WO2020228743A1 - Combinaison de cellules souches et de cytokines et son utilisation pour améliorer la motilité des spermatozoïdes - Google Patents

Combinaison de cellules souches et de cytokines et son utilisation pour améliorer la motilité des spermatozoïdes Download PDF

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Publication number
WO2020228743A1
WO2020228743A1 PCT/CN2020/090050 CN2020090050W WO2020228743A1 WO 2020228743 A1 WO2020228743 A1 WO 2020228743A1 CN 2020090050 W CN2020090050 W CN 2020090050W WO 2020228743 A1 WO2020228743 A1 WO 2020228743A1
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stem cells
pharmaceutical composition
adult stem
content
kit
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PCT/CN2020/090050
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English (en)
Chinese (zh)
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芦福建
刘玫
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美亚宜彬生物科技(北京)有限公司
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Publication of WO2020228743A1 publication Critical patent/WO2020228743A1/fr

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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
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/195—Chemokines, e.g. RANTES
    • 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

Definitions

  • the invention belongs to the field of biopharmaceuticals, and specifically relates to the use of a combination of stem cells and cytokines in improving sperm motility.
  • hematopoietic stem cells from the collected peripheral blood have been used for intravenous infusion.
  • This convenient and safe transplantation method can be used as a substitute for bone marrow transplantation.
  • Stem cell transplantation technology has been applied to some indications alone or in combination with other treatment methods (such as chemotherapy).
  • Stem cells are widely used because when they are administered to a subject, they can regenerate one or more tissue-specific cells in the subject.
  • stem cell transplants use stem cells provided by matched donors (allogeneic).
  • allogeneic transplantation has many disadvantages, such as immune rejection and graft-versus-host disease.
  • the economic cost of allotransplantation is also high.
  • autologous transplantation is that autologous cells (including peripheral blood stem cells) are reintroduced into the subject, thereby reducing the risk of rejection by the immune system.
  • Stem cells from a foreign body may cause transplant rejection and have the risk of so-called graft-versus-host disease, that is, the transplanted cells attack the cells in the recipient's body. This risk can usually only be suppressed by immunosuppressive drugs.
  • Sources of stem cells usually include embryonic stem cells, stem cells collected from cord blood, and adult stem cells.
  • embryonic stem cells although they are relatively easy to grow in culture, these cells are rarely found in adult tissues and the method to expand their numbers in cell culture is not mature, and their cell sources cannot match the needs of stem cell transplantation therapy. The actual demand for a large number of cells.
  • allogeneic embryonic stem cells are transplanted into the subject, it will increase the risk of transplant rejection.
  • stem cells collected from cord blood can be used for some treatments, but their cells are immature and the number of cells is small.
  • the current clinical application requires HLA matching and culture amplification technology.
  • Adult stem cells or somatic stem cells are undifferentiated cells found among differentiated cells in tissues or organs.
  • Adult stem cells can self-renew and can differentiate to produce the main specific cell types of the tissue or organ.
  • the main function of adult stem cells is to maintain and repair the tissues they are in.
  • Adult stem cells are a source of stem cell autologous transplantation, which can minimize the risk of transplant rejection. Using the subject's own adult stem cells will mean that the cells will not be rejected by the immune system. This advantage is unmatched by allograft. Therefore, the use of autologous transfer of adult stem cells has important practical significance.
  • stem cell components in peripheral blood after mobilization injection such as hematopoietic stem cells, circulating fibroblasts, vascular endothelial progenitor cells, and mesenchymal stem cells.
  • stem cell components such as hematopoietic stem cells, circulating fibroblasts, vascular endothelial progenitor cells, and mesenchymal stem cells.
  • stem cells Compared with adult stem cells from other parts of the body, their biggest advantages are that they are convenient to obtain materials, the large number of cells causes less pain to patients, and there are no viral infections and immune rejections. They are ideal sources of stem cells.
  • CN107693624A discloses a Chinese medicinal composition for clinical treatment of idiopathic asthenospermia and male infertility, which comprises rehmannia glutinosa, dodder seed, astragalus, epimedium, salvia, achyranthes bidentata, leeches, spatholobi and Passepartout.
