WO2021159547A1 - 一种预防和/或治疗卵巢癌的多肽药物及其用途 - Google Patents

一种预防和/或治疗卵巢癌的多肽药物及其用途 Download PDF

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WO2021159547A1
WO2021159547A1 PCT/CN2020/075601 CN2020075601W WO2021159547A1 WO 2021159547 A1 WO2021159547 A1 WO 2021159547A1 CN 2020075601 W CN2020075601 W CN 2020075601W WO 2021159547 A1 WO2021159547 A1 WO 2021159547A1
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leu
asp
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ser
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杨宝峰
刘宇
杜伟杰
王准
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珠海市藤栢医药有限公司
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Publication of WO2021159547A1 publication Critical patent/WO2021159547A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof

Definitions

  • the present invention relates to the field of medical biology, in particular to the use of a polypeptide in the preparation of drugs for preventing and/or treating ovarian cancer and a composition containing the polypeptide.
  • Ovarian cancer is the gynecological tumor with the highest fatality rate among women. Ovarian cancer is also known as the "silent killer" because of its invisibility and powerful "lethal power" at the initial stage of onset, which seriously threatens women's health. Globally, the incidence of ovarian cancer is 9.1 per 100,000 in developed countries and 5.0 per 100,000 in developing countries. It is estimated that there were 22,240 newly diagnosed ovarian cancer cases and 14,070 deaths from ovarian cancer in the United States in 2018. Ovarian cancer mostly occurs in perimenopausal women.
  • the treatment principle is platinum-based intravenous chemotherapy after cytoreductive surgery.
  • Tumor cytoreductive surgery and systemic chemotherapy with carboplatin combined with paclitaxel are the gold standard for first-line prevention and/or treatment of ovarian cancer.
  • the first-line chemotherapy regimen of carboplatin combined with paclitaxel is slightly different.
  • stage I Patients in stage I have 3-6 courses, while patients in stage II-IV have 6 courses directly, but the dosage is the same.
  • intraperitoneal chemotherapy (IP)/intravenous chemotherapy (IV) is recommended.
  • IP intraperitoneal chemotherapy
  • IV intravenous chemotherapy
  • the first-line anti-angiogenic drug bevacizumab can also be added.
  • anti-angiogenesis drugs or PARP inhibitors can be selected as maintenance therapy according to the specific situation.
  • biological therapy, targeted therapy, gene therapy and immunotherapy have been added.
  • polypeptide HYD-PEP06 composed of 30 amino acids has the following amino acid sequence:
  • Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro- Leu-Ser-Gly-Gly-Met shows the effect of inhibiting ovarian cancer.
  • the first aspect of the present invention relates to the use of a polypeptide in the preparation of a medicament for the prevention and/or treatment of ovarian cancer, and the amino acid sequence of the polypeptide is:
  • the second aspect of the present invention relates to a polypeptide for preventing and/or treating ovarian cancer, the amino acid sequence of the polypeptide is:
  • the third aspect of the present invention relates to a method for preventing and/or treating ovarian cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a polypeptide, the amino acid sequence of which is:
  • the fourth aspect of the present invention relates to a composition containing a polypeptide and excipients, the amino acid sequence of the polypeptide is:
  • composition is used for preventing and/or treating ovarian cancer.
  • HYD-PEP06 refers to a polypeptide having the following amino acid sequence:
  • prevention means that when used for a disease or condition (such as a tumor), the compound or drug can reduce the symptoms of a medical condition in the subject compared to a subject who has not been administered the compound or drug The frequency or delay of its onset.
  • treatment refers to alleviating, alleviating or ameliorating the symptoms of a disease or disorder (such as tumors), ameliorating the symptoms caused by potential metabolism, inhibiting the disease or symptoms, such as preventing the spread of the disease or disorder, alleviating the disease or A condition, causes the regression of a disease or condition, alleviates a condition caused by a disease or condition, or prevents the symptoms of a disease or condition.
  • metastasis includes ovarian cancer caused by tumor metastasis other than ovarian cancer, and metastasis from ovarian cancer to other organs and/or tissues of the body (the most common metastatic sites are the liver, pleura, Lung and bone) tumors.
  • the ways of metastasis include direct infiltration, blood metastasis, lymphatic metastasis and planting metastasis, among which lymphatic metastasis is the most common way of metastasis in ovarian cancer.
  • Tumors caused by ovarian cancer metastasis to other organs and/or tissues of the body include, but are not limited to: liver metastases from ovarian cancer, lung metastases from ovarian cancer, brain metastases from ovarian cancer, bone metastases from ovarian cancer, and ovarian cancer Lymphatic metastases, ovarian cancer and fallopian tube metastases.
  • tumor refers to a new organism formed by the proliferation of local tissue cells under the action of various tumor-causing factors, because this new organism is mostly a mass-occupying protrusion, also called a neoplasm. Tumors can be classified as benign tumors or malignant tumors. Malignant tumors can also be classified as cancer or sarcoma.
  • subject as used herein is meant to include humans (e.g., human patients) and animals (e.g., mice, rats, dogs, cats, rabbits, chickens, or monkeys, etc.).
  • animals e.g., mice, rats, dogs, cats, rabbits, chickens, or monkeys, etc.
  • the dosage is reasonably adjusted, and these adjusted technical solutions fall within the scope of the technical solution claimed by the present invention.
  • room temperature refers to 25°C ⁇ 1°C. At the same time, if the experiment temperature is not specified, it is room temperature.
