-IN-3(Compound 35)、BEBT-908、Gnetol、Gnetol、Gnetol、Ivaltinostat(CG-200745)及其药学可接受的盐、AR-42(HDAC-42)、Abexinostat(PCI-24781,CRA-024781)、姜黄素(Curcumin)、M344、SIS17、萝卜硫素(Sulforaphane)、BML-210、WT161、Santacruzamate A(CAY10683)、4-联苯磺酰氯、ACY-775和银莲花素A(Raddeanin A，Raddeanin R3和NSC382873)中的一种或多种。The histone deacetylase inhibitors of the present invention are, for example, Vorinostat (SAHA, MK0683, Zolinza), Romidepsin (FK 228), Belinostat (Belinostat, PXD101, PX105684), Panobinostat (Panobinostat, LBH589, NVP-LBH589), Chidamide (Tucidinostat, Chidamide), EOC103, HDAC-IN-4, Citarinostat (ACY-241, HDAC-IN-2), HDAC8-IN-1 , HDAC-IN-7(Chidamide impurity), HDAC1/2-IN-3, HDAC-IN-5, GSK3117391(GSK3117391A, HDAC-IN-3), HDAC/BET-IN-1, HDACs/mTOR Inhibitor 1, JAK/HDAC-IN-1, JAK/HDAC-IN-1, Quisinostat (JNJ-26481585) and its pharmaceutically acceptable salt, BRD-6929, CDK/HDAC-IN-1, PI3K/HDAC-IN-1, IDO1and HDAC1 Inhibitor (Compound 10), NKL 22 (Compound 4b), CRA-026440, Mocetinostat (MGCD0103), LMK-235, RTS-V5, TMP195, SR-4370, TMP269, CHDI-390576, CAY10603 (BML-281), EDO-S101 (Tinostamustine), Entinostat (Entinostat, MS-275, SNDX-275), ACY-957, Fimepinostat (CUDC-907), AES-135, Citarinostat (ACY241), Citarinostat (ACY241 ), Citarinostat (ACY241), Givinostat (ITF-2357) and its pharmaceutically acceptable salts, Ricolinostat (ACY-1215), Vorinostat-d5 (Vorinostat-d5, SAHA-d5), Droxinostat (NS41080), FNDR -20123 free base, ACY-738, RG2833 (RGFP109), BRD73954, Givinostat (ITF-2357) and its pharmaceutically acceptable salts, MI-192, Resminostat and its pharmaceutically acceptable salts, PTACH (NCH-51), TH34, Domatinostat (4SC-202 free base) and its pharmaceutically acceptable salts, BG45, Resminostat (Resminostat, RAS2410, 4SC-201), Chidamide-d4 (Tucidinostat D4, Chidamide D4), Tricurve Bacteriostatin A, Pimelic Diphenylamide 106 (Pimelic Diphenylamide 106, TC-H 106), 1- Naphthohydroxamic acid (Compound 2), HPOB, HPOB, Nexturastat A, Bufexamic acid, ACY-1083, SKLB-23bb, QTX125, AES-350, Tubacin, SW-100, Dacinostat (Dacinostat, LAQ824, NVP-LAQ824), BRD 4354, QTX125TFA, BRD3308, BRD 4354ditrifluoroacetate, valproic acid and its pharmaceutically acceptable salts, Corin, Ac-Arg-Gly-Lys(Ac)-AMC, acetyldinaline (Tacedinaline, N-acetyldinaline), RGFP966, Parthenolide, Ac-Lys-AMC (AML), Alteminostat (CKD-581), Tubastatin A and its pharmaceutically acceptable salts, Splitomicin , Splitomycin), PCI-34051, Pracinostat (SB939), Crotonoside (Crotonoside, Isoguanosine), MPT0G211 and pharmaceutically acceptable salts thereof, UF010, MPI-5a, CG347B, CG347B, Oxamflatin (Metacept-3), WT-161, WT -161, WT-161, Suberoyl bis-hydroxamic acid, Suberohydroxamic acid, SBHA, MC1568, Psammaplin A, Dihydrochlamydocin, Dihydrochlamydocin, ACY-775, 4-Phenylbutyric acid (4-Phenylbutyric acid, 4-PBA) and its pharmaceutically acceptable salts, Apicidin (OSI 2040), ITSA-1, ITSA-1, ITSA-1, Nanatinostat (CHR-3996), Nanatinostat (CHR-3996), Scriptaid (GCK1026) , CUDC-101, Remetinostat (SHP-141), FCHFHS-ST7612AA1, Butanoic acid-d7 (Butanoic acid-d7), KA2507 and its pharmaceutically acceptable salts, MAC-VC-PABC-ST7612AA1, Chlamydocin, Pivanex (AN -9), Tefinostat (CHR-2845), Tasquinimod, Nampt-IN-3 (Compound 35), BEBT-908, Gnetol, Gnetol, Gnetol, Ivaltinostat (CG-200745) and its pharmaceutically acceptable salts, AR-42 (HDAC-42), Abexinostat (PCI-24781, CRA-024781), Curcumin (Curcumin), M344, SIS17, Sulforaphane (Sulforaphane), BML-210, WT161, Santacruzamate A (CAY10683), 4-biphenyl One or more of sulfonyl chloride, ACY-775 and anemone A (Raddeanin A, Raddeanin R3 and NSC382873).
本发明所述组蛋白甲基转移酶抑制剂例如泰泽司他(Tazemetostat，EPZ-6438，E-7438)及其药学可接受的盐、氯苯氨啶(Metoprine，BW 197U)、甲氨蝶呤、埃他蝶呤、毛壳素(Chaetocin)、WDR5-IN-1、EZH2-IN-2、EZH2-IN-4、EPZ011989及其药学可接受的盐、GNA0020、新藤黄酸(Gambogenic acid)及其药学可接受的盐、CPI-360、EI1(KB-145943)、CPI-169(CPI 169R-enantiomer)、PARP/EZH2-IN-1、PF-06726304及其药学可接受的盐、GSK343、GSK126(GSK2816126A)、3-去氮腺嘌呤A(3-Deazaneplanocin A，DZNep，NSC 617989)、EBI-2511、UNC1999、EPZ005687、A-395、JQEZ5、DM-01、UNC0638、UNC0646、AMI-1、Lirametostat(CPI-1205)、MS1943、GSK503、Boc-5-氨基戊酸(5-Boc-amino-pentanoic acid，Boc-5-aminovaleric acid，Boc-NH-C4-acid，Boc-5-Ava-OH)、UNC1999、EPZ005687和CPI-169中的一种或多种。The histone methyltransferase inhibitors of the present invention such as Tazemetostat (Tazemetostat, EPZ-6438, E-7438) and pharmaceutically acceptable salts thereof, Metoprine (Metoprine, BW 197U), methotrexate Glycerin, Etapterin, Chaetocin, WDR5-IN-1, EZH2-IN-2, EZH2-IN-4, EPZ011989 and its pharmaceutically acceptable salts, GNA0020, Gambogenic acid and its pharmaceutically acceptable salt, CPI-360, EI1 (KB-145943), CPI-169 (CPI 169R-enantiomer), PARP/EZH2-IN-1, PF-06726304 and its pharmaceutically acceptable salt, GSK343, GSK126 (GSK2816126A), 3-Deazaneplanocin A (3-Deazaneplanocin A, DZNep, NSC 617989), EBI-2511, UNC1999, EPZ005687, A-395, JQEZ5, DM-01, UNC0638, UNC0646, AMI-1, Lirametostat (CPI-1205), MS1943, GSK503, Boc-5-amino-pentanoic acid (5-Boc-amino-pentanoic acid, Boc-5-aminovaleric acid, Boc-NH-C4-acid, Boc-5-Ava-OH ), UNC1999, EPZ005687 and CPI-169 in one or more.
本发明所述异柠檬酸脱氢酶抑制剂例如艾伏尼布(Ivosidenib，AG-120)、恩西地平 (Enasidenib，AG-221)及其药学上可接受的盐、Olutasidenib(FT-2102)、IDN-305、Mutant IDH1-IN-6、IDH889、Mutant IDH1-IN-1、IDH-C227、Vorasidenib(AG-881)、Mutant IDH1-IN-4(compound 434)、Mutant IDH1-IN-2、IDH1Inhibitor 3(compound 6f)、α-倒捻子素、倒捻子素-d3、AGI-6780、AGI-5198、Mutant IDH1inhibitor、AGI-5198(IDH-C35)、IDH1 Inhibitor 2(compound 13)、DS-1001b、GSK864、BAY-1436032、AGI-5198(IDH-C35)和FT-2102中的一种或多种。The isocitrate dehydrogenase inhibitors of the present invention such as Ivosidenib (Ivosidenib, AG-120), Ensidipine (Enasidenib, AG-221) and its pharmaceutically acceptable salts, Olutasidenib (FT-2102), IDN-305, Mutant IDH1-IN-6, IDH889, Mutant IDH1-IN-1, IDH-C227, Vorasidenib (AG -881), Mutant IDH1-IN-4(compound 434), Mutant IDH1-IN-2, IDH1Inhibitor 3(compound 6f), α-mangostin, mangostin-d3, AGI-6780, AGI-5198, Mutant One or more of IDH1 inhibitor, AGI-5198 (IDH-C35), IDH1 Inhibitor 2 (compound 13), DS-1001b, GSK864, BAY-1436032, AGI-5198 (IDH-C35) and FT-2102.
本发明所述组蛋白去甲基化酶抑制剂例如CC90011、domatinostat(4SC-202)、iadademstat(ORY-1001)及其药学可接受的盐、IMG-7289、seclidemstat(SP-2577)及其药学可接受的盐、vafidemstat、MK-4688、HLI373及其药学可接受的盐、RITA NSC 652287、GSK2879552及其药学可接受的盐、DDP-38003及其药学可接受的盐、TAK-418、思瑞德林(Siremadlin，HDM201)、Serdemetan(JNJ-26854165)、KDM5A-IN-1和IOX1中的一种或多种。The histone demethylase inhibitors of the present invention such as CC90011, domatinostat (4SC-202), iadademstat (ORY-1001) and pharmaceutically acceptable salts thereof, IMG-7289, seclidemstat (SP-2577) and pharmaceutical Acceptable salts, vafidemstat, MK-4688, HLI373 and its pharmaceutically acceptable salts, RITA NSC 652287, GSK2879552 and its pharmaceutically acceptable salts, DDP-38003 and its pharmaceutically acceptable salts, TAK-418, Sirui One or more of Siremadlin (Siremadlin, HDM201), Serdemetan (JNJ-26854165), KDM5A-IN-1 and IOX1.
本发明所述Bromodomain and Extra-Terminal(BET)抑制剂例如阿帕他隆(Apabetalone，RVX-208)、AZE-5153、BI-894999、birabresib(OTX-015,MK-8628)、BPI-23314、CCS-1477、米维布塞(mivebresib，ABBV-075)、PLX-2853、SF-1126、SYHA-1801、BET-BAY 002S、I-BET762(Molibresib，GSK525762A，PROTAC BRD4-binding moiety 2)及其药学可接受的盐、BET-IN-1、BET-BAY 002的S型对映异构体、I-BET151(GSK1210151A)及其药学可接受的盐、PROTAC BET-binding moiety 1、PROTAC BET-binding moiety 2、GSK040、BET-IN-2、BET-IN-4、BET bromodomain inhibitor、Molibresib besylate(GSK 525762C；I-BET 762besylate)、BETd-246、BET bromodomain inhibitor 1、GSK620、TD-428、JQ-1carboxylic acid、CF53、I-BET282、I-BET282E、PROTAC BRD2/BRD4degrader-1(compound 15)、BMS-986158、BET-IN-6、Desmethyl-QCA276(PROTAC BRD4-binding moiety 4)、GSK778(iBET-BD1)、INCB054329、INCB-057643、HJB97、Bromodomain inhibitor-8(Intermediate 21)、(S)-JQ-35(TEN-010)、CD235、CC-90010(compound 1)、(+)-JQ1PA、Alobresib(GS-5829)、PFI-1(PF-6405761)、(Rac)-BAY1238097、BAY1238097、Y06036、PNZ5、OXFBD04、ZL0420、PROTAC BRD4ligand-1、Y06137、(R)-BAY1238097、GSK097、(+)-JQ-1(JQ1)、甲基条叶蓟素(Cirsilineol)、NEO2734(EP31670)、HDAC/BET-IN-1、GS-626510、GSK1324726A(I-BET726)、CD161(NKR-P1A)、NHWD-870、BI-9564、MS645、AZD5153 6-Hydroxy-2-naphthoic acid、BY27、LT052、ZEN-3862、BETd-260(ZBC 260)、NVS-CECR2-1、GSK046(iBET-BD2)、MS417(GTPL7512)、ZEN-3411、ZEN-3219、RVX-297、SNIPER(BRD)-1、PLX51107、GNE-987、GSK973、MS402、BI 2536、ICG-001、 CCS1477、Pelabresib(CPI-0610)、SRX3207、GNE-781(compound 19)、姜黄素(Curcumin)、SGC-CBP30、Bromosporine、UNC669、BI-7273、CPI-637、dBET6、Emetine hydrochloride(NSC 33669)、Alobresib(GS-5829)、CPI-203、MS436、A-485、UNC-926、A1874、PFI-4、GSK2801、ZL0420、ARV-825、SF2523、INCB057643、PFI-3、KG-501(2-naphthol-AS-E-phosphate)、FL-411(BRD4-IN-1)、NEO2734(EP31670)、Y06036(Compound 6i)、Mivebresib(ABBV-075)、GSK5959、dBET57、dBET1、GSK6853、EED226、PF-CBP1HCl、PLX51107、AZD-5153 6-hydroxy-2-naphthoic acid(HNT salt)、PRI-724(C-82prodrug,ICG-001analog)、I-BRD9(GSK602)、GSK1324726A(I-BET726)、XMD8-92、P300/CBP-IN-3、BI 894999、INCB054329(INCB-054329,INCB-54329)、BI-9564和ABBV-744中的一种或多种。Bromodomain and Extra-Terminal (BET) inhibitors of the present invention such as Apabetalone (Apabetalone, RVX-208), AZE-5153, BI-894999, birabresib (OTX-015, MK-8628), BPI-23314, CCS-1477, mivebresib (ABBV-075), PLX-2853, SF-1126, SYHA-1801, BET-BAY 002S, I-BET762 (Molibresib, GSK525762A, PROTAC BRD4-binding moiety 2) and its Pharmaceutically acceptable salt, BET-IN-1, S-enantiomer of BET-BAY 002, I-BET151 (GSK1210151A) and its pharmaceutically acceptable salt, PROTAC BET-binding moiety 1, PROTAC BET-binding moiety 2, GSK040, BET-IN-2, BET-IN-4, BET bromodomain inhibitor, Molibresib besylate (GSK 525762C; I-BET 762besylate), BETd-246, BET bromodomain inhibitor 1, GSK620, TD-428, JQ- 1carboxylic acid, CF53, I-BET282, I-BET282E, PROTAC BRD2/BRD4degrader-1(compound 15), BMS-986158, BET-IN-6, Desmethyl-QCA276(PROTAC BRD4-binding moiety 4), GSK778(iBET- BD1), INCB054329, INCB-057643, HJB97, Bromodomain inhibitor-8(Intermediate 21), (S)-JQ-35(TEN-010), CD235, CC-90010(compound 1), (+)-JQ1PA, Alobresib (GS-5829), PFI-1(PF-6405761), (Rac)-BAY1238097, BAY1238097, Y06036, PNZ5, OXFBD04, ZL0420, PROTAC BRD4ligand-1, Y06137, (R)-BAY1238097, GSK097, (+)- JQ-1(JQ1), Cirsilineol, NEO2734(EP31670), HDAC/BET-IN-1, GS-626510, GSK1324726A(I-BET726), CD161(NKR-P1A), NHWD- 870, BI-9564, MS645, AZD5153 6-Hydroxy-2-naphthoic acid, BY27, LT052, ZEN-3862, BETd-260 (ZBC 260), NVS-CECR2-1, GSK046 (iBET-BD2), MS417 (GTPL7512 ), ZEN-3411, ZEN-3219, RVX-297, SNIPER(BRD)-1, PLX51107, GNE-987, GSK973, MS402, BI 2536, ICG-001, CCS1477, Pelabresib (CPI-0610), SRX3207, GNE-781 (compound 19), Curcumin (Curcumin), SGC-CBP30, Bromosporine, UNC669, BI-7273, CPI-637, dBET6, Emetine hydrochloride (NSC 33669), Alobresib (GS-5829), CPI-203, MS436, A-485, UNC-926, A1874, PFI-4, GSK2801, ZL0420, ARV-825, SF2523, INCB057643, PFI-3, KG-501 (2-naphthol -AS-E-phosphate), FL-411(BRD4-IN-1), NEO2734(EP31670), Y06036(Compound 6i), Mivebresib(ABBV-075), GSK5959, dBET57, dBET1, GSK6853, EED226, PF-CBP1HCl , PLX51107, AZD-5153 6-hydroxy-2-naphthoic acid (HNT salt), PRI-724 (C-82prodrug, ICG-001analog), I-BRD9 (GSK602), GSK1324726A (I-BET726), XMD8-92, One or more of P300/CBP-IN-3, BI 894999, INCB054329 (INCB-054329, INCB-54329), BI-9564 and ABBV-744.
在本发明一较佳实施方案中，所述表观遗传药物为地西他滨、西达本胺、泰泽司他、艾伏尼布、思瑞德林和阿帕他隆中的一种或多种。In a preferred embodiment of the present invention, the epigenetic drug is one of decitabine, chidamide, tezecistat, ivonibu, seridelin and apatalone or more.
本发明所述谷氨酰胺代谢调节剂能够促使肿瘤细胞、免疫细胞、血管内皮细胞、成纤维细胞、脂肪细胞和周细胞中的一种或多种发生谷氨酰胺相关的代谢改变或重编程。The glutamine metabolism regulator of the present invention can promote glutamine-related metabolic changes or reprogramming in one or more of tumor cells, immune cells, vascular endothelial cells, fibroblasts, adipocytes and pericytes.
在本发明一较佳实施方案中，所述谷氨酰胺代谢调节剂包括谷氨酰胺类似物、谷氨酰胺消耗药物、谷氨酰胺酶(GLS)抑制剂、溶质载体家族1成员5(Solute carrier family 1 member 5，SLC1A5；氨基酸转运体ASCT2)抑制剂、谷氨酸脱氢酶(Glutamate dehydrogenase，GLUD)抑制剂和氨基转移酶抑制剂和溶质载体家族7成员11(Solute carrier family 7member 11，SLC7A11；xCT系统)抑制剂中的一种或多种。In a preferred embodiment of the present invention, the glutamine metabolism regulator includes glutamine analogs, glutamine depleting drugs, glutaminase (GLS) inhibitors, solute carrier family 1 member 5 (Solute carrier family 1 member 5, SLC1A5; amino acid transporter ASCT2) inhibitor, glutamate dehydrogenase (Glutamate dehydrogenase, GLUD) inhibitor and aminotransferase inhibitor and solute carrier family 7 member 11 (Solute carrier family 7 member 11, SLC7A11 ; xCT system) inhibitors in one or more.
本发明所述谷氨酰胺类似物例如6-重氮-5-氧代-L-正亮氨酸(L-6-Diazo-5-oxonorleucine，DON)和5-重氮-4-氧代-L-正缬氨酸(L-DONV)及两者的前药、(S)-2-((S)-2-乙酰胺基-3-(1H-吲哚-3-基)丙酰胺基)-6-重氮-5-氧代己酸异丙基酯及其药学上可接受的盐、(S)-2-((S)-6-乙酰胺基-2-((3S,5S,7S)-金刚烷-1-甲酰胺基)己酰胺基)-6-重氮-5-氧代己酸酯及其药学上可接受的盐、(S)-2-((S)-2-乙酰胺基-3-(1H-吲哚-3-基)丙酰胺基)-6-重氮-5-氧代己酸及其药学上可接受的盐、JHU-083、JUH-395、重氮丝氨酸(Azaserine)、阿西维辛(Acivicin)和NQO1激活型6-重氮基-5-氧代-L-正亮氨酸前药(专利文献CN202110849576中LJR-101、LJR-102、LJR-103、LJR-104、LJR-105、LJR-106、LJR-107、LJR-108、LJR-109、LJR-110、LJR-111、LJR-112、LJR-113、LJR-401、LJR-201、LJR-202、LJR-203、LJR-204、LJR-205、LJR-206、LJR-207、LJR-208、LJR-209、LJR-210、LJR-211、LJR-212、LJR-213和LJR-501)中的一种或多种。Glutamine analogues of the present invention such as 6-diazo-5-oxo-L-norleucine (L-6-Diazo-5-oxonorleucine, DON) and 5-diazo-4-oxo- L-norvaline (L-DONV) and its prodrug, (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propionyl )-6-diazo-5-oxohexanoic acid isopropyl ester and its pharmaceutically acceptable salts, (S)-2-((S)-6-acetamido-2-((3S,5S ,7S)-adamantane-1-carboxamido)caproylamido)-6-diazo-5-oxohexanoate and its pharmaceutically acceptable salts, (S)-2-((S)- 2-Acetamido-3-(1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoic acid and its pharmaceutically acceptable salts, JHU-083, JUH-395 , diazoserine (Azaserine), acivicin (Acivicin) and NQO1 activated 6-diazo-5-oxo-L-norleucine prodrug (LJR-101, LJR-102 in patent document CN202110849576 , LJR-103, LJR-104, LJR-105, LJR-106, LJR-107, LJR-108, LJR-109, LJR-110, LJR-111, LJR-112, LJR-113, LJR-401, LJR -201, LJR-202, LJR-203, LJR-204, LJR-205, LJR-206, LJR-207, LJR-208, LJR-209, LJR-210, LJR-211, LJR-212, LJR-213 and LJR-501) in one or more.
在本发明一较佳实施方案中，所述谷氨酰胺类似物为DRP-104，或所述谷氨酰胺类 似物为DRP-104以及以下构成的组中的一种或多种：6-重氮-5-氧代-L-正亮氨酸和5-重氮-4-氧代-L-正缬氨酸及两者的前药、(S)-2-((S)-2-乙酰胺基-3-(1H-吲哚-3-基)丙酰胺基)-6-重氮-5-氧代己酸异丙基酯及其药学上可接受的盐、(S)-2-((S)-6-乙酰胺基-2-((3S,5S,7S)-金刚烷-1-甲酰胺基)己酰胺基)-6-重氮-5-氧代己酸酯及其药学上可接受的盐、(S)-2-((S)-2-乙酰胺基-3-(1H-吲哚-3-基)丙酰胺基)-6-重氮-5-氧代己酸及其药学上可接受的盐、JHU-083、JUH-395、DRP-104、重氮丝氨酸、阿西维辛和NQO1激活型6-重氮基-5-氧代-L-正亮氨酸前药。In a preferred embodiment of the present invention, the glutamine analog is DRP-104, or the glutamine The analog is DRP-104 and one or more of the group consisting of 6-diazo-5-oxo-L-norleucine and 5-diazo-4-oxo-L-norval Amino acid and prodrugs of both, (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propionamido)-6-diazo-5- Isopropyl oxohexanoate and its pharmaceutically acceptable salts, (S)-2-((S)-6-acetamido-2-((3S,5S,7S)-adamantane-1- Formamido)caproylamido)-6-diazo-5-oxohexanoate and its pharmaceutically acceptable salts, (S)-2-((S)-2-acetamido-3-( 1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoic acid and its pharmaceutically acceptable salts, JHU-083, JUH-395, DRP-104, diazoserine, Acivicin and NQO1-activating 6-diazo-5-oxo-L-norleucine prodrug.
本发明所述谷氨酰胺消耗药物例如L-天冬酰胺酶。The glutamine-depleting drug of the present invention is, for example, L-asparaginase.
本发明所述谷氨酰胺酶抑制剂例如Telaglenastat(CB-839)及其药学可接受的盐、化合物968、BPTES、IPN-60090及其药学可接受的盐、谷氨酰胺酶-抑制剂-3(Glutaminase-IN-3，compound 657)、Morphothiadin(GLS4)和UPGL00004中的一种或多种。Glutaminase inhibitors of the present invention such as Telaglenastat (CB-839) and pharmaceutically acceptable salts thereof, compound 968, BPTES, IPN-60090 and pharmaceutically acceptable salts thereof, glutaminase-inhibitor-3 One or more of (Glutaminase-IN-3, compound 657), Morphothiadin (GLS4) and UPGL00004.
本发明所述溶质载体家族1成员5抑制剂例如V-9302及其药学可接受的盐、苄基丝氨酸(Benzylserine)、γ-2-氟苄基脯氨酸(γ-2-fluorobenzyl proline，γ-FBP)、L-γ-谷氨酰基-4-硝基苯胺(L-γ-Glutamyl-p-nitroanilide，GPNA)及其药学可接受的盐和党参炔苷(Lobetyoli)中的一种或多种。Solute carrier family 1 member 5 inhibitors of the present invention such as V-9302 and pharmaceutically acceptable salts thereof, benzylserine (Benzylserine), γ-2-fluorobenzyl proline (γ-2-fluorobenzyl proline, γ -FBP), L-γ-glutamyl-4-nitroanilide (L-γ-Glutamyl-p-nitroanilide, GPNA) and its pharmaceutically acceptable salts, and one or more of tangshenoside (Lobetyoli) kind.
本发明所述谷氨酸脱氢酶抑制剂例如(-)-表没食子儿茶素没食子酸酯((-)-Epigallocatechin Gallate，EGCG)和/或2-烯丙基-1-羟基-9,10-蒽醌(2-Allyl-1-hydroxy-9,10-anthraquinone，R162)。Glutamate dehydrogenase inhibitors of the present invention such as (-)-epigallocatechin gallate ((-)-Epigallocatechin Gallate, EGCG) and/or 2-allyl-1-hydroxyl-9, 10-anthraquinone (2-Allyl-1-hydroxy-9,10-anthraquinone, R162).
本发明所述氨基转移酶抑制剂例如氨基氧乙酸(aminooxyacetic acid，AOA)、羟基丙酮酸(Hydroxypyruvic acid，β-Hydroxypyruvic acid)及其药学可接受的盐、L-副刀豆氨酸(L-Canaline)、L-环丝氨酸(L-Cycloserine((S)-4-Amino-3-isoxazolidone))、BCATc Inhibitor 2、6-氮杂胸腺嘧啶(6-Azathymine)、BCAT-IN-2和2-甲基-4(3H)-喹唑酮(2-Methylquinazolin-4-ol)中的一种或多种。Aminotransferase inhibitors of the present invention such as aminooxyacetic acid (aminooxyacetic acid, AOA), hydroxypyruvic acid (Hydroxypyruvic acid, β-Hydroxypyruvic acid) and pharmaceutically acceptable salts thereof, L-paracanavanine (L- Canaline), L-Cycloserine ((S)-4-Amino-3-isoxazolidone)), BCATc Inhibitor 2, 6-Azathymine (6-Azathymine), BCAT-IN-2 and 2- One or more of 2-Methylquinazolin-4-ol.
本发明所述溶质载体家族7成员11抑制剂例如柳氮磺吡啶、Erastin、索拉非尼(SRF)、干扰素-γ(IFN-γ)、转化生长因子(TGF1)、p53、Beclin 1、BRCA1关联蛋白1(BAP1)、毛细血管扩张性共济失调症突变蛋白(ATM)、干扰素-γ(IFN-γ)mRNA、转化生长因子(TGF1)mRNA、p53mRNA、Beclin 1mRNA、BRCA1关联蛋白1(BAP1)mRNA和毛细血管扩张性共济失调症突变蛋白(ATM)mRNA中的一种或多种。Solute carrier family 7 member 11 inhibitors of the present invention such as sulfasalazine, Erastin, Sorafenib (SRF), interferon-γ (IFN-γ), transforming growth factor (TGF1), p53, Beclin 1, BRCA1-associated protein 1 (BAP1), ataxia telangiectasia mutein (ATM), interferon-γ (IFN-γ) mRNA, transforming growth factor (TGF1) mRNA, p53 mRNA, Beclin 1 mRNA, BRCA1-associated protein 1 One or more of (BAP1) mRNA and ataxia telangiectasia mutein (ATM) mRNA.
更佳地，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸、L-天冬酰胺酶、Telaglenastat、V-9302、2-烯丙基-1-羟基-9,10-蒽醌、柳氮磺吡啶和JHU-083中的一种或多种。或所述谷氨酰胺代谢调节剂为DRP-104。或所述谷氨酰胺代谢调节剂为DRP-104以 及以下构成的组中的一种或多种：6-重氮-5-氧代-L-正亮氨酸、L-天冬酰胺酶、Telaglenastat、V-9302、2-烯丙基-1-羟基-9,10-蒽醌、柳氮磺吡啶和JHU-08。More preferably, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, L-asparaginase, Telaglenastat, V-9302, 2-allyl-1 One or more of -hydroxy-9,10-anthraquinone, sulfasalazine and JHU-083. Or the glutamine metabolism regulator is DRP-104. Or the glutamine metabolism regulator is DRP-104 with and one or more of the group consisting of: 6-diazo-5-oxo-L-norleucine, L-asparaginase, Telaglenastat, V-9302, 2-allyl-1 -Hydroxy-9,10-anthraquinone, sulfasalazine and JHU-08.
本发明所述药学上可接受的盐的非限制性例子包括、但不限于：盐酸盐、氢溴酸盐、氢碘化物、硫酸盐、硫酸氢盐、2-羟基乙磺酸盐、磷酸盐、磷酸氢盐、乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、甘油磷酸酯、半硫酸盐、庚酸盐、己酸盐、甲酸盐、琥珀酸盐、富马酸盐、马来酸盐、抗坏血酸盐、羟乙磺酸盐、水杨酸盐、甲磺酸盐、均三甲苯磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、扑酸盐(pamoate)、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐、十一酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡萄糖酸盐、甲磺酸盐、乙二磺酸盐、苯磺酸盐、对甲苯磺酸盐、锂盐、钠盐、钾盐、铵盐、镁盐、钙盐和铝盐中的一种或多种。Non-limiting examples of pharmaceutically acceptable salts of the present invention include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphoric acid Salt, Hydrogen Phosphate, Acetate, Adipate, Alginate, Aspartate, Benzoate, Bisulfate, Butyrate, Camphorate, Camphorsulfonate, Digluconate salt, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, Methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3- Phenylpropionate, Picrate, Pivalate, Propionate, Trichloroacetate, Trifluoroacetate, Phosphate, Glutamate, Bicarbonate, p-Toluenesulfonate, Deca Mono-acid salt, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, p-toluenesulfonate, lithium salt, sodium salt, potassium salt, One or more of ammonium salt, magnesium salt, calcium salt and aluminum salt.
在本发明一较佳实施方案中，所述表观遗传药物的份数为0.2～25份，所述谷氨酰胺代谢调节剂的份数为0.2～25份。In a preferred embodiment of the present invention, the number of parts of the epigenetic drug is 0.2-25 parts, and the number of parts of the regulator of glutamine metabolism is 0.2-25 parts.
在本发明一更佳实施方案中，所述表观遗传药物的份数0.3～22份，例如0.5～18份、0.8-15份、1-10份、1-5份或1-3份。In a more preferred embodiment of the present invention, the number of parts of the epigenetic drug is 0.3-22 parts, such as 0.5-18 parts, 0.8-15 parts, 1-10 parts, 1-5 parts or 1-3 parts.
在本发明一更佳实施方案中，所述谷氨酰胺代谢调节剂的份数为0.3～22份，例如0.5～18份、0.8-15份、1-10份、1-5份或1-3份。In a more preferred embodiment of the present invention, the number of parts of the regulator of glutamine metabolism is 0.3-22 parts, such as 0.5-18 parts, 0.8-15 parts, 1-10 parts, 1-5 parts or 1- 3 copies.
在本发明一较佳实施方案中，所述组合物还包括免疫佐剂或免疫检查点调节剂。所述免疫佐剂能够增强机体对抗原的应答能力或改变免疫应答类型。所述免疫检查点调节剂能够增强T细胞等免疫细胞的增殖活化以及对肿瘤细胞的识别。In a preferred embodiment of the present invention, the composition further includes an immune adjuvant or an immune checkpoint modulator. The immune adjuvant can enhance the body's ability to respond to antigens or change the type of immune response. The immune checkpoint regulator can enhance the proliferation and activation of immune cells such as T cells and the recognition of tumor cells.
在本发明一较佳实施方案中，所述免疫佐剂包括RIG-I/MDA5和TLR3激动剂、TLR4激动剂、TLR7/8激动剂、TLR9激动剂、细胞因子佐剂、细胞因子mRNA佐剂、STING激动剂和FLT3L激动剂中的一种或多种。In a preferred embodiment of the present invention, the immune adjuvant includes RIG-I/MDA5 and TLR3 agonist, TLR4 agonist, TLR7/8 agonist, TLR9 agonist, cytokine adjuvant, cytokine mRNA adjuvant , one or more of a STING agonist and a FLT3L agonist.
本发明所述RIG-I/MDA5和TLR3激动剂例如Poly-ICLC和/或BO112。The RIG-I/MDA5 and TLR3 agonists of the present invention are, for example, Poly-ICLC and/or BO112.
本发明所述TLR4激动剂例如吡喃葡萄糖脂A G100(Glucopyranosyl lipid A G100)和/或单磷酰酯质A(Monophosphoryl Lipid A，MPLA)。The TLR4 agonist of the present invention is, for example, glucopyranosyl lipid A G100 (Glucopyranosyl lipid A G100) and/or monophosphoryl lipid A (Monophosphoryl Lipid A, MPLA).
