WO2024251278A1 - 一种用于治疗卵巢功能不全的药物 - Google Patents

一种用于治疗卵巢功能不全的药物 Download PDF

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WO2024251278A1
WO2024251278A1 PCT/CN2024/098236 CN2024098236W WO2024251278A1 WO 2024251278 A1 WO2024251278 A1 WO 2024251278A1 CN 2024098236 W CN2024098236 W CN 2024098236W WO 2024251278 A1 WO2024251278 A1 WO 2024251278A1
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annexin
ovarian
use according
granulosa cells
composition
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French (fr)
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张文杰
王雅慧
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Shanghai Seme Cell Technology Co Ltd
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Shanghai Seme Cell Technology Co Ltd
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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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0681—Cells of the genital tract; Non-germinal cells from gonads
    • C12N5/0682—Cells of the female genital tract, e.g. endometrium; Non-germinal cells from ovaries, e.g. ovarian follicle cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/998—Proteins not provided for elsewhere

Definitions

  • the invention belongs to the field of medicines, and in particular relates to a medicine for treating ovarian insufficiency.
  • Ovarian insufficiency refers to ovarian failure in normally developed women before the age of 40, which leads to premature amenorrhea due to reasons other than pregnancy, accompanied by decreased serum estrogen levels and increased gonadotropin levels. POI is one of the main causes affecting female fertility. In recent years, the incidence rate has increased year by year and tends to be younger. Its etiology is relatively complex. Advanced age, genetics, tumor radiotherapy and chemotherapy, immune disorders, metabolic diseases, etc. are closely related to the onset of the disease. At present, hormone replacement therapy is mainly used in clinical practice, but long-term use leads to an increase in the incidence of ovarian cancer, making the application of this therapy controversial. Therefore, there is no reliable therapeutic drug that can help POI patients restore ovarian function.
  • the object of the present invention is to provide the use of annexin in preparing a pharmaceutical composition for preventing and/or treating ovarian insufficiency.
  • the present invention provides the use of annexin in the preparation of a pharmaceutical composition for preventing and/or treating ovarian insufficiency.
  • the annexin includes annexin A5.
  • annexin A5 accounts for 80%, 85%, 90%, 95%, 98% or 99% of the annexin.
  • the use comprises one or more features selected from the following group:
  • the use comprises one or more features selected from the following group:
  • the causes of ovarian insufficiency are: great mental stress, irregular diet, staying up late, weight loss, chemotherapy, radiotherapy, gynecological inflammation, congenital ovarian incomplete development, or a combination thereof.
  • the cause of ovarian insufficiency is: insufficient estrogen secretion, insufficient progesterone secretion, increased gonadotropin level, reduction or apoptosis of ovarian granulosa cells, or a combination thereof.
  • the annexin is human annexin or non-human mammal annexin.
  • the non-human mammal includes pigs, monkeys, cows, sheep, rats, mice or rabbits.
  • composition further comprises a pharmaceutically acceptable carrier.
  • the dosage form of the composition is selected from the following group: liquid dosage form, solid dosage form.
  • the dosage form of the composition is selected from the following group: tablets, capsules, microcapsules, powder injections, oral liquids, and injections.
  • the present invention provides a pharmaceutical composition for treating ovarian insufficiency, characterized in that the composition comprises:
  • the annexin includes annexin A5.
  • annexin A5 accounts for 80%, 85%, 90%, 95%, 98% or 99% of the annexin.
  • the dosage form of the composition is selected from the following group: liquid dosage form, solid dosage form.
  • the dosage form of the composition is selected from the following group: tablets, capsules, microcapsules, powder injections, oral liquids, and injections.
  • the third aspect of the present invention provides a method for promoting the proliferation of ovarian granulosa cells and/or inhibiting the apoptosis of ovarian granulosa cells, comprising the steps of contacting and culturing ovarian granulosa cells with annexin, thereby promoting the proliferation of ovarian granulosa cells and/or inhibiting the apoptosis of ovarian granulosa cells.
  • the annexin includes annexin A5, preferably, annexin A5 accounts for 80%, 85%, 90%, 95%, 98% or 99% of the annexin.
  • the concentration of the annexin is 1 ng/mL-10 ⁇ g/mL, preferably, 100 ng/mL-1 ⁇ g/mL.
  • the method is non-diagnostic and non-therapeutic.
  • the present invention provides a method for treating premature ovarian failure, comprising the steps of administering annexin or a pharmaceutical composition comprising annexin as an active ingredient to a subject in need thereof.