  • the term "about” refers to ⁇ 10% of the value modified by the term, more preferably ⁇ 5%, and most preferably ⁇ 2%, so those of ordinary skill in the art can clearly refer to the modified value Determine the scope of the term "about”.
  • the first aspect of the present invention relates to the use of a polypeptide in the preparation of a medicament for the prevention and/or treatment of ovarian cancer, and the amino acid sequence of the polypeptide is:
  • the drug is in the form of a white or off-white loose mass or powder. Further, the drug should be diluted with a 5% dextrose solution (for example, 5% dextrose injection), but cannot be diluted with sodium chloride injection.
  • a 5% dextrose solution for example, 5% dextrose injection
  • the drug can be administered by intravenous injection.
  • the ovarian cancer is ovarian cancer in situ or metastatic ovarian cancer.
  • the drug is in the form of a unit dose.
  • the unit dose contains the following amount of the polypeptide: about 0.6 mg, about 3 mg, about 6 mg, about 15 mg, about 24 mg, about 48 mg, about 96 mg, about 120 mg, about 150 mg, about 300 mg, about 600 mg or The polypeptide within the range between the respective amounts, for example, 0.6mg-600mg, 0.6mg-300mg, 0.6mg-150mg, 0.6mg-120mg, 0.6mg-96mg, 0.6mg-48mg, 0.6mg-24mg, 0.6mg-15mg, 0.6mg-6mg, 0.6mg-3mg, 3mg-600mg, 3mg-300mg, 3mg-150mg, 3mg-120mg, 3mg-96mg, 3mg-48mg, 3mg-24mg, 3mg-15mg, 3mg-6mg , 6mg-600m
  • the second aspect of the present invention relates to a polypeptide for preventing and/or treating ovarian cancer
  • the amino acid sequence of the polypeptide is: Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg -Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met.
  • the polypeptide is in the form of a white or off-white loose mass or powder. Further, the polypeptide should be diluted with 5% glucose solution (for example, 5% glucose injection), and not diluted with sodium chloride injection.
  • the polypeptide can be administered by intravenous injection.
  • the ovarian cancer is ovarian cancer in situ or metastatic ovarian cancer.
  • the polypeptide is in the form of a unit dose.
  • the unit dose contains the following amount of the polypeptide: about 0.6 mg, about 3 mg, about 6 mg, about 15 mg, about 24 mg, about 48 mg, about 96 mg, about 120 mg, about 150 mg, about 300 mg, about 600 mg or The polypeptide within the range between the respective amounts, for example, 0.6mg-600mg, 0.6mg-300mg, 0.6mg-150mg, 0.6mg-120mg, 0.6mg-96mg, 0.6mg-48mg, 0.6mg-24mg, 0.6mg-15mg, 0.6mg-6mg, 0.6mg-3mg, 3mg-600mg, 3mg-300mg, 3mg-150mg, 3mg-120mg, 3mg-96mg, 3mg-48mg, 3mg-24mg, 3mg-15mg, 3mg-6mg , 6mg-
  • the third aspect of the present invention relates to a method for preventing and/or treating ovarian cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a polypeptide whose amino acid sequence is: Arg-Gly- Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser- Gly-Gly-Met.
  • the polypeptide is in the form of a white or off-white loose mass or powder. Further, the polypeptide should be diluted with 5% glucose solution (for example, 5% glucose injection), and not diluted with sodium chloride injection.
  • the polypeptide can be administered by intravenous injection.
  • the ovarian cancer is ovarian cancer in situ or metastatic ovarian cancer.
  • the daily administration amount of the polypeptide is about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.25 mg/kg, about 0.4 mg/kg, about 0.8 mg/kg, About 1.6 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 5 mg/kg, about 10 mg/kg, or the polypeptide in the range between each amount, for example, 0.01 mg/kg-10 mg/kg , 0.01mg/kg-5mg/kg, 0.01mg/kg-2.5mg/kg, 0.01mg/kg-2mg/kg, 0.01mg/kg-1.6mg/kg, 0.01mg/kg-0.8mg/kg, 0.01 mg/kg-0.4mg/kg, 0.01mg/kg-0.25mg/kg, 0.01mg/kg-0.1mg/kg, 0.01mg/kg-0.05mg/kg, 0.05mg/kg-10mg/kg, 0.05mg /kg-5mg/kg,
  • the polypeptide is administered once a day.
  • the polypeptide is administered for 1 week, 2 weeks, or 3 weeks as needed.
  • the fourth aspect of the present invention relates to a composition containing a polypeptide and excipients, the amino acid sequence of the polypeptide is: Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln -Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met, the composition is used for the prevention and/or treatment of ovarian cancer.
  • the composition is in the form of a white or off-white loose mass or powder. Further, the composition should be diluted with 5% dextrose solution (for example, 5% dextrose injection), and not diluted with sodium chloride injection.
  • 5% dextrose solution for example, 5% dextrose injection
  • the adjuvant is mannitol.
  • the ovarian cancer is ovarian cancer in situ or metastatic ovarian cancer.
  • the composition is in the form of a unit dose.
  • the unit dose contains the following amount of the polypeptide: about 0.6 mg, about 3 mg, about 6 mg, about 15 mg, about 24 mg, about 48 mg, about 96 mg, about 120 mg, about 150 mg, about 300 mg, about 600 mg or The polypeptide within the range between the respective amounts, for example, 0.6mg-600mg, 0.6mg-300mg, 0.6mg-150mg, 0.6mg-120mg, 0.6mg-96mg, 0.6mg-48mg, 0.6mg-24mg, 0.6mg-15mg, 0.6mg-6mg, 0.6mg-3mg, 3mg-600mg, 3mg-300mg, 3mg-150mg, 3mg-120mg, 3mg-96mg, 3mg-48mg, 3mg-24mg, 3mg-15mg, 3mg-6mg , 6mg-600m
  • Example 1 The effect of HYD-PEP06 on ovarian cancer in situ in BALB/c/Nu/Nu athymic nude mice
  • HYD-PEP06 its amino acid sequence is shown in SEQ ID NO.1 (Harbin Medical University Pharmaceutical Co., Ltd.).
