WO2019129233A1 - Parp抑制剂和溶瘤病毒在制备抗肿瘤药物的应用 - Google Patents

Parp抑制剂和溶瘤病毒在制备抗肿瘤药物的应用 Download PDF

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WO2019129233A1
WO2019129233A1 PCT/CN2018/125014 CN2018125014W WO2019129233A1 WO 2019129233 A1 WO2019129233 A1 WO 2019129233A1 CN 2018125014 W CN2018125014 W CN 2018125014W WO 2019129233 A1 WO2019129233 A1 WO 2019129233A1
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virus
parp inhibitor
parp
group
tumor
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PCT/CN2018/125014
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French (fr)
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颜光美
朱文博
龚守芳
贺嵩敏
张海鹏
林园
梁剑开
蔡静
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广州威溶特医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention belongs to the field of biomedicine and relates to the application of a combination of a PARP inhibitor and an oncolytic virus in the preparation of an antitumor drug.
  • Oncolytic virus is a type of replicable virus that selectively infects and kills tumor cells without damaging normal cells.
  • Oncolytic virotherapy is an innovative tumor-targeted therapeutic strategy that uses natural or genetically engineered viruses to selectively infect tumor cells and replicate in tumor cells for targeted lysis. Kills the role of tumor cells, but does not damage normal cells.
  • the M1 virus (Alphavirus M1) belongs to the genus Alphavirus, and has a good application effect in the preparation of antitumor drugs.
  • Chinese invention patent application 201410425510.3 discloses that the M1 virus can selectively cause tumor cell death without affecting normal cell survival, and has a very good application prospect in anti-tumor.
  • different tumors have different sensitivities to the M1 virus. For some tumors, when the M1 virus is administered alone, the oncolytic effect is not ideal.
  • M1 when used as an anti-tumor drug, M1 is less effective for colorectal cancer, liver cancer, bladder cancer and breast cancer than pancreatic cancer, nasopharyngeal cancer, prostate cancer and melanoma; Tumor, cervical cancer, and lung cancer are second, while gastric cancer is the least significant.
  • Compounds that screen to increase the therapeutic effect of oncolytic virus tumors are expected to increase the antitumor profile and antitumor strength of oncolytic viruses.
  • One of the objects of the present invention is to provide an application of an oncolytic virus anti-tumor synergist.
  • Another object of the present invention is to provide an oncolytic virus potentiator which is less toxic, preferably non-toxic to normal cells.
  • Another object of the present invention is to provide an antitumor pharmaceutical composition which allows the oncolytic virus to exert a better antitumor effect.
  • Another object of the present invention is to provide an antitumor composition which minimizes the toxicity of a pharmaceutical composition while exerting an antitumor drug utility.
  • Another object of the present invention is to provide a safe and effective oncolytic virus potentiating drug against tumors which are insensitive to oncolytic viruses.
  • the inventors found through research and screening that PARP inhibitors unexpectedly enhance the oncolytic effect of oncolytic viruses.
  • the PARP inhibitor is a substance that inhibits PARP activity, or a substance that degrades PARP, or a genetic tool that lowers the level of PARP.
  • PARP inhibitors can inhibit the repair of DNA damage in tumor cells and enhance the sensitivity of tumor cell DNA to damage factors.
  • research on PARP inhibitors has received more and more attention.
  • PARP inhibitors are expected to play an important role in the field of cancer therapy.
  • the inventors can significantly enhance the oncolytic effect of oncolytic viruses by inhibiting PARP.
  • the inventors used a compound that inhibits PARP activity, Olaparib, and an oncolytic virus, especially an M1 virus, to act on tumor cells.
  • Olaparib can synergize with oncolytic viruses to enhance antitumor effects.
  • the present inventors have found for the first time that PARP inhibitors can be used as antitumor synergists/drug resistance reversal agents for oncolytic viruses.
  • the present invention provides the use of a PARP inhibitor for the preparation of an oncolytic virus anti-tumor synergist/drug reversal agent.
  • the drug resistance reversal agent means that when some oncolytic viruses are used as anti-tumor drugs for treating tumors, some tumors are not sensitive to oncolytic viruses, or these tumors are resistant to oncolytic viruses.
  • the oncolytic virus can be used in combination with a PARP inhibitor (as a drug resistance reversal agent) to reverse the tumor's resistance to the oncolytic virus.
  • the PARP inhibitor is selected from the group consisting of compounds.
  • the PARP inhibitor includes, but is not limited to, the following compounds or derivatives thereof having PARP inhibition, or pharmaceutically acceptable salts, solvates, tautomers, isomers thereof: Olaparib A compound which inhibits PARP activity, such as (Formula 1) or Veliparib (Formula 2).
  • Olaparib A compound which inhibits PARP activity such as (Formula 1) or Veliparib (Formula 2).
  • the manner in which the compound is obtained may be selected from, but not limited to, chemical separation or synthesis by itself or from commercial sources.