  • the annexin includes annexin A5.
  • annexin A5 accounts for 80%, 85%, 90%, 95%, 98% or 99% of the annexin.
  • the subject is a human or a non-human mammal.
  • the non-human mammal includes pigs, cows, sheep, rats, mice or rabbits.
  • the subject is a subject with ovarian insufficiency.
  • the subject is a subject who has received, is receiving, or will receive treatment for ovarian insufficiency.
  • FIG1 shows the protective effect of Annexin A5 on the ovaries of POI mice.
  • the inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, provided a drug for treating ovarian insufficiency.
  • the inventors unexpectedly discovered for the first time that annexin can be used to prevent and/or treat ovarian insufficiency, especially has significant effects in regulating ovarian function-related hormones, promoting ovarian granulosa cell proliferation, and inhibiting ovarian granulosa cell apoptosis.
  • the present invention was completed on this basis.
  • the term “about” means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
  • the term “comprising” or “including (comprising)” may be open, semi-closed and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • room temperature or "normal temperature” refers to a temperature of 4-40°C, preferably, 25 ⁇ 5°C.
  • Annexins are a class of widely distributed calcium-dependent phospholipid-binding proteins. Based on molecular phylogenetics and comparative genomics analysis, this protein family is uniformly named annexin (abbreviated as Anx), followed by capital letters to represent different species: A, B, C, D, E represent vertebrates, invertebrates, fungi and slime molds, plants, and protists, respectively. So far, the Anx A family has 12 members: A1-A11 and A13 (A12 is unspecified).
  • the annexin typically includes annexin A5.
  • Annexin A5 (AnxA5) is widely distributed in various tissue cells of the body. In vitro studies have found that AnxA5 has multiple functions such as anti-phospholipase, anti-coagulation, and anti-kinase, but its specific in vivo function is not very clear.
  • the annexins that can be used in the present invention are not particularly limited, and can be annexins derived from any organism, preferably from mammals (such as primates), more preferably from humans, monkeys, rats or mice.
  • the annexins of the present invention can also be functional analogs thereof, such as proteins having 50%, 60%, 70%, 75% or more, such as 80%, 85% or more, 90% or more, or even more preferably 95% or 99% or more identity with human annexin; it should be understood that "annexin” includes wild-type or mutant (including truncated) annexins, as long as the mutant annexins retain or maintain the detoxification activity of wild-type annexins, they can also be used in the present invention.
  • the annexins can also be polymers of natural annexins, fusion proteins, or chemically modified variants thereof (such as PEG modification), provided that these variants have the activity of wild-type annexins.
  • the present invention provides the use of annexin in preparing a pharmaceutical composition for preventing and/or treating ovarian insufficiency, and has a significant effect in regulating hormones, promoting ovarian granulosa cell proliferation and/or inhibiting ovarian granulosa cell apoptosis.
  • ovarian insufficiency refers to ovarian failure in normally developed women before the age of 40, which leads to premature amenorrhea due to reasons other than pregnancy, accompanied by characteristics such as decreased serum estrogen levels and increased gonadotropin levels. It is usually manifested as symptoms of abnormal menstruation (such as frequent menstruation, oligomenorrhea, amenorrhea or early menopause) and anovulation (which may lead to infertility).
  • the causes of ovarian insufficiency are complex, and common causes include long-term mental stress, irregular diet, staying up late, gynecological inflammation, weight loss, radiotherapy and chemotherapy, and congenital incomplete ovarian development.
  • the development of follicles and ovulation depend on the highly coordinated development between ovarian granulosa cells and oocytes, and this highly coordinated development is mainly achieved through continuous, complex, and bidirectional signal exchange between the two cells.
  • the gap junctions between the cumulus granulosa cells and the oocytes are formed through microvilli.
  • the two cells complete the transmission of nutrients, primary metabolites and some information molecules through gap junctions, thereby promoting the growth and differentiation of the two cells, so that the two achieve highly coordinated development.
  • the oocyte cannot effectively use glucose to generate energy, and can only use the carboxylic acids produced by the metabolism of granulosa cells to produce the energy required for development through oxidative phosphorylation reactions.
  • ovarian granulosa cells are important supporting cells that promote egg growth, maturation and ovulation.
  • the experiments of the present invention also prove that the annexin can promote the proliferation of ovarian granulosa cells and/or inhibit the apoptosis of ovarian granulosa cells, thereby promoting the growth, maturation and ovulation of eggs and improving the quality of eggs.
  • prevention means a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease. "Prevention” as used herein also includes delaying the onset of a disease and/or its attendant symptoms and reducing the risk of a subject acquiring a disease.