  • Penicillin/streptomycin stock solution (Institute of Biomedical Engineering, Chinese Academy of Medical Sciences)
  • mice Female, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
  • the test animals were kept in sterile independent air-supply IVC cages, 5 in each cage.
  • the litter is corncob litter sterilized by 60 Co radiation, with a particle size of 4-6mm. They are fed with sterilized feed specially formulated for nude mice, and they can drink pure water freely.
  • the temperature in the animal laboratory is maintained at about 25°C, the relative humidity is maintained at 40-70%, and the daily light is 12 hours.
  • PekinElmer IVIS Spectrum CT imaging system, supporting anesthesia machine and Livingimage 4.5.1 software.
  • A2780 cells were infected with lentivirus containing pCDH-luc2-GFP plasmid. After 24 hours, change to fresh DMEM cell culture medium containing 10% special grade fetal bovine serum, and add antibiotic puromycine (final concentration 1ug/ml) to kill A2780 cells that do not express pCDH-luc2-GFP plasmid. After 7 days Culture, observe the expression of GFP in the cells under a fluorescence microscope, and use the PekinElmer IVIS Spectrum CT imaging system to detect the detection of cell bioluminescence.
  • Cells are cultured in DMEM cell culture medium containing 10% special grade fetal bovine serum, supplemented with penicillin/streptomycin stock solution, placed in a cell culture incubator at 37°C containing 5% CO 2 and the culture medium is replaced every 1-2 days . Digested with 0.25% trypsin for passage, centrifuged at 1000 r/min for 5 minutes, discarded the supernatant, and added fresh medium for passage culture.
  • Use a micro syringe to inject the prepared cell suspension into the right ovary.
  • Each nude mouse was injected with 10 ⁇ l of cell suspension, that is, 2 ⁇ 10 5 cells. Then put the ovaries back into the nude mice, and suture the back muscles and skin in turn with surgical sutures.
  • the IVIS Spectrum CT imaging system is used for detection.
  • the tested nude mice were pre-anaesthetized with 2% isoflurane.
  • the tested nude mice were put into the IVIS Spectrum CT testing room, and 0.5% isoflurane was used to maintain the anesthesia state of the nude mice.
  • Select the bioluminescence imaging mode to detect the luminescence signal in nude mice.
  • Statistical tests were performed with GraphPad Prism 5 software. The statistical analysis between groups was one-way ANOVA and Tukey's test for pairwise comparison, and the statistical analysis between groups at different time points was two-way ANOVA and Bonferroni test for pairwise comparison.
  • the tumor-bearing mice were subjected to IVIS Spectrum CT in vivo imaging, and the tumor-bearing mice were randomly grouped according to the luminous intensity in the analysis results of the software. Divided into model control group, HYD-PEP06 5mg/kg group, 10mg/kg group, 20mg/kg group, each group has 10 animals.
  • the test drug HYD-PEP06 was administered by intravenous injection, once a day, for 20 days.
  • an orthotopic ovarian cancer model was used to evaluate the pharmacodynamic characteristics of HYD-PEP06, and the tumor bioluminescence intensity was used to calculate the tumor doubling rate and drug treatment effect.
  • the tumor luminescence intensity of nude mice in the model control group increased by 61.68 times, while the test drug HYD-PEP06's 5mg/kg, 10mg
  • the luminous intensity of the tumor in the /kg and 20mg/kg treatment groups was significantly lower than that of the model control group, which only increased by 15.12 times, 10.75 times and 4.18 times, respectively, showing a significant dose-effect relationship (see Table 3) .
  • the tumor doubling rate of each treatment group of HYD-PEP06 was significantly reduced (P ⁇ 0.001).
  • the tumor inhibition rate was calculated using the bioluminescence intensity of tumor-bearing nude mice.
  • the tumor inhibition rates of the 5 mg/kg, 10 mg/kg and 20 mg/kg treatment groups of the test drug HYD-PEP06 were 70.0%, respectively , 78.9% and 92.3%, showing a significant dose-response relationship (see Table 1), and the tumor inhibition rates of the 5 mg/kg, 10 mg/kg and 20 mg/kg treatment groups of the test drug HYD-PEP06 changed over time Compared with the model control group, there are significant differences and a significant dose-effect relationship (see Table 2 and Table 3);
  • the tumor inhibition rate is calculated by the bioluminescence intensity of the isolated ovary, the test drug HYD -The tumor inhibition rates of the 5mg/kg, 10mg/kg and 20mg/kg treatment groups of PEP06 were 74.5%, 83.8% and 94.8%, respectively, which also showed a significant dose-effect relationship (see Table 1).
  • HYD-PEP06 can significantly inhibit tumor growth in nude mouse models of ovarian cancer, presenting an obvious dose-effect relationship, and does not show obvious toxic side effects at effective doses. Therefore, HYD-PEP06 can be used for the prevention and treatment of ovarian cancer.