  • CN105395841A discloses a medicinal combination for treating oligoasthenospermia and its preparation method; its raw materials include 20-50 parts by weight, 15-30 parts of curculio, 15-30 parts of myrtle, and 10 parts by weight. ⁇ 30 parts, 10 ⁇ 30 parts of Cistanche, 15 ⁇ 50 parts of Chinese Yam, 15 ⁇ 40 parts of Rehmannia vulgaris, 10 ⁇ 30 parts of Ligustrum lucidum, 10-30 parts of Leek Seed, 10-30 parts of Xianling Spleen, 15-30 parts of Licorice . Its dosage form is decoction.
  • the preparation process includes: weighing the above-mentioned raw medicinal materials in parts by weight, and soaking in water; first frying: decocting on a fire until boiling, then decocting on a slow fire for 20-25 minutes, second frying: after the first frying, filtering the concoction Add water again, decocting until boiling, change to slow decocting for 15-20 minutes. Combine the first decoction and the second decoction to obtain the mixture. The mixture is preserved as a decoction.
  • WO2011048806A1 discloses a medicament for improving sperm motility and fertility, which contains gamma-linolenic acid.
  • this agent When this agent is administered to a male and the female is inseminated with semen from the male, the female's fertility can be improved.
  • the agent can improve the sperm motility of males, and can improve the fertility of females inseminated by male semen.
  • this program is mainly used to improve the fertility status of domestic animals. Whether it is applicable to humans is still unknown.
  • the inventors of the present invention have conducted a large number of persistent screenings and found that the combination of adult stem cells (preferably autologous peripheral blood stem cells) and specific cytokines has significant effects on improving sperm motility. The effect, and then provides a new therapy or means for the treatment of low sperm motility.
  • the inventors of the present invention provide a pharmaceutical composition or kit for improving hypospermia in a subject, and adult stem cells and cytokines are prepared for improving hypospermia in a subject.
  • the pharmaceutical composition or kit of the present invention has a significant therapeutic or improvement effect on asthenospermia or low sperm motility, and has small side effects and no immune rejection reaction.
  • the first aspect of the present invention provides a pharmaceutical composition or kit for improving hypospermia in a subject, which comprises adult stem cells and selected from monocyte chemotactic protein-1 (MCP-1) , Glial cell-derived neurotrophic factor (GDNF) and osteoprotegerin (OPG) one, two or three cytokines, and optionally a pharmaceutically acceptable carrier.
  • MCP-1 monocyte chemotactic protein-1
  • GDNF Glial cell-derived neurotrophic factor
  • OPG osteoprotegerin
  • the cytokine can be selected from monocyte chemotactic protein-1 (MCP-1), glial cell-derived neurotrophic factor (GDNF) and osteoprotegerin (OPG)
  • MCP-1 monocyte chemotactic protein-1
  • GDNF glial cell-derived neurotrophic factor
  • OPG osteoprotegerin
  • the cytokine can be selected from any one of the following substances or combinations: MCP-1, a combination of GDNF and OPG, a combination of MCP-1 and GDNF, a combination of GDNF and OPG, The combination of MCP-1 and OPG, MCP-1, GDNF, OPG.
  • the pharmaceutical composition or kit contains adult stem cells, MCP-1 and GDNF.
  • the dosage of the pharmaceutical composition or kit of this specific embodiment includes: relative to 1 kg of body weight, the content of the adult stem cells is 10 6 -10 8 and the content of the MCP-1 is 0.01-10 mg.
  • the content of GDNF is 0.01-10 mg.
  • the dosage of the pharmaceutical composition or kit of this specific embodiment includes: relative to 1 kg of body weight, the content of the adult stem cells is 10 6 -10 8 and the content of the MCP-1 is 0.02-5 mg, The content of the GDNF is 0.02-5 mg.
  • the dosage of the pharmaceutical composition or the kit of this specific embodiment includes: relative to 1 kg of body weight, the content of the adult stem cells is 10 6 -10 8 and the content of the MCP-1 is 0.1-0.5 mg The content of the GDNF is 0.1-0.5 mg.
  • the dosage of the pharmaceutical composition or kit of this specific embodiment includes: relative to 1 kg of body weight, the adult stem cells are peripheral blood stem cells with a content of (1-5) ⁇ 10 6 cells, and the MCP-1
  • the content of GDNF is 0.2-0.4mg, and the content of GDNF is 0.2-0.4mg.
  • the pharmaceutical composition or kit comprises adult stem cells, MCP-1, GDNF and OPG.
  • the dosage of the pharmaceutical composition or kit of this specific embodiment includes: relative to 1 kg of body weight, the content of the adult stem cells is 10 6 -10 8 and the content of the MCP-1 is 0.01-10 mg.
  • the content of GDNF is 0.01-10 mg, and the content of OPG is 0.01-10 mg.
  • the dosage of the pharmaceutical composition or kit of this specific embodiment includes: relative to 1 kg of body weight, the content of the adult stem cells is 10 6 -10 8 and the content of the MCP-1 is 0.02-5 mg, The content of the GDNF is 0.02-5 mg, and the content of the OPG is 0.02-5 mg.
  • the dosage of the pharmaceutical composition or the kit of this specific embodiment includes: relative to 1 kg of body weight, the content of the adult stem cells is 10 6 -10 8 and the content of the MCP-1 is 0.1-0.5 mg The content of the GDNF is 0.1-0.5 mg, and the content of the OPG is 0.1-0.5 mg.
  • the dosage of the pharmaceutical composition or kit of this specific embodiment includes: relative to 1 kg of body weight, the adult stem cells are peripheral blood stem cells with a content of (1-5) ⁇ 10 6 cells, and the MCP-1