  • the "treatment" of the present invention includes delaying and stopping the progression of the disease, or eliminating the disease, and does not require 100% inhibition, elimination, and reversal.
  • the acellular adipose extract of the present invention reduces, inhibits and/or reverses ovarian insufficiency, for example, by at least about 10%, at least about 30%, at least about 50%, or at least about 80%, compared to a cell-free adipose extract of a conventional adipose extract.
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned annexin as an active ingredient and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity.
  • Cosmetic here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Such carriers include (but are not limited to): saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof.
  • the dosage form of the drug should match the mode of administration.
  • compositions according to the present invention can be used for: parenteral, intravenous, intra-arterial, intraperitoneal, intramuscular or subcutaneous administration.
  • a sterile injectable solution can be prepared by merging the required amount of active ingredient in a suitable solvent with various other ingredients listed above (if necessary), and then sterilizing. It is best to use the above composition in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salt or glucose, to make the solution isotonic with blood. If necessary, the aqueous solution is appropriately buffered (preferably pH between 3-9).
  • Suitable pharmaceutical formulations can be easily prepared under aseptic conditions using standard pharmaceutical techniques well known to those skilled in the art.
  • the dosage of the active ingredient is a therapeutically effective amount, for example, about 10 micrograms/kg body weight-about 50 mg/kg body weight per day.
  • the active ingredient of the present invention can be used alone or together with one or more other drugs for diseases related to ovarian insufficiency, such as estrogen drugs, for example, progesterone, estradiol valerate, ethinyl estradiol, and the like.
  • estrogen drugs for example, progesterone, estradiol valerate, ethinyl estradiol, and the like.
  • the precise amount of active ingredient that provides a therapeutically effective amount to an individual will depend on the mode of administration, the type and severity of the disease and/or condition, and the characteristics of the individual, such as general health, age, sex, weight, and tolerance to drugs. One of ordinary skill in the art will be able to determine an appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, the "therapeutically effective amount" of any other therapeutic agent will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by one of ordinary skill in the art based on the individual's condition, the type of condition being treated, and the amount of the compound of the invention used by the following, for example, as reported in the literature and recommended in the Physician's Desk Reference (57th Edition, 2003).
  • the composition should be formulated so that an inhibitor dose of 0.01-100 mg/kg body weight/day can be administered to patients receiving these compositions.
  • the compositions of the present invention provide a dosage of 0.01 mg to 50 mg. In other embodiments, a dosage of 0.01 mg to 50 mg is provided. Dosage of 0.1mg-25mg or 5mg-40mg.
  • the present invention also provides a method for treating ovarian insufficiency, comprising the steps of: administering a pharmaceutical composition comprising annexin as an active ingredient to a subject in need thereof.
  • Examples of subjects to which the active ingredient of the present invention or a pharmaceutical composition comprising the same can be administered include mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).
  • annexin can be used to prevent and/or treat ovarian insufficiency.
  • annexin can regulate hormones related to ovarian function, promote the proliferation of ovarian granulosa cells, and inhibit the apoptosis of ovarian granulosa cells.
  • Annexin A5 extracted and purified from human adipose tissue, accession number: P08758:
  • mice Female C57 mice, 4-6 weeks old, were selected and set up in experimental and control groups, with 15 mice in the experimental group and 10 mice in the control group.
  • the experimental group received a single intraperitoneal injection of cyclophosphamide loading dose of 120 mg/kg combined with intradermal injection of busulfan 12 mg/kg, totaling 0.1 mL (with PBS as solvent) to establish the POI model; the control group was raised normally.
  • samples were collected from 5 mice in the experimental group, and hormones including AMH (anti-Muller test tube hormone), E2 (estradiol), FSH (follicle stimulating hormone) levels and ovarian histology were tested to determine that the ovarian insufficiency (POI) model was successfully established.
  • AMH anti-Muller test tube hormone
  • E2 estradiol
  • FSH follicle stimulating hormone
  • mice in the experimental group were treated with annexin A5.
  • concentration of annexin A5 was adjusted to 1 mg/ml for intraperitoneal injection, and the drug was administered twice a week, 0.1 ml each time.
  • the mice in the experimental group were killed on days 14 and 28 after treatment, and the ovaries of 5 mice were sampled. The same number of samples were collected from mice in the control group at the same time, and hormones including AMH, E2, FSH levels and ovarian histology were tested.
