CN116510024A - 一种组合物、其制备方法及应用 - Google Patents
一种组合物、其制备方法及应用 Download PDFInfo
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- CN116510024A CN116510024A CN202310045843.2A CN202310045843A CN116510024A CN 116510024 A CN116510024 A CN 116510024A CN 202310045843 A CN202310045843 A CN 202310045843A CN 116510024 A CN116510024 A CN 116510024A
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- immune checkpoint
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Abstract
本发明公开了一种组合物,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。
Description
技术领域
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。
背景技术
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 EpigeneticPrograms Inhibit PD-1Blockade-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(Glutamineblockade induces divergent metabolic programs to overcome tumor immuneevasion[J].Science,366.)。
发明内容
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。
为解决上述技术问题,本发明提供以下技术方案:
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。
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。
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 methyltransferase,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(Isocitratedehydrogenase,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。
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。
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、IDO1 and HDAC1 Inhibitor(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)、BRD4354、QTX125 TFA、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(Butanoicacid-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(Compound35)、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。
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,NSC617989)、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-pentanoicacid,Boc-5-aminovaleric acid,Boc-NH-C4-acid,Boc-5-Ava-OH)、UNC1999、EPZ005687和CPI-169中的一种或多种。
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)、MutantIDH1-IN-4(compound 434)、Mutant IDH1-IN-2、IDH1 Inhibitor 3(compound 6f)、α-倒捻子素、倒捻子素-d3、AGI-6780、AGI-5198、Mutant IDH1 inhibitor、AGI-5198(IDH-C35)、IDH1Inhibitor 2(compound 13)、DS-1001b、GSK864、BAY-1436032、AGI-5198(IDH-C35)和FT-2102中的一种或多种。
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。
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/BRD4 degrader-1(compound15)、BMS-986158、BET-IN-6、Desmethyl-QCA276(PROTAC BRD4-binding moiety4)、GSK778(iBET-BD1)、INCB054329、INCB-057643、HJB97、Bromodomain inhibitor-8(Intermediate 21)、(S)-JQ-35(TEN-010)、CD235、CC-90010(compound 1)、(+)-JQ1 PA、Alobresib(GS-5829)、PFI-1(PF-6405761)、(Rac)-BAY1238097、BAY1238097、Y06036、PNZ5、OXFBD04、ZL0420、PROTAC BRD4 ligand-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-CBP1 HCl、PLX51107、AZD-5153 6-hydroxy-2-naphthoic acid(HNTsalt)、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。
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。
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。
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 carrierfamily1member 5,SLC1A5;氨基酸转运体ASCT2)抑制剂、谷氨酸脱氢酶(Glutamatedehydrogenase,GLUD)抑制剂和氨基转移酶抑制剂和溶质载体家族7成员11(Solutecarrier family 7member 11,SLC7A11;xCT系统)抑制剂中的一种或多种。
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。
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。
本发明所述谷氨酰胺消耗药物例如L-天冬酰胺酶。
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。
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。
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)。
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 Inhibitor2、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。
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、p53 mRNA、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。
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。
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。
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。
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。
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。
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。
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。
本发明所述RIG-I/MDA5和TLR3激动剂例如Poly-ICLC和/或BO112。
本发明所述TLR4激动剂例如吡喃葡萄糖脂AG100(Glucopyranosyl lipid AG100)和/或单磷酰酯质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。
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。
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。
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、CCL21 mRNA、IL-10mRNA和IL-15mRNA中的一种或多种。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
本发明所述荷正电的磷脂例如硬脂酰胺(SA)胆固醇衍生物。
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。
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。
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。
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。
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。
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。
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。
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。
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;
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;
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;
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;
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;
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;
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;
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。
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。
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。
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。
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。
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。
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。
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。
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、Nectin4、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。
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。
本发明所述由驱动癌基因调控的靶点抗原例如HER2和/或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。
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。
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。
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。
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
在本发明一较佳实施方案中,组合物可以与手术治疗联用。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
技术方案之三:本发明所述药物组合物在制备肿瘤或癌症治疗剂中的应用。
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。
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。