本发明所述TLR7/8激动剂例如咪喹莫特R837、Motolimod(VTX-2337)、雷西莫特R848、鱼精蛋白RNA、LHC165、Motolimod、MEDI-9197、Gardiquimod、3M-001(852A)、GSK2245035和GS-9620中的一种或多种。TLR7/8 agonists of the present invention such as imiquimod R837, Motolimod (VTX-2337), Resimod R848, protamine RNA, LHC165, Motolimod, MEDI-9197, Gardiquimod, 3M-001 (852A) One or more of , GSK2245035 and GS-9620.
本发明所述TLR9激动剂例如CpG ODN寡脱氧核苷酸和CMP-001中的一种或多种。 The TLR9 agonist of the present invention, such as one or more of CpG ODN oligodeoxynucleotide and CMP-001.
本发明所述细胞因子佐剂例如IL-2、IL-1、IFNγ、IL-12、GM-CSF、IL-23、IL-36γ、CCL21、IL-10和IL-15中的一种或多种。One or more of the cytokine adjuvant of the present invention such as IL-2, IL-1, IFNγ, IL-12, GM-CSF, IL-23, IL-36γ, CCL21, IL-10 and IL-15 kind.
本发明所述细胞因子mRNA佐剂例如IL-2mRNA、IL-1mRNA、IFNγmRNA、IL-12mRNA、GM-CSF mRNA、IL-23mRNA、IL-36γmRNA、CCL21mRNA、IL-10mRNA和IL-15mRNA中的一种或多种。The cytokine mRNA adjuvant of the present invention is for example one in IL-2mRNA, IL-1mRNA, IFNγmRNA, IL-12mRNA, GM-CSF mRNA, IL-23mRNA, IL-36γmRNA, CCL21mRNA, IL-10mRNA and IL-15mRNA or more.
本发明所述STING激动剂例如Ulevostina(MK-1454)、E7766及其药学可接受的盐、ADU-S100(MIW815)、GSK3745417、BMS-986301、SB-11285、HG381、IMSA101(GB492)、DN-015089、SYN-STING(SYNB1891)、BI-1387446、TAK-676、SNX-281、BI-STING、CDK-002、2,5-己酮可可碱(vadimezan，DMXAA)、MSA-2及其二聚体、STING agonist-1(G10)、IACS-8779、IACS-8803、c-di-AMP(Cyclic diadenylate)及其药学可接受的盐、diABZI-C2-NH2、SR717及其药学可接受的盐、diABZI STING激动剂(diABZI STING agonist-1,化合物3)、C176、C171、C-178、SN-011、H-151、AstinC、EFAA、CMA、BNBC、a-Mangositin、ABZI以及ABZI类似物、STING激动剂-3、CDG、2',3'-cGAMP、3',3'-cGAMP和RpRp二硫2',3'-CDA中的一种或多种。STING agonists of the present invention such as Ulevostina (MK-1454), E7766 and pharmaceutically acceptable salts thereof, ADU-S100 (MIW815), GSK3745417, BMS-986301, SB-11285, HG381, IMSA101 (GB492), DN- 015089, SYN-STING (SYNB1891), BI-1387446, TAK-676, SNX-281, BI-STING, CDK-002, 2,5-pentoxifylline (vadimezan, DMXAA), MSA-2 and its dimer body, STING agonist-1 (G10), IACS-8779, IACS-8803, c-di-AMP (Cyclic diadenylate) and its pharmaceutically acceptable salt, diABZI-C2-NH2, SR717 and its pharmaceutically acceptable salt, diABZI STING agonist (diABZI STING agonist-1, compound 3), C176, C171, C-178, SN-011, H-151, AstinC, EFAA, CMA, BNBC, a-Mangositin, ABZI and ABZI analogs, STING Agonist-3, one or more of CDG, 2',3'-cGAMP, 3',3'-cGAMP and RpRp disulfide 2',3'-CDA.
本发明所述FLT3L激动剂例如Ad-hCMV-TK、Ad-hCMV-Flt3L、rhuFlt3L、CDX-301和CDX-1401中的一种或多种。The FLT3L agonist of the present invention is, for example, one or more of Ad-hCMV-TK, Ad-hCMV-Flt3L, rhuFlt3L, CDX-301 and CDX-1401.
所在本发明一较佳实施方案中，述免疫佐剂为Poly-ICLC、单磷酰酯质A、雷西莫特、CpG寡脱氧核苷酸、IL-2、GM-CSF、IL-15mRNA、Ulevostina、BMS-986301、MSA-2及其二聚体和HG381中的一种或多种。In a preferred embodiment of the present invention, the immune adjuvant is Poly-ICLC, monophosphoryl ester A, resimod, CpG oligodeoxynucleotide, IL-2, GM-CSF, IL-15mRNA, One or more of Ulevostina, BMS-986301, MSA-2 and its dimer, and HG381.
在本发明一较佳实施方案中，所述免疫检查点调节剂包括免疫检查点抑制剂和/或免疫检查点激动剂。In a preferred embodiment of the present invention, the immune checkpoint modulator includes immune checkpoint inhibitors and/or immune checkpoint agonists.
在本发明一较佳实施方案中，所述免疫检查点抑制剂为免疫检查点抗体抑制剂及其mRNA、免疫检查点小分子抑制剂和免疫检查点肽类抑制剂中的一种或多种。In a preferred embodiment of the present invention, the immune checkpoint inhibitor is one or more of immune checkpoint antibody inhibitors and their mRNA, immune checkpoint small molecule inhibitors and immune checkpoint peptide inhibitors .
本发明所述免疫检查点抗体抑制剂包括靶向以下一种或多种靶点的抗体：CTLA-4、PD-1、PD-L1、LAG-3、TIM-3、TIGIT、VISTA、CD47、SIRPα、B7-H3、B7-H4、B7-H7、BTLA、CD160、KIR、CD96、PVRIG、CD155、PVRL2、NKG2A、HLA-E、ILT2、HLA-G、PSGL1、CEACAM1、CD200、CD24、SIGLEC10和SIGLEC7。The immune checkpoint antibody inhibitors of the present invention include antibodies targeting one or more of the following targets: CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, TIGIT, VISTA, CD47, SIRPα, B7-H3, B7-H4, B7-H7, BTLA, CD160, KIR, CD96, PVRIG, CD155, PVRL2, NKG2A, HLA-E, ILT2, HLA-G, PSGL1, CEACAM1, CD200, CD24, SIGLEC10 and SIGLEC7.
在本发明一较佳实施方案中，所述免疫检查点激动剂为免疫检查点抗体激动剂及其mRNA、免疫检查点小分子激动剂和免疫检查点肽类激动剂中的一种或多种。In a preferred embodiment of the present invention, the immune checkpoint agonist is one or more of an immune checkpoint antibody agonist and its mRNA, an immune checkpoint small molecule agonist and an immune checkpoint peptide agonist .
本发明所述免疫检查点激动剂抗体包括靶向以下一种或多种靶点的抗体：OX40、4-1BB、CD40、ICOS、GITR、CD28、CD27、CD122、LIGHT、DNAM-1、CD226、CD48、 DC-SIGN和DR3。The immune checkpoint agonist antibodies of the present invention include antibodies targeting one or more of the following targets: OX40, 4-1BB, CD40, ICOS, GITR, CD28, CD27, CD122, LIGHT, DNAM-1, CD226, CD48, DC-SIGN and DR3.
在本发明一具体实施方案中，所述免疫检查点调节剂为靶向以下一种或多种靶点的抗体：PD-1、PD-L1、LAG-3、TIM-3、TIGIT、OX40、4-1BB、CD40和CD47。In a specific embodiment of the present invention, the immune checkpoint regulator is an antibody targeting one or more of the following targets: PD-1, PD-L1, LAG-3, TIM-3, TIGIT, OX40, 4-1BB, CD40 and CD47.
在本发明一具体实施方案中，所述免疫检查点调节剂为双特异性抗体，所述双特异性抗体的一个靶点为CTLA-4、PD-1、PD-L1、LAG-3、TIM-3、TIGIT、VISTA、B7-H3、B7-H4、B7-H7、BTLA、CD160、KIR、CD96、PVRIG、CD155、PVRL2、NKG2A、HLA-E、ILT2、HLA-G、PSGL1、CEACAM1、CD47、SIRPα、CD200、CD24、SIGLEC10或SIGLEC7，另一个靶点为OX40、4-1BB、CD40、ICOS、GITR、CD28、CD27、CD122、LIGHT、DNAM-1、CD226、CD48、DC-SIGN、TL1A，或所述双特异性抗体的一个靶点为VEGF。较佳地，所述双特异性抗体为靶向以下靶点组合的抗体中的一种或多种：PD-L1/4-1BB、PD-L1/CD47、PD-1/LAG-3、PD-1/TIM-3和PD-1/TIGIT-3。In a specific embodiment of the present invention, the immune checkpoint regulator is a bispecific antibody, and one target of the bispecific antibody is CTLA-4, PD-1, PD-L1, LAG-3, TIM -3, TIGIT, VISTA, B7-H3, B7-H4, B7-H7, BTLA, CD160, KIR, CD96, PVRIG, CD155, PVRL2, NKG2A, HLA-E, ILT2, HLA-G, PSGL1, CEACAM1, CD47 , SIRPα, CD200, CD24, SIGLEC10 or SIGLEC7, another target is OX40, 4-1BB, CD40, ICOS, GITR, CD28, CD27, CD122, LIGHT, DNAM-1, CD226, CD48, DC-SIGN, TL1A, Or one target of the bispecific antibody is VEGF. Preferably, the bispecific antibody is one or more of the antibodies targeting the following target combinations: PD-L1/4-1BB, PD-L1/CD47, PD-1/LAG-3, PD -1/TIM-3 and PD-1/TIGIT-3.
本发明所述双特异性抗体能够同时具备相应免疫检查点抗体抑制剂和/或免疫检查点抗体激动剂的双重功能。The bispecific antibody of the present invention can simultaneously have dual functions of corresponding immune checkpoint antibody inhibitor and/or immune checkpoint antibody agonist.
在本发明一较佳实施方案中，所述组合物还包括缓释材料，所述缓释材料为调节药物释放速率，起缓释、控释效果的载体材料及其制备成的制剂中间体。In a preferred embodiment of the present invention, the composition further includes a slow-release material, which is a carrier material that regulates the release rate of the drug and plays a slow-release or controlled-release effect, and a preparation intermediate prepared therefrom.
在本发明一较佳实施方案中，所述缓释材料包括具有缓释功能的阻滞剂、骨架材料、包衣材料和原位成胶基质材料中的一种或多种。In a preferred embodiment of the present invention, the sustained-release material includes one or more of a retarder with a sustained-release function, a matrix material, a coating material and an in-situ gel-forming matrix material.
本发明所述阻滞剂例如动物脂肪、蜂蜡、巴西棕榈蜡、氢化植物油、硬脂酸、硬脂醇和单硬脂酸甘油酯中的一种或多种。The blocking agent of the present invention is for example one or more of animal fat, beeswax, carnauba wax, hydrogenated vegetable oil, stearic acid, stearyl alcohol and glyceryl monostearate.
本发明所述骨架材料包括亲水凝胶骨架和不溶性骨架材料中的一种或多种。The skeleton material in the present invention includes one or more of a hydrophilic gel skeleton and an insoluble skeleton material.
本发明所述亲水凝胶骨架材料例如天然胶，如海藻酸盐(海藻酸钠、海藻酸钾、海藻酸铵)、琼脂、黄原胶、西黄蓍胶、甲基纤维素(MC)、羧甲基纤维素钠(CMC-Na)、羟丙甲纤维素(HPMC)、羟乙基纤维素(HEC)、甲壳素、壳聚糖、卡波姆、透明质酸，硫酸软骨素、聚维酮(PVP)、乙烯聚合物、丙烯酸树脂和聚乙烯醇(PVA)中的一种或多种。The hydrophilic gel skeleton material of the present invention is such as natural gum, as alginate (sodium alginate, potassium alginate, ammonium alginate), agar, xanthan gum, tragacanth gum, methyl cellulose (MC) , sodium carboxymethylcellulose (CMC-Na), hypromellose (HPMC), hydroxyethylcellulose (HEC), chitin, chitosan, carbomer, hyaluronic acid, chondroitin sulfate, One or more of povidone (PVP), ethylene polymer, acrylic resin and polyvinyl alcohol (PVA).
本发明所述不溶性骨架材料例如乙基纤维素(EC)、聚甲基丙烯酸酯、无毒聚氯乙烯、聚乙烯、乙烯一-醋酸乙烯共聚物和硅橡胶中的一种或多种。The insoluble skeleton material of the present invention is, for example, one or more of ethyl cellulose (EC), polymethacrylate, non-toxic polyvinyl chloride, polyethylene, ethylene-vinyl acetate copolymer and silicone rubber.
本发明所述包衣材料例如醋酸纤维素(CA)、乙基纤维素(EC)、聚丙烯酸树脂、硅酮弹性体及交联海藻酸盐、纤维醋法酯(CAP)、羟丙甲纤维素酞酸酯(HPMCP)、EudragitL和EudragitR中的一种或多种。The coating material of the present invention is such as cellulose acetate (CA), ethyl cellulose (EC), polyacrylic acid resin, silicone elastomer and cross-linked alginate, cellulose acetate (CAP), hypromellose One or more of phthalate (HPMCP), EudragitL and EudragitR.
本发明所述原位成胶基质材料例如血清白蛋白、纤维蛋白原、胶原、丁聚糖、明胶、 淀粉、羧甲基纤维素钠、甘油磷酸钠、氰基丙烯酸酯、丙烯酰胺、聚氧乙烯、聚乙二醇、聚乙烯醇、泊洛沙姆、聚乙内酯和甾类化合物中的一种或多种。The in situ gel-forming matrix material of the present invention is for example serum albumin, fibrinogen, collagen, tetracan, gelatin, One of starch, sodium carboxymethylcellulose, sodium glycerophosphate, cyanoacrylate, acrylamide, polyoxyethylene, polyethylene glycol, polyvinyl alcohol, poloxamer, polyglycolide, and steroids one or more species.
在本发明一较佳实施方案中，所述制剂中间体包括微球、脂质体和固体分散体中的一种或多种。In a preferred embodiment of the present invention, the preparation intermediate includes one or more of microspheres, liposomes and solid dispersions.
本发明所述微球例如明胶微球、PLA微球、PVA微球、PELA微球、PLGA微球、PGA微球、PCL微球和四氧化三铁微球中的一种或多种。The microspheres of the present invention are, for example, one or more of gelatin microspheres, PLA microspheres, PVA microspheres, PELA microspheres, PLGA microspheres, PGA microspheres, PCL microspheres and ferric oxide microspheres.
本发明所述脂质体可选用的膜材包括中性磷脂、荷负电的磷脂(酸性磷脂)、荷正电的磷脂(碱性磷脂)、胆固醇和两性磷脂中的一种或多种。The optional membrane material of the liposome in the present invention includes one or more of neutral phospholipids, negatively charged phospholipids (acid phospholipids), positively charged phospholipids (basic phospholipids), cholesterol and amphoteric phospholipids.
本发明所述中性磷脂例如磷脂酰胆碱(PC)、卵磷脂、大豆磷脂、二棕榈酰胆碱(DPPC)、二硬脂酰胆碱(DSPC)和二肉豆蔻酰磷脂酰胆碱(DMPC)中的一种或多种。Neutral phospholipids of the present invention such as phosphatidylcholine (PC), lecithin, soybean lecithin, dipalmitoylcholine (DPPC), distearoylcholine (DSPC) and dimyristoylphosphatidylcholine ( DMPC) in one or more.
本发明所述荷负电的磷脂例如磷脂酸(PA)、磷脂酰甘油(PG)和磷脂酰肌醇(PI)中的一种或多种。The negatively charged phospholipids of the present invention are one or more of phosphatidic acid (PA), phosphatidylglycerol (PG) and phosphatidylinositol (PI).
本发明所述荷正电的磷脂例如硬脂酰胺(SA)胆固醇衍生物。The positively charged phospholipids of the present invention are, for example, stearylamide (SA) cholesterol derivatives.
本发明所述固体分散体例如乙基纤维素(EC)固体分散体、EudragitE固体分散体、EudragitR固体分散体、EudragitL固体分散体、脂质固体分散体、醋酸纤维素酞酸酯(CAP)固体分散体和羟丙甲纤维素酞酸酯(HPMCP)固体分散体中的一种或多种。The solid dispersion of the present invention is for example ethyl cellulose (EC) solid dispersion, EudragitE solid dispersion, EudragitR solid dispersion, EudragitL solid dispersion, lipid solid dispersion, cellulose acetate phthalate (CAP) solid One or more of dispersion and hypromellose phthalate (HPMCP) solid dispersion.
在本发明一更佳实施方案中，所述缓释材料为海藻酸盐、透明质酸、泊洛沙姆、明胶微球、PLGA微球和四氧化三铁微球中的一种或多种。In a more preferred embodiment of the present invention, the sustained-release material is one or more of alginate, hyaluronic acid, poloxamer, gelatin microspheres, PLGA microspheres and ferric oxide microspheres .
在本发明一较佳实施方案中，所述免疫佐剂的份数为1.875～30份，所述免疫检查点调节剂0.1875～7.5份，所述缓释材料的份数为10～250份。In a preferred embodiment of the present invention, the number of parts of the immune adjuvant is 1.875-30 parts, the number of parts of the immune checkpoint regulator is 0.1875-7.5 parts, and the number of parts of the slow-release material is 10-250 parts.
较佳地，所述表观遗传药物的份数为0.3～22份，例如0.5～18份、0.8-15份、1-10份、1-5份或1-3份。Preferably, the number of parts of the epigenetic drug is 0.3-22 parts, such as 0.5-18 parts, 0.8-15 parts, 1-10 parts, 1-5 parts or 1-3 parts.
较佳地，所述谷氨酰胺代谢调节剂的份数为0.3～22份，例如0.5～18份、0.8～15份、1～10份、1～5份或1～3份。Preferably, the glutamine metabolism regulator has an amount of 0.3-22 parts, such as 0.5-18 parts, 0.8-15 parts, 1-10 parts, 1-5 parts or 1-3 parts.
较佳地，所述免疫佐剂的份数为1.875～30份，例如2～25份、2.5～20份、3～15份、4～10份或5～7.5份。Preferably, the number of parts of the immune adjuvant is 1.875-30 parts, such as 2-25 parts, 2.5-20 parts, 3-15 parts, 4-10 parts or 5-7.5 parts.
较佳地，所述免疫检查点调节剂0.1875～7.5份，例如0.2～5份、0.25～4份、0.3～3份、0.4～2份或0.5～1份。Preferably, the immune checkpoint regulator is 0.1875-7.5 parts, such as 0.2-5 parts, 0.25-4 parts, 0.3-3 parts, 0.4-2 parts or 0.5-1 part.
较佳地，所述缓释材料的份数为10～250份，例如20-200份或50-100份。Preferably, the number of parts of the slow-release material is 10-250 parts, such as 20-200 parts or 50-100 parts.
在本发明一较佳实施方案中，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸； In a preferred embodiment of the present invention, the epigenetic drug is decitabine, and the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine;
或，所述表观遗传药物为西达本胺、泰泽司他、艾伏尼布、思瑞德林或阿帕他隆，所述谷氨酰胺代谢调节剂为L-天冬酰胺酶CB-839、V-9302、2-烯丙基-1-羟基-9,10-蒽醌或柳氮磺吡啶；Or, the epigenetic drug is chidamide, tezecistat, evonib, seridelin or apatalone, and the glutamine metabolism regulator is L-asparaginase CB -839, V-9302, 2-allyl-1-hydroxy-9,10-anthraquinone or sulfasalazine;
或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述免疫佐剂为Poly-ICLC、单磷酰酯质A、雷西莫特、CpG ODN寡脱氧核苷酸、白细胞介素-2、巨噬细胞集落刺激因子、趋化因子21、白细胞介素-15mRNA、MK-1454、BMS-986301、MSA-2或HG381；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the immune adjuvant is Poly-ICLC, Monophosphoryl A, Resimod, CpG ODN oligodeoxynucleotide, Interleukin-2, Macrophage colony-stimulating factor, Chemokine 21, Interleukin-15 mRNA, MK-1454, BMS- 986301, MSA-2 or HG381;
或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述组合物还包括免疫检查点抑制剂、所述免疫检查点激动剂、免疫检查点调节剂双特异性抗体和所述免疫检查点抑制剂抗体mRNA中的一种或多种，所述免疫检查点抑制剂为anti-PD-L1抗体，所述免疫检查点激动剂为anti-4-1BB抗体、anti-CD40抗体，所述免疫检查点调节剂双特异性抗体为anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体或anti-PD-1/TIGIT-3双特异性抗体，所述免疫检查点抑制剂抗体mRNA为anti-PD-L1抗体mRNA，免疫检查点激动剂抗体mRNA为anti-4-1BB抗体mRNA；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the composition also includes immune checkpoint inhibition One or more of the immune checkpoint agonist, the immune checkpoint regulator bispecific antibody and the immune checkpoint inhibitor antibody mRNA, the immune checkpoint inhibitor is anti-PD-L1 Antibody, the immune checkpoint agonist is anti-4-1BB antibody, anti-CD40 antibody, the immune checkpoint regulator bispecific antibody is anti-PD-L1/4-1BB bispecific antibody, anti- PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 bispecific antibody, anti-PD-1/TIM-3 bispecific antibody or anti-PD-1/TIGIT-3 bispecific antibody Antibody, the immune checkpoint inhibitor antibody mRNA is anti-PD-L1 antibody mRNA, and the immune checkpoint agonist antibody mRNA is anti-4-1BB antibody mRNA;
或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述组合物还包括免疫检查点抑制剂、所述免疫检查点激动剂、免疫检查点调节剂双特异性抗体和所述免疫检查点抑制剂抗体mRNA中的一种或多种，所述免疫检查点抑制剂为anti-PD-1抗体或anti-PD-L1抗体，所述免疫检查点激动剂为anti-4-1BB抗体、anti-CD40抗体，所述免疫检查点调节剂双特异性抗体为anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体或anti-PD-1/TIGIT-3双特异性抗体，所述免疫检查点抑制剂抗体mRNA为anti-PD-L1抗体mRNA，免疫检查点激动剂抗体mRNA为anti-4-1BB抗体mRNA；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the composition also includes immune checkpoint inhibition One or more of the immune checkpoint agonist, the immune checkpoint regulator bispecific antibody and the immune checkpoint inhibitor antibody mRNA, the immune checkpoint inhibitor is anti-PD-1 Antibody or anti-PD-L1 antibody, the immune checkpoint agonist is anti-4-1BB antibody, anti-CD40 antibody, and the immune checkpoint regulator bispecific antibody is anti-PD-L1/4-1BB Bispecific antibody, anti-PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 bispecific antibody, anti-PD-1/TIM-3 bispecific antibody or anti-PD-1 /TIGIT-3 bispecific antibody, the immune checkpoint inhibitor antibody mRNA is anti-PD-L1 antibody mRNA, and the immune checkpoint agonist antibody mRNA is anti-4-1BB antibody mRNA;
或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述组合物还包括免疫检查点抑制剂、所述免疫检查点激动剂、免疫检查点调节剂双特异性抗体和所述免疫检查点抑制剂抗体mRNA中的一种或多种，所述免疫检查点抑制剂为anti-PD-1抗体或anti-PD-L1抗体，所述免疫检查点激动剂为anti-4-1BB抗体、anti-CD40抗体，所述免疫检查点调节剂双特异性抗体为anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体、anti-PD-1/TIGIT-3双特异性抗体或anti-PD-1/VEGF双特异性抗体，所述免疫检查点抑制剂抗体mRNA为anti-PD-L1抗体mRNA，免疫检查点激动剂抗体 mRNA为anti-4-1BB抗体mRNA；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the composition also includes immune checkpoint inhibition One or more of the immune checkpoint agonist, the immune checkpoint regulator bispecific antibody and the immune checkpoint inhibitor antibody mRNA, the immune checkpoint inhibitor is anti-PD-1 Antibody or anti-PD-L1 antibody, the immune checkpoint agonist is anti-4-1BB antibody, anti-CD40 antibody, and the immune checkpoint regulator bispecific antibody is anti-PD-L1/4-1BB Bispecific antibody, anti-PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 bispecific antibody, anti-PD-1/TIM-3 bispecific antibody, anti-PD-1 /TIGIT-3 bispecific antibody or anti-PD-1/VEGF bispecific antibody, the immune checkpoint inhibitor antibody mRNA is anti-PD-L1 antibody mRNA, immune checkpoint agonist antibody mRNA is anti-4-1BB antibody mRNA;
或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述免疫佐剂为MSA-2，所述免疫检查点调节剂双特异性抗体为anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体或anti-PD-1/TIGIT-3双特异性抗体，所述缓释材料为明胶微球、海藻酸钠、透明质酸、泊洛沙姆温敏凝胶、PLGA微球或四氧化三铁微球；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the immune adjuvant is MSA-2, The immune checkpoint regulator bispecific antibody is anti-PD-L1/4-1BB bispecific antibody, anti-PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 bispecific antibody Antibody, anti-PD-1/TIM-3 bispecific antibody or anti-PD-1/TIGIT-3 bispecific antibody, the sustained-release material is gelatin microspheres, sodium alginate, hyaluronic acid, polo Sharm thermosensitive gel, PLGA microspheres or ferric oxide microspheres;
或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述免疫佐剂为MSA-2，所述免疫检查点调节剂为anti-PD-1抗体、anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体、anti-PD-1/TIGIT-3双特异性抗体或anti-PD-1/VEGF双特异性抗体，所述缓释材料为明胶微球、海藻酸钠、透明质酸、泊洛沙姆温敏凝胶、PLGA微球或四氧化三铁微球。Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the immune adjuvant is MSA-2, The immune checkpoint regulator is anti-PD-1 antibody, anti-PD-L1/4-1BB bispecific antibody, anti-PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 Bispecific antibody, anti-PD-1/TIM-3 bispecific antibody, anti-PD-1/TIGIT-3 bispecific antibody or anti-PD-1/VEGF bispecific antibody, the slow-release material Gelatin microspheres, sodium alginate, hyaluronic acid, poloxamer thermosensitive gel, PLGA microspheres or ferric oxide microspheres.
较佳地，所述表观遗传药物为1份地西他滨和1份6-重氮-5-氧代-L-正亮氨酸。Preferably, the epigenetic drug is 1 part of decitabine and 1 part of 6-diazo-5-oxo-L-norleucine.
在本发明一较佳实施方案中，组合物可与溶瘤病毒联用，所述溶瘤病毒能够选择性感染和杀伤肿瘤细胞的病毒，具有特异性复制能力，并能激发机体产生抗肿瘤免疫反应。In a preferred embodiment of the present invention, the composition can be used in combination with an oncolytic virus, which can selectively infect and kill tumor cells, has specific replication ability, and can stimulate the body to produce anti-tumor immunity reaction.
在本发明一较佳实施方案中，所述溶瘤病毒包括天然溶瘤病毒和转基因溶瘤病毒中的一种或多种。In a preferred embodiment of the present invention, the oncolytic virus includes one or more of natural oncolytic virus and transgenic oncolytic virus.
本发明所述天然溶瘤病毒例如呼肠孤病毒、新城疫病毒(NDV)、塞内卡病毒、M1病毒、盖塔病毒、腺病毒、单纯疱疹病毒(HSV)、溶瘤痘病毒、脊髓灰质炎溶瘤病毒、禽痘病毒、仙台病毒、肠病毒、甲病毒、水泡口炎病毒和麻疹病毒(MV)中的一种或多种。Natural oncolytic viruses of the present invention, such as reovirus, Newcastle disease virus (NDV), Seneca virus, M1 virus, Getta virus, adenovirus, herpes simplex virus (HSV), oncolytic poxvirus, polio One or more of inflammatory oncolytic virus, fowl pox virus, Sendai virus, enterovirus, alphavirus, vesicular stomatitis virus and measles virus (MV).
本发明所述天然溶瘤病毒例如转基因呼肠孤病毒、转基因新城疫病毒(NDV)、转基因塞内卡病毒、转基因M1溶瘤病毒、转基因盖塔病毒、转基因腺病毒、转基因单纯疱疹病毒(HSV)、转基因溶瘤痘病毒、转基因脊髓灰质炎溶瘤病毒、转基因禽痘病毒、转基因仙台病毒、转基因肠病毒、转基因甲病毒、转基因水泡口炎病毒和转基因麻疹病毒(MV)中的一种或多种。The natural oncolytic virus of the present invention is for example transgenic reovirus, transgenic Newcastle disease virus (NDV), transgenic Seneca virus, transgenic M1 oncolytic virus, transgenic getta virus, transgenic adenovirus, transgenic herpes simplex virus (HSV) ), genetically modified oncolytic poxvirus, genetically modified poliovirus, genetically modified fowlpox virus, genetically modified Sendai virus, genetically modified enterovirus, genetically modified alphavirus, genetically modified vesicular stomatitis virus and genetically modified measles virus (MV) or Various.
在本发明一较佳实施方案中，组合物可以制备为抗体偶联药物(ADC)，所述抗体偶联药物能够将单克隆抗体药物的高特异性和小分子细胞毒药物的高活性相结合，用以提高肿瘤药物的靶向性、减少毒副作用。In a preferred embodiment of the present invention, the composition can be prepared as an antibody-drug conjugate (ADC), which can combine the high specificity of a monoclonal antibody drug with the high activity of a small molecule cytotoxic drug , to improve the targeting of tumor drugs and reduce toxic and side effects.
在本发明一较佳实施方案中，所述抗体偶联药物的靶点抗原包括癌细胞过表达靶点抗原、肿瘤血管和基底膜上的靶点抗原、由驱动癌基因调控的靶点抗原和血液学恶性肿 瘤中的靶点抗原中的一种或多种。In a preferred embodiment of the present invention, the target antigens of the antibody-drug conjugates include target antigens overexpressed by cancer cells, target antigens on tumor blood vessels and basement membranes, target antigens regulated by driver oncogenes, and hematological malignancies One or more of the target antigens in the tumor.
本发明所述癌细胞过表达靶点抗原例如GPNMB、CD56、TACSTD2(TROP2)、CEACAM5、Folate receptor、Mucin 1(Sialoglycotope CA6)、STEAP1、Mesothenlin、Nectin 4、ENPP3、Guanylyl cyclase C(GCC)、SLC44A4、NaPi2b、CD70(TNFSF7)、CA9(Carbonic anhydrase)、ST4(TPBG)、SLTRK6、SC-16(anti-Fyn3)、Tissue factor、LIV-1(ZIP6)、P-Cadherin和PSMA中的一种或多种。Cancer cells of the present invention overexpress target antigens such as GPNMB, CD56, TACSTD2 (TROP2), CEACAM5, Folate receptor, Mucin 1 (Sialoglycotope CA6), STEAP1, Mesothenlin, Nectin 4, ENPP3, Guanylyl cyclase C (GCC), SLC44A4 , NaPi2b, CD70(TNFSF7), CA9(Carbonic anhydrase), ST4(TPBG), SLTRK6, SC-16(anti-Fyn3), Tissue factor, LIV-1(ZIP6), P-Cadherin and PSMA, or Various.