  • the PARP inhibitor is Olaparib, and the structural formula is as shown in Formula 1:
  • the PARP inhibitor is Veliparib, and its structural formula is as shown in Formula 2:
  • the PARP inhibitors also include tools for PARP gene expression inhibition, including but not limited to gene interference, gene silencing, and gene editing or knockout.
  • the PARP inhibitor is selected from the group consisting of DNA, RNA, PNA or DNA-RNA-hybrid. They can be single-stranded or double-stranded.
  • PARP inhibitors may include small inhibitory nucleic acid molecules such as short interfering RNA (siRNA), double stranded RNA (dsRNA), microRNA (miRNA), ribozyme, and small hairpin RNA (shRNA), all of which attenuate or eliminate Expression of PARP.
  • siRNA short interfering RNA
  • dsRNA double stranded RNA
  • miRNA microRNA
  • ribozyme ribozyme
  • shRNA small hairpin RNA
  • the PARP inhibitor further comprises one or more of an antibody, an antibody functional fragment, a peptide, and a peptidomimetic.
  • the antibody may be a monoclonal antibody, a polyclonal antibody, a multivalent antibody, a multispecific antibody (eg, a bispecific antibody), and/or an antibody fragment ligated to PARP.
  • the antibody may be a chimeric antibody, a humanized antibody, a CDR-grafted antibody or a human-type antibody.
  • the antibody fragment may be, for example, Fab, Fab', F(ab')2, Fv, Fd, single-chain Fv (scFv), a disulfide-bonded FV (sdFv), or a VL, VH domain.
  • the antibody may be in a conjugated form, for example, in combination with a label, a detectable label, or a cytotoxic agent.
  • the antibody may be a homotypic IgG (eg, IgGl, IgG2, IgG3, IgG4), IgA, IgM, IgE or IgD.
  • the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; wherein the alphavirus is selected from the group consisting of an M1 virus, Gaeta virus.
  • the oncolytic virus is selected from the group consisting of an M1 virus, a Gaeta virus, or a combination thereof.
  • the oncolytic virus (M1 virus, Gaeta virus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus, and herpes simplex virus) according to the present invention may especially refer to an existing oncolytic virus, but Some natural mutations that may occur or viruses that have undergone mutations (natural mutations, mandatory mutations, or selective mutations), genetic modifications, sequence additions or deletions, or partial replacements are not excluded.
  • the oncolytic viruses described herein include viruses that have undergone the above changes. Preferably, the above changes do not affect the effect of said oncolytic virus as described herein.
  • the PARP inhibitor is a substance (for example, a compound, or an amino acid sequence, a nucleotide sequence, etc.) or a tool capable of knocking down or affecting the expression of a PARP gene or reducing the amount or activity of PARP.
  • a person skilled in the art may modify, replace, change, etc. the inhibitory compound or the gene tool, but as long as the above-mentioned PARP inhibition is performed, the PARP inhibitor belonging to the present invention belongs to the homogeneity of the above substances, compounds or tools. replace.
  • the alphavirus is the M1 virus deposited under the accession number CCTCC V201423 (as deposited with the China Center for Type Culture Collection, deposited on July 17, 2014).
  • Genbank Accession No. EF011023 records a sequence of M1.
  • the Gita virus is a virus having a homology of up to 97.8% (Wen et al. Virus Genes. 2007; 35(3): 597-603) with the M1 virus, and the two have a high identity, and the M1 virus is also somewhat
  • the literature is classified as a Gaetavirus. Both can be expected to have the same effect.
  • a single alphavirus strain can also be administered. In other embodiments, a variety of strains and/or types of alphaviruses can also be used.
  • the invention also provides a pharmaceutical composition for treating a tumor comprising a PARP inhibitor and an oncolytic virus.
  • the invention also provides a pharmaceutical kit for treating a tumor comprising a PARP inhibitor or a derivative thereof or a combination thereof, and an oncolytic virus.
  • the drug kit differs from the composition in that the PARP inhibitor is different from the oncolytic virus in the form of a separate package (eg, a pill, or a capsule, or a tablet or vial containing a PARP inhibitor; additional pills, Or capsules, or tablets or vials containing oncolytic viruses).
  • an oncolytic virus, a PARP inhibitor, and a combination of an oncolytic virus and a PARP inhibitor may also contain one or more adjuvants.
  • the adjuvant refers to an ingredient which can assist the therapeutic effect of the drug in the composition of the drug.
  • the kit may also contain individually packaged PARP inhibitors as well as individually packaged oncolytic viruses.
  • the PARP inhibitor in the drug kit, and the administration of the oncolytic virus may be administered simultaneously or in any anterior-posterior sequence, such as administration of a PARP inhibitor prior to the oncolytic virus, or administration of a PARP inhibitor following the oncolytic virus, or Both are administered simultaneously.
  • the patient can be a mammal. In some embodiments, the mammal can be a human.