  • the experimental results showed that (1) the levels of E2 (estradiol) and AMH (anti-Mullerian hormone) in POI mice decreased significantly. Two weeks after intraperitoneal injection of annexin A5, the E2 hormone level increased significantly and remained stable until the four-week observation endpoint. The difference in hormone levels before and after injection of annexin A5 was statistically significant. (2) The experimental results also showed that the FSH (follicle-stimulating hormone) hormone level in mice with ovarian insufficiency caused by chemotherapy increased significantly. After intraperitoneal injection of annexin A5, the FSH value decreased significantly, and at the four-week observation endpoint, the value continued to decrease and gradually stabilized. The difference in hormone levels before and after injection of annexin A5 was statistically significant.
  • a cell suspension was prepared and 2000 cells/well were inoculated into a 96-well plate. Incubate in a 37°C incubator for 24 hours. The next day, treat the 96-well plate cells with different concentrations of annexin A5, with the concentrations set as: 0, 1, 10, 100, 1000 ng/ml, 4 replicates per group, and continue to culture for 72 hours. After 72 hours of drug incubation, take out the 96-well plate, add 10ul CCK8 solution to each well of cells, mix well, and incubate in a 37°C incubator for 1 hour, then use an ELISA reader to detect and calculate the proliferation capacity of each group of cells.
  • annexin A5 can significantly promote the proliferation of ovarian granulosa cells and inhibit the apoptosis of ovarian granulosa cells.

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Abstract

提供一种用于治疗卵巢功能不全的药物。具体涉及膜联蛋白在制备用于预防和/或治疗卵巢功能不全的药物组合物中的用途。

Description

一种用于治疗卵巢功能不全的药物 技术领域
本发明属于药物领域，具体涉及一种用于治疗卵巢功能不全的药物。
背景技术