本发明所述肿瘤血管和基底膜上的靶点抗原例如Fibronectin Extra-domain B(ED-B)、Endothelin receptor ETB、VEGFR2(CD309)、Tenascin c、CollagenⅣ和Perionstin中的一种或多种。The target antigens on the tumor blood vessels and basement membrane of the present invention are, for example, one or more of Fibronectin Extra-domain B (ED-B), Endothelin receptor ETB, VEGFR2 (CD309), Tenascin c, Collagen IV and Perionstin.
本发明所述由驱动癌基因调控的靶点抗原例如HER2和/或EGFR。The target antigen regulated by the driver cancer gene of the present invention is HER2 and/or EGFR.
本发明所述血液学恶性肿瘤中的靶点抗原例如CD30、CD22、CD79b、CD19、CD138、CD74、CD37、CD33、CD19和CD98中的一种或多种。The target antigen in the hematological malignancies of the present invention is one or more of CD30, CD22, CD79b, CD19, CD138, CD74, CD37, CD33, CD19 and CD98.
在本发明一较佳实施方案中，组合物可以制备为多肽偶联药物(PDC)，所述多肽偶联药物能够将靶向肽药物的高特异性和小分子细胞毒药物的高活性相结合，用以提高肿瘤药物的靶向性、减少毒副作用。In a preferred embodiment of the present invention, the composition can be prepared as a polypeptide conjugated drug (PDC), which can combine the high specificity of targeting peptide drugs with the high activity of small molecule cytotoxic drugs , to improve the targeting of tumor drugs and reduce toxic and side effects.
在本发明一较佳实施方案中，所述多肽偶联药物的多肽包括细胞穿透肽(CPPs)和细胞靶向肽(CTPs)中的一种或多种。In a preferred embodiment of the present invention, the polypeptide of the polypeptide-drug conjugate includes one or more of cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs).
在本发明一较佳实施方案中，组合物可以与放射治疗联用，所述放射治疗能够通过射线的电离辐射作用杀灭肿瘤。In a preferred embodiment of the present invention, the composition can be used in combination with radiotherapy, which can kill tumors through the action of ionizing radiation of rays.
本发明所述放射治疗例如常规放射治疗、γ-辐射、中子束放射疗法、电子束放射疗法、质子疗法、近距离放射疗法和全身性放射性同位素疗法中的一种或多种Radiation therapy according to the present invention, such as one or more of conventional radiation therapy, gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy and systemic radioisotope therapy
在本发明一较佳实施方案中，组合物可以与手术治疗联用。In a preferred embodiment of the present invention, the composition can be used in combination with surgical treatment.
在本发明一较佳实施方案中，组合物可以与射频消融疗法联用，所述射频消融疗法能够将射频脉冲能量通过多极针传导到肿瘤组织中，使肿瘤组织产生局部高温，使肿瘤组织及其邻近的可能被扩散的组织凝固坏死的目的。In a preferred embodiment of the present invention, the composition can be used in combination with radiofrequency ablation therapy, and the radiofrequency ablation therapy can conduct radiofrequency pulse energy into tumor tissue through multipolar needles, so as to generate local high temperature in tumor tissue, and make tumor tissue The purpose of coagulation and necrosis of the adjacent tissue may be spread.
在本发明一较佳实施方案中，组合物可以与高强度聚焦超声消融(HIFU)疗法联用，所述高强度聚焦超声消融疗法能够将体外低能量超声波聚焦于体内靶区，在肿瘤内产生瞬态高温(60-120摄氏度)、空化、机械作用等生物学效应，杀死靶区内的肿瘤细胞。In a preferred embodiment of the present invention, the composition can be used in combination with high-intensity focused ultrasound ablation (HIFU) therapy, which can focus low-energy ultrasound outside the body on the target area in the body to generate Biological effects such as transient high temperature (60-120 degrees Celsius), cavitation, and mechanical action kill tumor cells in the target area.
在本发明一较佳实施方案中，组合物可以与蛋白降解疗法联用，所述蛋白降解疗法能够将特定蛋白与泛素连接酶连接在一起，使其被运送到蛋白酶体系统中进行降解，从而治疗肿瘤。 In a preferred embodiment of the present invention, the composition can be used in combination with protein degradation therapy, which can link specific proteins with ubiquitin ligases to be transported to the proteasome system for degradation, thereby treating tumors.
在本发明一较佳实施方案中，蛋白降解疗法包括小分子诱导法、溶酶体途径降解法中的一种或多种。In a preferred embodiment of the present invention, protein degradation therapy includes one or more of small molecule induction method and lysosomal pathway degradation method.
本发明所述小分子诱导法例如小分子疏水标签(HYT)诱导法和蛋白质水解靶向嵌合(PROTAC)诱导法中的一种或多种。One or more of the small molecule induction methods of the present invention, such as small molecule hydrophobic tag (HYT) induction method and proteolysis targeting chimera (PROTAC) induction method.
本发明所述溶酶体途径降解法例如溶酶体靶向嵌合体法(LYTAC)、自噬靶向嵌合体法(AUTAC)和自噬-栓系复合物法(ATTEC)中的一种或多种。One or more of the lysosomal pathway degradation method described in the present invention such as lysosome targeting chimera method (LYTAC), autophagy targeting chimera method (AUTAC) and autophagy-tethering complex method (ATTEC) Various.
在本发明一较佳实施方案中，组合物可以与肿瘤疫苗疗法联用，所述肿瘤疫苗疗法能够将肿瘤抗原以多种形式导入患者体内，克服肿瘤引起的免疫抑制状态，增强免疫原性，激活患者自身的免疫系统，诱导机体细胞免疫和体液免疫应答，从而控制或清除肿瘤。In a preferred embodiment of the present invention, the composition can be used in combination with tumor vaccine therapy, which can introduce tumor antigens into patients in various forms, overcome the immunosuppressive state caused by tumors, and enhance immunogenicity, Activate the patient's own immune system and induce the body's cellular and humoral immune responses to control or eliminate tumors.
在本发明一较佳实施方案中，肿瘤疫苗包括细胞疫苗、病毒载体疫苗、分子疫苗和原位肿瘤疫苗。In a preferred embodiment of the present invention, tumor vaccines include cell vaccines, virus vector vaccines, molecular vaccines and in situ tumor vaccines.
本发明所述细胞疫苗例如自体肿瘤细胞疫苗和装载有肿瘤抗原的自体抗原呈递细胞疫苗中的一种或多种。One or more of the cellular vaccines of the present invention, such as autologous tumor cell vaccines and autologous antigen-presenting cell vaccines loaded with tumor antigens.
本发明所述病毒载体疫苗例如呼肠孤病毒载体疫苗、新城疫病毒(NDV)载体疫苗、塞内卡病毒载体疫苗、M1病毒载体疫苗、盖塔病毒载体疫苗、腺病毒载体疫苗、单纯疱疹病毒(HSV)载体疫苗、溶瘤痘病毒载体疫苗、脊髓灰质炎溶瘤病毒载体疫苗、禽痘病毒载体疫苗、仙台病毒载体疫苗、肠病毒载体疫苗、甲病毒载体疫苗、水泡口炎病毒载体疫苗和麻疹病毒(MV)载体疫苗中的一种或多种。The virus vector vaccine of the present invention is such as reovirus vector vaccine, Newcastle disease virus (NDV) vector vaccine, Seneca virus vector vaccine, M1 virus vector vaccine, getta virus vector vaccine, adenovirus vector vaccine, herpes simplex virus (HSV) vector vaccine, oncolytic pox virus vector vaccine, polio oncolytic virus vector vaccine, fowlpox virus vector vaccine, Sendai virus vector vaccine, enterovirus vector vaccine, alphavirus vector vaccine, vesicular stomatitis virus vector vaccine and One or more of the measles virus (MV) vector vaccines.
本发明所述分子疫苗例如多肽分子疫苗、DNA分子疫苗和RNA分子疫苗中的一种或多种。The molecular vaccines of the present invention are, for example, one or more of polypeptide molecular vaccines, DNA molecular vaccines and RNA molecular vaccines.
本发明所述原位肿瘤疫苗例如化疗诱导型肿瘤原位疫苗、放射治疗诱导型肿瘤原位疫苗、射频消融诱导型肿瘤原位疫苗和高强度聚焦超声消融(HIFU)诱导型肿瘤原位疫苗中的一种或多种。In situ tumor vaccines described in the present invention, such as chemotherapy-induced tumor in situ vaccines, radiotherapy-induced tumor in situ vaccines, radiofrequency ablation-induced tumor in situ vaccines, and high-intensity focused ultrasound ablation (HIFU)-induced tumor in situ vaccines one or more of.
在本发明一较佳实施方案中，所述组合物可以与免疫原性死亡(ICD)化疗药物联用，所述免疫原性死亡化疗药物能够使肿瘤细胞受到外界刺激发生死亡的同时，由非免疫原性转变为免疫原性而介导机体产生抗肿瘤免疫应答。In a preferred embodiment of the present invention, the composition can be used in combination with immunogenic death (ICD) chemotherapy drugs, and the immunogenic death chemotherapy drugs can cause tumor cells to die due to external stimuli, and at the same time, non- Immunogenicity transforms into immunogenicity and mediates the body to generate an anti-tumor immune response.
本发明所述免疫原性死亡化疗药物例如阿霉素、表阿霉素、米托蒽醌、奥沙利铂、环磷酰胺、硼替佐米、吉西他滨、五氟尿嘧啶和美登素中的一种或多种。One or more of the immunogenic death chemotherapy drugs of the present invention such as doxorubicin, epirubicin, mitoxantrone, oxaliplatin, cyclophosphamide, bortezomib, gemcitabine, pentafluorouracil and maytansine Various.
技术方案之二：一种表观遗传药物和谷氨酰胺代谢调节剂组合物的制备方法，其包括如下步骤：将所述表观遗传药物和所述谷氨酰胺代谢调节剂混合均匀，得所述表观遗 传药物和谷氨酰胺代谢调节剂组合物；当所述表观遗传药物和谷氨酰胺代谢调节剂组合物还包括免疫检查点调节剂或免疫佐剂时，任选地还包括缓释材料，将所述表观遗传药物、所述谷氨酰胺代谢调节剂和缓释材料，与免疫检查点调节剂或免疫佐剂混合均匀，得所述表观遗传药物和谷氨酰胺代谢调节剂组合物。The second technical solution: a preparation method of an epigenetic drug and a glutamine metabolism regulator composition, which includes the following steps: uniformly mixing the epigenetic drug and the glutamine metabolism regulator to obtain the obtained Epigenetic Genetic drug and glutamine metabolism regulator composition; when the epigenetic drug and glutamine metabolism regulator composition also includes immune checkpoint regulator or immune adjuvant, optionally also includes slow-release material, The epigenetic drug, the glutamine metabolism regulator and the slow-release material are uniformly mixed with the immune checkpoint regulator or immune adjuvant to obtain the epigenetic drug and glutamine metabolism regulator composition .
技术方案之三：本发明所述药物组合物在制备肿瘤治疗剂中的应用。The third technical solution: the application of the pharmaceutical composition of the present invention in the preparation of tumor therapeutic agents.
在本发明一较佳实施方案中，所述肿瘤是新诊断的、复发性和/或难治性肿瘤，优选为结直肠癌、肺癌、乳腺癌、肝癌、胃癌、食管癌、胰腺癌、黑色素瘤、头颈癌、前列腺癌和肾癌中的一种或多种。In a preferred embodiment of the present invention, the tumor is a newly diagnosed, recurrent and/or refractory tumor, preferably colorectal cancer, lung cancer, breast cancer, liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, melanin One or more of tumors, head and neck cancer, prostate cancer, and kidney cancer.
在本发明一具体实施方案中，所述治疗剂的剂型为注射剂、凝胶剂、原位胶凝系统、软膏剂、栓剂、喷雾剂、溶液剂、混悬剂、乳剂、植入剂、透皮剂、微针剂或口服制剂。In a specific embodiment of the present invention, the dosage form of the therapeutic agent is injection, gel, in-situ gelling system, ointment, suppository, spray, solution, suspension, emulsion, implant, penetrant, etc. Skin agent, microneedle or oral preparation.
在本发明一具体实施方案中，所述治疗剂的给药途径包括瘤内注射给药、静脉推注给药、静脉滴注给药、腹腔注射给药、肝动脉输注给药、肌肉注射给药、皮下注射给药、植入给药、舌下给药、透皮吸收给药、口服给药、舌下给药、直肠给药、吸入给药和介入途径给药中的一种或多种。In a specific embodiment of the present invention, the administration route of the therapeutic agent includes intratumoral injection administration, intravenous bolus administration, intravenous drip administration, intraperitoneal injection administration, hepatic artery infusion administration, intramuscular injection Administration, subcutaneous injection administration, implant administration, sublingual administration, transdermal administration, oral administration, sublingual administration, rectal administration, inhalation administration and interventional route administration or Various.
在本发明一具体实施方案中，所述肿瘤治疗剂为肿瘤原位治疗性疫苗。In a specific embodiment of the present invention, the tumor therapeutic agent is a tumor in situ therapeutic vaccine.
技术方案之四：一种套装药盒，其包含药盒A和药盒B，其中：The fourth technical solution: a set of medicine boxes, which includes a medicine box A and a medicine box B, wherein:
所述药盒A含有如本发明所述的组合物；The kit A contains a composition as described in the present invention;
所述药盒B含有如本发明所述的嵌合抗原受体-T细胞、如本发明所述的自然杀伤细胞、如本发明所述的嵌合抗原受体-自然杀伤细胞、如本发明所述的淋巴因子激活的杀伤细胞细胞、如本发明所述的肿瘤浸润淋巴细胞细胞、如本发明所述的T细胞表面的特异性受体-T细胞、如本发明所述的树突状细胞与细胞因子诱导的杀伤细胞共培养联合细胞、如本发明所述的自然杀伤T细胞和如本发明所述的嵌合抗原受体-巨噬细胞细胞中的一种或多种。The kit B contains chimeric antigen receptor-T cells as described in the present invention, natural killer cells as described in the present invention, chimeric antigen receptor-natural killer cells as described in the present invention, natural killer cells as described in the present invention, The lymphokine-activated killer cells, the tumor-infiltrating lymphocyte cells according to the present invention, the specific receptor-T cells on the surface of T cells according to the present invention, the dendritic cells according to the present invention The cells are co-cultured with cytokine-induced killer cells, one or more of the cells, natural killer T cells as described in the present invention, and chimeric antigen receptor-macrophage cells as described in the present invention.
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of conforming to common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：The positive progress effect of the present invention is:
本发明所述组合物将表观遗传药物与谷氨酰胺代谢调节剂结合，能够对肿瘤微环境进行代谢与表观遗传重编程，极大程度地协同激活机体对肿瘤的免疫反应，对肿瘤产生超出预料的协同治疗效果。并且实施组合物可与现行免疫佐剂、免疫检查点调控剂、溶瘤病毒、过继细胞疗法、肿瘤疫苗等联合使用，并可配合各类缓释材料如凝胶、药物载体 等联合使用，对各类肿瘤产生广谱且更好的治疗效果。The composition of the present invention combines epigenetic drugs with glutamine metabolism regulators, which can perform metabolism and epigenetic reprogramming on the tumor microenvironment, greatly synergistically activate the body's immune response to tumors, and have a strong impact on tumors. Synergistic therapeutic effects beyond expectations. And the implementation composition can be used in combination with current immune adjuvants, immune checkpoint regulators, oncolytic viruses, adoptive cell therapy, tumor vaccines, etc., and can be combined with various slow-release materials such as gels and drug carriers Combined use, etc., can produce broad-spectrum and better therapeutic effect on various tumors.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.
实施例1组合物的制备及效果验证Preparation and effect verification of the composition of embodiment 1
本实施例所涉及的药物：表观遗传药物为地西他滨(购自：上海阿拉丁生化科技股份有限公司，货号：A119533)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(购自：GLPBIO，货号：GC41224)，为固体粉末。The drug involved in this example: the epigenetic drug is decitabine (purchased from: Shanghai Aladdin Biochemical Technology Co., Ltd., product number: A119533), which is a solid powder; the glutamine metabolism regulator is 6-diazo - 5-oxo-L-norleucine (purchased from: GLPBIO, product number: GC41224), which is a solid powder.
组合物制备方法：将地西他滨、6-重氮-5-氧代-L-正亮氨酸溶解于水相溶液中，使地西他滨的终剂量为5mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量为1mg/kg，后将混合液冻干得到组合物冻干粉。冻干粉采用注射用水、0.9％氯化钠注射液或5％葡萄糖注射液进行复溶，复溶后不能产生浑浊或絮状沉淀。Composition preparation method: dissolve decitabine and 6-diazo-5-oxo-L-norleucine in the aqueous phase solution, so that the final dose of decitabine is 5 mg/kg, 6-weight The final dose of nitrogen-5-oxo-L-norleucine is 1 mg/kg, and then the mixed solution is freeze-dried to obtain a freeze-dried powder of the composition. The lyophilized powder is reconstituted with water for injection, 0.9% sodium chloride injection or 5% glucose injection, and no turbidity or flocculent precipitation can occur after reconstitution.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following is decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (glutamine metabolism regulator) freeze-dried powder injection in bilateral colon cancer xenografts (left and right sides) Each has a tumor) effect validation study on the model.
在小鼠(雄性Balb/c，购自：江苏集萃药康生物科技股份有限公司)左右腋下分别用CT26-luc细胞系接种小鼠结肠癌肿瘤(左边视为原位肿瘤，右边视为远端肿瘤)，并将荷瘤小鼠分为4组，每组8只进行效果验证实验。Mouse colon cancer tumors were inoculated with CT26-luc cell line in the left and right armpit of mice (male Balb/c, purchased from: Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) end tumor), and the tumor-bearing mice were divided into 4 groups, 8 mice in each group for the effect verification experiment.
第1组：原位瘤内注射生理盐水；Group 1: intratumoral injection of normal saline;
第2组：原位瘤内注射地西他滨冻干粉针剂；Group 2: Orthotopic intratumoral injection of decitabine freeze-dried powder injection;
第3组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸冻干粉针剂；Group 3: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine freeze-dried powder injection;
第4组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂；Group 4: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection;
待小鼠肿瘤体积到达70mm3后，每隔4天对左侧原位肿瘤进行注射，共注射3次，对右侧远端肿瘤则不进行注射。在第一次注射组合物后每隔两天测量并记录小鼠的体重，并用游标卡尺测量并记录原位肿瘤和远端肿瘤的长和宽，肿瘤的体积为(长乘以(宽的平方))除以2。同时，每隔两天观察并记录小鼠的生存状况，用于绘制生存期曲线(小鼠肿瘤体积到达2000mm3后也视为死亡并予以安乐死)。After the tumor volume of the mice reached 70 mm 3 , the left orthotopic tumor was injected every 4 days for a total of 3 injections, and the right distal tumor was not injected. After the first injection of the composition, measure and record the body weight of the mice every two days, and measure and record the length and width of the tumor in situ and the distal tumor with a vernier caliper. The volume of the tumor is (length multiplied by the square of width) ) divided by 2. At the same time, the survival status of the mice was observed and recorded every two days for drawing the survival curve (the mice were considered dead and euthanized after the tumor volume reached 2000 mm 3 ).
另外，参照以上分组与方法再次开展肿瘤免疫微环境验证实验，待小鼠肿瘤体积到达70mm3后，对左侧原位肿瘤进行注射，对右侧远端肿瘤则不进行注射。在注射后第4天获取小鼠左右侧肿瘤组织样本，切成小块后使用0.25％胰酶溶液在37℃或室温条件下震荡消化20～30min后终止消化并收集细胞悬液，300目尼龙网过滤出去细胞团块，低速 离心除去细胞碎片。将制备好的单细胞悬液使用anti-CD8流式抗体进行染色后，通过流式细胞术对小鼠左右肿瘤内CD8+T细胞的浸润水平进行测定和分选。并对分选出的CD8+肿瘤浸润T细胞采用RNA抽提试剂盒进行RNA抽提后进行RNA测序，并对其转录组进行分析。In addition, the tumor immune microenvironment verification experiment was carried out again referring to the above grouping and methods. After the tumor volume of the mice reached 70mm 3 , the left orthotopic tumor was injected, and the right distal tumor was not injected. On the 4th day after the injection, the left and right tumor tissue samples of the mice were obtained, cut into small pieces, and digested with 0.25% trypsin solution at 37°C or room temperature for 20-30 minutes, then the digestion was terminated and the cell suspension was collected, 300 mesh nylon Mesh filter out cell clumps, low speed Cell debris was removed by centrifugation. After the prepared single cell suspension was stained with anti-CD8 flow cytometry antibody, the infiltration level of CD8+ T cells in the left and right tumors of the mouse was measured and sorted by flow cytometry. The sorted CD8+ tumor-infiltrating T cells were extracted using RNA extraction kits, followed by RNA sequencing, and their transcriptomes were analyzed.
结果见表1-表3，与对应的对照组相比，第4组小鼠的原位瘤和远端瘤都得到了有效的抑制，几乎不再生长，生存期得到了显著的延长。The results are shown in Table 1-Table 3. Compared with the corresponding control group, the tumors in situ and distant tumors of mice in group 4 were effectively inhibited, almost no longer grew, and the survival period was significantly prolonged.
表1小鼠体重变化
Table 1 Changes in body weight of mice
表2小鼠原位瘤体积
Table 2 Tumor volume in situ in mice
与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
表3小鼠远端瘤体积
Table 3 Distal tumor volume of mice
与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
实施例2不同剂量的表观遗传药物和谷氨酰胺代谢调节剂组合物的制备及效果验证Example 2 Preparation and Effect Verification of Epigenetic Drugs and Glutamine Metabolism Regulator Compositions in Different Dosages
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同实施例1)，为固体粉末。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine Acid (with embodiment 1), is solid powder.
组合物制备方法参见实施例1，使地西他滨的终剂量分别为0.2mg/kg、1mg/kg、2.5mg/kg、5mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量分别为0.2mg/kg、1mg/kg、2.5mg/kg、5mg/kg。For the preparation method of the composition, refer to Example 1, so that the final doses of decitabine are 0.2 mg/kg, 1 mg/kg, 2.5 mg/kg, 5 mg/kg, 6-diazo-5-oxo-L-normal The final doses of leucine were 0.2 mg/kg, 1 mg/kg, 2.5 mg/kg, and 5 mg/kg, respectively.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following is decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (glutamine metabolism regulator) freeze-dried powder injection in bilateral colon cancer xenografts (left and right sides) Each has a tumor) effect validation study on the model.
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：原位瘤内注射生理盐水；Group 1: intratumoral injection of normal saline;
第2组：原位瘤内注射地西他滨(0.2mg/kg)冻干粉针剂；Group 2: Orthotopic intratumoral injection of decitabine (0.2 mg/kg) freeze-dried powder injection;
第3组：原位瘤内注射地西他滨(1mg/kg)冻干粉针剂；Group 3: Orthotopic intratumoral injection of decitabine (1 mg/kg) freeze-dried powder injection;
第4组：原位瘤内注射地西他滨(2.5mg/kg)冻干粉针剂；Group 4: Orthotopic intratumoral injection of decitabine (2.5 mg/kg) freeze-dried powder injection;
第5组：原位瘤内注射地西他滨(5mg/kg)冻干粉针剂；Group 5: Orthotopic intratumoral injection of decitabine (5mg/kg) freeze-dried powder injection;
第6组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(0.2mg/kg)冻干粉针剂；Group 6: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine (0.2 mg/kg) freeze-dried powder injection;
第7组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(1mg/kg)冻干粉针剂；Group 7: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine (1mg/kg) freeze-dried powder injection;
第8组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(2.5mg/kg)冻干粉针剂；Group 8: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine (2.5 mg/kg) freeze-dried powder injection;
第9组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(5mg/kg)冻干粉针剂；Group 9: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine (5 mg/kg) freeze-dried powder injection;
第10组：原位瘤内注射地西他滨(0.2mg/kg)和6-重氮-5-氧代-L-正亮氨酸(0.2mg/kg)组合物冻干粉针剂；Group 10: Orthotopic intratumoral injection of decitabine (0.2 mg/kg) and 6-diazo-5-oxo-L-norleucine (0.2 mg/kg) composition freeze-dried powder injection;
第11组：原位瘤内注射地西他滨(1mg/kg)和6-重氮-5-氧代-L-正亮氨酸(1mg/kg)组合物冻干粉针剂；Group 11: Orthotopic intratumoral injection of decitabine (1 mg/kg) and 6-diazo-5-oxo-L-norleucine (1 mg/kg) composition freeze-dried powder injection;
第12组：原位瘤内注射地西他滨(2.5mg/kg)和6-重氮-5-氧代-L-正亮氨酸(2.5mg/kg)组合物冻干粉针剂；Group 12: Orthotopic intratumoral injection of decitabine (2.5 mg/kg) and 6-diazo-5-oxo-L-norleucine (2.5 mg/kg) composition freeze-dried powder injection;
第13组：原位瘤内注射地西他滨(5mg/kg)和6-重氮-5-氧代-L-正亮氨酸(5mg/kg)组合物冻干粉针剂；Group 13: Orthotopic intratumoral injection of decitabine (5 mg/kg) and 6-diazo-5-oxo-L-norleucine (5 mg/kg) composition freeze-dried powder injection;
结果见表4-表6。与对应的对照组相比，第10、11、12、13组小鼠的原位瘤和远端肿瘤都得到了有效的抑制，几乎不再生长，生存期也得到了显著的延长。其中第10、11组小鼠在疗效良好的同时，体重仍然保持稳定，第12、13组小鼠体重显著下降，表现出较高的副作用。 The results are shown in Table 4-Table 6. Compared with the corresponding control group, the tumors in situ and distant tumors of the mice in the 10th, 11th, 12th, and 13th groups were effectively inhibited, almost no longer grew, and the survival period was also significantly prolonged. Among them, the mice in the 10th and 11th groups had a good curative effect, but their body weight remained stable, and the mice in the 12th and 13th groups lost weight significantly, showing relatively high side effects.
表4小鼠体重变化
Table 4 Changes in body weight of mice
表5小鼠原位瘤体积