  • the PARP inhibitors include, but are not limited to, compounds that inhibit PARP activity, such as Olaparib (Formula 1) or Veliparib (Formula 2). Or targeting PARP gene expression inhibition tools, including but not limited to gene interference, gene silencing, and gene editing or knockout tools.
  • the PARP inhibitor is at least one selected from the group consisting of Olaparib and Veliparib.
  • the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; wherein the alphavirus is selected from the group consisting of an M1 virus and Gaeta virus. In a preferred embodiment, the oncolytic virus is selected from at least one of an M1 virus and a Gata virus.
  • the ratio of Olaparib or Veliparib to the oncolytic virus is optionally 0.01 to 200 mg: 10 3 to 10 9 PFU; preferably 0.1 to 200 mg: 10 4 to 10 9 PFU; further preferably 0.1 to 100 mg: 10 5 to 10 9 PFU.
  • the dosage is: Olaparib or Veliparib is used in the range of 0.01 mg/kg to 200 mg/kg, and the oncolytic virus uses a titer of MOI from 10 3 to 10 9 (PFU/kg); preferably Olaparib or Veliparib is used in the range of 0.1 mg. /kg to 200mg/kg, while the oncolytic virus uses a titer of MOI from 10 4 to 10 9 (PFU / kg); more preferably Olaparib or Veliparib is used from 0.1 mg / kg to 100 mg / kg, while the oncolytic virus is used The titer is MOI from 10 5 to 10 9 (PFU/kg).
  • the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; wherein the alphavirus is selected from the group consisting of an M1 virus and Gaeta virus.
  • the oncolytic virus is selected from at least one of an M1 virus and a Gata virus.
  • the M1 virus belongs to the Gaeta-like virus, and the homology of the two is as high as 97.8%.
  • the tumor is a solid tumor or a hematoma.
  • the solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer, or gastric cancer.
  • the tumor is a tumor that is insensitive to oncolytic viruses.
  • the tumor is a tumor that is insensitive to Ml oncolytic virus.
  • the Olaparib or Veliparib provided by the present invention may be an injection, a tablet, a capsule, a patch, a kit, or the like.
  • the synergistic drug of the present invention is an injection; preferably, intravenous injection can be employed.
  • the present inventors have discovered that PARP inhibitors, especially Olaparib, can increase the antitumor effect of oncolytic viruses to improve the therapeutic effectiveness of oncolytic viruses as antitumor drugs. Cytological experiments show that the combination of M1 virus and Olaparib can significantly cause morphological lesions of tumor cells, thereby significantly enhancing the inhibition of tumor cells.
  • the present inventors have found that the combination of Olaparib and oncolytic virus treats tumor cells, and the killing effect on tumor cells is significantly better than that of Olaparib alone. For example, when tumor cells are treated with, for example, 6.33 ⁇ M of Olaparib, the tumor cell survival rate is still as high. At 85.6%, when the 6.25 ⁇ M Olaparib was combined with the M1 virus, the tumor cell survival rate dropped significantly to 43.3%. It can be seen that the greatly enhanced oncolytic effect of Olaparib combined with M1 is due to the synergistic mechanism between Olaparib and M1 virus, not simply through the anti-tumor mechanism of Olaparib.
  • Olaparib is a product of nearly half a century of research, and studies have shown that PARPs can help repair DNA damage. If not repaired, DNA double-strand breaks trigger cell death. Inhibition of this enzyme is unlikely to kill healthy cells because healthy cells possess multiple signaling pathways that repair broken DNA. But cancer cells sometimes have mutations that destroy other types of repairs, making them especially sensitive to PARP inhibition. Therefore, drugs that function by this mechanism can bypass healthy cells while targeting cancer cells, avoiding some side effects caused by conventional chemotherapy.
  • Oncolytic viruses, especially alphaviruses can dissolve tumor tumor cells, and the use of synergists can increase their oncolysis effect, which is advantageous in this respect, but if the synergist itself brings toxicity, it will limit the application prospects.
  • the PARP inhibitor for example, Olaparib
  • the present invention not only enhances the oncolytic effect when combined with the alphavirus, but also the drug itself does not affect the normal cells, and the safety is high, and at the same time, the benefits of both are achieved. It is rare and has important and positive significance for the health of cancer patients.
  • Example 1 Olaparib combined with M1 virus significantly reduced the survival rate of human hepatocellular carcinoma Hep3B material:
  • Human hepatocellular carcinoma Hep3B purchased from ATCC
  • M1 virus accesion No. CCTCC V201423
  • high glucose DMEM medium accesion No. CCTCC V201423
  • automatic enzyme-linked detection microplate reader accesion No. CCTCC V201423
  • MTT and intracellular succinate dehydrogenase reaction when cultured to 48h, add 20 ⁇ l (5mg/ml) of MTT to each well and continue to incubate for 4 hours. At this time, microscopically formed granular particles can be observed in living cells. Blue-purple nails crystallize.