卵巢功能不全(POI)是指正常发育女性在40周岁前发生卵巢功能衰竭，因妊娠以外的原因导致提前闭经，并伴有血清雌激素水平下降，促性腺激素水平上升等特征。POI是影响女性生育的主要原因之一，近年来发病率逐年上升并趋于年轻化，其病因较为复杂，高龄、遗传、肿瘤放化疗、免疫紊乱、代谢性疾病等都与发病密切相关。目前临床主要应用激素替代疗法，但长期应用导致卵巢癌患病率增加，使得该疗法的应用存在较大争议。因此，尚未有可靠的治疗药物可以帮助POI患者恢复卵巢功能。
因此，本领域需要开发一种有效治疗卵巢功能不全(POI)的药物。
发明内容
本发明的目的在于提供膜联蛋白在制备预防和/或治疗卵巢功能不全的药物组合物中的用途。
本发明第一方面，提供了膜联蛋白在制备用于预防和/或治疗卵巢功能不全的药物组合物中的应用。
在另一优选例中，所述的膜联蛋白包括膜联蛋白A5，较佳地，膜联蛋白A5占所述膜联蛋白的80％、85％、90％、95％、98％或99％。
在另一优选例中，所述用途包括选自下组的一个或多个特征：
(i)提高雌二醇(E2)水平；
(ii)提高抗缪勒氏管激素(AMH)水平；
(iii)降低抗卵泡刺激素(FSH)水平；和/或
(iv)降低卵泡刺激素与黄体生成素的比值(FSH/LH)。
在另一优选例中，所述用途包括选自下组的一个或多个特征：
(1)促进卵巢颗粒细胞增殖；
(2)抑制卵巢颗粒细胞凋亡；
(3)促进卵子生长、成熟和排卵正常化；和/或
(4)促进月经(周期、血量)正常化。
在另一优选例中，所述卵巢功能不全的原因为：精神压力大、饮食不规律、熬夜、减肥、化疗、放疗、妇科炎症、先天卵巢发育不完全，或其组合。
在另一优选例中，所述卵巢功能不全的原因为：雌激素分泌不足、孕激素分泌不足、促性腺激素水平上升、卵巢颗粒细胞减少或凋亡、或其组合。
在另一优选例中，所述的膜联蛋白为人膜联蛋白、或非人哺乳动物膜联蛋白。
在另一优选例中，所述非人哺乳动物包括猪、猴、牛、羊、大鼠、小鼠或兔。
在另一优选例中，所述组合物还包括药学上可接受的载体。
在另一优选例中，所述组合物的剂型选自下组：液体剂型、固体剂型。
在另一优选例中，所述组合物的剂型选自下组：片剂、胶囊、微囊、粉针、口服液、注射剂。
本发明第二方面，提供了一种用于治疗卵巢功能不全的药物组合物，其特征在于，所述组合物包括：
(a)膜联蛋白；
(b)另外的选自下组的药物：黄体酮、戊酸雌二醇、乙烯雌酚、或其组合；和
(c)药学上可接受的载体。
在另一优选例中，所述的膜联蛋白包括膜联蛋白A5，较佳地，膜联蛋白A5占所述膜联蛋白的80％、85％、90％、95％、98％或99％。
在另一优选例中，所述组合物的剂型选自下组：液体剂型、固体剂型。
在另一优选例中，所述组合物的剂型选自下组：片剂、胶囊、微囊、粉针、口服液、注射剂。
本发明第三方面，提供了一种促进卵巢颗粒细胞增殖和/或抑制卵巢颗粒细胞凋亡的方法，包括步骤：将膜联蛋白与卵巢颗粒细胞接触并培养，从而促进卵巢颗粒细胞增殖和/或抑制卵巢颗粒细胞凋亡。
在另一优选例中，所述的膜联蛋白包括膜联蛋白A5，较佳地，膜联蛋白 A5占所述膜联蛋白的80％、85％、90％、95％、98％或99％。
在另一优选例中，所述膜联蛋白的浓度为1ng/mL-10μg/mL，较佳地，100ng/mL-1μg/mL。
在另一优选例中，所述方法是非诊断非治疗的。
本发明第四方面，提供了一种治疗卵巢功能早衰的方法，包括步骤：给予有需要的对象膜联蛋白或包含膜联蛋白作为活性成分的药物组合物。
在另一优选例中，所述的膜联蛋白包括膜联蛋白A5，较佳地，膜联蛋白A5占所述膜联蛋白的80％、85％、90％、95％、98％或99％。
在另一优选例中，所述的对象为人、或非人哺乳动物。
在另一优选例中，所述非人哺乳动物包括猪、牛、羊、大鼠、小鼠或兔。
在另一优选例中，所述的对象为卵巢功能不全对象。
在另一优选例中，所述的对象为已经、正在、或将要接受卵巢功能不全治疗的对象。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了膜联蛋白A5对POI小鼠卵巢的保护作用。
具体实施方式
本发明人经过广泛而深入的研究，通过大量筛选和测试，提供了一种用于治疗卵巢功能不全的药物。本发明人首次意外地发现膜联蛋白能够用于预防和/或治疗卵巢功能不全，尤其是调节卵巢功能相关激素、促进卵巢颗粒细胞增殖和抑制卵巢颗粒细胞凋亡方面具有显著效果。在此基础上完成了本发明。
术语
除非另有定义，否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“室温”或“常温”是指温度为4-40℃，较佳地，25±5oC。
膜联蛋白