Table 5 Tumor volume in situ in mice

与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
表6小鼠远端瘤体积

Table 6 Mouse distal tumor volume

与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
实施例3不同比例的表观遗传药物和谷氨酰胺代谢调节剂组合物的制备及效果验证Example 3 Preparation and Effect Verification of Epigenetic Drugs and Glutamine Metabolism Modulator Compositions in Different Proportions
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同实施例1)，为固体粉末。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine Acid (with embodiment 1), is solid powder.
组合物制备方法参见实施例1，使地西他滨的终剂量分别为0.2mg/kg、1mg/kg、2.5mg/kg、5mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量为1mg/kg。For the preparation method of the composition, refer to Example 1, so that the final doses of decitabine are 0.2 mg/kg, 1 mg/kg, 2.5 mg/kg, 5 mg/kg, 6-diazo-5-oxo-L-normal The final dose of leucine was 1 mg/kg.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following is decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (glutamine metabolism regulator) freeze-dried powder injection in bilateral colon cancer xenografts (left and right sides) Each has a tumor) effect validation study on the model.
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：原位瘤内注射生理盐水；Group 1: intratumoral injection of normal saline;
第2组：原位瘤内注射地西他滨(0.2mg/kg)冻干粉针剂；Group 2: Orthotopic intratumoral injection of decitabine (0.2 mg/kg) freeze-dried powder injection;
第3组：原位瘤内注射地西他滨(1mg/kg)冻干粉针剂；Group 3: Orthotopic intratumoral injection of decitabine (1 mg/kg) freeze-dried powder injection;
第4组：原位瘤内注射地西他滨(2.5mg/kg)冻干粉针剂；Group 4: Orthotopic intratumoral injection of decitabine (2.5 mg/kg) freeze-dried powder injection;
第5组：原位瘤内注射地西他滨(5mg/kg)冻干粉针剂；Group 5: Orthotopic intratumoral injection of decitabine (5mg/kg) freeze-dried powder injection;
第6组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(1mg/kg)冻干粉针剂；Group 6: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine (1mg/kg) freeze-dried powder injection;
第7组：原位瘤内注射地西他滨(0.2mg/kg)和6-重氮-5-氧代-L-正亮氨酸(1mg/kg)组合物冻干粉针剂；Group 7: Orthotopic intratumoral injection of decitabine (0.2 mg/kg) and 6-diazo-5-oxo-L-norleucine (1 mg/kg) composition freeze-dried powder injection;
第8组：原位瘤内注射地西他滨(1mg/kg)和6-重氮-5-氧代-L-正亮氨酸(1mg/kg)组合物冻干粉针剂；Group 8: Orthotopic intratumoral injection of decitabine (1 mg/kg) and 6-diazo-5-oxo-L-norleucine (1 mg/kg) composition freeze-dried powder injection;
第9组：原位瘤内注射地西他滨(2.5mg/kg)和6-重氮-5-氧代-L-正亮氨酸(1mg/kg)组合物冻干粉针剂；Group 9: Orthotopic intratumoral injection of decitabine (2.5 mg/kg) and 6-diazo-5-oxo-L-norleucine (1 mg/kg) composition freeze-dried powder injection;
第10组：原位瘤内注射地西他滨(5mg/kg)和6-重氮-5-氧代-L-正亮氨酸(1mg/kg)组合物冻干粉针剂；Group 10: Orthotopic intratumoral injection of decitabine (5 mg/kg) and 6-diazo-5-oxo-L-norleucine (1 mg/kg) composition freeze-dried powder injection;
结果见表7-表9，与对应的对照组相比，第7、8、9、10组小鼠的原位瘤和远端肿瘤都得到了有效的抑制，几乎不再生长，生存期也得到了显著的延长。其中第7、8、9组小鼠在疗效良好的同时，体重仍然保持稳定，第10组小鼠体重显著下降，表现出较高的 副作用。The results are shown in Table 7-Table 9. Compared with the corresponding control group, the tumors in situ and distant tumors of the mice in the 7th, 8th, 9th, and 10th groups were effectively inhibited, almost no longer grew, and the survival period was longer. was significantly extended. The mice in the 7th, 8th, and 9th groups had a good curative effect, but their body weight remained stable, and the weight of the mice in the 10th group decreased significantly, showing a high side effect.
表7小鼠体重变化
Table 7 Changes in body weight of mice
表8小鼠原位瘤体积

Table 8 Mouse orthotopic tumor volume

与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
表9小鼠远端瘤体积
Table 9 Mouse distal tumor volume
与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
实施例4不同比例的表观遗传药物和谷氨酰胺代谢调节剂组合物的制备及效果验证Example 4 Preparation and Effect Verification of Epigenetic Drugs and Glutamine Metabolism Modulator Compositions in Different Proportions
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同实施例1)，为固体粉末。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine Acid (with embodiment 1), is solid powder.
组合物制备方法参见实施例1，使地西他滨的终剂量为2.5mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量分别为0.2mg/kg、1mg/kg、2.5mg/kg、5mg/kg。For the preparation method of the composition, refer to Example 1, so that the final dose of decitabine is 2.5 mg/kg, and the final dose of 6-diazo-5-oxo-L-norleucine is 0.2 mg/kg and 1 mg, respectively. /kg, 2.5mg/kg, 5mg/kg.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂) 冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following are decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (modulator of glutamine metabolism) Validation study on the effect of freeze-dried powder injection on the model of bilateral colon cancer xenografts (one tumor on each side).
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：原位瘤内注射生理盐水；Group 1: intratumoral injection of normal saline;
第2组：原位瘤内注射地西他滨(2.5mg/kg)冻干粉针剂；Group 2: Orthotopic intratumoral injection of decitabine (2.5 mg/kg) freeze-dried powder injection;
第3组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(0.2mg/kg)冻干粉针剂；Group 3: Intratumoral injection of 6-diazo-5-oxo-L-norleucine (0.2 mg/kg) freeze-dried powder injection;
第4组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(1mg/kg)冻干粉针剂；Group 4: Intratumoral injection of 6-diazo-5-oxo-L-norleucine (1mg/kg) freeze-dried powder injection;
第5组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(2.5mg/kg)冻干粉针剂；Group 5: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine (2.5 mg/kg) freeze-dried powder injection;
第6组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸(5mg/kg)冻干粉针剂；Group 6: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine (5 mg/kg) freeze-dried powder injection;
第7组：原位瘤内注射地西他滨(2.5mg/kg)和6-重氮-5-氧代-L-正亮氨酸(0.2mg/kg)组合物冻干粉针剂；Group 7: Orthotopic intratumoral injection of decitabine (2.5 mg/kg) and 6-diazo-5-oxo-L-norleucine (0.2 mg/kg) composition freeze-dried powder injection;
第8组：原位瘤内注射地西他滨(2.5mg/kg)和6-重氮-5-氧代-L-正亮氨酸(1mg/kg)组合物冻干粉针剂；Group 8: Orthotopic intratumoral injection of decitabine (2.5 mg/kg) and 6-diazo-5-oxo-L-norleucine (1 mg/kg) composition freeze-dried powder injection;
第9组：原位瘤内注射地西他滨(2.5mg/kg)和6-重氮-5-氧代-L-正亮氨酸(2.5mg/kg)组合物冻干粉针剂；Group 9: Orthotopic intratumoral injection of decitabine (2.5 mg/kg) and 6-diazo-5-oxo-L-norleucine (2.5 mg/kg) composition freeze-dried powder injection;
第10组：原位瘤内注射地西他滨(2.5mg/kg)和6-重氮-5-氧代-L-正亮氨酸(5mg/kg)组合物冻干粉针剂；Group 10: orthotopic intratumoral injection of decitabine (2.5 mg/kg) and 6-diazo-5-oxo-L-norleucine (5 mg/kg) composition freeze-dried powder injection;
结果见表10-表12，与对应的对照组相比，第7、8、9、10组小鼠的原位瘤和远端肿瘤都得到了有效的抑制，几乎不再生长，生存期也得到了显著的延长。其中第7、8、9组小鼠在疗效良好的同时，体重仍然保持稳定，第10组小鼠体重显著下降，表现出较高的副作用。The results are shown in Table 10-Table 12. Compared with the corresponding control group, the tumors in situ and distant tumors of the mice in the 7th, 8th, 9th, and 10th groups were all effectively inhibited, almost no longer growing, and the survival period was longer. was significantly extended. The mice in the 7th, 8th and 9th groups had a good curative effect, but their body weight remained stable, and the mice in the 10th group lost weight significantly, showing relatively high side effects.
表10小鼠体重变化

Table 10 Changes in body weight of mice

表11小鼠原位瘤体积
Table 11 Tumor volume in situ in mice
与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
表12小鼠远端瘤体积