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Abstract

PARP抑制剂和溶瘤病毒在制备抗肿瘤药物的应用。PARP抑制剂可以用于制备溶瘤病毒抗肿瘤增效剂。一种包含PARP抑制剂以及溶瘤病毒的药物组合物，包含PARP抑制剂及溶瘤病毒的药品套装，以及PARP抑制剂与溶瘤病毒在治疗肿瘤，特别是对所述溶瘤病毒不敏感的肿瘤中的用途。

Description

PARP抑制剂和溶瘤病毒在制备抗肿瘤药物的应用 技术领域
本发明属于生物医药领域，涉及PARP抑制剂与溶瘤病毒的联合在制备抗肿瘤药物中的应用。
背景技术
溶瘤病毒(oncolytic virus)是一类选择性的感染并杀伤肿瘤细胞，而不损伤正常细胞的可复制病毒。溶瘤病毒疗法(oncolytic virotherapy)是一种创新的肿瘤靶向治疗策略，它利用天然的或经基因工程改造的病毒选择性的感染肿瘤细胞，并在肿瘤细胞中复制，达到靶向性溶解、杀伤肿瘤细胞的作用，但是对正常细胞没有损伤。
M1病毒(Alphavirus M1)属于甲病毒属(Alphavirus)，其在制备抗肿瘤药物方面具有较好的应用效果。例如中国发明专利申请201410425510.3公开了M1病毒能选择性引起肿瘤细胞死亡而不影响正常细胞存活，其在抗肿瘤方面具有非常好的应用前景。然而，不同肿瘤对M1病毒的敏感性不一，对于某些肿瘤，M1病毒单独用药时，溶瘤作用还不够理想。例如中国发明专利申请201410425510.3所记载的，M1作为抗肿瘤药物使用时，对于结直肠癌、肝癌、膀胱癌和乳腺癌的效果不如胰腺癌、鼻咽癌、前列腺癌和黑色素瘤明显；而胶质瘤、宫颈癌、肺癌则更其次；而胃癌则最不显著。筛选增加溶瘤病毒肿瘤治疗效果的化合物有望增加溶瘤病毒的抗瘤谱及抗瘤强度。
已经报道了现有的多种抗肿瘤药物可以增强溶瘤病毒对肿瘤的杀伤力，然而，在这些众多的现有的抗肿瘤药物中，某些药物本身毒性较大，对正常的细胞可能也产生毒性。虽然抗肿瘤的效果提升了，然而副作用也随之增强，为患者的健康带来不利的影响。因此，本领域一直在孜孜不倦寻找低毒，最好是对 正常细胞没有毒性的溶瘤病毒的增效剂。
发明内容
本发明的目的之一在于提供一种溶瘤病毒抗瘤增效剂方面的应用。
本发明的另一个目的在于提供一种低毒、最好是对正常细胞没有毒性的溶瘤病毒增效剂。
本发明的另一个目的在于提供一种抗瘤药物组合物，其可以使得溶瘤病毒发挥更好的抗瘤效果。
本发明的另一个目的在于提供一种抗肿瘤组合物，在发挥抗肿瘤药物效用的同时，尽量小化药物组合物的毒性。
本发明的另一个目的在于提供一种针对溶瘤病毒不敏感的肿瘤，安全有效的溶瘤病毒增效药物。
发明通过以下技术方案实现上述目的：
发明人通过研究、筛选发现，PARP抑制剂出人意料地可以增强溶瘤病毒的溶瘤效果。
所述的PARP抑制剂为抑制PARP活性的物质、或降解PARP的物质、或降低PARP水平的基因工具。
聚ADP核糖聚合酶(poly ADP-ribose polymerase,PARP)具有保持染色体结构完整性、参与DNA的复制和转录、维持基因组稳定等重要作用。因此PARP抑制剂能够抑制肿瘤细胞DNA损伤修复、增强肿瘤细胞DNA对损伤因素的敏感性。近年来PARP抑制剂的研究收到了越来越多的关注。PARP抑制剂有望在肿瘤治疗领域发挥重要作用。
发明人通过抑制PARP可以显著增强溶瘤病毒的溶瘤效应。发明人采用了抑制PARP活性的化合物Olaparib协同溶瘤病毒尤其是M1病毒作用于肿瘤细胞，实验结果发现，Olaparib可以协同溶瘤病毒增强抗肿瘤效应。
本发明首次发现，PARP抑制剂可以作为溶瘤病毒的抗瘤增效剂/耐药逆转 剂。
本发明提供了PARP抑制剂在制备溶瘤病毒抗瘤增效剂/耐药逆转剂方面的应用。
耐药逆转剂是指，当采用一些溶瘤病毒作为抗肿瘤药物用于治疗肿瘤时，存在着一些肿瘤对溶瘤病毒并不太敏感，或者说这些肿瘤对溶瘤病毒具有抗性，此时，可以采用与PARP抑制剂(作为耐药逆转剂)联用溶瘤病毒的方式，以逆转肿瘤对所述溶瘤病毒的抗性。
所述的PARP抑制剂选自化合物。优选地，所述的PARP抑制剂包括但不限于以下化合物或其具有PARP抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Olaparib(式1)或Veliparib(式2)等抑制PARP活性的化合物。化合物的获取方式可选但不限于：自己化学分离或合成或者从商业途径购买。
在本发明一优选的实施例中，所述的PARP抑制剂为Olaparib，其结构式如式1所示：
Figure PCTCN2018125014-appb-000001
在本发明另一优选的实施例中，所述的PARP抑制剂为Veliparib，其结构式如式2所示：
Figure PCTCN2018125014-appb-000002
或者，所述的PARP抑制剂还包括针对PARP基因表达抑制工具，包括但不限于基因干扰、基因沉默以及基因编辑或敲除等工具手段。