膜联蛋白是一类广泛分布的钙依赖性磷脂结合蛋白，基于分子系统发生学和比较基因组学分析，该蛋白家族被统一命名为annexin(缩写为Anx)，其后加上大写英文字母代表不同种属：A、B、C、D、E分别代表脊椎动物、无脊椎动物、真菌和粘菌虫类、植物、原生生物。截至目前，Anx A家族共有12个成员：A1-A11和A13(A12未指定)。
代表性地，所述的膜联蛋白包括膜联蛋白A5。膜联蛋白A5(AnxA5)广泛分布于机体的各种组织细胞中，体外研究发现，AnxA5具有抗磷脂酶、抗凝血、抗激酶等多种功能，但其具体的体内功能却不是很清楚。
可用于本发明的膜联蛋白并没有特别限制，可以是来源于任何生物体的膜联蛋白，优选来自于哺乳动物(如灵长类动物)，更佳地来源于人、猴、大鼠或小鼠。本发明的膜联蛋白还可以是其功能类似物，如与人膜联蛋白具有50％、60％、70％、75％以上，如80％、85％以上，90％以上，或甚至更优选95％或99％以上的同一性的蛋白质；应理解，“膜联蛋白”包括野生型或突变型(包括截断型)的膜联蛋白，只要该突变型膜联蛋白保留或保持了野生型膜联蛋白的解毒活性也可用于本发明。此外，膜联蛋白还可以是天然膜联蛋白的多聚体，融合蛋白，或其经化学修饰的变体(如PEG修饰)，前提是这些变体拥有野生型膜联蛋白的活性。
人源的膜联蛋白A5序列如下：

用途
本发明提供了膜联蛋白在制备用于预防和/或治疗卵巢功能不全的药物组合物中的用途。尤其是在调节激素、促进卵巢颗粒细胞增殖和/或抑制卵巢颗粒细胞凋亡方面具有显著效果。
本发明所用，卵巢功能不全(POI)是指正常发育女性在40周岁前发生卵巢功能衰竭，因妊娠以外的原因导致提前闭经，并伴有血清雌激素水平下降，促性腺激素水平上升等特征。通常表现为月经异常(如月经频发、月经稀发、闭经或更年期提前)以及不排卵(可能导致不孕症)的症状。卵巢功能不全原因复杂，常见原因包括长期精神压力大、饮食不规律、熬夜、妇科炎症、减肥、放化疗、先天卵巢发育不完全等。
卵巢颗粒细胞存在于雌性动物卵泡腔内，一般颗粒细胞可分为两大类，一类是包裹在卵母细胞周围的卵丘颗粒细胞，一类是排列在卵泡壁上的壁层颗粒细胞。包裹卵母细胞的卵丘颗粒细胞会在排卵前发生扩散，排卵后壁层颗粒细胞会发生黄体化形成粒黄体细胞，之后与膜细胞形成黄体，这一过程对维持妊娠至关重要。卵泡的发育及排卵依赖于卵巢颗粒细胞和卵母细胞之间的高度协调发育，而这种高度协调发育主要通过2种细胞之间持续、复杂、双向的信号交流完成。卵丘颗粒细胞与卵母细胞之间通过微绒毛形成缝隙连接，2种细胞通过缝隙连接完成营养物质、初级代谢产物和一些信息分子的传递，进而促进2种细胞的生长和分化，使两者达到高度协调发育。此外，卵母细胞无法有效利用葡萄糖产生能量，只能利用颗粒细胞代谢产生的羧酸进行氧化磷酸化反应产生发育所需的能量。总之，卵巢颗粒细胞是促进卵子生长、成熟以及排卵的重要支持细胞。本发明的实验还证明，所述膜联蛋白能够促进卵巢颗粒细胞增殖和/或抑制卵巢颗粒细胞凋亡，从而促进卵子生长、成熟以及排卵，提高卵子质量。
在本发明中，术语“预防”表示预防疾病和/或它的附随症状的发作或者保护对象免于获得疾病的方法。本文中使用的"预防"还包括延迟疾病和/或它的附随症状的发作和降低对象的得病的风险。
本发明所述的“治疗”包括延缓和终止疾病的进展，或消除疾病，并不需要100％抑制、消灭和逆转。在一些实施方案中，与不存在本发明所述的无细胞脂 肪提取物观相比，本发明所述无细胞脂肪提取物减轻、抑制和/或逆转了卵巢功能不全例如至少约10％、至少约30％、至少约50％、或至少约80％。
药物组合物
本发明还提供了一种药物组合物，其包含上述膜联蛋白作为活性成分，以及药学上可接受的载体。
术语“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低化合物的药效。这类载体包括(但并不限于)：盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物剂型应与给药方式相匹配。
根据本发明的组合物可以用于：胃肠外、静脉内、动脉内、腹膜内、肌内或皮下给药。可通过将合适溶剂中所需量的活性成分与如上所列举的各种其他成分(如果需要)合并，然后通过灭菌制得无菌可注射溶液。最好以无菌水溶液的形式使用上述组合物，所述无菌水溶液可含有其他物质，如足量的盐或葡萄糖，以使溶液与血液等渗。如果需要，将水溶液进行适当的缓冲(优选pH在3-9之间)。可利用本领域技术人员熟知的标准制药技术容易地在无菌条件下制备合适的药物配方。活性成分的给药量是治疗有效量，例如每天约10微克/千克体重-约50毫克/千克体重。