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Abstract

本发明提供一种多肽、含有多肽的组合物及其在制备用于预防和/或治疗卵巢癌的药物中的用途，所述多肽的氨基酸序列为：Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。

Description

一种预防和/或治疗卵巢癌的多肽药物及其用途 技术领域
本发明涉及医药生物领域，特别涉及一种多肽在制备预防和/或治疗卵巢癌的药物中的用途以及含有该多肽的组合物。
背景技术
卵巢癌(ovarian cancer，OC)是女性病死率最高的妇科肿瘤，因其发病初期的隐匿性和强大的“杀伤力”，卵巢癌也被称为“沉默的杀手”，严重威胁妇女健康。在全球范围内，发达国家的卵巢癌发病率为9.1/10万，发展中国家为5.0/10万。据估计，2018年美国有22,240例新确诊的卵巢癌病例和14,070例卵巢癌死亡病例。卵巢癌多发于围绝经期的女性，因其解剖位置特殊，深藏于盆腔，患者早期症状不明显，导致70％的卵巢癌确诊时已是晚期；70％的患者生存率不足5年；对于治愈后的患者，仍有约70％会在3年内复发。目前，其治疗原则是肿瘤细胞减灭术后行以铂类为主的静脉化疗，肿瘤细胞减灭术及卡铂联合紫杉醇的系统化疗是一线预防和/或治疗卵巢癌的金标准。根据不同的临床分期，卡铂联合紫杉醇的一线化疗方案略有不同，I期患者是3-6个疗程，而Ⅱ～Ⅳ期的患者直接是6个疗程，但是用药剂量相同。此外针对满意减灭的Ⅱ～Ⅲ期卵巢癌患者，推荐腹腔化疗(IP)/静脉化疗(IV)方案。对于未达到满意的肿瘤细胞减灭术的患者，以及术前或术中发现有腹水的患者，一线也可加用抗血管生成药物贝伐珠单抗。一线化疗以后，可根据具体情况选择以抗血管生成药物或PARP抑制剂作为维持治疗。近些年，在手术、化疗基础上，再添生物治疗、靶向治疗、基因治疗以及免疫治疗等手段，虽然卵巢癌的治疗方式有了显著提高，但其生存率几乎没有改变，特别是化疗药物的使用中，带来多种副作用，具有很高的并发症的风险； 往往容易出现耐药现象，使得肿瘤细胞对化疗药物失去敏感性，药物疗效降低。
因此，寻找有效的预防和/或治疗卵巢癌的药物仍是非常迫切和必要的。
发明内容
本申请发明人在研究中发现由30个氨基酸组成的下述多肽HYD-PEP06，其氨基酸序列为：
Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met，显示出抑制卵巢癌的作用。
因此，本发明的第一方面涉及一种多肽在制备用于预防和/或治疗卵巢癌的药物中的用途，所述多肽的氨基酸序列为：
Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
本发明的第二方面涉及一种用于预防和/或治疗卵巢癌的多肽，所述多肽的氨基酸序列为：
Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
本发明的第三方面涉及一种预防和/或治疗卵巢癌的方法，所述方法包括对有此需要的受试者施用治疗有效量的多肽，所述多肽的氨基酸序列为：
Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
本发明的第四方面涉及一种含有多肽和辅料的组合物，所述多肽的氨基酸序列为：
Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met，所述组合物用于预防和/或治疗卵巢癌。
发明详述
在本文中使用的术语“HYD-PEP06”是指具有下述氨基酸序列的多肽：
Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met(请参见SEQ ID No.1)。申请号为201410658306.6的中国专利申请通过全文引用的方式并入本文作为参考。
在本文使用的术语“预防”是指当用于疾病或病症(例如肿瘤)时，与未施用化合物或药物的受试者相比，所述化合物或药物能降低受试者体内的医学病症症状的频率或推迟其发病。
在本文中使用的术语“治疗”是指减轻、缓解或改善疾病或病症的症状(例如肿瘤)，改善潜在的代谢引起的症状，抑制疾病或症状，例如阻止疾病或病症的房展、缓解疾病或病症、引起疾病或病症的消退、缓解疾病或病症引起的病况、或阻止疾病或病症的症状。
在本文中使用的术语“转移的卵巢癌”包括由除卵巢癌以外的肿瘤转移导致的卵巢癌，以及由卵巢癌转移至身体其它器官和/或组织(最常见的转移部位为肝脏、胸膜、肺及骨)导致的肿瘤。转移途径有直接浸润、血液转移、淋巴转移和种植转移，其中淋巴转移是卵巢癌中最常见的转移方式。由卵巢癌转移至身体其它器官和/或组织导致的肿瘤包括但不限于：卵巢癌的肝转移瘤、卵巢癌的肺转移瘤、卵巢癌的脑转移瘤、卵巢癌的骨骼转移瘤、卵巢癌的淋巴转移瘤、卵巢癌的输卵管转移瘤。
在本文中使用的术语“肿瘤”是指机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物，因为这种新生物多呈占位性块状突起，也称赘生物。肿瘤可分为良性肿瘤或恶性肿瘤。恶性肿瘤还可以分为癌症或肉瘤。
在本文中使用的术语“受试者”是指包括人类(例如，人类患者)和动物(例如，小鼠、大鼠、犬、猫、兔、鸡或猴等)。当受试者是人 类患者时(体重通常按60kg来计算)，除非另有说明，本发明所述的剂量可采用与实验动物的转换因子(例如，人用剂量＝小鼠剂量/12.3)进行换算得到(请参考Kin Tam.“Estimating the“First in human”dose-a revisit with particular emphasis on oncology drugs,ADMET&DMPK 1(4)(2013)63-75)。本领域的普通技术人员能够根据一般常识，根据受试者的具体体重、疾病的种类和严重程度以及其它因素对所述剂量进行合理调整，这些调整的技术方案均落入本发明要求保护的技术方案的范围之内。