作为一种可选的实施方式，所述PARP抑制剂选自DNA、RNA、PNA或DNA-RNA-杂合体。它们可以是单链的或双链的。
PARP抑制剂可包括一些小的抑制核酸分子，例如短干扰RNA(siRNA)，双链RNA(dsRNA)，microRNA(miRNA)，核酶，以及小发夹RNA(shRNA)，这些都能减弱或消除PARP的表达。
或者，所述的PARP抑制剂还包括抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种。其中，所述的抗体可能是单克隆抗体，多克隆抗体，多价抗体，多特异性抗体(例如：双特异性抗体)，和/或连接在PARP上的抗体片段。该抗体可以是嵌合抗体、人源化抗体、CDR移植抗体或人型抗体。抗体片段可以是，例如，Fab，Fab’，F(ab’)2，Fv，Fd，单链Fv(scFv)，具二硫键的FV(sdFv)，或VL、VH结构域。抗体可能是一个共轭的形式，例如，结合一个标签、一个可检测标记，或一种细胞毒性剂。抗体可能是同型IgG(例如：IgG1、IgG2、IgG3、IgG4)、IgA、IgM、IgE或IgD。
所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；其中，所述的甲病毒选自M1病毒、盖塔病毒。作为优选的实施方式，所述的溶瘤病毒选自M1病毒、盖塔病毒或者它们的组合。
本发明所说的溶瘤病毒(M1病毒、盖塔病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒)可以尤其地指目前已有的溶瘤病毒， 但也不排除一些可能发生的自然变异或者进行了突变(自然突变、强制性突变、或选择性突变)、基因修饰、序列增加或删除或部分替换的病毒。这里所述的溶瘤病毒包括已经进行了上述改变的病毒。最好是上述改变并不影响所说的溶瘤病毒发挥本发明所述的作用。所说的PARP抑制剂为能起到敲低或影响PARP基因表达或者降低PARP量或活性的物质(例如化合物、或氨基酸序列、核苷酸序列等)或工具等。本领域技术人员可以对其抑制化合物或者基因工具进行修饰、替换、改变等，但只要起到上述抑制PARP作用的，则属于本发明的PARP抑制剂，属于上述物质、化合物或工具等的同质替换。
在一些实施例中，甲病毒是保藏编号CCTCC V201423(保藏于中国典型培养物保藏中心，保藏日期2014年7月17日)的M1病毒。作为很可能来源于同一毒株的病毒，Genbank Accession No.EF011023记录了一株M1的序列。盖塔病毒作为与M1病毒具有高达97.8％(Wen et al.Virus Genes.2007；35(3):597-603)同源性的病毒，两者具有很高的同一性，M1病毒也被一些文献归类为类盖塔病毒。可以预期二者具有相同的效果。单个甲病毒株也可以施用。在其他实施方案中，也可使用多种菌株和/或类型的甲病毒。
本发明还提供一种用于治疗肿瘤的药物组合物，其包含PARP抑制剂以及溶瘤病毒。本发明还提供用于治疗肿瘤的药品套装，其包含PARP抑制剂或其衍生物或它们的组合，以及溶瘤病毒。药品套装区别于组合物的地方在于，PARP抑制剂不同于溶瘤病毒的剂型，而是独立包装(例如：药丸、或胶囊、或药片或安剖瓶中，含有PARP抑制剂；另外的药丸、或胶囊、或药片或安剖瓶中，含有溶瘤病毒)。在一些实施例中，溶瘤病毒、PARP抑制剂，以及溶瘤病毒和PARP抑制剂的组合，也可含一种或多种佐剂。所述的佐剂是指在药物组成中，可辅助药物疗效的成分。药品套装也可以包含独立包装的PARP抑制剂，以及独立包装的溶瘤病毒。药物套装中PARP抑制剂，以及溶瘤病毒的施用，可以是同时施用或者是以任意的前后顺序施用，例如在溶瘤病毒之前施用PARP抑制剂，或者在溶瘤病毒之后施用PARP抑制剂，或者两者同时施用。在各种实施例中，患者 可以是哺乳动物。在一些实施例中，哺乳动物可以是人。
所述的PARP抑制剂包括但不限于Olaparib(式1)或Veliparib(式2)这一类的抑制PARP活性的化合物。或者针对PARP基因表达抑制工具，包括但不限于基因干扰、基因沉默以及基因编辑或敲除等工具手段。作为本发明优选的实施方式，所述的PARP抑制剂选自Olaparib和Veliparib中的至少一种。
所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；其中，所述的甲病毒选自M1病毒和盖塔病毒。作为优选的实施方式，所述的溶瘤病毒选自M1病毒和盖塔病毒的至少一种。
在组合物或药品套装中，Olaparib或Veliparib与溶瘤病毒的配比可选地为：0.01～200mg:10 3～10 9PFU；优选0.1～200mg:10 4～10 9PFU；进一步优选0.1～100mg:10 5～10 9PFU。