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。
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。
技术方案之四:一种套装药盒,其包含药盒A和药盒B,其中:
所述药盒A含有如本发明所述的组合物;
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。
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。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
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。
具体实施方式
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。
实施例1组合物的制备及效果验证
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。
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。
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。
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。
第1组:原位瘤内注射生理盐水;
第2组:原位瘤内注射地西他滨冻干粉针剂;
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;
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;
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)。
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。
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。
表1小鼠体重变化
表2小鼠原位瘤体积
与第1组相比,*P<0.05,**P<0.01,***P<0.001。
表3小鼠远端瘤体积
与第1组相比,*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
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。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:原位瘤内注射生理盐水;
第2组:原位瘤内注射地西他滨(0.2mg/kg)冻干粉针剂;
第3组:原位瘤内注射地西他滨(1mg/kg)冻干粉针剂;
第4组:原位瘤内注射地西他滨(2.5mg/kg)冻干粉针剂;
第5组:原位瘤内注射地西他滨(5mg/kg)冻干粉针剂;
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;
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;
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;
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;
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;
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;
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;
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;
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。
表4小鼠体重变化
表5小鼠原位瘤体积
与第1组相比,*P<0.05,**P<0.01,***P<0.001。
表6小鼠远端瘤体积
与第1组相比,*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
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。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:原位瘤内注射生理盐水;
第2组:原位瘤内注射地西他滨(0.2mg/kg)冻干粉针剂;
第3组:原位瘤内注射地西他滨(1mg/kg)冻干粉针剂;
第4组:原位瘤内注射地西他滨(2.5mg/kg)冻干粉针剂;
第5组:原位瘤内注射地西他滨(5mg/kg)冻干粉针剂;
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;
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;
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;
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;
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;
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。
表7小鼠体重变化
表8小鼠原位瘤体积
与第1组相比,*P<0.05,**P<0.01,***P<0.001。
表9小鼠远端瘤体积
与第1组相比,*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
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。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:原位瘤内注射生理盐水;
第2组:原位瘤内注射地西他滨(2.5mg/kg)冻干粉针剂;
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;
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;
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;
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;
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;
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;
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;
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;
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。
表10小鼠体重变化
表11小鼠原位瘤体积
与第1组相比,*P<0.05,**P<0.01,***P<0.001。
表12小鼠远端瘤体积
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与第1组相比,*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
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。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:原位瘤内注射生理盐水;
第2组:原位瘤内注射西达本胺冻干粉针剂;
第3组:原位瘤内注射CB-839冻干粉针剂;
第4组:原位瘤内注射西达本胺和CB-839组合物冻干粉针剂;
第5组:原位瘤内注射泰泽司他冻干粉针剂;
第6组:原位瘤内注射L-天冬酰胺酶冻干粉针剂;
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;
第8组:原位瘤内注射艾伏尼布冻干粉针剂;
第9组:原位瘤内注射V-9302冻干粉针剂;
第10组:原位瘤内注射艾伏尼布和V-9302组合物冻干粉针剂;
第11组:原位瘤内注射思瑞德林冻干粉针剂;
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;
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;
第14组:原位瘤内注射阿帕他隆冻干粉针剂;
第15组:原位瘤内注射柳氮磺吡啶冻干粉针剂;
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;
肿瘤免疫微环境验证研究方法参见实施例1。
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。
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。
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
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。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:原位瘤内注射生理盐水;
第2组:原位瘤内注射地西他滨冻干粉针剂;
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;
第4组:原位瘤内注射Poly-ICLC冻干粉针剂;
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;
第6组:原位瘤内注射单磷酰酯质A冻干粉针剂;
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;
第8组:原位瘤内注射雷西莫特冻干粉针剂;
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;
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;
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;
第12组:原位瘤内注射白细胞介素-2冻干粉针剂;
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;
第14组:原位瘤内注射巨噬细胞集落刺激因子冻干粉针剂;
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;
第16组:原位瘤内注射趋化因子21冻干粉针剂;
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;
第18组:原位瘤内注射白细胞介素-15mRNA冻干粉针剂;
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;
第20组:原位瘤内注射MK-1454冻干粉针剂;
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;
第22组:原位瘤内注射BMS-986301冻干粉针剂;
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;
第24组:原位瘤内注射MSA-2冻干粉针剂;
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;
第26组:原位瘤内注射HG381冻干粉针剂;
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;
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。
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
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。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:原位瘤内注射生理盐水;
第2组:原位瘤内注射地西他滨冻干粉针剂;
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;
第4组:原位瘤内注射anti-PD-L1抗体冻干粉针剂;
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;
第6组:原位瘤内注射anti-4-1BB抗体冻干粉针剂;
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;
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;
第9组:原位瘤内注射anti-CD40抗体冻干粉针剂;
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
第11组:原位瘤内注射anti-PD-L1/4-1BB双抗冻干粉针剂;
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;
第13组:原位瘤内注射anti-PD-L1/CD47双抗冻干粉针剂;
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;
第15组:原位瘤内注射anti-PD-1/LAG-3双抗冻干粉针剂;
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;
第17组:原位瘤内注射anti-PD-1/TIM-3双抗冻干粉针剂;
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;
第19组:原位瘤内注射anti-PD-1/TIGIT-3双抗冻干粉针剂;
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;