  • the content of GDNF is 0.2-0.4mg, the content of GDNF is 0.2-0.4mg, and the content of OPG is 0.2-0.4mg.
  • the monocyte chemoattractant protein-1, glial cell-derived neurotrophic factor and osteoprotegerin are recombinant proteins.
  • the storage method of adult stem cells and cytokines in the pharmaceutical composition or kit is not particularly limited, and they can be stored separately or mixed.
  • the adult stem cell is an autologous stem cell, more preferably a subject's autologous peripheral blood stem cell.
  • the pharmaceutical composition or kit may also contain other active pharmaceutical ingredients for treating or improving male sperm motility, as long as the other ingredients do not counteract the activity of the aforementioned cytokines and adult stem cells.
  • the cytokines of MCP-1, GDNF and OPG of the present invention can be obtained according to conventional methods in the art, or commercially available.
  • the cDNA sequence information of MCP-1, GDNF and OPG can be obtained by logging into the NCBI database.
  • the protein can be modified or loaded on other carriers to increase its half-life in the body; or can be linked to a known penetrating peptide to promote transdermal absorption of the compound of the present invention or cross the blood-brain barrier.
  • those skilled in the art can make various modifications to the compounds of the present invention to improve delivery efficiency or for other purposes while maintaining their activity.
  • cytokines as active ingredients in the present invention can be used together with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier including excipients and auxiliaries that facilitate the processing of the active ingredients into preparations (for example, preparations suitable for injection or infusion) .
  • Formulations suitable for injection or infusion may include aqueous and non-aqueous sterile injections and aqueous and non-aqueous sterile suspensions.
  • the sterile injections may optionally contain antioxidants, buffers, bacteriostatic agents and A solute capable of making the preparation equal to the blood of the intended recipient.
  • the sterile suspension may include a suspending agent and a thickening agent.
  • the preparations can be presented in unit-dose or multi-dose containers, such as sealed ampoules, and can be stored in freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use.
  • the active ingredient of the present invention may optionally be combined with solid excipients, and the resulting mixture may optionally be ground, and if necessary, after adding suitable auxiliaries, the mixture of granules is processed to obtain the desired dosage form .
  • Suitable excipients are especially fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose or starch preparations, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, carboxylate Sodium methylcellulose and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the second aspect of the present invention provides the use of adult stem cells (preferably peripheral blood stem cells) in preparing the pharmaceutical composition or kit described in the first aspect of the present invention for treating or improving male sperm motility in a subject.
  • adult stem cells preferably peripheral blood stem cells
  • the third aspect of the present invention provides that one, two or three of MCP-1, GDNF and OPG are used for the preparation of any one of claims 1-8 for improving the patient’s health.
  • the use in a pharmaceutical composition or a kit for the subject's sperm motility is low.
  • the present invention provides a method for treating or improving male sperm motility in a subject, which comprises simultaneously or sequentially administering adult stem cells and cytokines to the subject.
  • other active pharmaceutical ingredients for treating or improving male sperm motility can also be administered simultaneously or sequentially.
  • the subject of the present invention is preferably a mammal, more preferably a human.
  • the amount of adult stem cells and cytokines administered in the present invention can be any amount that can synergistically treat the subject or improve male sperm motility.
  • the dosage unit includes: relative to 1 kg body weight, 0.01-10 mg of each cytokine and 10 6 -10 8 adult stem cells; preferably 0.02-5 mg of each cytokine and 10 6 -10 8 adult stem cells; more preferably 0.1-0.5 mg of each cytokine and 10 6 -10 8 adult stem cells; most preferably 0.2- 0.4 mg of each cytokine and (1-5) ⁇ 10 6 peripheral blood stem cells.
  • the determination of an effective amount is within the abilities of those skilled in the art, especially under the inspiration of the disclosure provided herein.
  • the pharmaceutical product (drug, medicament) or pharmaceutical composition of the present invention can be administered to a subject at any effective dose.
  • the pharmaceutical product (medicine, medicament or kit) or pharmaceutical composition of the present invention can be administered in multiple doses, for example, from about 2 to about 10 doses, more preferably from about 3-5 doses, most preferably About 3 doses.
  • the pharmaceutical product (drug, medicament) or pharmaceutical composition of the present invention is administered to the subject at a frequency of about once every two months, such as injection or infusion.