优选使用剂量为：Olaparib或Veliparib使用范围为0.01mg/kg至200mg/kg，同时溶瘤病毒使用滴度为MOI从10 3至10 9(PFU/kg)；优选Olaparib或Veliparib使用范围为0.1mg/kg至200mg/kg，同时溶瘤病毒使用滴度为MOI从10 4至10 9(PFU/kg)；更优选Olaparib或Veliparib使用范围为0.1mg/kg至100mg/kg，同时溶瘤病毒使用滴度为MOI从10 5至10 9(PFU/kg)。
所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；其中，所述的甲病毒选自M1病毒和盖塔病毒。作为优选的实施方式，所述的溶瘤病毒选自M1病毒和盖塔病毒的至少一种。M1病毒属于盖塔相似病毒，这两者的同源性高达97.8％。
在一个实施方式中，所述肿瘤为实体瘤或血液瘤。在一个实施方式中，所述实体瘤为肝癌、结直肠癌、膀胱癌、乳腺癌、宫颈癌、前列腺癌、胶质瘤、黑色素瘤、胰腺癌、鼻咽癌、肺癌、或胃癌。在优选的实施方式中，所述肿瘤为对溶瘤病毒不敏感的肿瘤。在更优选的实施方式中，所述肿瘤为对M1溶瘤病毒不敏感的肿瘤。
作为可选的实施方案，本发明所提供的Olaparib或Veliparib可以是注射剂、片剂、胶囊、贴剂、试剂盒等。作为优选的实施方案，本发明的增效药物是注射剂；优选地，可采用静脉注射。
作为本发明进一步优选的实施方案：
本发明发现了PARP抑制剂，尤其是Olaparib可以增加溶瘤病毒的抗肿瘤效应，以提高溶瘤病毒作为抗肿瘤药物时的治疗有效性。细胞学实验证明M1病毒和Olaparib联合应用，可显著引起肿瘤细胞的形态学病变，从而显著增强对肿瘤细胞的抑制作用。
我们联合Olaparib和M1病毒作用于人肝细胞癌Hep3B株，出人意料的发现抗病毒化合物Olaparib和M1病毒联合应用时，显著增加肿瘤细胞形态病变，显著降低肿瘤细胞生存率。例如在本发明的一个实施例中，当M1病毒(MOI＝0.001)单独处理肝癌细胞时，肿瘤细胞存活率为79.9％，而当以6.25μM的Olaparib与同样MOI的M1病毒联用时，肿瘤细胞存活率大幅下降至43.3％。与单用M1病毒的抗肿瘤效果相比，Olaparib与M1联用时，溶瘤效果显著提升。
本发明发现，Olaparib与溶瘤病毒联合应用处理肿瘤细胞，对肿瘤细胞杀伤作用显著优于单用相同浓度的Olaparib，例如当同样例如以6.25μM的Olaparib处理肿瘤细胞时，肿瘤细胞存活率仍高达85.6％，当以6.25μM的Olaparib与M1病毒联用时，肿瘤细胞存活率大幅下降至43.3％。可见，Olaparib与M1联用时大幅提升的溶瘤效果，是得益于Olaparib与M1病毒之间的协同性机制，并非简单地通过Olaparib的抗肿瘤机制发挥作用。
Olaparib是近半个世纪研究的产物，研究表明PARPs可帮助修复DNA损伤。如果得不到修复，DNA双链断裂会触发细胞死亡。抑制该酶的作用不太可能杀死健康细胞，因为健康细胞拥有多条修复断裂DNA的信号通路。但癌细胞有时候会发生一些突变，破坏其他类型的修复，使得它们尤其对PARP抑制敏感。因此，以这种机制发挥作用的药物可在靶向癌细胞的同时，绕过健康细胞，避免了常规化疗带来的一些毒副作用。溶瘤病毒尤其是甲病毒可以溶解瘤肿瘤细胞， 运用增效剂可以提高其溶瘤效果，这方面是有利的，但是如果增效剂本身带来毒性的话，又会限制了应用前景。而本发明发现的PARP抑制剂(例如Olaparib)与甲病毒联用后，不仅增强了溶瘤效果，并且，药物本身不对正常细胞造成影响，安全性较高，同时实现两方面的益出，这是难得的，对肿瘤患者的健康具有重要且积极的意义。
附图说明
图1Olaparib与M1病毒联合处理显著降低人肝细胞癌株Hep3B生存率；
具体实施方式
以下实施方式是对本发明作进一步说明，但本发明的实施方式不局限于以下的实施例介绍，凡依照本发明的原理或理念所作的等同的变化或变通都应视为本发明保护的范畴。
在没有特别指明的情况下，本发明采用的材料及实验方法为常规材料及方法。
实施例1 Olaparib与M1病毒联合处理显著降低人肝细胞癌株Hep3B生存率材料：
人肝细胞癌Hep3B(购于ATCC)，M1病毒(保藏编号CCTCC V201423)，高糖DMEM培养基(保藏编号CCTCC V201423)，自动酶联检测酶标仪。
方法：
a)接种细胞、给药处理：选择对数生长期细胞，DMEM完全培养液(含10％胎牛血清、1％双抗)制成细胞悬液，以每孔4×10 3/孔的密度接种在96孔培养板内。12小时后见细胞完全贴壁，实验分对照组，单独Olaparib组，M1感染组和Olaparib/M1联用组。所用剂量为：所用剂量为：M1病毒(MOI＝0.001)感染细胞；Olaparib为6.25μM。
b)MTT与细胞内的琥珀酸脱氢酶反应：培养至48h时，每孔加入MTT 20μl (5mg/ml)，继续孵育4小时，此时镜检可观察到、活细胞内形成的颗粒状蓝紫色甲臜结晶。