如本文使用的术语“室温”是指25℃±1℃。同时，若没有具体指明实验温度，均为室温。
如本文使用的术语“约”是指该术语所修饰的数值的±10％，更优选为±5％，最优选为±2％，因此本领域的普通技术人员能够清楚地根据所修饰的数值确定术语“约”的范围。
本发明的第一方面涉及一种多肽在制备用于预防和/或治疗卵巢癌的药物中的用途，所述多肽的氨基酸序列为：
Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
在一些实施方案中，所述药物呈白色或类白色疏松块状物或粉末形式。进一步地，所述药物应使用5％葡萄糖溶液(例如，5％葡萄糖注射液)稀释，而不能使用氯化钠注射液稀释。
在一些实施方案中，所述药物可以通过静脉注射施用。
在一些实施方案中，所述卵巢癌是原位卵巢癌或转移的卵巢癌。
在一些实施方案中，所述药物呈单位剂量的形式。进一步地，所述单位剂量含有下述量的所述多肽：约0.6mg、约3mg、约6mg、约15mg、约24mg、约48mg、约96mg、约120mg、约150mg、约300mg、约600mg或所述各量之间范围内的所述多肽，例如，0.6mg-600mg、0.6mg-300mg、0.6mg-150mg、0.6mg-120mg、0.6mg-96mg、0.6mg-48mg、0.6mg-24mg、0.6mg-15mg、0.6mg-6mg、0.6mg-3mg、3mg-600mg、3mg-300mg、3mg-150mg、3mg-120mg、 3mg-96mg、3mg-48mg、3mg-24mg、3mg-15mg、3mg-6mg、6mg-600mg、6mg-300mg、6mg-150mg、6mg-120mg、6mg-96mg、6mg-48mg、6mg-24mg、6mg-15mg、15mg-600mg、15mg-300mg、15mg-150mg、15mg-120mg、15mg-96mg、15mg-48mg、15mg-24mg、24mg-600mg、24mg-300mg、24mg-150mg、24mg-120mg、24mg-96mg、24mg-48mg、48mg-600mg、48mg-300mg、48mg-150mg、48mg-120mg、48mg-96mg、96mg-600mg、96mg-300mg、96mg-150mg、96mg-120mg、120mg-600mg、120mg-300mg、120mg-150mg、150mg-600mg、150mg-300mg或300mg-600mg。
本发明的第二方面涉及一种用于预防和/或治疗卵巢癌的多肽，所述多肽的氨基酸序列为：Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
在一些实施方案中，所述多肽呈白色或类白色疏松块状物或粉末形式。进一步地，所述多肽应使用5％葡萄糖溶液(例如，5％葡萄糖注射液)稀释，不得使用氯化钠注射液稀释。
在一些实施方案中，所述多肽可以通过静脉注射施用。
在一些实施方案中，所述卵巢癌是原位卵巢癌或转移的卵巢癌。
在一些实施方案中，所述多肽呈单位剂量的形式。进一步地，所述单位剂量含有下述量的所述多肽：约0.6mg、约3mg、约6mg、约15mg、约24mg、约48mg、约96mg、约120mg、约150mg、约300mg、约600mg或所述各量之间范围内的所述多肽，例如，0.6mg-600mg、0.6mg-300mg、0.6mg-150mg、0.6mg-120mg、0.6mg-96mg、0.6mg-48mg、0.6mg-24mg、0.6mg-15mg、0.6mg-6mg、0.6mg-3mg、3mg-600mg、3mg-300mg、3mg-150mg、3mg-120mg、3mg-96mg、3mg-48mg、3mg-24mg、3mg-15mg、3mg-6mg、6mg-600mg、6mg-300mg、6mg-150mg、6mg-120mg、6mg-96mg、6mg-48mg、6mg-24mg、6mg-15mg、15mg-600mg、15mg-300mg、 15mg-150mg、15mg-120mg、15mg-96mg、15mg-48mg、15mg-24mg、24mg-600mg、24mg-300mg、24mg-150mg、24mg-120mg、24mg-96mg、24mg-48mg、48mg-600mg、48mg-300mg、48mg-150mg、48mg-120mg、48mg-96mg、96mg-600mg、96mg-300mg、96mg-150mg、96mg-120mg、120mg-600mg、120mg-300mg、120mg-150mg、150mg-600mg、150mg-300mg或300mg-600mg。
本发明的第三方面涉及一种预防和/或治疗卵巢癌的方法，所述方法包括对有此需要的受试者施用治疗有效量的多肽，所述多肽的氨基酸序列为：Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
在一些实施方案中，所述多肽呈白色或类白色疏松块状物或粉末形式。进一步地，所述多肽应使用5％葡萄糖溶液(例如，5％葡萄糖注射液)稀释，不得使用氯化钠注射液稀释。
在一些实施方案中，所述多肽可以通过静脉注射施用。
在一些实施方案中，所述卵巢癌是原位卵巢癌或转移的卵巢癌。