本发明的活性成分可以单独使用或与一种或多种其他用于卵巢功能不全的相关疾病的药物一起使用，如雌激素类药物，例如黄体酮、戊酸雌二醇、乙烯雌酚等。
向个体提供治疗有效量的活性成分的精确量将取决于给药方式、疾病和/或病症的类型和严重程度以及个体的特征，例如一般健康状况、年龄、性别、体重和对药物的耐受性。本领域普通技术人员将能够根据这些和其他因素确定合适的剂量。当与其他治疗剂组合施用时，任何其他治疗剂的“治疗有效量”将取决于所用药物的类型。合适的剂量对于批准的治疗剂是已知的，并且可以由本领域普通技术人员根据个体的状况、治疗的病症类型和通过以下使用的本发明化合物的量进行调整，例如，在文献中报道和在Physician’s Desk Reference(第57版，2003)中推荐的剂量。优选地，应如此配制组合物，使得可以将0.01-100mg/kg体重/天的抑制剂剂量施用给接受这些组合物的患者。在某些实施方案中，本发明的组合物提供了0.01mg至50mg的剂量。在其它实施方案中，提供了 0.lmg-25mg或5mg-40mg的剂量。
本发明还提供了一种治疗卵巢功能不全的方法，包括步骤：给予有需要的对象包含膜联蛋白作为活性成分的药物组合物。
本发明的活性成分或包含其的药物组合物的给药对象的实例包括哺乳动物(例如，人、小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴等)。
本发明的主要优点包括：
本发明人首次发现膜联蛋白能够用于预防和/或治疗卵巢功能不全。
本发明人首次发现膜联蛋白能够调节卵巢功能相关激素、促进卵巢颗粒细胞增殖以及抑制卵巢颗粒细胞凋亡。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
膜联蛋白A5：从人体脂肪组织提取和纯化获得，登录号Accession：P08758：
实施例1
1.动物实验内容
1.1模型制备
选择雌性C57小鼠，4-6周龄，设置实验组与对照组，实验组15只，对照组10只。实验组一次性腹腔注射环磷酰胺负荷剂量120mg/kg联合皮内注射白消安12mg/kg共0.1mL(以PBS为溶剂)，建立POI模型；对照组正常饲养。2周后对5只实验组小鼠进行取材，进行激素包括AMH(抗穆勒试管激素)、E2(雌二醇)、FSH(卵泡刺激素)水平、卵巢组织学的检测，确定卵巢功能不全(POI)模型建立成功。
1.2给药实验
确定建立POI小鼠模型成功后，给予实验组小鼠膜联蛋白A5治疗。调整膜联蛋白A5浓度为1mg/ml进行腹腔注射，每周给药2次，每次0.1ml。实验组小鼠于处理后14d、28d分别处死，取材5只小鼠卵巢，对照组小鼠于相同时间进行相同数量取材，进行激素包括AMH、E2、FSH水平、卵巢组织学的检测。
实验结果显示，(1)POI小鼠E2(雌二醇)、AMH(抗缪勒氏管激素)激素水平大幅下降，经腹腔注射膜联蛋白A5两周后，E2激素水平有明显提高，且稳定维持至观察时间的四周终末点。注射膜联蛋白A5前后的激素水平差异具有统计学意义。(2)实验结果还显示，化疗导致卵巢功能不全的小鼠FSH(促卵泡激素)激素水平大幅升高，经腹腔注射膜联蛋白A5后，FSH数值有明显下降，且在四周的观察终末点时数值持续下降并逐渐趋于稳定。注射膜联蛋白A5前后的激素水平差异具有统计学意义。
该结果证明，膜联蛋白A5对于POI小鼠E2、AMH激素水平具有明显的提升作用，对于FSH激素水平具有明显的降低作用，有利于卵巢功能的恢复(*P<0.05)，且这一点从卵巢组织学结果中能够得到确证，如图1所示，对照组(Control)卵巢组织结构基本正常，视野内可见完整的卵泡结构，卵母细胞结构清晰，胞质丰富，呈嗜酸性；颗粒细胞胞核圆润，数量丰富，排列整齐紧密，未见坏死；间质未见明显炎症细胞浸润；POI模型组(Model)卵巢组织结构轻至中度异常，视野可见卵泡内少量颗粒细胞坏死，细胞核固缩深染，细胞嗜碱性增强，如红色箭头所示；部分间质腺内细胞坏死，胞核碎裂、固缩深染，细胞嗜碱性增强，如蓝色箭头所示；间质未见明显炎症细胞浸润；黑色箭头表示闭锁卵泡；实验组(AnxA5)卵巢组织结构基本正常，视野内可见完整的卵泡结构，卵母细胞结构清晰，胞质丰富，呈嗜酸性；颗粒细胞胞核圆润，数量丰富，排列整齐紧密，未见坏死；间质腺内膜细胞体积增大，胞质内充满脂滴，结缔组织和血管分隔成细胞团索状，紫色箭头表示间质腺；间质未见明显炎症细胞浸润，可见膜联蛋白A5对于POI小鼠卵巢功能具有明显的保护作用。