c)溶解甲臜颗粒：小心吸去上清，加DMSO 100μl/孔溶解形成的结晶，在微型振荡器上震荡5min，然后在酶联检测仪上用波长570nm检测各孔的光密度(OD值)。细胞存活率＝药物处理组OD值/对照组OD值×100％。
结果:
如图1所示，M1病毒(MOI＝0.001)单独处理对肿瘤细胞Hep3B具有较小的生存率抑制作用，肿瘤细胞存活率达到79.9％，6.25μM的Olaparib处理组肿瘤细胞存活率仍高达85.6％，然而，当同样的6.25μM的Olaparib与M1病毒(MOI＝0.001)联用(Olaparib+M1)时，肿瘤细胞存活率大幅下降至43.3％。

Claims (9)

  1. PARP抑制剂在制备溶瘤病毒抗肿瘤增效剂或耐药逆转剂方面的应用；
    优选地，所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；
    优选地，所述的甲病毒选自M1病毒和盖塔病毒中的至少一种。
  2. 如权利要求1所述的应用，其特征在于，所述的PARP抑制剂为抑制PARP活性的物质、或降解PARP的物质、或降低PARP水平的基因工具、或它们的任意组合；
    优选地，所述的PARP抑制剂选自化合物；
    更优选地，所述的PARP抑制剂选自以下化合物或其具有PARP抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Olaparib、Veliparib；
    更优选地，所述的Olaparib的结构式如式1所示：
    Figure PCTCN2018125014-appb-100001
    更优选地，所述的Veliparib的结构式如式2所示；
    Figure PCTCN2018125014-appb-100002
    Figure PCTCN2018125014-appb-100003
    或者优选地，所述的PARP抑制剂选自抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种；
    或者优选地，所述的PARP抑制剂选自基因干扰、基因沉默、基因编辑或基因敲除材料；
    或者优选地，所述的PARP抑制剂选自：DNA、RNA、PNA和DNA-RNA-杂合体中的一种或几种；
    更优选地，所述PARP抑制剂选自：siRNA、dsRNA、miRNA、shRNA和核酶中的一种或几种；
    更优选地，所述的PARP抑制剂为肿瘤靶向PARP抑制剂。
  3. 一种治疗肿瘤的药物组合物，包含：
    (a)PARP抑制剂；
    所述的PARP抑制剂为抑制PARP活性的物质、或降解PARP的物质、或降低PARP水平的基因工具、或它们的任意组合；
    优选地，所述的PARP抑制剂选自化合物；
    更优选地，所述的PARP抑制剂选自以下化合物或其具有PARP抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Olaparib、Veliparib；
    更优选地，所述的Olaparib的结构式如式1所示：
    Figure PCTCN2018125014-appb-100004
    更优选地，所述的Veliparib的结构式如式2所示；
    Figure PCTCN2018125014-appb-100005
    或者优选地，所述的PARP抑制剂选自抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种；
    或者优选地，所述的PARP抑制剂选自基因干扰、基因沉默、基因编辑或基因敲除材料；
    或者优选地，所述的PARP抑制剂选自：DNA、RNA、PNA和DNA-RNA-杂合体中的一种或几种；
    更优选地，所述PARP抑制剂选自：siRNA、dsRNA、miRNA、shRNA和核酶中的一种或几种；
    更优选地，所述的PARP抑制剂为肿瘤靶向PARP抑制剂；
    (b)溶瘤病毒；所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；
    优选地，所述的甲病毒选自M1病毒和盖塔病毒中的至少一种。
  4. 一种药品套装，包含：
    (a)PARP抑制剂；
    所述的PARP抑制剂为抑制PARP蛋白活性的物质、或降解PARP蛋白的物质、或降低PARP蛋白水平的基因工具、或它们的任意组合；
    优选地，所述的PARP抑制剂选自化合物；
    更优选地，所述的PARP抑制剂选自以下化合物或其具有PARP抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体： Olaparib、Veliparib；
    更优选地，所述的Olaparib的结构式如式1所示：