在一些实施方案中，所述多肽的每天施用量为约0.01mg/kg、约0.05mg/kg、约0.1mg/kg、约0.25mg/kg、约0.4mg/kg、约0.8mg/kg、约1.6mg/kg、约2mg/kg、约2.5mg/kg、约5mg/kg、约10mg/kg或所述各量之间范围内的所述多肽，例如，0.01mg/kg-10mg/kg、0.01mg/kg-5mg/kg、0.01mg/kg-2.5mg/kg、0.01mg/kg-2mg/kg、0.01mg/kg-1.6mg/kg、0.01mg/kg-0.8mg/kg、0.01mg/kg-0.4mg/kg、0.01mg/kg-0.25mg/kg、0.01mg/kg-0.1mg/kg、0.01mg/kg-0.05mg/kg、0.05mg/kg-10mg/kg、0.05mg/kg-5mg/kg、0.05mg/kg-2.5mg/kg、0.05mg/kg-2mg/kg、0.05mg/kg-1.6mg/kg、0.05mg/kg-0.8mg/kg、0.05mg/kg-0.4mg/kg、0.05mg/kg-0.25mg/kg、0.05mg/kg-0.1mg/kg、0.1mg/kg-10mg/kg、0.1mg/kg-5mg/kg、0.1mg/kg-2.5mg/kg、0.1mg/kg-2mg/kg、0.1mg/kg-1.6mg/kg、0.1mg/kg-0.8mg/kg、 0.1mg/kg-0.4mg/kg、0.1mg/kg-0.25mg/kg、0.25mg/kg-10mg/kg、0.25mg/kg-5mg/kg、0.25mg/kg-2.5mg/kg、0.25mg/kg-2mg/kg、0.25mg/kg-1.6mg/kg、0.25mg/kg-0.8mg/kg、0.25mg/kg-0.4mg/kg、0.4mg/kg-10mg/kg、0.4mg/kg-5mg/kg、0.4mg/kg-2.5mg/kg、0.4mg/kg-2mg/kg、0.4mg/kg-1.6mg/kg、0.4mg/kg-0.8mg/kg、0.8mg/kg-10mg/kg、0.8mg/kg-5mg/kg、0.8mg/kg-2.5mg/kg、0.8mg/kg-2mg/kg、0.8mg/kg-1.6mg/kg、1.6mg/kg-10mg/kg、1.6mg/kg-5mg/kg、1.6mg/kg-2.5mg/kg、1.6mg/kg-2mg/kg、2mg/kg-10mg/kg、2mg/kg-5mg/kg、2mg/kg-2.5mg/kg、2.5mg/kg-10mg/kg、2.5mg/kg-5mg/kg或5mg/kg-10mg/kg。
在一些实施方案中，将所述多肽每天施用1次。
在一些实施方案中，根据需要将所述多肽施用1周、2周或3周。
本发明的第四方面涉及含有多肽和辅料的组合物，所述多肽的氨基酸序列为：Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met，所述组合物用于预防和/或治疗卵巢癌。
在一些实施方案中，所述组合物呈白色或类白色疏松块状物或粉末形式。进一步地，所述组合物应使用5％葡萄糖溶液(例如，5％葡萄糖注射液)稀释，不得使用氯化钠注射液稀释。
在一些实施方案中，所述辅料是甘露醇。
在一些实施方案中，所述卵巢癌是原位卵巢癌或转移的卵巢癌。
在一些实施方案中，所述组合物呈单位剂量的形式。进一步地，所述单位剂量含有下述量的所述多肽：约0.6mg、约3mg、约6mg、约15mg、约24mg、约48mg、约96mg、约120mg、约150mg、约300mg、约600mg或所述各量之间范围内的所述多肽，例如，0.6mg-600mg、0.6mg-300mg、0.6mg-150mg、0.6mg-120mg、0.6mg-96mg、0.6mg-48mg、0.6mg-24mg、0.6mg-15mg、0.6mg-6mg、0.6mg-3mg、3mg-600mg、3mg-300mg、3mg-150mg、3mg-120mg、 3mg-96mg、3mg-48mg、3mg-24mg、3mg-15mg、3mg-6mg、6mg-600mg、6mg-300mg、6mg-150mg、6mg-120mg、6mg-96mg、6mg-48mg、6mg-24mg、6mg-15mg、15mg-600mg、15mg-300mg、15mg-150mg、15mg-120mg、15mg-96mg、15mg-48mg、15mg-24mg、24mg-600mg、24mg-300mg、24mg-150mg、24mg-120mg、24mg-96mg、24mg-48mg、48mg-600mg、48mg-300mg、48mg-150mg、48mg-120mg、48mg-96mg、96mg-600mg、96mg-300mg、96mg-150mg、96mg-120mg、120mg-600mg、120mg-300mg、120mg-150mg、150mg-600mg、150mg-300mg或300mg-600mg。
具体实施方式
下面通过实施例进一步说明本发明，但是，应当理解为，下述实施例仅仅是用于更详细具体地说明之用，而不应理解为用于以任何形式限制本发明。
实施例1 HYD-PEP06对BALB/c/Nu/Nu无胸腺裸鼠原位卵巢癌的影响
一、实验材料以及实验方法
(一)实验材料
1.实验试剂
HYD-PEP06，其氨基酸序列如SEQ ID NO.1所示(哈尔滨医大药业有限公司)。
氯化钠注射液(石家庄四药有限公司)
5％葡萄糖注射液(四川科伦药业股份有限公司)
氯胺酮(福建古田药业有限公司)
甲苯噻嗪(Sigma-Aldrich公司，美国)
萤火虫荧光素酶底物Luciferin(珀金埃尔默仪器有限公司)
胎牛血清(北京元亨圣马生物技术研究所)
DMEM(Gibco公司，美国)
抗生素puromycine(Invivogen公司，美国)
青霉素/链霉素原液(中国医学科学院生物医学工程研究所)
胰酶(中国医学科学院生物医学工程研究所)
2.肿瘤细胞株
人卵巢癌细胞株A2780，中国医学科学院协和药物研究所李燕教授实验室惠赠。
3.实验动物及饲养条件
成年BALB/c/Nu/Nu无胸腺裸鼠(小鼠)，17～21g，雌性，购自北京维通利华实验动物技术有限公司。受试动物饲养于无菌的独立送风IVC笼中，每笼5只。垫料为 60Co辐射消毒的玉米芯垫料，粒径4-6mm。饲以专门为裸鼠配制的消毒饲料，自由饮用纯净水。动物实验室内温度保持在25℃左右，相对湿度保持在40-70％，每日光照12小时。