Table 12 Mouse distal tumor volume

与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
实施例5不同表观遗传药物和谷氨酰胺代谢调节剂组合物的制备及效果验证Example 5 Preparation and Effect Verification of Different Epigenetic Drugs and Glutamine Metabolism Regulator Compositions
本实施例所涉及的药物：表观遗传药物为西达本胺(购自：MCE，货号：HY-109015)，泰泽司他(购自：MCE，货号：HY-13803)，艾伏尼布(购自：MCE，货号：HY-18767)，思瑞德林(购自：MCE，货号：HY-18658)，阿帕他隆(购自：MCE，货号：HY-16652)，为固体粉末；谷氨酰胺代谢调节剂为L-天冬酰胺酶(购自：MCE，货号：HY-P1923)，CB-839(购自：MCE，货号：HY-12248)，V-9302(购自：MCE，货号：HY-112683)，2-烯丙基-1-羟基-9,10-蒽醌(购自：MCE，货号：HY-103096)，柳氮磺吡啶(购自：MCE，货号：HY-14655)，为固体粉末。Drugs involved in this example: epigenetic drugs are chidamide (purchased from: MCE, product number: HY-109015), tezecistat (purchased from: MCE, product number: HY-13803), Avoni Cloth (purchased from: MCE, product number: HY-18767), siroidelin (purchased from: MCE, product number: HY-18658), apaltalone (purchased from: MCE, product number: HY-16652), as solid powder; glutamine metabolism regulators are L-asparaginase (purchased from: MCE, product number: HY-P1923), CB-839 (purchased from: MCE, product number: HY-12248), V-9302 (purchased from : MCE, product number: HY-112683), 2-allyl-1-hydroxy-9,10-anthraquinone (purchased from: MCE, product number: HY-103096), sulfasalazine (purchased from: MCE, product number : HY-14655), as solid powder.
组合物制备方法参见实施例1，使西达本胺的终剂量为1mg/kg，泰泽司他的终剂量为0.5mg/kg，艾伏尼布的终剂量为2.5mg/kg，思瑞德林的终剂量为1mg/kg，阿帕他隆的终剂量为25mg/kg，L-天冬酰胺酶的终剂量为25mg/kg，CB-839的终剂量为1mg/kg，V-9302的终剂量为5mg/kg，2-烯丙基-1-羟基-9,10-蒽醌的终剂量为12.5mg/kg，柳氮磺吡啶的终剂量为10mg/kg。For the preparation method of the composition, refer to Example 1, so that the final dose of chidamide is 1 mg/kg, the final dose of tezelustat is 0.5 mg/kg, the final dose of ivonibu is 2.5 mg/kg, and the final dose of Sirui The final dose of Delin is 1 mg/kg, the final dose of apaltalone is 25 mg/kg, the final dose of L-asparaginase is 25 mg/kg, the final dose of CB-839 is 1 mg/kg, V-9302 The final dose of 2-allyl-1-hydroxy-9,10-anthraquinone is 12.5 mg/kg, and the final dose of sulfasalazine is 10 mg/kg.
如下为西达本胺、泰泽司他、艾伏尼布、思瑞德林、阿帕他隆(表观遗传药物)、L-天冬酰胺酶、CB-839、V-9302、2-烯丙基-1-羟基-9,10-蒽醌、柳氮磺吡啶(谷氨酰胺代谢调节剂)冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following are Chidamide, Tezestat, Ivonib, Seridelin, Apatalone (epigenetic drug), L-asparaginase, CB-839, V-9302, 2- Validation of the effect of allyl-1-hydroxy-9,10-anthraquinone and sulfasalazine (modulator of glutamine metabolism) freeze-dried powder injection on bilateral colon cancer xenografts (one tumor on each side) Research.
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：原位瘤内注射生理盐水；Group 1: intratumoral injection of normal saline;
第2组：原位瘤内注射西达本胺冻干粉针剂； Group 2: intratumoral injection of Chidamide freeze-dried powder injection;
第3组：原位瘤内注射CB-839冻干粉针剂；Group 3: intratumoral injection of CB-839 freeze-dried powder injection;
第4组：原位瘤内注射西达本胺和CB-839组合物冻干粉针剂；Group 4: Orthotopic intratumoral injection of chidamide and CB-839 composition freeze-dried powder injection;
第5组：原位瘤内注射泰泽司他冻干粉针剂；Group 5: Orthotopic intratumoral injection of freeze-dried powder injection of Tezecistat;
第6组：原位瘤内注射L-天冬酰胺酶冻干粉针剂；Group 6: intratumoral injection of L-asparaginase freeze-dried powder injection;
第7组：原位瘤内注射泰泽司他和L-天冬酰胺酶组合物冻干粉针剂；Group 7: Orthotopic intratumoral injection of lyophilized powder injection of a combination of tezecistat and L-asparaginase;
第8组：原位瘤内注射艾伏尼布冻干粉针剂；Group 8: Orthotopic intratumoral injection of ivonib freeze-dried powder injection;
第9组：原位瘤内注射V-9302冻干粉针剂；Group 9: Orthotopic intratumoral injection of V-9302 freeze-dried powder injection;
第10组：原位瘤内注射艾伏尼布和V-9302组合物冻干粉针剂；Group 10: Orthotopic intratumoral injection of ivonib and V-9302 composition freeze-dried powder injection;
第11组：原位瘤内注射思瑞德林冻干粉针剂；Group 11: Orthotopic intratumoral injection of Seridelin freeze-dried powder injection;
第12组：原位瘤内注射2-烯丙基-1-羟基-9,10-蒽醌冻干粉针剂；Group 12: Orthotopic intratumoral injection of 2-allyl-1-hydroxy-9,10-anthraquinone freeze-dried powder injection;
第13组：原位瘤内注射思瑞德林和2-烯丙基-1-羟基-9,10-蒽醌组合物冻干粉针剂；Group 13: Orthotopic intratumoral injection of a combination of seridelin and 2-allyl-1-hydroxy-9,10-anthraquinone freeze-dried powder injection;
第14组：原位瘤内注射阿帕他隆冻干粉针剂；Group 14: Orthotopic intratumoral injection of apatalone freeze-dried powder injection;
第15组：原位瘤内注射柳氮磺吡啶冻干粉针剂；Group 15: Orthotopic intratumoral injection of sulfasalazine freeze-dried powder injection;
第16组：原位瘤内注射阿帕他隆和柳氮磺吡啶组合物冻干粉针剂；Group 16: Orthotopic intratumoral injection of apaltalone and sulfasalazine combination freeze-dried powder injection;
肿瘤免疫微环境验证研究方法参见实施例1。Refer to Example 1 for the verification research method of the tumor immune microenvironment.
与对应的对照组相比，第4、7、10、13、16组小鼠的原位瘤和远端瘤都得到了有效的抑制，几乎不再生长，生存期得到了显著的延长。Compared with the corresponding control group, the tumors in situ and distant tumors of mice in groups 4, 7, 10, 13, and 16 were effectively inhibited, almost no longer grew, and the survival period was significantly prolonged.
与对应的对照组相比，第4、7、10、13、16组小鼠的原位瘤和远端瘤中CD8+T细胞的浸润水平显著增加，且该组CD8+肿瘤浸润T细胞的转录组结果表现出了增殖能力增强、抗癌活性增强和不耗竭等特点。Compared with the corresponding control group, the infiltration levels of CD8+ T cells in the tumors in situ and distant tumors of mice in groups 4, 7, 10, 13, and 16 were significantly increased, and the transcription of CD8+ tumor-infiltrating T cells in this group The results of the group showed the characteristics of enhanced proliferation ability, enhanced anticancer activity and non-exhaustion.
实施例6表观遗传药物和谷氨酰胺代谢调节剂与不同免疫佐剂组合物的制备及效果验证Example 6 Preparation and effect verification of epigenetic drugs, glutamine metabolism regulators and different immune adjuvant compositions
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同实施例1)，为固体粉末；免疫佐剂为：Poly-ICLC(购自：InvivoGen，货号：tlrl-pic)，单磷酰酯质A(购自：Sigma，货号：699800P)，雷西莫特(购自：MCE，货号：HY-13740)，CpG ODN寡脱氧核苷酸(购自：苏州泓迅生物科技股份有限公司，货号：20211015011)，白细胞介素-2(购自：近岸蛋白质科技有限公司，货号：C013)：巨噬细胞集落刺激因子(购自：近岸蛋白质科技有限公司，货号：CK02)：趋化因子21(购自：近岸蛋白质科技有限公司，货号：CG27)：白细胞介素-15mRNA(购自：近岸蛋白质科技有限公司，货号：无)：MK-1454(购自：MCE，货号：HY-139586)，BMS-986301(来自：上海复东生物医药有限责任公司，货号：无)， MSA-2(购自：MCE，货号：HY-136927)，HG381(来自：上海复东生物医药有限责任公司，货号：无)，为固体粉末。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine Acid (same as Example 1), which is a solid powder; the immune adjuvant is: Poly-ICLC (purchased from: InvivoGen, article number: tlrl-pic), monophosphoryl ester A (purchased from: Sigma, article number: 699800P), Resimot (purchased from: MCE, article number: HY-13740), CpG ODN oligodeoxynucleotide (purchased from: Suzhou Synbio Biotechnology Co., Ltd., article number: 20211015011), interleukin-2 (purchased from : Nearshore Protein Technology Co., Ltd., product number: C013): macrophage colony-stimulating factor (purchased from: Nearshore Protein Technology Co., Ltd., product number: CK02): chemokine 21 (purchased from: Nearshore Protein Technology Co., Ltd., Product number: CG27): Interleukin-15mRNA (purchased from: Nearshore Protein Technology Co., Ltd., product number: none): MK-1454 (purchased from: MCE, product number: HY-139586), BMS-986301 (from: Shanghai Fu East Biomedical Co., Ltd., Cat. No.: None), MSA-2 (purchased from: MCE, article number: HY-136927), HG381 (from: Shanghai Fudong Biomedicine Co., Ltd., article number: none), are solid powders.
组合物制备方法参见实施例1，使地西他滨的终剂量分别为2.5mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量分别为1mg/kg，Poly-ICLC的最终剂量为15mg/kg，单磷酰酯质A的最终剂量为30mg/kg，雷西莫特的最终剂量为7.5mg/kg，CpG寡脱氧核苷酸(SD-101)的最终剂量为7.5mg/kg，白细胞介素-2的最终剂量为1.875mg/kg，巨噬细胞集落刺激因子的最终剂量为1.875mg/kg，趋化因子21的最终剂量为1.875mg/kg，白细胞介素-15mRNA的最终剂量为2mg/kg，MK-1454的最终剂量为10mg/kg，BMS-986301的最终剂量为10mg/kg，MSA-2的最终剂量为10mg/kg，HG381的最终剂量为10mg/kg。Refer to Example 1 for the preparation method of the composition, so that the final dose of decitabine is 2.5 mg/kg, the final dose of 6-diazo-5-oxo-L-norleucine is 1 mg/kg, Poly - The final dose of ICLC is 15 mg/kg, the final dose of monophosphoryl esterase A is 30 mg/kg, the final dose of resimod is 7.5 mg/kg, the final dose of CpG oligodeoxynucleotide (SD-101) The dose was 7.5 mg/kg, the final dose of interleukin-2 was 1.875 mg/kg, the final dose of macrophage colony-stimulating factor was 1.875 mg/kg, the final dose of chemokine 21 was 1.875 mg/kg, leukocyte The final dose of interleukin-15 mRNA was 2 mg/kg, the final dose of MK-1454 was 10 mg/kg, the final dose of BMS-986301 was 10 mg/kg, the final dose of MSA-2 was 10 mg/kg, and the final dose of HG381 was 10mg/kg.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)、Poly-ICLC、单磷酰酯质A、雷西莫特、CpG寡脱氧核苷酸、白细胞介素-2、巨噬细胞集落刺激因子、趋化因子21、白细胞介素-15mRNA、MK-1454、BMS-986301、MSA-2、HG381(免疫佐剂)冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following are decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (glutamine metabolism regulator), Poly-ICLC, monophosphoryl ester A, leucine Simote, CpG oligodeoxynucleotide, interleukin-2, macrophage colony-stimulating factor, chemokine 21, interleukin-15 mRNA, MK-1454, BMS-986301, MSA-2, HG381 (immune Adjuvant) lyophilized powder injection on bilateral colon cancer xenografts (one tumor on each side) model.
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：原位瘤内注射生理盐水；Group 1: intratumoral injection of normal saline;
第2组：原位瘤内注射地西他滨冻干粉针剂；Group 2: Orthotopic intratumoral injection of decitabine freeze-dried powder injection;
第3组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸冻干粉针剂；Group 3: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine freeze-dried powder injection;
第4组：原位瘤内注射Poly-ICLC冻干粉针剂；Group 4: Orthotopic intratumoral injection of Poly-ICLC freeze-dried powder injection;
第5组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和Poly-ICLC组合物冻干粉针剂；Group 5: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and Poly-ICLC composition freeze-dried powder injection;
第6组：原位瘤内注射单磷酰酯质A冻干粉针剂；Group 6: Orthotopic intratumoral injection of monophosphoryl ester A freeze-dried powder injection;
第7组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和单磷酰酯质A组合物冻干粉针剂；Group 7: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and monophosphoryl ester A composition freeze-dried powder injection;
第8组：原位瘤内注射雷西莫特冻干粉针剂；Group 8: Orthotopic intratumoral injection of Resimod freeze-dried powder injection;
第9组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、雷西莫特组合物冻干粉针剂；Group 9: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, and resimod combination freeze-dried powder injection;
第10组：原位瘤内注射CpG ODN寡脱氧核苷酸(SD-101)抗冻干粉针剂；Group 10: Orthotopic intratumoral injection of CpG ODN oligodeoxynucleotide (SD-101) anti-lyophilized powder injection;
第11组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和CpG寡脱氧核苷酸(SD-101)冻干粉针剂；Group 11: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and CpG oligodeoxynucleotide (SD-101) freeze-dried powder injection;
第12组：原位瘤内注射白细胞介素-2冻干粉针剂； Group 12: Orthotopic intratumoral injection of interleukin-2 freeze-dried powder injection;
第13组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和白细胞介素-2组合物冻干粉针剂；Group 13: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and interleukin-2 composition freeze-dried powder injection;
第14组：原位瘤内注射巨噬细胞集落刺激因子冻干粉针剂；Group 14: Orthotopic intratumoral injection of macrophage colony-stimulating factor freeze-dried powder injection;
第15组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和巨噬细胞集落刺激因子组合物冻干粉针剂；Group 15: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and macrophage colony-stimulating factor composition freeze-dried powder injection;
第16组：原位瘤内注射趋化因子21冻干粉针剂；Group 16: Orthotopic intratumoral injection of chemokine 21 freeze-dried powder injection;
第17组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和趋化因子21组合物冻干粉针剂；Group 17: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and chemokine 21 composition freeze-dried powder injection;
第18组：原位瘤内注射白细胞介素-15mRNA冻干粉针剂；Group 18: Orthotopic intratumoral injection of interleukin-15mRNA freeze-dried powder injection;
第19组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和白细胞介素-15mRNA组合物冻干粉针剂；Group 19: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and interleukin-15mRNA composition freeze-dried powder injection;
第20组：原位瘤内注射MK-1454冻干粉针剂；Group 20: Orthotopic intratumoral injection of MK-1454 freeze-dried powder injection;
第21组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和MK-1454组合物冻干粉针剂；Group 21: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and MK-1454 composition freeze-dried powder injection;
第22组：原位瘤内注射BMS-986301冻干粉针剂；Group 22: Orthotopic intratumoral injection of BMS-986301 freeze-dried powder injection;
第23组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和BMS-986301组合物冻干粉针剂；Group 23: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and BMS-986301 composition freeze-dried powder injection;
第24组：原位瘤内注射MSA-2冻干粉针剂；Group 24: Orthotopic intratumoral injection of MSA-2 freeze-dried powder injection;
第25组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和MSA-2组合物冻干粉针剂；Group 25: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and MSA-2 composition freeze-dried powder injection;
第26组：原位瘤内注射HG381冻干粉针剂；Group 26: intratumoral injection of HG381 freeze-dried powder injection;
第27组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和HG381组合物冻干粉针剂；Group 27: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and HG381 composition freeze-dried powder injection;
与对应的对照组相比，第5、7、9、11、13、15、17、19、21、23、25、27组小鼠的原位瘤和远端瘤都得到了有效的抑制，几乎不再生长，生存期得到了显著的延长。Compared with the corresponding control group, the tumors in situ and distal tumors of mice in groups 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27 were effectively inhibited, Almost no longer grows, and the survival period has been significantly extended.
实施例7表观遗传药物和谷氨酰胺代谢调节剂与不同免疫检查点调节剂组合物的制备及效果验证Example 7 Preparation and Effect Verification of Compositions of Epigenetic Drugs, Glutamine Metabolism Modulators and Different Immune Checkpoint Modulators
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同实施例1)，为固体粉末；免疫检查点抑制剂为anti-PD-L1抗体(购自：Bio X Cell，货号：BE0101)，为溶液；免疫检查点激动剂为anti-4-1BB抗体(购自：Bio X Cell，货号：BE0169)，anti-CD40抗体(购自：Bio  X Cell，货号：BE0016-2)，为溶液；免疫检查点调节剂双抗为anti-PD-L1/4-1BB双抗(购自：近岸蛋白质科技有限公司，货号：无)，anti-PD-L1/CD47双抗(购自：近岸蛋白质科技有限公司，货号：无)，anti-PD-1/LAG-3双抗(购自：近岸蛋白质科技有限公司，货号：无)，anti-PD-1/TIM-3双抗(购自：近岸蛋白质科技有限公司，货号：无)，anti-PD-1/TIGIT-3双抗(购自：近岸蛋白质科技有限公司，货号：无)，为溶液；免疫检查点抑制剂抗体mRNA为anti-PD-L1抗体mRNA(购自：近岸蛋白质科技有限公司，货号：无)，为固体；免疫检查点激动剂抗体mRNA为anti-4-1BB抗体mRNA(购自：近岸蛋白质科技有限公司，货号：无)，为固体粉末。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine Acid (same as Example 1), which is solid powder; immune checkpoint inhibitor is anti-PD-L1 antibody (purchased from: Bio X Cell, product number: BE0101), which is a solution; immune checkpoint agonist is anti-4- 1BB antibody (purchased from: Bio X Cell, product number: BE0169), anti-CD40 antibody (purchased from: Bio X Cell, product number: BE0016-2), is a solution; the immune checkpoint regulator double antibody is anti-PD-L1/4-1BB double antibody (purchased from: Nearshore Protein Technology Co., Ltd., product number: none), anti- PD-L1/CD47 double antibody (purchased from: Nearshore Protein Technology Co., Ltd., article number: None), anti-PD-1/LAG-3 double antibody (purchased from: Nearshore Protein Technology Co., Ltd., article number: None), Anti-PD-1/TIM-3 double antibody (purchased from: Nearshore Protein Technology Co., Ltd., catalog number: None), anti-PD-1/TIGIT-3 double antibody (purchased from: Nearshore Protein Science and Technology Co., Ltd., catalog number : no), as a solution; immune checkpoint inhibitor antibody mRNA as anti-PD-L1 antibody mRNA (purchased from: Nearshore Protein Technology Co., Ltd., article number: no), as a solid; immune checkpoint agonist antibody mRNA as anti - 4-1BB antibody mRNA (purchased from: Nearshore Protein Technology Co., Ltd., article number: none), in the form of solid powder.
组合物制备方法参见实施例1，使地西他滨的终剂量为2.5mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量为1mg/kg，anti-PD-L1抗体的终剂量为0.5mg/kg，anti-4-1BB抗体的终剂量为0.5mg/kg，anti-CD40抗体的终剂量为0.5mg/kg，anti-PD-L1/4-1BB双抗的终剂量为1mg/kg，anti-PD-L1/CD47双抗的终剂量为1mg/kg，anti-PD-1/LAG-3双抗的终剂量为1mg/kg，anti-PD-1/TIM-3双抗的终剂量为1mg/kg，anti-PD-1/TIGIT-3双抗的终剂量为1mg/kg，anti-PD-L1抗体mRNA的终剂量为0.5mg/kg和anti-4-1BB抗体mRNA的终剂量为0.5mg/kg。For the preparation method of the composition, refer to Example 1, so that the final dose of decitabine is 2.5 mg/kg, the final dose of 6-diazo-5-oxo-L-norleucine is 1 mg/kg, anti-PD - The final dose of L1 antibody is 0.5mg/kg, the final dose of anti-4-1BB antibody is 0.5mg/kg, the final dose of anti-CD40 antibody is 0.5mg/kg, anti-PD-L1/4-1BB double The final dose of anti-PD-L1/CD47 double antibody is 1mg/kg, the final dose of anti-PD-1/LAG-3 double antibody is 1mg/kg, anti-PD-1 The final dose of anti-PD-1/TIGIT-3 double antibody is 1mg/kg, the final dose of anti-PD-L1 antibody mRNA is 0.5mg/kg and anti - The final dose of 4-1BB antibody mRNA was 0.5 mg/kg.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)、anti-PD-L1抗体(免疫检查点抑制剂)，anti-4-1BB抗体、anti-CD40抗体(免疫检查点激动剂)、anti-PD-L1/4-1BB双抗、anti-PD-L1/CD47双抗、anti-PD-1/LAG-3双抗、anti-PD-1/TIM-3双抗、anti-PD-1/TIGIT-3双抗(免疫检查点调节剂双抗)、anti-PD-L1抗体mRNA(免疫检查点抑制剂抗体mRNA)和anti-4-1BB抗体mRNA(免疫检查点抗体激动剂mRNA)冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following are decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (modulator of glutamine metabolism), anti-PD-L1 antibody (immune checkpoint inhibitor ), anti-4-1BB antibody, anti-CD40 antibody (immune checkpoint agonist), anti-PD-L1/4-1BB double antibody, anti-PD-L1/CD47 double antibody, anti-PD-1/LAG -3 double antibody, anti-PD-1/TIM-3 double antibody, anti-PD-1/TIGIT-3 double antibody (immune checkpoint regulator double antibody), anti-PD-L1 antibody mRNA (immune checkpoint inhibition Antibody mRNA) and anti-4-1BB antibody mRNA (immune checkpoint antibody agonist mRNA) lyophilized powder injection on bilateral colon cancer xenografts (one tumor on each side) model.
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：原位瘤内注射生理盐水；Group 1: intratumoral injection of normal saline;
第2组：原位瘤内注射地西他滨冻干粉针剂；Group 2: Orthotopic intratumoral injection of decitabine freeze-dried powder injection;
第3组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸冻干粉针剂；Group 3: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine freeze-dried powder injection;
第4组：原位瘤内注射anti-PD-L1抗体冻干粉针剂；Group 4: Orthotopic intratumoral injection of anti-PD-L1 antibody freeze-dried powder injection;
第5组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-L1抗体组合物冻干粉针剂；Group 5: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-L1 antibody composition freeze-dried powder injection;
第6组：原位瘤内注射anti-4-1BB抗体冻干粉针剂；Group 6: Intratumoral injection of anti-4-1BB antibody freeze-dried powder injection;
第7组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-4-1BB抗体组合 物冻干粉针剂；Group 7: orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-4-1BB antibody combination Freeze-dried powder injection;
第8组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-L1抗体和anti-4-1BB抗体组合物冻干粉针剂；Group 8: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-L1 antibody and anti-4-1BB antibody composition freeze-dried powder injection ;
第9组：原位瘤内注射anti-CD40抗体冻干粉针剂；Group 9: intratumoral injection of anti-CD40 antibody freeze-dried powder injection;
第10组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-CD40抗体组合物冻干粉针剂Group 10: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-CD40 antibody composition freeze-dried powder injection
第11组：原位瘤内注射anti-PD-L1/4-1BB双抗冻干粉针剂；Group 11: Intratumoral injection of anti-PD-L1/4-1BB dual-antibody freeze-dried powder injection;
第12组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-L1/4-1BB双抗组合物冻干粉针剂；Group 12: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-L1/4-1BB double antibody composition lyophilized powder injection;
第13组：原位瘤内注射anti-PD-L1/CD47双抗冻干粉针剂；Group 13: Orthotopic intratumoral injection of anti-PD-L1/CD47 dual-antibody freeze-dried powder injection;
第14组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-L1/CD47双抗组合物冻干粉针剂；Group 14: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-L1/CD47 double antibody composition lyophilized powder injection;
第15组：原位瘤内注射anti-PD-1/LAG-3双抗冻干粉针剂；Group 15: Intratumoral injection of anti-PD-1/LAG-3 dual anti-lyophilized powder injection;
第16组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-1/LAG-3双抗组合物冻干粉针剂；Group 16: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-1/LAG-3 double antibody composition lyophilized powder injection;
第17组：原位瘤内注射anti-PD-1/TIM-3双抗冻干粉针剂；Group 17: Orthotopic intratumoral injection of anti-PD-1/TIM-3 dual-antibody freeze-dried powder injection;
第18组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-1/TIM-3双抗组合物冻干粉针剂；Group 18: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-1/TIM-3 double antibody composition lyophilized powder injection;
第19组：原位瘤内注射anti-PD-1/TIGIT-3双抗冻干粉针剂；Group 19: orthotopic intratumoral injection of anti-PD-1/TIGIT-3 dual-antibody freeze-dried powder injection;
第20组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-1/TIGIT-3双抗组合物冻干粉针剂；Group 20: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-1/TIGIT-3 double antibody composition lyophilized powder injection;
第21组：原位瘤内注射anti-PD-L1抗体mRNA冻干粉针剂；Group 21: Orthotopic intratumoral injection of anti-PD-L1 antibody mRNA freeze-dried powder injection;
第22组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-L1抗体mRNA组合物冻干粉针剂；Group 22: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-L1 antibody mRNA composition freeze-dried powder injection;
第23组：原位瘤内注射anti-4-1BB抗体mRNA冻干粉针剂；Group 23: Orthotopic intratumoral injection of anti-4-1BB antibody mRNA freeze-dried powder injection;
第24组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-4-1BB抗体mRNA组合物冻干粉针剂；Group 24: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-4-1BB antibody mRNA composition freeze-dried powder injection;
与对应的对照组相比，第5、7、8、10、12、14、16、18、20、22、24组小鼠的原位瘤和远端瘤都得到了有效的抑制，几乎不再生长，生存期得到了显著的延长。Compared with the corresponding control group, the tumors in situ and distal tumors of the mice in the 5th, 7th, 8th, 10th, 12th, 14th, 16th, 18th, 20th, 22nd, and 24th groups were effectively inhibited, almost no Re-growth, the survival period has been significantly extended.
实施例8表观遗传药物和谷氨酰胺代谢调节剂与不同免疫检查点调节剂和/或缓释材料组合物的制备及效果验证 Example 8 Preparation and Effect Verification of Compositions of Epigenetic Drugs and Glutamine Metabolism Modulators and Different Immune Checkpoint Modulators and/or Sustained Release Materials
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同时实例1)，为固体粉末；免疫佐剂为MSA-2(购自：MCE，货号：HY-13740)，为固体粉末；免疫检查点抗体为anti-PD-1抗体(购自：Bio X Cell；货号：BE0146)，免疫检查点调节剂双抗为anti-PD-L1/4-1BB双抗(同实施例7)，anti-PD-L1/CD47双抗(同实施例7)，anti-PD-1/LAG-3双抗(同实施例7)，anti-PD-1/TIM-3双抗(同实施例7)，anti-PD-1/TIGIT-3双抗(同实施例7)，为溶液；缓释材料为明胶微球(购自:北京华龛生物科技有限公司，货号：无)，海藻酸钠(购自：上海阿拉丁生化科技股份有限公司，货号：S100127)、透明质酸(购自：Sigma，货号：53747)、泊洛沙姆温敏凝胶(购自：Sigma，货号：16758)、PLGA微球(购自：西安瑞禧生物科技有限公司，货号：无)、四氧化三铁微球(购自：中科雷鸣(北京)科技有限公司，货号：Mag9400)，为固体粉末。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine Acid (simultaneous example 1), is a solid powder; the immune adjuvant is MSA-2 (purchased from: MCE, product number: HY-13740), which is a solid powder; the immune checkpoint antibody is anti-PD-1 antibody (purchased from: Bio X Cell; product number: BE0146), the immune checkpoint regulator double antibody is anti-PD-L1/4-1BB double antibody (same as Example 7), anti-PD-L1/CD47 double antibody (same as Example 7) , anti-PD-1/LAG-3 double antibody (same as Example 7), anti-PD-1/TIM-3 double antibody (same as Example 7), anti-PD-1/TIGIT-3 double antibody (same as Example 7) Embodiment 7), is a solution; the slow-release material is gelatin microspheres (purchased from: Beijing Huakan Biotechnology Co., Ltd., article number: none), sodium alginate (purchased from: Shanghai Aladdin Biochemical Technology Co., Ltd., article number: S100127), hyaluronic acid (purchased from: Sigma, product number: 53747), poloxamer thermosensitive gel (purchased from: Sigma, product number: 16758), PLGA microspheres (purchased from: Xi’an Ruixi Biotechnology Co., Ltd., product number : None), Fe3O4 microspheres (purchased from: Zhongke Leiming (Beijing) Technology Co., Ltd., article number: Mag9400), which are solid powders.
组合物制备方法参见实施例1，使地西他滨的终剂量分别为10mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量分别为2mg/kg，MSA-2的终剂量分别为7.5mg/kg，anti-PD-1抗体的终剂量分别为0.75mg/kg，anti-PD-L1/4-1BB双抗的终剂量分别为0.75mg/kg，anti-PD-L1/CD47双抗的终剂量分别为0.75mg/kg，anti-PD-1/LAG-3双抗的终剂量分别为0.75mg/kg，anti-PD-1/TIM-3双抗的终剂量分别为0.75mg/kg，anti-PD-1/TIGIT-3双抗的终剂量分别为0.75mg/kg，明胶微球的终剂量为125mg/kg、海藻酸钠的终剂量为0.5mg/kg、透明质酸的终剂量为10mg/kg、泊洛沙姆温敏凝胶的终剂量为50mg/kg、PLGA微球的终剂量为100mg/kg、四氧化三铁微球的终剂量为250mg/kg。For the preparation method of the composition, refer to Example 1, so that the final doses of decitabine are 10 mg/kg, the final doses of 6-diazo-5-oxo-L-norleucine are 2 mg/kg, and the final doses of MSA- The final dose of 2 is 7.5 mg/kg, the final dose of anti-PD-1 antibody is 0.75 mg/kg, the final dose of anti-PD-L1/4-1BB double antibody is 0.75 mg/kg, anti- The final dose of PD-L1/CD47 double antibody is 0.75 mg/kg, the final dose of anti-PD-1/LAG-3 double antibody is 0.75 mg/kg, and the final dose of anti-PD-1/TIM-3 double antibody is 0.75 mg/kg. The final dose is 0.75 mg/kg, the final dose of anti-PD-1/TIGIT-3 double antibody is 0.75 mg/kg, the final dose of gelatin microspheres is 125 mg/kg, and the final dose of sodium alginate is 0.5 mg /kg, the final dose of hyaluronic acid is 10 mg/kg, the final dose of poloxamer thermosensitive gel is 50 mg/kg, the final dose of PLGA microspheres is 100 mg/kg, and the final dose of ferric oxide microspheres is 250 mg /kg.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)、MSA-2(免疫佐剂)，anti-PD-1抗体，anti-PD-L1/4-1BB双抗，anti-PD-L1/CD47双抗，anti-PD-1/LAG-3双抗，anti-PD-1/TIM-3双抗，anti-PD-1/TIGIT-3双抗(免疫检查点激动剂)和明胶微球、海藻酸钠、透明质酸、泊洛沙姆温敏凝胶、PLGA微球、四氧化三铁微球(缓释材料)冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following are decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (glutamine metabolism regulator), MSA-2 (immune adjuvant), anti-PD -1 antibody, anti-PD-L1/4-1BB double antibody, anti-PD-L1/CD47 double antibody, anti-PD-1/LAG-3 double antibody, anti-PD-1/TIM-3 double antibody, Anti-PD-1/TIGIT-3 double antibody (immune checkpoint agonist) and gelatin microspheres, sodium alginate, hyaluronic acid, poloxamer thermosensitive gel, PLGA microspheres, ferric oxide microspheres (slow Validation study on the effect of freeze-dried powder injection on bilateral colon cancer xenograft tumor (one tumor on each side) model.
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：原位瘤内注射生理盐水；Group 1: intratumoral injection of normal saline;
第2组：原位瘤内注射地西他滨冻干粉针剂；Group 2: Orthotopic intratumoral injection of decitabine freeze-dried powder injection;
第3组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸冻干粉针剂；Group 3: Orthotopic intratumoral injection of 6-diazo-5-oxo-L-norleucine freeze-dried powder injection;
第4组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂；Group 4: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection;
第5组：原位瘤内注射anti-PD-1抗体冻干粉针剂； Group 5: Orthotopic intratumoral injection of anti-PD-1 antibody freeze-dried powder injection;
第6组：原位瘤内注射anti-PD-L1/4-1BB双抗冻干粉针剂；Group 6: Intratumoral injection of anti-PD-L1/4-1BB dual-antibody freeze-dried powder injection;
第7组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-1抗体组合物冻干粉针剂；Group 7: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-1 antibody composition freeze-dried powder injection;
第8组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-1抗体冻干粉针剂和明胶微球组合物冻干粉针剂；Group 8: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-1 antibody freeze-dried powder injection and gelatin microsphere composition freeze-dried powder injection;
第9组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-L1/4-1BB双抗组合物冻干粉针剂；Group 9: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-L1/4-1BB double antibody composition lyophilized powder injection;
第10组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-L1/4-1BB双抗和明胶微球组合物冻干粉针剂；Group 10: orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-L1/4-1BB double antibody and gelatin microsphere composition freeze-dried powder injection;
第11组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-1/LAG-3双抗和海藻酸钠组合物冻干粉针剂；Group 11: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-1/LAG-3 double antibody and sodium alginate composition freeze-dried powder injection;
第12组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-1/TIM-3双抗和透明质酸组合物冻干粉针剂；Group 12: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-1/TIM-3 double antibody and hyaluronic acid composition freeze-dried powder injection;
第13组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-1/TIGIT-3双抗和泊洛沙姆温敏凝胶组合物冻干粉针剂；Group 13: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-1/TIGIT-3 double antibody and poloxamer thermosensitive gel composition Freeze-dried powder injection;
第14组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-L1/CD47双抗和PLGA微球组合物冻干粉针剂；Group 14: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-L1/CD47 double antibody and PLGA microsphere composition freeze-dried powder injection ;
第15组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-L1/4-1BB双抗和四氧化三铁微球组合物冻干粉针剂；Group 15: Combination of orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-L1/4-1BB double antibody and ferric oxide microspheres Freeze-dried powder injection;
第16组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和anti-PD-1/VEGF双抗组合物冻干粉针剂；Group 16: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and anti-PD-1/VEGF double antibody composition lyophilized powder injection;
第17组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸、anti-PD-1/VEGF双抗和明胶微球组合物冻干粉针剂。Group 17: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine, anti-PD-1/VEGF double antibody and gelatin microsphere composition freeze-dried powder injection .
待小鼠肿瘤体积到达70mm3后，每隔6天对左侧原位肿瘤进行注射，共注射2次，对右侧远端肿瘤则不进行注射。在注射组合物后每隔两天测量并记录小鼠的体重，并用游标卡尺测量并记录原位肿瘤和远端肿瘤的长和宽，肿瘤的体积为(长乘以(宽的平方))除以2。同时，每隔两天观察并记录小鼠的生存状况，用于绘制生存期曲线(小鼠肿瘤体积到达2000mm3后也视为死亡并予以安乐死)。After the tumor volume of the mice reached 70 mm 3 , the left orthotopic tumor was injected every 6 days for a total of 2 injections, and the right distal tumor was not injected. After injecting the composition, measure and record the body weight of the mice every two days, and measure and record the length and width of the tumor in situ and the distal tumor with a vernier caliper. The volume of the tumor is (length multiplied by the square of width) divided by 2. At the same time, the survival status of the mice was observed and recorded every two days for drawing the survival curve (the mice were considered dead and euthanized after the tumor volume reached 2000 mm 3 ).
结果如表13-表15，与对应的对照组相比，第7、8、9、10、11、12、13、14、15、16、17组小鼠的原位瘤和远端瘤都得到了有效的抑制，几乎不再生长，生存期得到了显著的延长；与第7组相比，第8、9、10、11、12、13组小鼠的原位瘤和远端瘤在得到了 相近的抑制效果后，小鼠体重更加稳定，毒副作用显著减轻。The results are shown in Table 13-Table 15. Compared with the corresponding control group, the tumors in situ and distal tumors of mice in groups 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, and 17 were all have been effectively inhibited, almost no longer grow, and the survival period has been significantly prolonged; compared with group 7, the tumors in situ and distal tumors of mice in groups 8, 9, 10, 11, 12, and 13 were within Got After a similar inhibitory effect, the body weight of the mice was more stable, and the toxic side effects were significantly reduced.
表13小鼠体重变化
Table 13 Changes in body weight of mice
表14小鼠原位瘤体积