    Figure PCTCN2018125014-appb-100006
    更优选地，所述的Veliparib的结构式如式2所示；
    Figure PCTCN2018125014-appb-100007
    或者优选地，所述的PARP抑制剂选自抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种；
    或者优选地，所述的PARP抑制剂选自基因干扰、基因沉默、基因编辑或基因敲除材料；
    或者优选地，所述的PARP抑制剂选自：DNA、RNA、PNA和DNA-RNA-杂合体中的一种或几种；
    更优选地，所述PARP抑制剂选自：siRNA、dsRNA、miRNA、shRNA和核酶中的一种或几种；
    更优选地，所述的PARP抑制剂为肿瘤靶向PARP抑制剂；
    (b)溶瘤病毒；所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；
    优选地，所述的甲病毒选自M1病毒和盖塔病毒中的至少一种；
    优选地，包含独立包装的PARP抑制剂及独立包装的溶瘤病毒。
  5. PARP抑制剂及溶瘤病毒的组合在制备治疗肿瘤药物中的应用；
    所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；
    优选地，所述的甲病毒选自M1病毒和盖塔病毒中的至少一种；
    所述的PARP抑制剂为抑制PARP活性的物质、或降解PARP的物质、或降低PARP水平的基因工具、或它们的任意组合；
    优选地，所述的PARP抑制剂选自化合物；
    更优选地，所述的PARP抑制剂选自以下化合物或其具有PARP抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Olaparib、Veliparib；
    更优选地，所述的Olaparib的结构式如式1所示：
    Figure PCTCN2018125014-appb-100008
    更优选地，所述的Veliparib的结构式如式2所示；
    Figure PCTCN2018125014-appb-100009
    或者优选地，所述的PARP抑制剂选自抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种；
    或者优选地，所述的PARP抑制剂选自基因干扰、基因沉默、基因编辑或基因敲除材料；
    或者优选地，所述的PARP抑制剂选自：DNA、RNA、PNA和DNA-RNA-杂合体中的一种或几种；
    更优选地，所述PARP抑制剂选自：siRNA、dsRNA、miRNA、shRNA和核酶中的一种或几种；
    更优选地，所述的PARP抑制剂为肿瘤靶向PARP抑制剂。
  6. 根据权利要求3所述的药物组合物，其中所述药物组合物还包含药学上可接受的载体；所述载体优选地选自冻干粉针、注射剂、片剂、胶囊、试剂盒或贴剂。
  7. 如权利要求1-6任一所述的应用/组合物/药品套装，其特征在于所述的PARP抑制剂为Olaparib和/或Veliparib。
  8. 如权利要求3、4、6或7任一所述的组合物/药品套装，其特征在于所述的Olaparib或Veliparib与溶瘤病毒的配比为：0.01～200mg:10 3～10 9PFU；优选0.1～200mg:10 4～10 9PFU；进一步优选0.1～100mg:10 5～10 9PFU；
    进一步优选地，使用剂量为：Olaparib或Veliparib使用范围为0.01mg/kg至200mg/kg，同时溶瘤病毒使用滴度为MOI从10 3至10 9(PFU/kg)；优选Olaparib或Veliparib使用范围为0.1mg/kg至200mg/kg，同时溶瘤病毒使用滴度为MOI 从10 4至10 9(PFU/kg)；更优选Olaparib或Veliparib使用范围为0.1mg/kg至100mg/kg，同时溶瘤病毒使用滴度为MOI从10 5至10 9(PFU/kg)。
  9. 如权利要求1-8任一所述的应用/组合物/药品套装，其特征在于所述的肿瘤为实体瘤或血液瘤；优选地，所述的实体瘤为肝癌、结直肠癌、膀胱癌、乳腺癌、宫颈癌、前列腺癌、胶质瘤、黑色素瘤、胰腺癌、鼻咽癌、肺癌或胃癌；或者优选地，所述的肿瘤为对溶瘤病毒不敏感的肿瘤；
    更优选地，所述肿瘤为对溶瘤病毒不敏感的肝癌、结直肠癌、膀胱癌、乳腺癌、宫颈癌、前列腺癌、胶质瘤、黑色素瘤、胰腺癌、鼻咽癌、肺癌或胃癌。
PCT/CN2018/125014 2017-12-29 2018-12-28 Parp抑制剂和溶瘤病毒在制备抗肿瘤药物的应用 WO2019129233A1 (zh)

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