  • the administration is the administration of cytokines and adult stem cells by intravenous infusion.
  • the pharmaceutical product drug, medicament or kit
  • pharmaceutical composition of the present invention can be formulated in any suitable manner for administration by any suitable route.
  • the dosage unit of the pharmaceutical product (medicine, medicament) or pharmaceutical composition of the present invention is based on routine administration to the subject.
  • the dosage unit can be administered more than once a day, once a week, once a month, etc.
  • the dosage unit can be administered on a twice/week basis, that is, twice a week, for example, once every three days.
  • the pharmaceutical product (e.g., pharmaceutical composition or kit) of the present invention may include instructions related to the pharmaceutical product, and the instructions may contain the following contents: indications (e.g., ovarian cancer), dosage (e.g., the exemplified above ) And possible side effects, etc.
  • indications e.g., ovarian cancer
  • dosage e.g., the exemplified above
  • possible side effects etc.
  • the effective component in the pharmaceutical composition of the present invention is present in an effective amount.
  • the term "effective amount” refers to an amount that is sufficient to treat (therapeutically or prophylactically) this target disorder when it is administered in an appropriate dosage regimen.
  • an effective amount is sufficient to reduce or improve the severity, duration, or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the deterioration of the disorder being treated, or enhance or improve another therapy The preventive or therapeutic effect.
  • treatment includes both therapeutic treatment and preventive treatment (reducing the possibility of development).
  • the term refers to reducing, inhibiting, attenuating, reducing, stopping or stabilizing the development or progression of a disease (such as the disease or condition described herein, male sperm motility deficiency), reducing the severity of the disease or improving the disease associated with the disease Symptoms.
  • the granulocyte colony stimulating factor In order to mobilize and recruit more adult stem cells from the subject, especially peripheral blood stem cells, it is preferable to administer the granulocyte colony stimulating factor to the subject for at least 5 days before collecting the peripheral blood stem cells from the subject (G-CSF), for example, about 5ug/kg/day to 10ug/kg/day; more preferably, the granulocyte colony stimulating factor is administered to the subject at a dose of about 6-8 ⁇ g/kg/day or equivalent, and Monitor white blood cells daily.
  • G-CSF peripheral blood stem cells from the subject
  • mobilizer (recombinant human granulocyte stimulating factor GCSF) at a dose of 5-10ug/kg/day, continuous injection of mobilizer for 5 days, and 1ml of venous blood daily from the next day to monitor white blood cells, when white blood cells rise To 2.5 ⁇ 10 9 /L, the amount of mobilizer does not exceed (5ug/kg/day).
  • PBMC can be collected when the white blood cell value reaches 2.5 ⁇ 10 9 /L or more.
  • white blood cells can reach 4.5 ⁇ 10 9 /L, which is the "ideal mobilization state", that is, GCSF successfully stimulates the bone marrow colony .
  • PBMC stem cells
  • the blood preservation solution was used in the collection process: the use ratio of 22.0g sodium citrate (C6H5Na307.2H2O) blood preservation solution to PBMC in 1000ml glucose was 1:10.
  • the collected PBMCs are divided into bags for infusion.
  • Example 2 The composition improves male sperm motility
  • Sperm motility has a significant positive correlation with parameters such as VSL, VCL, and VAP.
  • Sperm motility parameters such as VSL, VCL, and VAP are conventional indicators that reflect sperm motility.
  • the effect of the composition of the present invention on improving sperm motility of healthy men with normal sexual life was investigated. The specific method is as follows. For 16 normal male volunteers aged 22-44 who were married, healthy and sexually active, before the start of the experiment, peripheral blood stem cells were prepared by the method of Example 1, and He Jiang et al. (Chinese Journal of Eugenics and Genetics, 2010, 18(5): 110) collected semen and measured VSL, VCL, VAP values and sperm motility values (a+b%).
  • the pharmaceutical composition of the present invention was administered to all subjects by infusion, that is, 1 ⁇ 10 6 cells/kg body weight of peripheral blood stem cells + 0.3 mg MCP-1 + 0.3 mg GDNF were used to return the pharmaceutical composition of the present invention along the vein Infused into the patient, one dose.
  • Example 3 The composition improves the effect of male asthenospermia
  • PBMC was collected according to Example 1, and the cytokine composition 0.3mgMCP-1+0.3mgGDNF+0.3mgOPG was added to 50ml PBMC, infused once every two months, a total of three reinfusions, a total of 150ml PBMC (which contains Stem cell number is about 6X10 7 th), wherein the first recirculation date September 18, 2016; second recirculation date November 20, 2016; third recirculation date January 20, 2017.
  • Table 2 The semen indexes of Mr. Wu two months after the first infusion
  • Table 3 The semen indexes of Mr. Wu two months after the second infusion