Table 14 Mouse orthotopic tumor volume

与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
表15小鼠远端瘤体积

Table 15 Mouse distal tumor volume

与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
实施例9表观遗传药物和谷氨酰胺代谢调节剂组合物的制备及在不同癌症模型上的效果验证Example 9 Preparation of Epigenetic Medicine and Glutamine Metabolism Modulator Composition and Validation of Effects on Different Cancer Models
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同实施例1)，为固体粉末。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine Acid (with embodiment 1), is solid powder.
组合物制备方法参见实施例1，使地西他滨的终剂量分别为50mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量分别为20mg/kg。Refer to Example 1 for the preparation method of the composition, so that the final doses of decitabine and 6-diazo-5-oxo-L-norleucine are respectively 50 mg/kg and 20 mg/kg respectively.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)冻干粉针剂在双边乳腺癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following is decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (glutamine metabolism regulator) freeze-dried powder injection in bilateral breast cancer transplanted tumors (left and right sides) Each has a tumor) effect validation study on the model.
在小鼠左右腋下分别用4T1、A549、HepG2、AKR、MGC-803、KB、TE-1、AsPC-1、B16F10、HN-5、PC-3和HRC-A498肿瘤细胞系接种小鼠乳腺癌、肺癌、肝癌、食管癌、胃癌、胰腺癌、黑色素瘤、头颈癌、前列腺癌和肾癌肿瘤(左边视为原位肿瘤，右边视为远端肿瘤)，并将荷瘤小鼠分为15组，每组8只进行效果验证实验。Mouse mammary glands were inoculated with 4T1, A549, HepG2, AKR, MGC-803, KB, TE-1, AsPC-1, B16F10, HN-5, PC-3, and HRC-A498 tumor cell lines in the left and right axilla of mice, respectively. Carcinoma, lung cancer, liver cancer, esophageal cancer, gastric cancer, pancreatic cancer, melanoma, head and neck cancer, prostate cancer and kidney cancer tumors (the left side is regarded as in situ tumor, the right side is regarded as distant tumor), and the tumor-bearing mice were divided into 15 groups, 8 rats in each group, were used to verify the effect.
第1组：原位瘤内注射生理盐水(乳腺癌)；Group 1: intratumoral injection of normal saline (breast cancer);
第2组：原位瘤内注射地西他滨冻干粉针剂(乳腺癌)；Group 2: Orthotopic intratumoral injection of decitabine freeze-dried powder injection (breast cancer);
第3组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸冻干粉针剂(乳腺癌)；Group 3: intratumoral injection of 6-diazo-5-oxo-L-norleucine freeze-dried powder injection (breast cancer);
第4组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(乳腺癌)；Group 4: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (breast cancer);
第5组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(肺癌)；Group 5: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (lung cancer);
第6组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(肝癌)； Group 6: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (liver cancer);
第7组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(食管癌)；Group 7: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (esophageal cancer);
第8组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(胃癌)；Group 8: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (gastric cancer);
第9组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(胰腺癌)；Group 9: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (pancreatic cancer);
第10组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(黑色素瘤)；Group 10: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (melanoma);
第11组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(头颈癌)；Group 11: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (head and neck cancer);
第12组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(前列腺癌)；Group 12: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (prostate cancer);
第13组：原位瘤内注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂(肾癌)；Group 13: Orthotopic intratumoral injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection (kidney cancer);
与对应的对照组相比，第4～13组小鼠的原位瘤和远端肿瘤都得到了有效的抑制，几乎不再生长，生存期得到了延长。Compared with the corresponding control group, the tumors in situ and distant tumors of the mice in the 4th to 13th groups were effectively inhibited, almost no longer grew, and the survival period was prolonged.
实施例10表观遗传药物和谷氨酰胺代谢调节剂组合物的制备及在不同给药途径下的效果验证Example 10 Preparation of Epigenetic Medicine and Glutamine Metabolism Regulator Composition and Validation of Effects under Different Administration Routes
本实施例所涉及的药物：表观遗传药物为SGI-110(购自：MCE，货号：HY-13542)，为固体粉末；谷氨酰胺代谢调节剂为JHU-083(购自：MCE，货号：HY-122218)，为固体粉末。Drugs involved in this example: the epigenetic drug is SGI-110 (purchased from: MCE, product number: HY-13542), which is a solid powder; the glutamine metabolism regulator is JHU-083 (purchased from: MCE, product number: HY-13542) : HY-122218), as solid powder.
组合物制备方法参见实施例1，使SGI-110的终剂量为mg/kg，JHU-083的终剂量为mg/kg。Refer to Example 1 for the preparation method of the composition, so that the final dose of SGI-110 is mg/kg, and the final dose of JHU-083 is mg/kg.
如下为SGI-110(表观遗传药物)、JHU-083(谷氨酰胺代谢调节剂)冻干粉针剂在结肠癌移植瘤模型上的效果验证研究。The following is the effect verification study of SGI-110 (epigenetic drug) and JHU-083 (glutamine metabolism regulator) freeze-dried powder injection on colon cancer xenograft model.
在小鼠腋下用CT26-luc细胞系接种小鼠结肠癌肿瘤，并将荷瘤小鼠分为6组，每组8只进行效果验证实验。Colon cancer tumors in mice were inoculated with CT26-luc cell line in the axilla of mice, and the tumor-bearing mice were divided into 6 groups, with 8 mice in each group for the effect verification experiment.
第1组：静脉注射生理盐水；Group 1: Intravenous injection of normal saline;
第2组：静脉注射SGI-110冻干粉针剂；Group 2: Intravenous injection of SGI-110 freeze-dried powder injection;
第3组：静脉注射JHU-083冻干粉针剂；Group 3: Intravenous injection of JHU-083 freeze-dried powder injection;
第4组：静脉注射SGI-110和JHU-083组合物冻干粉针剂； Group 4: intravenous injection of SGI-110 and JHU-083 composition freeze-dried powder injection;
第5组：腹腔注射SGI-110和JHU-083组合物冻干粉针剂；Group 5: intraperitoneal injection of freeze-dried powder injection of SGI-110 and JHU-083 composition;
第6组：皮下注射SGI-110和JHU-083组合物冻干粉针剂；Group 6: subcutaneous injection of freeze-dried powder injection of SGI-110 and JHU-083 composition;
与对应的对照组相比，第4～6组小鼠的原位瘤和远端肿瘤都得到了有效的抑制，几乎不再生长，生存期得到了延长。Compared with the corresponding control group, the tumors in situ and distant tumors of mice in groups 4 to 6 were effectively inhibited, almost no longer grew, and the survival period was prolonged.
实施例11表观遗传药物和谷氨酰胺代谢调节剂组合物的制备及与细胞疗法联合使用的效果验证Example 11 Preparation of Epigenetic Medicine and Glutamine Metabolism Regulator Composition and Verification of the Effect of Combined Use with Cell Therapy
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同实施例1)，为固体粉末；细胞疗法为CAR-T疗法(购自：原启生物科技(上海)有限责任公司，货号：无)。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine The acid (same as Example 1) is a solid powder; the cell therapy is CAR-T therapy (purchased from: Yuanqi Biotechnology (Shanghai) Co., Ltd., article number: none).
组合物制备方法参见实施例1，使地西他滨的终剂量为0.2mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量分别为0.2mg/kg，CAR-T细胞的剂量为3×106/kg。For the preparation method of the composition, refer to Example 1, so that the final dose of decitabine is 0.2 mg/kg, the final dose of 6-diazo-5-oxo-L-norleucine is 0.2 mg/kg, and the final dose of CAR - The dose of T cells is 3×10 6 /kg.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)冻干粉针剂与CAR-T细胞疗法在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following is decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (glutamine metabolism regulator) freeze-dried powder injection and CAR-T cell therapy in bilateral colon Effect verification study on cancer xenograft tumor (one tumor on each side of the left and right sides) model.
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：静脉注射注射生理盐水；Group 1: Intravenous injection of normal saline;
第2组：静脉注射地西他滨冻干粉针剂；Group 2: Intravenous injection of decitabine freeze-dried powder injection;
第3组：静脉注射6-重氮-5-氧代-L-正亮氨酸冻干粉针剂；Group 3: Intravenous injection of 6-diazo-5-oxo-L-norleucine freeze-dried powder injection;
第4组：静脉注射CAR-T细胞；Group 4: intravenous injection of CAR-T cells;
第5组：静脉注射地西他滨和6-重氮-5-氧代-L-正亮氨酸组合物冻干粉针剂与CAR-T细胞；Group 5: Intravenous injection of decitabine and 6-diazo-5-oxo-L-norleucine composition freeze-dried powder injection and CAR-T cells;
与对应的对照组相比，第5组小鼠的原位瘤和远端肿瘤都得到了有效的抑制，几乎不再生长，生存期也得到了显著的延长。Compared with the corresponding control group, the tumors in situ and distant tumors of mice in group 5 were effectively suppressed, almost no longer grew, and the survival period was also significantly prolonged.
实施例12表观遗传药物、谷氨酰胺代谢调节剂和缓释材料组合物的制备及与效果验证Example 12 Preparation and Effect Verification of Epigenetic Drugs, Glutamine Metabolism Regulators and Sustained Release Material Compositions
本实施例所涉及的药物：表观遗传药物为地西他滨(同实施例1)，为固体粉末；谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸(同实施例1)，为固体粉末；缓释材料为明胶微球(同实施例8)和海藻酸钠(同实施例8)。The medicine involved in this embodiment: the epigenetic medicine is decitabine (same as embodiment 1), which is a solid powder; the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine The acid (same as Example 1) is a solid powder; the slow-release material is gelatin microspheres (same as Example 8) and sodium alginate (same as Example 8).
组合物制备方法参见实施例1，使地西他滨的终剂量为0.2mg/kg，6-重氮-5-氧代-L-正亮氨酸的终剂量分别为0.2mg/kg，明胶微球的终剂量为125mg/kg，海藻酸钠的终剂 量为0.5mg/kg。For the preparation method of the composition, refer to Example 1, so that the final dose of decitabine is 0.2 mg/kg, the final dose of 6-diazo-5-oxo-L-norleucine is 0.2 mg/kg, gelatin The final dose of microspheres is 125mg/kg, the final dose of sodium alginate The amount is 0.5 mg/kg.
如下为地西他滨(表观遗传药物)、6-重氮-5-氧代-L-正亮氨酸(谷氨酰胺代谢调节剂)与缓释材料组合物冻干粉针剂在双边结肠癌移植瘤(左右两边各有一个肿瘤)模型上的效果验证研究。The following is decitabine (epigenetic drug), 6-diazo-5-oxo-L-norleucine (glutamine metabolism regulator) and slow-release material composition freeze-dried powder injection in bilateral colon Effect verification study on cancer xenograft tumor (one tumor on each side of the left and right sides) model.
效果验证研究方法参见实施例1，其中分组如下。For the research method of effect verification, refer to Example 1, wherein the grouping is as follows.
第1组：原位瘤内注射明胶微球冻干粉针剂；Group 1: intratumoral injection of gelatin microsphere freeze-dried powder injection;
第2组：原位瘤内注射地西他滨和明胶微球组合物冻干粉针剂；Group 2: Orthotopic intratumoral injection of decitabine and gelatin microsphere composition freeze-dried powder injection;
第3组：原位瘤内注射6-重氮-5-氧代-L-正亮氨酸和明胶微球组合物冻干粉针剂；Group 3: intratumoral injection of 6-diazo-5-oxo-L-norleucine and gelatin microspheres composition freeze-dried powder injection;
第4组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和明胶微球组合物冻干粉针剂；Group 4: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and gelatin microspheres composition freeze-dried powder injection;
第5组：原位瘤内注射地西他滨、6-重氮-5-氧代-L-正亮氨酸和海藻酸钠组合物冻干粉针剂；Group 5: Orthotopic intratumoral injection of decitabine, 6-diazo-5-oxo-L-norleucine and sodium alginate composition freeze-dried powder injection;
待小鼠肿瘤体积到达70mm3后，每隔6天对左侧原位肿瘤进行注射，共注射2次，对右侧远端肿瘤则不进行注射。在第一次注射组合物后每隔两天测量并记录小鼠的体重，并用游标卡尺测量并记录原位肿瘤和远端肿瘤的长和宽，肿瘤的体积为(长乘以(宽的平方))除以2。同时，每隔两天观察并记录小鼠的生存状况，用于绘制生存期曲线(小鼠肿瘤体积到达2000mm3后也视为死亡并予以安乐死)After the tumor volume of the mice reached 70 mm 3 , the left orthotopic tumor was injected every 6 days for a total of 2 injections, and the right distal tumor was not injected. After the first injection of the composition, measure and record the body weight of the mice every two days, and measure and record the length and width of the tumor in situ and the distal tumor with a vernier caliper. The volume of the tumor is (length multiplied by the square of width) ) divided by 2. At the same time, the survival status of the mice was observed and recorded every two days, which was used to draw the survival curve (the tumor volume of the mice reached 2000mm 3 was also considered dead and euthanized)
结果见表16-表18，与对应的对照组相比，第4和5组小鼠的原位瘤和远端肿瘤都得到了有效的抑制，几乎不再生长，生存期也得到了显著的延长。The results are shown in Table 16-Table 18. Compared with the corresponding control group, the tumors in situ and distant tumors of mice in groups 4 and 5 were effectively inhibited, almost no longer grew, and the survival period was also significantly improved. extend.
表16小鼠体重变化
Table 16 Changes in body weight of mice
表17小鼠原位瘤体积

Table 17 Mouse orthotopic tumor volume

与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
表18小鼠远端瘤体积
Table 18 Mouse distal tumor volume
与第1组相比，*P＜0.05，**P＜0.01，***P＜0.001。Compared with group 1, * P<0.05, ** P<0.01, *** P<0.001.
实施例13表观遗传药物和谷氨酰胺代谢调节剂组合物的制备及在不同给药途径下的效果验证Example 13 Preparation of Epigenetic Medicine and Glutamine Metabolism Modulator Composition and Validation of Effects under Different Administration Routes
本实施例所涉及的药物：表观遗传药物为SGI-110(购自：MCE，货号：HY-13542)，为固体粉末；谷氨酰胺代谢调节剂为DRP-104(购自：MCE，货号：HY-132832)，为固体粉末。Drugs involved in this example: the epigenetic drug is SGI-110 (purchased from: MCE, product number: HY-13542), which is a solid powder; the glutamine metabolism regulator is DRP-104 (purchased from: MCE, product number: : HY-132832), as solid powder.
组合物制备方法参见实施例1，使SGI-110的终剂量为mg/kg，DRP-104的终剂量为mg/kg。For the composition preparation method, refer to Example 1, so that the final dose of SGI-110 is mg/kg, and the final dose of DRP-104 is mg/kg.
如下为SGI-110(表观遗传药物)、DRP-104(谷氨酰胺代谢调节剂)冻干粉针剂在结肠癌移植瘤模型上的效果验证研究。 The following is the effect verification study of SGI-110 (epigenetic drug) and DRP-104 (glutamine metabolism regulator) freeze-dried powder injection on colon cancer xenograft tumor model.
在小鼠腋下用CT26-luc细胞系接种小鼠结肠癌肿瘤，并将荷瘤小鼠分为6组，每组8只进行效果验证实验。Colon cancer tumors in mice were inoculated with CT26-luc cell line in the axilla of mice, and the tumor-bearing mice were divided into 6 groups, with 8 mice in each group for the effect verification experiment.
第1组：静脉注射生理盐水；Group 1: Intravenous injection of normal saline;
第2组：静脉注射SGI-110冻干粉针剂；Group 2: Intravenous injection of SGI-110 freeze-dried powder injection;
第3组：静脉注射DRP-104冻干粉针剂；Group 3: Intravenous injection of DRP-104 freeze-dried powder;
第4组：静脉注射SGI-110和DRP-104组合物冻干粉针剂；Group 4: Intravenous injection of SGI-110 and DRP-104 composition freeze-dried powder;
第5组：腹腔注射SGI-110和DRP-104组合物冻干粉针剂；Group 5: intraperitoneal injection of freeze-dried powder injection of SGI-110 and DRP-104 composition;
第6组：皮下注射SGI-110和DRP-104组合物冻干粉针剂；Group 6: Subcutaneous injection of SGI-110 and DRP-104 composition freeze-dried powder injection;
与对应的对照组相比，第4～6组小鼠的原位瘤和远端肿瘤都得到了有效的抑制，几乎不再生长，生存期得到了延长。 Compared with the corresponding control group, the tumors in situ and distant tumors of mice in groups 4 to 6 were effectively inhibited, almost no longer grew, and the survival period was prolonged.