第21组:原位瘤内注射anti-PD-L1抗体mRNA冻干粉针剂;
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;
第23组:原位瘤内注射anti-4-1BB抗体mRNA冻干粉针剂;
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;
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。
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
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。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:原位瘤内注射生理盐水;
第2组:原位瘤内注射地西他滨冻干粉针剂;
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;
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;
第5组:原位瘤内注射anti-PD-1抗体冻干粉针剂;
第6组:原位瘤内注射anti-PD-L1/4-1BB双抗冻干粉针剂;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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。
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)。
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。
表13小鼠体重变化
表14小鼠原位瘤体积
与第1组相比,*P<0.05,**P<0.01,***P<0.001。
表15小鼠远端瘤体积
与第1组相比,*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
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。
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。
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。
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。
第1组:原位瘤内注射生理盐水(乳腺癌);
第2组:原位瘤内注射地西他滨冻干粉针剂(乳腺癌);
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);
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);
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);
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);
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);
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);
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);
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);
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);
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);
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);
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。
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
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。
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。
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。
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。
第1组:静脉注射生理盐水;
第2组:静脉注射SGI-110冻干粉针剂;
第3组:静脉注射JHU-083冻干粉针剂;
第4组:静脉注射SGI-110和JHU-083组合物冻干粉针剂;
第5组:腹腔注射SGI-110和JHU-083组合物冻干粉针剂;
第6组:皮下注射SGI-110和JHU-083组合物冻干粉针剂;
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。
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
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)。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:静脉注射注射生理盐水;
第2组:静脉注射地西他滨冻干粉针剂;
第3组:静脉注射6-重氮-5-氧代-L-正亮氨酸冻干粉针剂;
第4组:静脉注射CAR-T细胞;
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;
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。
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
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)。
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。
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。
效果验证研究方法参见实施例1,其中分组如下。
第1组:原位瘤内注射明胶微球冻干粉针剂;
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;
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;
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;
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;
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)
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。
表16小鼠体重变化
表17小鼠原位瘤体积
与第1组相比,*P<0.05,**P<0.01,***P<0.001。
表18小鼠远端瘤体积
与第1组相比,*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
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。
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。
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。
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。
第1组:静脉注射生理盐水;
第2组:静脉注射SGI-110冻干粉针剂;
第3组:静脉注射DRP-104冻干粉针剂;
第4组:静脉注射SGI-110和DRP-104组合物冻干粉针剂;
第5组:腹腔注射SGI-110和DRP-104组合物冻干粉针剂;
第6组:皮下注射SGI-110和DRP-104组合物冻干粉针剂;
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。
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。
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;
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 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、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、IDH1Inhibitor 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 NSC652287、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 002S、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 moiety1、PROTAC BET-binding moiety 2、GSK040、BET-IN-2、BET-IN-4、BET bromodomaininhibitor例如Bromodomain inhibitor 1、Molibresib besylate、BETd-246、GSK620、TD-428、JQ-1carboxylic 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-51536-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;
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。
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;
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;
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。
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;
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;
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CpGODN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-2mRNA、IL-1mRNA、IFNγmRNA、IL-12mRNA、GM-CSF mRNA、IL-23mRNA、IL-36γmRNA、CCL21 mRNA、IL-10mRNA和IL-15mRNA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;
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-15mRNA、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。
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;
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。
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。
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;
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;
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。
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;
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;
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;
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;
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;
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;
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;
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;
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。
9.一种套装药盒,其包含药盒A和药盒B,其中:所述药盒A含有如权利要求1-8任一项所述的组合物;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。
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。
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;
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。
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