实施例2
细胞实验
1.2实验细胞处理
人原代卵巢颗粒细胞(KGN)，购买于上海驭咖生物科技有限公司，用含10％胎牛血清及1％双抗的DMEM/F12培养基进行培养，待细胞密度达到90％时进行细胞传代。在培养基内加入250uM环磷酰胺(CTX)，对KGN细胞进行48h损伤诱导，对细胞活性进行检测。
1.3药物处理
2.2.1膜联蛋白A5对KGN-CTX增殖能力的影响：
待细胞消化后制成细胞悬液，以2000个/孔的细胞量接种于96孔板中，置 于37℃培养箱中培养24小时。次日，分别使用不同浓度的膜联蛋白A5处理96孔板细胞，浓度设置为：0、1、10、100、1000ng/ml，每组4个复孔，继续培养72h。药物孵育72h后，取出96孔板，在每孔细胞中加入10ul CCK8溶液，混匀后置于37℃培养箱中孵育1小时，随后使用酶标仪进行检测，并计算各组细胞的增殖能力。
2.2.2膜联蛋白A5对KGN-CTX抗凋亡能力的影响
使用TUNEL细胞凋亡检测试剂盒(碧云天)对正常KGN细胞、KGN-CTX细胞及经过不同浓度的膜联蛋白A5处理过的KGN-CTX细胞(浓度设置为：0、1、10、100、1000ng/m)l进行抗凋亡能力检测。按照厂家说明书，收集细胞与TUNEL检测溶液共同孵育，使细胞核被Hoechst 33342标记，通过荧光显微镜进行样本分析。
实验结果显示，膜联蛋白A5能够显著促进卵巢颗粒细胞增殖；并且抑制卵巢颗粒细胞凋亡。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 膜联蛋白在制备用于预防和/或治疗卵巢功能不全的药物组合物中的用途。
  2. 如权利要求1所述的用途，其特征在于，所述的膜联蛋白包括膜联蛋白A5，较佳地，膜联蛋白A5占所述膜联蛋白的80％、85％、90％、95％、98％或99％。
  3. 如权利要求1所述的用途，其特征在于，所述用途包括选自下组的一个或多个特征：
    (i)提高雌二醇(E2)水平；
    (ii)提高抗缪勒氏管激素(AMH)水平；
    (iii)降低抗卵泡刺激素(FSH)水平；和/或
    (iv)降低卵泡刺激素与黄体生成素的比值(FSH/LH)。
  4. 如权利要求1所述的用途，其特征在于，所述用途包括选自下组的一个或多个特征：
    (1)促进卵巢颗粒细胞增殖；
    (2)抑制卵巢颗粒细胞凋亡；
    (3)促进卵子生长、成熟和排卵正常化；和/或
    (4)促进月经(周期、血量)正常化。
  5. 如权利要求1所述的用途，其特征在于，所述卵巢功能不全的原因为：雌激素分泌不足、孕激素分泌不足、促性腺激素水平上升、卵巢颗粒细胞减少或凋亡、或其组合。
  6. 如权利要求1所述的用途，其特征在于，所述卵巢功能不全的原因为：精神压力大、饮食不规律、熬夜、减肥、化疗、放疗、妇科炎症、先天卵巢发育不完全，或其组合。
  7. 如权利要求1所述的用途，其特征在于，所述的膜联蛋白为人膜联蛋白、或非人哺乳动物膜联蛋白。
  8. 如权利要求7所述的用途，其特征在于，所述膜联蛋白为人膜联蛋白A5。
  9. 如权利要求1所述的用途，其特征在于，所述组合物还包括药学上可接受的载体。
  10. 如权利要求1所述的用途，其特征在于，所述组合物的剂型选自下组： 液体剂型、固体剂型。
  11. 如权利要求1所述的用途，其特征在于，所述组合物的剂型选自下组：片剂、胶囊、微囊、粉针、口服液、注射剂。
  12. 一种用于治疗卵巢功能不全的药物组合物，其特征在于，所述组合物包括：
    (a)膜联蛋白；
    (b)另外的选自下组的药物：黄体酮、戊酸雌二醇、乙烯雌酚、或其组合；和
    (c)药学上可接受的载体。
  13. 如权利要求12所述的药物组合物，其特征在于，所述的膜联蛋白包括膜联蛋白A5。
  14. 如权利要求12所述的药物组合物，其特征在于，所述组合物的剂型选自下组：片剂、胶囊、微囊、粉针、口服液、注射剂。
  15. 一种促进卵巢颗粒细胞增殖和/或抑制卵巢颗粒细胞凋亡的方法，包括步骤：将膜联蛋白与卵巢颗粒细胞接触并培养，从而促进卵巢颗粒细胞增殖和/或抑制卵巢颗粒细胞凋亡。
PCT/CN2024/098236 2023-06-08 2024-06-07 一种用于治疗卵巢功能不全的药物 Pending WO2024251278A1 (zh)

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