Claims (11)

  1. 一种组合物，其包括表观遗传药物和谷氨酰胺代谢调节剂。A composition comprising an epigenetic drug and a modulator of glutamine metabolism.
  2. 如权利要求1所述的组合物，其特征在于，所述表观遗传药物包括DNA甲基转移酶抑制剂、组蛋白去乙酰化酶抑制剂、组蛋白甲基转移酶抑制剂、异柠檬酸脱氢酶抑制剂、组蛋白去甲基化酶抑制剂和BET抑制剂中的一种或多种；The composition according to claim 1, wherein the epigenetic drug comprises DNA methyltransferase inhibitors, histone deacetylase inhibitors, histone methyltransferase inhibitors, isocitrate One or more of dehydrogenase inhibitors, histone demethylase inhibitors and BET inhibitors;
    较佳地，所述DNA甲基转移酶抑制剂为阿扎胞苷、地西他滨、6-巯基嘌呤、SGI-1027、γ-谷维素、CM-272、EML741、NSC232003、DS-437、Guadecitabine及其药学上可接受的盐、DC_517、DC-05、CM-579及其药学上可接受的盐、GSK-3484862、七尾霉素A、GSK-3685032、5-氟脱氧胞苷、N-邻苯二酰-L-色氨酸、Isofistularin-3、硫鸟嘌呤、Zebularine、盐酸普鲁卡因胺和(-)-表没食子儿茶素没食子酸酯中的一种或多种；所述组蛋白去乙酰化酶抑制剂为伏立诺他例如伏立诺他-d5、罗来地辛、贝利斯他、帕比司他、西达本胺、EOC103、HDAC-IN-4、Citarinostat、HDAC8-IN-1、HDAC-IN-7、HDAC1/2-IN-3、HDAC-IN-5、GSK3117391、HDAC/BET-IN-1、HDACs/mTOR Inhibitor 1、JAK/HDAC-IN-1、Quisinostat及其药学可接受的盐、BRD-6929、CDK/HDAC-IN-1、PI3K/HDAC-IN-1、IDO1和HDAC1抑制剂、NKL 22、CRA-026440、Mocetinostat、LMK-235、RTS-V5、TMP195、SR-4370、TMP269、CHDI-390576、CAY10603、EDO-S101、恩替诺特、ACY-957、非美诺、AES-135、Givinostat及其药学可接受的盐、Ricolinostat、Droxinostat、FNDR-20123游离碱、ACY-738、RG2833、BRD73954、Givinostat及其药学可接受的盐、MI-192、Resminostat及其药学可接受的盐、PTACH、TH34、Domatinostat及其药学可接受的盐、BG45、瑞诺司他、西达本胺-d4、曲古抑菌素A、吡美尔二苯胺106、1-Naphthohydroxamic acid、HPOB、HPOB、Nexturastat A、丁苯羟酸、ACY-1083、SKLB-23bb、QTX125、AES-350、Tubacin、SW-100、达诺司他、BRD 4354、QTX125 TFA、BRD3308、BRD 4354 ditrifluoroacetate、丙戊酸及其药学可接受的盐、Corin、Ac-Arg-Gly-Lys(Ac)-AMC、乙酰地那林、RGFP966、小白菊内酯、Ac-Lys-AMC、Alteminostat、Tubastatin A及其药学可接受的盐、斯普利特麻一辛、PCI-34051、Pracinostat、巴豆苷、MPT0G211及其药学可接受的盐、UF010、MPI_5a、CG347B、CG347B、Oxamflatin、WT-161、辛二酰双羟肟酸、MC1568、Psammaplin A、DihydrochlamydocinACY-775、4-苯基丁酸及其药学可接受的盐、Apicidin、ITSA-1、Nanatinostat、Scriptaid、CUDC-101、FCHFHS-ST7612AA1、正丁酸-d7、KA2507及其药学可接受的盐、MAC-VC-PABC-ST7612AA1、Chlamydocin、Pivanex(AN-9)、Tefinostat、Tasquinimod、Nampt-IN-3、BEBT-908、Gnetol、Gnetol、Gnetol、Ivaltinostat 及其药学可接受的盐、AR-42、Abexinostat、姜黄素、M344、SIS17、萝卜硫素、BML-210、WT161、Santacruzamate A、4-联苯磺酰氯、ACY-775和银莲花素A中的一种或多种；所述组蛋白甲基转移酶抑制剂为泰泽司他及其药学可接受的盐、氯苯氨啶、甲氨蝶呤、埃他蝶呤、毛壳素、WDR5-IN-1、EZH2-IN-2、EZH2-IN-4、EPZ011989及其药学可接受的盐、GNA0020、新藤黄酸及其药学可接受的盐、CPI-360、EI1(KB-145943)、CPI-169、PARP/EZH2-IN-1、PF-06726304及其药学可接受的盐、GSK343、GSK126、3-去氮腺嘌呤A、EBI-2511、UNC1999、EPZ005687、A-395、JQEZ5、DM-01、UNC0638、UNC0646、AMI-1、Lirametostat、MS1943、GSK503、Boc-5-氨基戊酸、UNC1999、EPZ005687和CPI-169中的一种或多种；所述异柠檬酸脱氢酶抑制剂为艾伏尼布、恩西地平及其药学上可接受的盐、Olutasidenib、IDN-305、Mutant IDH1-IN-6、IDH889、Mutant IDH1-IN-1、IDH-C227、Vorasidenib、Mutant IDH1-IN-4、Mutant IDH1-IN-2、IDH1 Inhibitor 3、α-倒捻子素、倒捻子素-d3、AGI-6780、AGI-5198、Mutant IDH1 inhibitor、AGI-5198、IDH1 Inhibitor 2、DS-1001b、GSK864、BAY-1436032、AGI-5198和FT-2102中的一种或多种；所述组蛋白去甲基化酶抑制剂为CC90011、iadademstat及其药学可接受的盐、IMG-7289、seclidemstat及其药学可接受的盐、vafidemstat、MK-4688、HLI373及其药学可接受的盐、RITA NSC 652287、GSK2879552及其药学可接受的盐、DDP-38003及其药学可接受的盐、TAK-418、思瑞德林、Serdemetan、KDM5A-IN-1和IOX1中的一种或多种；所述BET抑制剂为阿帕他隆、AZE-5153、BI-894999、birabresib、BPI-23314、CCS-1477、米维布塞、PLX-2853、SF-1126、SYHA-1801、BET-BAY 002 S、I-BET762及其药学可接受的盐、BET-IN-1、BET-BAY 002的S型对映异构体、I-BET151及其药学可接受的盐、PROTAC BET-binding moiety 1、PROTAC BET-binding moiety 2、GSK040、BET-IN-2、BET-IN-4、BET bromodomain inhibitor例如Bromodomain inhibitor 1、Molibresib besylate、BETd-246、GSK620、TD-428、JQ-1 carboxylic acid、CF53、I-BET282、I-BET282E、PROTAC BRD2/BRD4 degrader-1、BMS-986158、BET-IN-6、Desmethyl-QCA276、GSK778、INCB054329、INCB-057643、HJB97、Bromodomain inhibitor-8、(S)-JQ-35、CD235、CC-90010、(+)-JQ1 PA、Alobresib、PFI-1、BAY1238097例如(Rac)-BAY1238097、Y06036、PNZ5、OXFBD04、ZL0420、PROTAC BRD4 ligand-1、Y06137、GSK097、(+)-JQ-1、甲基条叶蓟素、NEO2734、HDAC/BET-IN-1、GS-626510、GSK1324726A、CD161、NHWD-870、BI-9564、MS645、AZD5153 6-Hydroxy-2-naphthoic acid、BY27、LT052、ZEN-3862、BETd-260、NVS-CECR2-1、GSK046、MS417、ZEN-3411、ZEN-3219、RVX-297、SNIPER(BRD)-1、PLX51107、GNE-987、GSK973、MS402、BI 2536、ICG-001、CCS1477、Pelabresib、SRX3207、GNE-781、姜黄素、SGC- CBP30、C、UNC669、BI-7273、CPI-637、dBET6、Emetine hydrochloride、Alobresib、CPI-203、MS436、A-485、UNC-926、A1874、PFI-4、GSK2801、ZL0420、ARV-825、SF2523、INCB057643、PFI-3、KG-501、FL-411、NEO2734、Y06036、Mivebresib、GSK5959、dBET57、dBET1、GSK6853、EED226、PF-CBP1 HCl、PLX51107、AZD-5153 6-hydroxy-2-naphthoic acid、PRI-724、I-BRD9、XMD8-92、P300/CBP-IN-3、BI 894999、INCB054329、BI-9564和ABBV-744中的一种或多种；Preferably, the DNA methyltransferase inhibitor is azacitidine, decitabine, 6-mercaptopurine, SGI-1027, γ-oryzanol, CM-272, EML741, NSC232003, DS-437, Guadecitabine and its pharmaceutically acceptable salts, DC_517, DC-05, CM-579 and its pharmaceutically acceptable salts, GSK-3484862, hematocycin A, GSK-3685032, 5-fluorodeoxycytidine, N-o One or more of phthaloyl-L-tryptophan, Isofistularin-3, thioguanine, Zebularine, procainamide hydrochloride and (-)-epigallocatechin gallate; the group Protein deacetylase inhibitors are vorinostat such as vorinostat-d5, roledesine, belistat, panobinostat, chidamide, EOC103, HDAC-IN-4, Citarinostat, HDAC8-IN-1, HDAC-IN-7, HDAC1/2-IN-3, HDAC-IN-5, GSK3117391, HDAC/BET-IN-1, HDACs/mTOR Inhibitor 1, JAK/HDAC-IN-1, Quisinostat and its pharmaceutically acceptable salts, BRD-6929, CDK/HDAC-IN-1, PI3K/HDAC-IN-1, IDO1 and HDAC1 inhibitors, NKL 22, CRA-026440, Mocetinostat, LMK-235, RTS- V5, TMP195, SR-4370, TMP269, CHDI-390576, CAY10603, EDO-S101, Entinostat, ACY-957, Feminol, AES-135, Givinostat and its pharmaceutically acceptable salts, Ricolinostat, Droxinostat, FNDR-20123 free base, ACY-738, RG2833, BRD73954, Givinostat and its pharmaceutically acceptable salts, MI-192, Resminostat and its pharmaceutically acceptable salts, PTACH, TH34, Domatinostat and its pharmaceutically acceptable salts, BG45 , Renostat, Chidamide-d4, Trichostatin A, Pimeler diphenylamine 106, 1-Naphthohydroxamic acid, HPOB, HPOB, Nexturastat A, Butylhydroxy acid, ACY-1083, SKLB- 23bb, QTX125, AES-350, Tubacin, SW-100, Danostat, BRD 4354, QTX125 TFA, BRD3308, BRD 4354 ditrifluoroacetate, Valproic acid and its pharmaceutically acceptable salts, Corin, Ac-Arg-Gly- Lys(Ac)-AMC, Acetyldinaline, RGFP966, Parthenolide, Ac-Lys-AMC, Alteminostat, Tubastatin A and its pharmaceutically acceptable salts, Splitmaxin, PCI-34051, Pracinostat , crotonin, MPT0G211 and its pharmaceutically acceptable salts, UF010, MPI_5a, CG347B, CG347B, Oxamflatin, WT-161, suberoyl dihydroxamic acid, MC1568, Psammaplin A, Dihydrochlamydocin ACY-775, 4-phenylbutyric acid And its pharmaceutically acceptable salt, Apicidin, ITSA-1, Nanatinostat, Scriptaid, CUDC-101, FCHFHS-ST7612AA1, n-butyric acid-d7, KA2507 and its pharmaceutically acceptable salt, MAC-VC-PABC-ST7612AA1, Chlamydocin , Pivanex (AN-9), Tefinostat, Tasquinimod, Nampt-IN-3, BEBT-908, Gnetol, Gnetol, Gnetol, Ivaltinostat and its pharmaceutically acceptable salts, AR-42, Abexinostat, curcumin, M344, SIS17, sulforaphane, BML-210, WT161, Santacruzamate A, 4-biphenylsulfonyl chloride, ACY-775 and anemone A one or more of; the histone methyltransferase inhibitors are tezestat and pharmaceutically acceptable salts thereof, chlorpheniramine, methotrexate, etathotrexate, chaetocin, WDR5 -IN-1, EZH2-IN-2, EZH2-IN-4, EPZ011989 and its pharmaceutically acceptable salt, GNA0020, neogambogic acid and its pharmaceutically acceptable salt, CPI-360, EI1(KB-145943), CPI-169, PARP/EZH2-IN-1, PF-06726304 and its pharmaceutically acceptable salts, GSK343, GSK126, 3-deazaadenine A, EBI-2511, UNC1999, EPZ005687, A-395, JQEZ5, DM -01, UNC0638, UNC0646, AMI-1, Lirametostat, MS1943, GSK503, Boc-5-aminovaleric acid, UNC1999, EPZ005687, and CPI-169; the isocitrate dehydrogenase inhibitor Ivonib, Ensidipine and its pharmaceutically acceptable salts, Olutasidenib, IDN-305, Mutant IDH1-IN-6, IDH889, Mutant IDH1-IN-1, IDH-C227, Vorasidenib, Mutant IDH1-IN -4, Mutant IDH1-IN-2, IDH1 Inhibitor 3, α-Mangostin, Mangostin-d3, AGI-6780, AGI-5198, Mutant IDH1 inhibitor, AGI-5198, IDH1 Inhibitor 2, DS-1001b, One or more of GSK864, BAY-1436032, AGI-5198 and FT-2102; the histone demethylase inhibitors are CC90011, iadademstat and pharmaceutically acceptable salts thereof, IMG-7289, seclidemstat and Its pharmaceutically acceptable salt, vafidemstat, MK-4688, HLI373 and its pharmaceutically acceptable salt, RITA NSC 652287, GSK2879552 and its pharmaceutically acceptable salt, DDP-38003 and its pharmaceutically acceptable salt, TAK-418, One or more of Seridelin, Serdemetan, KDM5A-IN-1, and IOX1; the BET inhibitor is apaltalone, AZE-5153, BI-894999, birabresib, BPI-23314, CCS-1477 , Mivibuxel, PLX-2853, SF-1126, SYHA-1801, BET-BAY 002 S, I-BET762 and its pharmaceutically acceptable salts, BET-IN-1, S-type enantiomer of BET-BAY 002 Isomers, I-BET151 and pharmaceutically acceptable salts thereof, PROTAC BET-binding moiety 1, PROTAC BET-binding moiety 2, GSK040, BET-IN-2, BET-IN-4, BET bromodomain inhibitor such as Bromodomain inhibitor 1 , Molibresib besylate, BETd-246, GSK620, TD-428, JQ-1 carboxylic acid, CF53, I-BET282, I-BET282E, PROTAC BRD2/BRD4 degrader-1, BMS-986158, BET-IN-6, Desmethyl- QCA276, GSK778, INCB054329, INCB-057643, HJB97, Bromodomain inhibitor-8, (S)-JQ-35, CD235, CC-90010, (+)-JQ1 PA, Alobresib, PFI-1, BAY1238097 eg (Rac)- BAY1238097, Y06036, PNZ5, OXFBD04, ZL0420, PROTAC BRD4 ligand-1, Y06137, GSK097, (+)-JQ-1, Methyl phyllin, NEO2734, HDAC/BET-IN-1, GS-626510, GSK1324726A , CD161, NHWD-870, BI-9564, MS645, AZD5153 6-Hydroxy-2-naphthoic acid, BY27, LT052, ZEN-3862, BETd-260, NVS-CECR2-1, GSK046, MS417, ZEN-3411, ZEN -3219, RVX-297, SNIPER(BRD)-1, PLX51107, GNE-987, GSK973, MS402, BI 2536, ICG-001, CCS1477, Pelabresib, SRX3207, GNE-781, Curcumin, SGC- CBP30, C, UNC669, BI-7273, CPI-637, dBET6, Emetine hydrochloride, Alobresib, CPI-203, MS436, A-485, UNC-926, A1874, PFI-4, GSK2801, ZL0420, ARV-825, SF2523 , INCB057643, PFI-3, KG-501, FL-411, NEO2734, Y06036, Mivebresib, GSK5959, dBET57, dBET1, GSK6853, EED226, PF-CBP1 HCl, PLX51107, AZD-5153 6-hydroxy-2-naphthoic acid , One or more of PRI-724, I-BRD9, XMD8-92, P300/CBP-IN-3, BI 894999, INCB054329, BI-9564 and ABBV-744;
    更佳地，所述表观遗传药物为地西他滨、西达本胺、泰泽司他、艾伏尼布、思瑞德林阿帕他隆和Guadecitabine中的一种或多种。More preferably, the epigenetic drug is one or more of decitabine, chidamide, tezecistat, ivonib, seredrin apatalone and Guadecitabine.
  3. 如权利要求1所述的组合物，其特征在于，所述谷氨酰胺代谢调节剂包括谷氨酰胺类似物、谷氨酰胺消耗药物、谷氨酰胺酶抑制剂、溶质载体家族1成员5抑制剂、谷氨酸脱氢酶抑制剂和氨基转移酶抑制剂和溶质载体家族7成员11抑制剂中的一种或多种；The composition according to claim 1, wherein the glutamine metabolism regulator comprises glutamine analogs, glutamine depleting drugs, glutaminase inhibitors, solute carrier family 1 member 5 inhibitors , one or more of glutamate dehydrogenase inhibitors, aminotransferase inhibitors, and solute carrier family 7 member 11 inhibitors;
    较佳地，所述谷氨酰胺类似物为6-重氮-5-氧代-L-正亮氨酸和5-重氮-4-氧代-L-正缬氨酸及两者的前药、(S)-2-((S)-2-乙酰胺基-3-(1H-吲哚-3-基)丙酰胺基)-6-重氮-5-氧代己酸异丙基酯及其药学上可接受的盐、(S)-2-((S)-6-乙酰胺基-2-((3S,5S,7S)-金刚烷-1-甲酰胺基)己酰胺基)-6-重氮-5-氧代己酸酯及其药学上可接受的盐、(S)-2-((S)-2-乙酰胺基-3-(1H-吲哚-3-基)丙酰胺基)-6-重氮-5-氧代己酸及其药学上可接受的盐、JHU-083、JUH-395、重氮丝氨酸、阿西维辛和NQO1激活型6-重氮基-5-氧代-L-正亮氨酸前药中的一种或多种，或所述谷氨酰胺类似物为DRP-104，或所述谷氨酰胺类似物为DRP-104以及以下构成的组中的一种或多种：6-重氮-5-氧代-L-正亮氨酸和5-重氮-4-氧代-L-正缬氨酸及两者的前药、(S)-2-((S)-2-乙酰胺基-3-(1H-吲哚-3-基)丙酰胺基)-6-重氮-5-氧代己酸异丙基酯及其药学上可接受的盐、(S)-2-((S)-6-乙酰胺基-2-((3S,5S,7S)-金刚烷-1-甲酰胺基)己酰胺基)-6-重氮-5-氧代己酸酯及其药学上可接受的盐、(S)-2-((S)-2-乙酰胺基-3-(1H-吲哚-3-基)丙酰胺基)-6-重氮-5-氧代己酸及其药学上可接受的盐、JHU-083、JUH-395、DRP-104、重氮丝氨酸、阿西维辛和NQO1激活型6-重氮基-5-氧代-L-正亮氨酸前药；所述谷氨酰胺消耗药物为L-天冬酰胺酶；所述谷氨酰胺酶抑制剂为Telaglenastat及其药学可接受的盐、化合物968、BPTES、IPN-60090及其药学可接受的盐、谷氨酰胺酶-抑制剂-3、Morphothiadin和UPGL00004中的一种或多种；所述溶质载体家族1成员5抑制剂为V-9302及其药学可接受的盐、苄基丝氨酸、γ-2-氟苄基脯氨酸、L-γ-谷氨酰基-4-硝基苯胺及其药学可接受的盐和党参炔苷中的一种或多种；所述谷氨酸脱氢酶抑制剂为(-)-表没食子儿茶素没食子酸酯和/或2-烯丙基-1-羟基-9,10-蒽醌；所述氨基转移酶抑制剂为氨基氧乙酸、羟基丙酮 酸及其药学可接受的盐、L-副刀豆氨酸、L-环丝氨酸、BCATc Inhibitor 2、6-氮杂胸腺嘧啶、BCAT-IN-2和2-甲基-4(3H)-喹唑酮中的一种或多种；所述溶质载体家族7成员11抑制剂为柳氮磺吡啶、Erastin、索拉非尼、干扰素-γ或其mRNA、转化生长因子或其mRNA、p53或其mRNA、Beclin 1或其mRNA、BRCA1关联蛋白1或其mRNA和毛细血管扩张性共济失调症突变蛋白或其mRNA中的一种或多种；Preferably, the glutamine analogs are 6-diazo-5-oxo-L-norleucine and 5-diazo-4-oxo-L-norvaline and their precursors Drug, (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoic acid isopropyl Esters and their pharmaceutically acceptable salts, (S)-2-((S)-6-acetamido-2-((3S,5S,7S)-adamantane-1-carboxamido)hexanoyl )-6-diazo-5-oxohexanoate and its pharmaceutically acceptable salts, (S)-2-((S)-2-acetamido-3-(1H-indole-3- (yl)propionamido)-6-diazo-5-oxohexanoic acid and its pharmaceutically acceptable salts, JHU-083, JUH-395, diazoserine, acivexin and NQO1 activated 6-hexanoic acid One or more of the nitrogen-5-oxo-L-norleucine prodrugs, or the glutamine analogue is DRP-104, or the glutamine analogue is DRP-104 and One or more of the group consisting of 6-diazo-5-oxo-L-norleucine and 5-diazo-4-oxo-L-norvaline and their precursors Drug, (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoic acid isopropyl Esters and their pharmaceutically acceptable salts, (S)-2-((S)-6-acetamido-2-((3S,5S,7S)-adamantane-1-carboxamido)hexanoyl )-6-diazo-5-oxohexanoate and its pharmaceutically acceptable salts, (S)-2-((S)-2-acetamido-3-(1H-indole-3- (yl)propionamido)-6-diazo-5-oxohexanoic acid and its pharmaceutically acceptable salts, JHU-083, JUH-395, DRP-104, diazoserine, acivectin and NQO1 activation Type 6-diazo-5-oxo-L-norleucine prodrug; the glutamine depleting drug is L-asparaginase; the glutaminase inhibitor is Telaglenastat and its pharmaceutically acceptable One or more of accepted salts, Compound 968, BPTES, IPN-60090 and pharmaceutically acceptable salts thereof, glutaminase-inhibitor-3, Morphothiadin, and UPGL00004; said solute carrier family 1 member 5 inhibits The agent is V-9302 and its pharmaceutically acceptable salt, benzylserine, γ-2-fluorobenzylproline, L-γ-glutamyl-4-nitroaniline and its pharmaceutically acceptable salt, and Codonopsis pilosula One or more of the alkyne glycosides; the glutamate dehydrogenase inhibitor is (-)-epigallocatechin gallate and/or 2-allyl-1-hydroxyl-9,10- Anthraquinone; the aminotransferase inhibitor is aminooxyacetic acid, hydroxyacetone acid and its pharmaceutically acceptable salts, L-canavanine, L-cycloserine, BCATc Inhibitor 2, 6-azathymine, BCAT-IN-2 and 2-methyl-4(3H)-quinone One or more of azolone; the solute carrier family 7 member 11 inhibitor is sulfasalazine, Erastin, Sorafenib, interferon-γ or its mRNA, transforming growth factor or its mRNA, p53 or One or more of its mRNA, Beclin 1 or its mRNA, BRCA1-associated protein 1 or its mRNA, and telangiectasia ataxia mutant protein or its mRNA;
    更佳地，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸、L-天冬酰胺酶、Telaglenastat、V-9302、2-烯丙基-1-羟基-9,10-蒽醌、柳氮磺吡啶和JHU-083中的一种或多种；或所述谷氨酰胺代谢调节剂为DRP-104；或所述谷氨酰胺代谢调节剂为DRP-104以及以下构成的组中的一种或多种：6-重氮-5-氧代-L-正亮氨酸、L-天冬酰胺酶、Telaglenastat、V-9302、2-烯丙基-1-羟基-9,10-蒽醌、柳氮磺吡啶和JHU-08。More preferably, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, L-asparaginase, Telaglenastat, V-9302, 2-allyl-1 -one or more of hydroxy-9,10-anthraquinone, sulfasalazine and JHU-083; or the glutamine metabolism regulator is DRP-104; or the glutamine metabolism regulator is DRP-104 and one or more of the group consisting of: 6-diazo-5-oxo-L-norleucine, L-asparaginase, Telaglenastat, V-9302, 2-allyl 1-hydroxy-9,10-anthraquinone, sulfasalazine and JHU-08.
  4. 如权利要求1-3任一项所述的组合物，其特征在于，所述组合物还包括免疫佐剂或免疫检查点调节剂；The composition according to any one of claims 1-3, wherein the composition further comprises an immune adjuvant or an immune checkpoint regulator;
    较佳地，所述免疫佐剂包括RIG-I/MDA5和TLR3激动剂、TLR4激动剂、TLR7/8激动剂、TLR9激动剂、细胞因子佐剂、细胞因子mRNA佐剂、STING激动剂和FLT3L激动剂中的一种或多种；所述免疫检查点调节剂包括免疫检查点抑制剂和/或免疫检查点激动剂，所述免疫检查点抑制剂为免疫检查点抗体抑制剂或其mRNA、免疫检查点小分子抑制剂和免疫检查点肽类抑制剂中的一种或多种，所述免疫检查点激动剂为免疫检查点抗体激动剂或其mRNA、免疫检查点小分子激动剂和免疫检查点肽类激动剂中的一种或多种；Preferably, the immune adjuvant includes RIG-I/MDA5 and TLR3 agonist, TLR4 agonist, TLR7/8 agonist, TLR9 agonist, cytokine adjuvant, cytokine mRNA adjuvant, STING agonist and FLT3L One or more of the agonists; the immune checkpoint regulators include immune checkpoint inhibitors and/or immune checkpoint agonists, and the immune checkpoint inhibitors are immune checkpoint antibody inhibitors or their mRNA, One or more of immune checkpoint small molecule inhibitors and immune checkpoint peptide inhibitors, the immune checkpoint agonist is immune checkpoint antibody agonist or its mRNA, immune checkpoint small molecule agonist and immune checkpoint one or more of checkpoint peptide agonists;