4.实验仪器设备
PekinElmer IVIS Spectrum CT成像系统、配套麻醉机及Living image 4.5.1软件。
(二)实验模型的建立
1.稳定表达萤火虫荧光素酶(luc2)的A2780细胞的建立
用包含pCDH-luc2-GFP质粒的慢病毒感染A2780细胞。24小时后，换新鲜的含10％特级胎牛血清的DMEM细胞培养液，并加入抗生素puromycine(终浓度1ug/ml)，杀死没有表达pCDH-luc2-GFP质粒的A2780细胞，经过7天的培养，在荧光显微镜下观察细胞GFP的表达，并用PekinElmer IVIS Spectrum CT成像系统检测细胞生物发光的检测。
2.细胞培养：
细胞培养于含10％特级胎牛血清的DMEM细胞培养液中,并补充青霉素/链霉素原液，置于37℃含5％CO 2的细胞培养箱中，每1-2天更换培养液一次。用0.25％胰酶消化传代，1000r/min离心5分钟后，弃上清液，加入新鲜培养基传代培养。
3.原位卵巢癌模型的建立：
将对数生长期的A2780-luc2-GFP细胞用胰酶消化收集，并用PBS洗涤重悬，再按PBS:Metrigel＝2:1的比例，加入Metrigel，使细胞终浓度达到2×10 7个细胞/ml混悬液。将待手术造模的BALB/c/Nu/Nu无胸腺裸鼠用麻醉剂(10ml/kg)麻醉后，固定在手术台上，消毒背部皮肤，覆盖手术洞巾，在背部右下侧剪开约1cm切口，暴露右侧卵巢。用微量注射器将准备好的细胞悬液，注射到右侧卵巢内。每只裸鼠注射10μl细胞悬液，即2×10 5个细胞。然后将卵巢放回裸鼠体内，用手术缝合针线依次缝合背部肌肉和皮肤。
4.BALB/c/Nu/Nu无胸腺裸鼠原位卵巢癌生物发光的检测：
在各个检测时间点，使用IVIS Spectrum CT成像系统进行检测。在麻醉机内，用2％异氟烷对受试裸鼠进行预麻醉。将受试裸鼠放入IVIS Spectrum CT检测室内，并用0.5％异氟烷维持裸鼠的麻醉状态。选择生物发光成像模式，检测裸鼠体内发光信号。利用IVIS Spectrum CT系统配套的Living image 4.5.1软件对检测信号进行定量。
(三)数据处理
数据用平均值±SEM表示；肿瘤生长的发光强度抑制率＝(模型对照组发光强度－给药组发光强度)/模型对照组发光强度×100％。用GraphPad Prism 5软件进行统计检验，各组间统计分析为单因素ANOVA及两两比较的Tukey’s检验，结合不同时间点的各组间统计分析为双因素ANOVA及两两比较的Bonferroni检验。
(四)实验分组及治疗方案
手术造模6天后，将荷瘤鼠进行IVIS Spectrum CT活体成像，根据软件分析结果中的发光强度对荷瘤鼠进行随机分组。分为模型对照组、HYD-PEP06的5mg/kg组、10mg/kg组、20mg/kg组，每组10只动物。受试药HYD-PEP06为静脉注射给药，1次/日，给药持续20天。
每天观察动物存活状况。从实验分组的第1天(即手术造模6天后)、第10天以及第20天进行三次活体成像发光检测；依据动物存活及身体状况，调整活体成像发光检测的时间。实验结束后(第20天)颈部脱臼 处死动物，剥离取出卵巢进行离体生物发光成像，保存于4％甲醛溶液中，以备常规病理学检测。
二、实验结果
本研究利用原位卵巢癌模型评价HYD-PEP06的药效学特点，采用肿瘤生物发光强度来计算肿瘤倍增速率和药物治疗效果。与实验分组时(第1天)肿瘤发光强度相比，20天后(第20天)，模型对照组裸鼠的肿瘤发光强度增长了61.68倍，而受试药HYD-PEP06的5mg/kg、10mg/kg和20mg/kg治疗组的肿瘤发光强度显著低于模型对照组的肿瘤发光强度，分别仅增长了15.12倍、10.75倍和4.18倍，呈现出明显的剂量-效应关系(请参见表3)。HYD-PEP06各治疗组的肿瘤倍增速率，与模型对照组相比均显著降低(P<0.001)。
实验结束时，(1)用荷瘤裸鼠的活体生物发光强度计算抑瘤率，受试药HYD-PEP06的5mg/kg、10mg/kg和20mg/kg治疗组的抑瘤率分别为70.0％、78.9％和92.3％，呈现出明显的剂量-效应关系(请参见表1)，且随时间变化受试药HYD-PEP06的5mg/kg、10mg/kg和20mg/kg治疗组的抑瘤率与模型对照组相比均具有显著差异，且呈现出明显的剂量-效应关系(请参见表2和表3)；(2)用离体卵巢生物发光强度来计算抑瘤率，受试药HYD-PEP06的5mg/kg、10mg/kg和20mg/kg治疗组的抑瘤率分别为74.5％、83.8％和94.8％，同样呈现出明显的剂量-效应关系(请参见表1)。与模型对照组相比，各组荷瘤裸鼠的体重(请参见表4)未见明显差异。
三、小结
总之，HYD-PEP06可以显著抑制卵巢癌裸鼠模型中的肿瘤生长，呈现出明显的剂量-效应关系，且在有效剂量下并未显示出明显毒副作用。因此，HYD-PEP06可以用于卵巢癌的预防和治疗。
Figure PCTCN2020075601-appb-000001
表2各组荷瘤裸鼠生物发光信号强度绝对值随时间变化统计表
Figure PCTCN2020075601-appb-000002
与模型对照组相比，*P<0.05,**P<0.01,***P<0.001；
双因素ANOVA及两两比较的Bonferroni检验
表3各组荷瘤裸鼠生物发光信号强度增长倍数随时间变化统计表
Figure PCTCN2020075601-appb-000003
与模型对照组相比，*P<0.05,**P<0.01,***P<0.001；
双因素ANOVA及两两比较的Bonferroni检验
表4各组荷瘤裸鼠体重随时间变化统计表
Figure PCTCN2020075601-appb-000004

Claims (9)

  1. 一种多肽在制备用于预防和/或治疗卵巢癌的药物中的用途，所述多肽的氨基酸序列为：
    Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
  2. 根据权利要求1的用途，所述药物呈白色或类白色疏松块状物或粉末形式。
  3. 根据权利要求1-2中任一项的用途，其中所述卵巢癌是原位卵巢癌或转移的卵巢癌。
  4. 一种用于预防和/或治疗卵巢癌的多肽，所述多肽的氨基酸序列为：
    Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
  5. 一种预防和/或治疗卵巢癌的方法，所述方法包括对有此需要的受试者施用治疗有效量的多肽，所述多肽的氨基酸序列为：
    Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-Leu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met。
  6. 根据权利要求5的所述方法，其中所述多肽的每天施用量为0.1mg/kg-10mg/kg。
  7. 一种含有多肽和辅料的组合物，所述多肽的氨基酸序列为：
    Arg-Gly-Asp-Arg-Gly-Asp-Met-His-Ser-His-Arg-Asp-Phe-Gln-Pro-Val-L eu-His-Leu-Val-Ala-Leu-Asn-Ser-Pro-Leu-Ser-Gly-Gly-Met，所述组合物用于预防和/或治疗卵巢癌。
  8. 根据权利要求7的组合物，所述组合物呈白色或类白色疏松块状物或粉末形式。
  9. 根据权利要求7-8中任一项的组合物，所述辅料是甘露醇。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104530199A (zh) * 2014-11-18 2015-04-22 哈尔滨医科大学 一种抗肿瘤多肽及其制备方法和应用
CN107245103A (zh) * 2016-12-30 2017-10-13 广西壮族自治区药用植物园 抗肿瘤重组蛋白ifti及其编码基因与应用
CN107778362A (zh) * 2017-11-22 2018-03-09 哈尔滨医科大学 一种用于抑制口腔鳞状细胞癌迁移和侵袭能力的多肽及其用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1247609C (zh) * 2002-06-05 2006-03-29 中国人民解放军军事医学科学院野战输血研究所 一种卵巢癌相关基因及其编码的蛋白质

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104530199A (zh) * 2014-11-18 2015-04-22 哈尔滨医科大学 一种抗肿瘤多肽及其制备方法和应用
CN107245103A (zh) * 2016-12-30 2017-10-13 广西壮族自治区药用植物园 抗肿瘤重组蛋白ifti及其编码基因与应用
CN107778362A (zh) * 2017-11-22 2018-03-09 哈尔滨医科大学 一种用于抑制口腔鳞状细胞癌迁移和侵袭能力的多肽及其用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DONG XIAONA, YIWEI ZHANG, ZHIYUN MENG, XIAOXIA ZHU, HUI GAN, RUOLAN GU, ZHUONA WU, JIAN LI, YING ZHENG, BAOFENG YANG, GUIFANG DOU: "A LC-MS/MS Method to Monitor the Concentration of HYD-PEP06, a RGDmodified Endostar Mimetic Peptide in Rat Blood", JOURNAL OF CHROMATOGRAPHY B, vol. 1092, 29 May 2018 (2018-05-29), pages 296 - 305, XP055834950, DOI: 10.1016/j.jchromb.2018.05.042 *
KONG HAIHONG ·, JIN ZHIJUN, YANG YUNFANG: "Advances in the Study of Tumor Angiogenesis in Ovarian Cancer", CHINESE JOURNAL OF OBSTETRICS AND GYNECOLOGY, vol. 36, no. 2, 1 February 2001 (2001-02-01), pages 126 - 128, XP055835326 *
ZHANG YIWEI: "The Preclinical Pharmacokinetics Study of Steroid EAD and Peptide HYD-PEP06", CHINESE MASTER’S THESES FULL-TEXT DATABASE (MEDICINE AND HEALTH SCIENCES), 15 August 2019 (2019-08-15), XP055835320 *
赖军明，等 (LAI, JUNMING ET AL.): "重组人血管内皮抑制素在女性恶性肿瘤治疗中的临床应用 ( Application of Recombinant Human Endostatin in Treatment of Female Malignant Tumors)", 实用临床医学 (PRACTICAL CLINICAL MEDICINE), vol. 18, no. 11, 31 December 2017 (2017-12-31) *

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