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Abstract

La présente invention concerne le domaine des produits biopharmaceutiques, et concerne ainsi une composition pharmaceutique ou un kit utilisé pour améliorer la faible motilité des spermatozoïdes chez un sujet, et une utilisation de cellules souches adultes et de cytokines dans la préparation d'une composition pharmaceutique ou d'un kit utilisé pour améliorer la faible motilité des spermatozoïdes chez un sujet, respectivement. La composition ou le kit pharmaceutique utilisé pour améliorer la faible motilité des spermatozoïdes chez un sujet comprend : des cellules souches adultes ; un, deux ou trois types de cytokines choisis parmi la protéine-1 chimioattractive monocytaire, le facteur neurotrophique dérivé des cellules gliales et l'ostéoprotégérine ; et un support pharmaceutiquement acceptable facultatif.
PCT/CN2020/090050 2019-05-14 2020-05-13 Combinaison de cellules souches et de cytokines et son utilisation pour améliorer la motilité des spermatozoïdes WO2020228743A1 (fr)

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CN110025769A (zh) * 2019-05-14 2019-07-19 美亚宜彬生物科技(北京)有限公司 干细胞和细胞因子的组合及其在改善精子活力的用途
CN110882274A (zh) * 2019-10-21 2020-03-17 浙江生创精准医疗科技有限公司 间充质干细胞在降低地西他滨毒副作用的用途及相关药物
CN114159473B (zh) * 2022-02-11 2022-05-27 美亚宜彬生物科技(北京)有限公司 一种用于改善男性生殖系统干细胞复合制剂及制备方法

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