    更佳地，所述RIG-I/MDA5和TLR3激动剂例如为Poly-ICLC和/或BO112；所述TLR4激动剂例如为吡喃葡萄糖脂A G100和单磷酰酯质A中的一种或多种；所述TLR7/8激动剂例如为咪喹莫特R837、Motolimod、雷西莫特R848、鱼精蛋白RNA、LHC165、Motolimod、MEDI-9197、Gardiquimod、3M-001、GSK2245035和GS-9620中的一种或多种；所述TLR9激动剂例如为CpG ODN寡脱氧核苷酸和CMP-001中的一种或多种；所述细胞因子佐剂例如为IL-2、IL-1、IFNγ、IL-12、GM-CSF、IL-23、IL-36γ、CCL21、IL-10和IL-15中的一种或多种；所述细胞因子mRNA佐剂例如为IL-2 mRNA、IL-1 mRNA、IFNγmRNA、IL-12 mRNA、GM-CSF mRNA、IL-23 mRNA、IL-36γmRNA、CCL21 mRNA、IL-10 mRNA和IL-15 mRNA中的一种或多种；所述STING激动剂例如为Ulevostina、E7766及其药学可接受的盐、ADU-S100、GSK3745417、BMS-986301、SB-11285、HG381、IMSA101、DN-015089、SYN-STING、BI-1387446、TAK-676、SNX-281、BI-STING、CDK-002、2,5-己酮可可碱、MSA-2及其二聚体、STING agonist-1、IACS-8779、IACS-8803、 c-di-AMP及其药学可接受的盐、diABZI-C2-NH2、SR717及其药学可接受的盐、diABZI STING激动剂、C176、C171、C-178、SN-011、H-151、AstinC、EFAA、CMA、BNBC、a-Mangositin、ABZI以及ABZI类似物、STING激动剂-3、CDG、2',3'-cGAMP、3',3'-cGAMP和RpRp二硫2',3'-CDA中的一种或多种；所述FLT3L激动剂例如为Ad-hCMV-TK、Ad-hCMV-Flt3L、rhuFlt3L、CDX-301和CDX-1401中的一种或多种；所述免疫检查点抗体抑制剂包括靶向以下一种或多种靶点的抗体：CTLA-4、PD-1、PD-L1、LAG-3、TIM-3、TIGIT、VISTA、CD47、SIRPα、B7-H3、B7-H4、B7-H7、BTLA、CD160、KIR、CD96、PVRIG、CD155、PVRL2、NKG2A、HLA-E、ILT2、HLA-G、PSGL1、CEACAM1、CD200、CD24、SIGLEC10和SIGLEC7；所述免疫检查点激动剂抗体包括靶向以下一种或多种靶点的抗体：OX40、4-1BB、CD40、ICOS、GITR、CD28、CD27、CD122、LIGHT、DNAM-1、CD226、CD48、DC-SIGN和DR3；More preferably, the RIG-I/MDA5 and TLR3 agonist is for example Poly-ICLC and/or BO112; the TLR4 agonist is for example one of glucopyranose lipid A G100 and monophosphoryl ester A or Various; the TLR7/8 agonists are, for example, imiquimod R837, Motolimod, Resimod R848, protamine RNA, LHC165, Motolimod, MEDI-9197, Gardiquimod, 3M-001, GSK2245035 and GS-9620 One or more of; the TLR9 agonist is, for example, one or more of CpG ODN oligodeoxynucleotide and CMP-001; the cytokine adjuvant is, for example, IL-2, IL-1, One or more of IFNγ, IL-12, GM-CSF, IL-23, IL-36γ, CCL21, IL-10 and IL-15; the cytokine mRNA adjuvant is, for example, IL-2 mRNA, IL One or more of -1 mRNA, IFNγ mRNA, IL-12 mRNA, GM-CSF mRNA, IL-23 mRNA, IL-36γ mRNA, CCL21 mRNA, IL-10 mRNA and IL-15 mRNA; the STING agonist For example Ulevostina, E7766 and pharmaceutically acceptable salts thereof, ADU-S100, GSK3745417, BMS-986301, SB-11285, HG381, IMSA101, DN-015089, SYN-STING, BI-1387446, TAK-676, SNX-281 , BI-STING, CDK-002, 2,5-pentoxifylline, MSA-2 and its dimer, STING agonist-1, IACS-8779, IACS-8803, c-di-AMP and its pharmaceutically acceptable salt, diABZI-C2-NH2, SR717 and its pharmaceutically acceptable salt, diABZI STING agonist, C176, C171, C-178, SN-011, H-151, AstinC , EFAA, CMA, BNBC, a-Mangositin, ABZI and ABZI analogs, STING agonist-3, CDG, 2',3'-cGAMP, 3',3'-cGAMP and RpRp disulfide 2',3'- One or more of CDA; the FLT3L agonist is, for example, one or more of Ad-hCMV-TK, Ad-hCMV-Flt3L, rhuFlt3L, CDX-301 and CDX-1401; the immune checkpoint Antibody inhibitors include antibodies targeting one or more of the following targets: CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, TIGIT, VISTA, CD47, SIRPα, B7-H3, B7 -H4, B7-H7, BTLA, CD160, KIR, CD96, PVRIG, CD155, PVRL2, NKG2A, HLA-E, ILT2, HLA-G, PSGL1, CEACAM1, CD200, CD24, SIGLEC10, and SIGLEC7; the immune checkpoints Agonist antibodies include antibodies targeting one or more of the following targets: OX40, 4-1BB, CD40, ICOS, GITR, CD28, CD27, CD122, LIGHT, DNAM-1, CD226, CD48, DC-SIGN, and DR3 ;
    进一步更佳地，所述免疫佐剂为Poly-ICLC、单磷酰酯质A、雷西莫特、CpG寡脱氧核苷酸、IL-2、GM-CSF、IL-15 mRNA、Ulevostina、BMS-986301、MSA-2及其二聚体和HG381中的一种或多种；所述免疫检查点调节剂为靶向以下一种或多种靶点的抗体：PD-1、PD-L1、LAG-3、TIM-3、TIGIT、OX40、4-1BB、CD40和CD47。Further more preferably, the immune adjuvant is Poly-ICLC, monophosphoryl ester A, Resimod, CpG oligodeoxynucleotide, IL-2, GM-CSF, IL-15 mRNA, Ulevostina, BMS - one or more of 986301, MSA-2 and its dimers, and HG381; the immune checkpoint modulator is an antibody targeting one or more of the following targets: PD-1, PD-L1, LAG-3, TIM-3, TIGIT, OX40, 4-1BB, CD40 and CD47.
  5. 如权利要求4所述的组合物，其特征在于，所述免疫检查点调节剂为双特异性抗体，所述双特异性抗体的一个靶点为CTLA-4、PD-1、PD-L1、LAG-3、TIM-3、TIGIT、VISTA、B7-H3、B7-H4、B7-H7、BTLA、CD160、KIR、CD96、PVRIG、CD155、PVRL2、NKG2A、HLA-E、ILT2、HLA-G、PSGL1、CEACAM1、CD47、SIRPα、CD200、CD24、SIGLEC10或SIGLEC7，另一个靶点为OX40、4-1BB、CD40、ICOS、GITR、CD28、CD27、CD122、LIGHT、DNAM-1、CD226、CD48、DC-SIGN、TL1A或VEGF；The composition according to claim 4, wherein the immune checkpoint regulator is a bispecific antibody, and one target of the bispecific antibody is CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, TIGIT, VISTA, B7-H3, B7-H4, B7-H7, BTLA, CD160, KIR, CD96, PVRIG, CD155, PVRL2, NKG2A, HLA-E, ILT2, HLA-G, PSGL1, CEACAM1, CD47, SIRPα, CD200, CD24, SIGLEC10 or SIGLEC7, another target is OX40, 4-1BB, CD40, ICOS, GITR, CD28, CD27, CD122, LIGHT, DNAM-1, CD226, CD48, DC - SIGN, TL1A or VEGF;
    较佳地，所述双特异性抗体为靶向以下靶点组合的抗体中的一种或多种：PD-L1/4-1BB、PD-L1/CD47、PD-1/LAG-3、PD-1/TIM-3和PD-1/TIGIT-3。Preferably, the bispecific antibody is one or more of the antibodies targeting the following target combinations: PD-L1/4-1BB, PD-L1/CD47, PD-1/LAG-3, PD -1/TIM-3 and PD-1/TIGIT-3.
  6. 如权利要求1-5任一项所述的组合物，其特征在于，所述组合物还包括缓释材料，所述缓释材料为具有缓释功能的阻滞剂、骨架材料、包衣材料和原位成胶基质材料中的一种或多种；较佳地，所述缓释材料为海藻酸盐、透明质酸、泊洛沙姆、明胶微球、PLGA微球和四氧化三铁微球中的一种或多种。The composition according to any one of claims 1-5, characterized in that, the composition also includes a slow-release material, and the slow-release material is a blocker with a slow-release function, a matrix material, a coating material and one or more of in-situ gel-forming matrix materials; preferably, the slow-release material is alginate, hyaluronic acid, poloxamer, gelatin microspheres, PLGA microspheres and ferric oxide One or more of the microspheres.
  7. 如权利要求1-6任一项所述的组合物，其特征在于，所述表观遗传药物的份数为0.2～25份，所述谷氨酰胺代谢调节剂的份数为0.2～25份；The composition according to any one of claims 1-6, wherein the number of parts of the epigenetic drug is 0.2 to 25 parts, and the number of parts of the glutamine metabolism regulator is 0.2 to 25 parts ;
    较佳地，所述免疫佐剂的份数为1.875～30份，所述免疫检查点调节剂0.1875～7.5份，所述缓释材料的份数为10～250份； Preferably, the number of parts of the immune adjuvant is 1.875-30 parts, the number of parts of the immune checkpoint regulator is 0.1875-7.5 parts, and the number of parts of the slow-release material is 10-250 parts;
    更佳地，所述表观遗传药物的份数为0.3～22份，例如0.5～18份、0.8-15份、1-10份、1-5份或1-3份；和/或，所述谷氨酰胺代谢调节剂的份数为0.3～22份，例如0.5～18份、0.8～15份、1～10份、1～5份或1～3份；和/或，所述免疫佐剂的份数为1.875～30份，例如2～25份、2.5～20份、3～15份、4～10份或5～7.5份；和/或，所述免疫检查点调节剂0.1875～7.5份，例如0.2～5份、0.25～4份、0.3～3份、0.4～2份或0.5～1份；和/或，所述缓释材料的份数为10～250份，例如20-200份或50-100份。More preferably, the number of parts of the epigenetic drug is 0.3-22 parts, such as 0.5-18 parts, 0.8-15 parts, 1-10 parts, 1-5 parts or 1-3 parts; and/or, all The number of parts of the glutamine metabolism regulator is 0.3 to 22 parts, such as 0.5 to 18 parts, 0.8 to 15 parts, 1 to 10 parts, 1 to 5 parts or 1 to 3 parts; and/or, the immune adjuvant The number of parts of the agent is 1.875-30 parts, such as 2-25 parts, 2.5-20 parts, 3-15 parts, 4-10 parts or 5-7.5 parts; and/or, the immune checkpoint regulator is 0.1875-7.5 parts parts, such as 0.2 to 5 parts, 0.25 to 4 parts, 0.3 to 3 parts, 0.4 to 2 parts or 0.5 to 1 part; and/or, the number of parts of the sustained-release material is 10 to 250 parts, such as 20-200 parts servings or 50-100 servings.
  8. 如权利要求1所述的组合物，其特征在于，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸；The composition according to claim 1, wherein the epigenetic drug is decitabine, and the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine acid;
    或，所述表观遗传药物为西达本胺、泰泽司他、艾伏尼布、思瑞德林或阿帕他隆，所述谷氨酰胺代谢调节剂为L-天冬酰胺酶CB-839、V-9302、2-烯丙基-1-羟基-9,10-蒽醌或柳氮磺吡啶；Or, the epigenetic drug is chidamide, tezecistat, evonib, seridelin or apatalone, and the glutamine metabolism regulator is L-asparaginase CB -839, V-9302, 2-allyl-1-hydroxy-9,10-anthraquinone or sulfasalazine;
    或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述免疫佐剂为Poly-ICLC、单磷酰酯质A、雷西莫特、CpG ODN寡脱氧核苷酸、白细胞介素-2、巨噬细胞集落刺激因子、趋化因子21、白细胞介素-15 mRNA、MK-1454、BMS-986301、MSA-2或HG381；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the immune adjuvant is Poly-ICLC, Monophosphoryl A, resimod, CpG ODN oligodeoxynucleotide, interleukin-2, macrophage colony-stimulating factor, chemokine 21, interleukin-15 mRNA, MK-1454, BMS -986301, MSA-2 or HG381;
    或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述组合物还包括免疫检查点抑制剂、所述免疫检查点激动剂、免疫检查点调节剂双特异性抗体和所述免疫检查点抑制剂抗体mRNA中的一种或多种，所述免疫检查点抑制剂为anti-PD-L1抗体，所述免疫检查点激动剂为anti-4-1BB抗体、anti-CD40抗体，所述免疫检查点调节剂双特异性抗体为anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体或anti-PD-1/TIGIT-3双特异性抗体，所述免疫检查点抑制剂抗体mRNA为anti-PD-L1抗体mRNA，免疫检查点激动剂抗体mRNA为anti-4-1BB抗体mRNA；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the composition also includes immune checkpoint inhibition One or more of the immune checkpoint agonist, the immune checkpoint regulator bispecific antibody and the immune checkpoint inhibitor antibody mRNA, the immune checkpoint inhibitor is anti-PD-L1 Antibody, the immune checkpoint agonist is anti-4-1BB antibody, anti-CD40 antibody, the immune checkpoint regulator bispecific antibody is anti-PD-L1/4-1BB bispecific antibody, anti- PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 bispecific antibody, anti-PD-1/TIM-3 bispecific antibody or anti-PD-1/TIGIT-3 bispecific antibody Antibody, the immune checkpoint inhibitor antibody mRNA is anti-PD-L1 antibody mRNA, and the immune checkpoint agonist antibody mRNA is anti-4-1BB antibody mRNA;
    或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述组合物还包括免疫检查点抑制剂、所述免疫检查点激动剂、免疫检查点调节剂双特异性抗体和所述免疫检查点抑制剂抗体mRNA中的一种或多种，所述免疫检查点抑制剂为anti-PD-1抗体或anti-PD-L1抗体，所述免疫检查点激动剂为anti-4-1BB抗体、anti-CD40抗体，所述免疫检查点调节剂双特异性抗体为anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体或anti-PD-1/TIGIT-3双特异性抗体，所述免疫检查点抑制剂抗体mRNA为anti-PD-L1抗体mRNA，免疫检查点激动剂抗体mRNA为anti-4-1BB抗体mRNA； Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the composition also includes immune checkpoint inhibition One or more of the immune checkpoint agonist, the immune checkpoint regulator bispecific antibody and the immune checkpoint inhibitor antibody mRNA, the immune checkpoint inhibitor is anti-PD-1 Antibody or anti-PD-L1 antibody, the immune checkpoint agonist is anti-4-1BB antibody, anti-CD40 antibody, and the immune checkpoint regulator bispecific antibody is anti-PD-L1/4-1BB Bispecific antibody, anti-PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 bispecific antibody, anti-PD-1/TIM-3 bispecific antibody or anti-PD-1 /TIGIT-3 bispecific antibody, the immune checkpoint inhibitor antibody mRNA is anti-PD-L1 antibody mRNA, and the immune checkpoint agonist antibody mRNA is anti-4-1BB antibody mRNA;
    或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述组合物还包括免疫检查点抑制剂、所述免疫检查点激动剂、免疫检查点调节剂双特异性抗体和所述免疫检查点抑制剂抗体mRNA中的一种或多种，所述免疫检查点抑制剂为anti-PD-1抗体或anti-PD-L1抗体，所述免疫检查点激动剂为anti-4-1BB抗体、anti-CD40抗体，所述免疫检查点调节剂双特异性抗体为anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体、anti-PD-1/TIGIT-3双特异性抗体或anti-PD-1/VEGF双特异性抗体，所述免疫检查点抑制剂抗体mRNA为anti-PD-L1抗体mRNA，免疫检查点激动剂抗体mRNA为anti-4-1BB抗体mRNA；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the composition also includes immune checkpoint inhibition One or more of the immune checkpoint agonist, the immune checkpoint regulator bispecific antibody and the immune checkpoint inhibitor antibody mRNA, the immune checkpoint inhibitor is anti-PD-1 Antibody or anti-PD-L1 antibody, the immune checkpoint agonist is anti-4-1BB antibody, anti-CD40 antibody, and the immune checkpoint regulator bispecific antibody is anti-PD-L1/4-1BB Bispecific antibody, anti-PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 bispecific antibody, anti-PD-1/TIM-3 bispecific antibody, anti-PD-1 /TIGIT-3 bispecific antibody or anti-PD-1/VEGF bispecific antibody, the immune checkpoint inhibitor antibody mRNA is anti-PD-L1 antibody mRNA, and the immune checkpoint agonist antibody mRNA is anti-4 - 1BB antibody mRNA;
    或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述免疫佐剂为MSA-2，所述免疫检查点调节剂双特异性抗体为anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体或anti-PD-1/TIGIT-3双特异性抗体，所述缓释材料为明胶微球、海藻酸钠、透明质酸、泊洛沙姆温敏凝胶、PLGA微球或四氧化三铁微球；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the immune adjuvant is MSA-2, The immune checkpoint regulator bispecific antibody is anti-PD-L1/4-1BB bispecific antibody, anti-PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 bispecific antibody Antibody, anti-PD-1/TIM-3 bispecific antibody or anti-PD-1/TIGIT-3 bispecific antibody, the sustained-release material is gelatin microspheres, sodium alginate, hyaluronic acid, polo Sharm thermosensitive gel, PLGA microspheres or ferric oxide microspheres;
    或，所述表观遗传药物为地西他滨，所述谷氨酰胺代谢调节剂为6-重氮-5-氧代-L-正亮氨酸，所述免疫佐剂为MSA-2，所述免疫检查点调节剂为anti-PD-1抗体、anti-PD-L1/4-1BB双特异性抗体、anti-PD-L1/CD47双特异性抗体、anti-PD-1/LAG-3双特异性抗体、anti-PD-1/TIM-3双特异性抗体、anti-PD-1/TIGIT-3双特异性抗体或anti-PD-1/VEGF双特异性抗体，所述缓释材料为明胶微球、海藻酸钠、透明质酸、泊洛沙姆温敏凝胶、PLGA微球或四氧化三铁微球；Or, the epigenetic drug is decitabine, the glutamine metabolism regulator is 6-diazo-5-oxo-L-norleucine, and the immune adjuvant is MSA-2, The immune checkpoint regulator is anti-PD-1 antibody, anti-PD-L1/4-1BB bispecific antibody, anti-PD-L1/CD47 bispecific antibody, anti-PD-1/LAG-3 Bispecific antibody, anti-PD-1/TIM-3 bispecific antibody, anti-PD-1/TIGIT-3 bispecific antibody or anti-PD-1/VEGF bispecific antibody, the slow-release material Gelatin microspheres, sodium alginate, hyaluronic acid, poloxamer thermosensitive gel, PLGA microspheres or ferric oxide microspheres;
    较佳地，所述表观遗传药物为1份地西他滨和1份6-重氮-5-氧代-L-正亮氨酸。Preferably, the epigenetic drug is 1 part of decitabine and 1 part of 6-diazo-5-oxo-L-norleucine.
  9. 一种套装药盒，其包含药盒A和药盒B，其中：A kind of set medicine box, it comprises medicine box A and medicine box B, wherein:
    所述药盒A含有如权利要求1-8任一项所述的组合物；The kit A contains the composition according to any one of claims 1-8;
    所述药盒B含有嵌合抗原受体-T细胞、自然杀伤细胞、嵌合抗原受体-自然杀伤细胞、淋巴因子激活的杀伤细胞细胞、肿瘤浸润淋巴细胞细胞、T细胞表面的特异性受体-T细胞、树突状细胞与细胞因子诱导的杀伤细胞共培养联合细胞、自然杀伤T细胞和嵌合抗原受体-巨噬细胞中的一种或多种。The kit B contains chimeric antigen receptor-T cells, natural killer cells, chimeric antigen receptor-natural killer cells, lymphokine-activated killer cells, tumor-infiltrating lymphocyte cells, and specific receptors on the surface of T cells. Somatic-T cells, dendritic cells and cytokine-induced killer cells co-culture combined cells, one or more of natural killer T cells and chimeric antigen receptor-macrophages.
  10. 一种制备如权利要求1-8任一项所述的组合物的方法，其包括如下步骤：将所述表观遗传药物和所述谷氨酰胺代谢调节剂混合均匀，得所述表观遗传药物和谷氨酰胺代谢调节剂组合物；当所述表观遗传药物和谷氨酰胺代谢调节剂组合物还包括免疫检查点调节剂或免疫佐剂时，任选地还包括缓释材料，将所述表观遗传药物、所述谷氨酰胺代 谢调节剂和缓释材料，与免疫检查点调节剂或免疫佐剂混合均匀，得所述表观遗传药物和谷氨酰胺代谢调节剂组合物。A method for preparing the composition according to any one of claims 1-8, comprising the steps of: mixing the epigenetic drug and the glutamine metabolism regulator uniformly to obtain the epigenetic Medicine and glutamine metabolism regulator composition; when described epigenetic drug and glutamine metabolism regulator composition also include immune check point regulator or immune adjuvant, optionally also include slow-release material, will The epigenetic drug, the glutamine generation The epigenetic medicine and the glutamine metabolism regulator composition are obtained by uniformly mixing the epigenetic drug and the glutamine metabolism regulator with the immune checkpoint regulator or the immune adjuvant.
  11. 如权利要求1-8任一项所述的组合物在制备肿瘤或癌症治疗剂中的应用；Use of the composition according to any one of claims 1-8 in the preparation of a tumor or cancer therapeutic agent;
    较佳地，所述肿瘤或癌症为新诊断的、复发性和/或难治性肿瘤，优选为结直肠癌、肺癌、乳腺癌、肝癌、胃癌、食管癌、胰腺癌、黑色素瘤、头颈癌、前列腺癌和肾癌中的一种或多种；和/或，所述治疗剂的剂型为注射剂、凝胶剂、原位胶凝系统、软膏剂、栓剂、喷雾剂、溶液剂、混悬剂、乳剂、植入剂、透皮剂中的一种或多种；和/或，所述肿瘤治疗剂为肿瘤原位治疗性疫苗。 Preferably, the tumor or cancer is a newly diagnosed, recurrent and/or refractory tumor, preferably colorectal cancer, lung cancer, breast cancer, liver cancer, gastric cancer, esophageal cancer, pancreatic cancer, melanoma, head and neck cancer , one or more of prostate cancer and kidney cancer; and/or, the dosage form of the therapeutic agent is injection, gel, in situ gelling system, ointment, suppository, spray, solution, suspension One or more of agents, emulsions, implants, and transdermal agents; and/or, the tumor therapeutic agent is a tumor in situ therapeutic vaccine.
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