WO2016190387A1 - Agent thérapeutique destiné à des tumeurs et utilisation de celui-ci - Google Patents

Agent thérapeutique destiné à des tumeurs et utilisation de celui-ci Download PDF

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Publication number
WO2016190387A1
WO2016190387A1 PCT/JP2016/065568 JP2016065568W WO2016190387A1 WO 2016190387 A1 WO2016190387 A1 WO 2016190387A1 JP 2016065568 W JP2016065568 W JP 2016065568W WO 2016190387 A1 WO2016190387 A1 WO 2016190387A1
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aim
tumor
therapeutic agent
cells
tumors
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PCT/JP2016/065568
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English (en)
Japanese (ja)
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智洋 米澤
萌菜 内田
直章 松木
優香 金村
和夫 川上
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国立大学法人東京大学
共立製薬株式会社
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Priority to JP2017520801A priority Critical patent/JPWO2016190387A1/ja
Publication of WO2016190387A1 publication Critical patent/WO2016190387A1/fr

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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

Definitions

  • the present invention relates to a therapeutic agent for a tumor, a pharmaceutical composition for treating a tumor, a method for treating a tumor, and an AIM for producing the therapeutic agent for a tumor or a protein variant having substantially the same activity as the AIM.
  • This application claims priority based on provisional application No. 62 / 167,274 filed in the United States on May 28, 2015, the contents of which are incorporated herein by reference.
  • Non-epithelial cell-derived malignant tumors are malignant tumors derived from mesoderm that occur in bones, soft tissues, blood vessels, blood systems, and the like. What can be removed is eligible for surgery, but chemotherapy is a common treatment if metastases are advanced, have multiple manifestations, or are blood-borne tumors .
  • Various anticancer agents have been researched and developed so far, and progress has been made, but conventional anticancer agents have strong side effects and may be difficult to use.
  • chemotherapy with molecular targeted drugs can exert a specific and powerful effect, it is effective for only a small part of cancer cells in which the target molecule is expressed. Development of molecular target drugs is desired.
  • Apotosis Inhibitor of Macrophage is a protein with a molecular weight of about 40 k that is specifically expressed in macrophages. AIM was discovered as an apoptosis inhibitor and is known to have an anticancer effect via complement in hepatocellular carcinoma (see, for example, Non-Patent Document 1).
  • Non-Patent Document 1 discloses that accumulation of AIM on the cell surface in hepatocellular carcinoma activates complement and causes cytotoxicity to cause cancer cell-specific necrosis. There is little follow-up on AIM.
  • the present invention has been made in view of the above circumstances, and provides a novel therapeutic agent for tumors that is highly effective against various malignant tumors.
  • AIM has a cell-killing effect on various malignant tumors by a mechanism not involving complement, and has completed the present invention. It was.
  • a therapeutic agent for tumors comprising an apoptosis inhibitor of macrophage (AIM) or a protein variant having substantially the same activity as that of the AIM as an active ingredient and substantially no complement.
  • AIM apoptosis inhibitor of macrophage
  • a protein variant having substantially the same activity as that of the AIM as an active ingredient and substantially no complement consists of an amino acid sequence that is 60% or more identical to the amino acid sequence shown in SEQ ID NO: 1 and has a cytocidal effect on tumor cells, a derivative thereof, or a salt or ester thereof as an active ingredient
  • a pharmaceutical composition for treating a tumor comprising the therapeutic agent according to any one of [1] to [3] and a pharmaceutically acceptable carrier or diluent.
  • a method for treating a tumor comprising administering to a mammal an effective amount of AIM or a protein variant having substantially the same activity as the AIM.
  • FIG. 1 It is a graph which shows the cell survival rate in the various tumor cells which added AIM of each concentration in Example 1.
  • 2 is a photograph showing the presence or absence of apoptosis by genomic DNA electrophoresis in a histiocytic sarcoma cell line (CHS-5) with or without AIM in Example 1.
  • FIG. 1 is a photograph showing the presence or absence of apoptosis by genomic DNA electrophoresis in a histiocytic sarcoma cell line (CHS-5) with or without AIM in Example 1.
  • the present invention comprises an apoptosis inhibitor of macrophage (AIM) or a protein variant having substantially the same activity as the AIM as an active ingredient, and a therapeutic agent for tumors substantially free of complement.
  • AIM apoptosis inhibitor of macrophage
  • I will provide a.
  • tumor therapeutic agent of this embodiment various malignant tumors can be effectively treated.
  • containing as an active ingredient means containing a therapeutically effective amount of a peptide.
  • substantially free of complement means that it contains no complement at all, or contains only a trace amount that does not activate and cause cell damage. Therefore, in the tumor therapeutic agent of this embodiment, AIM or a protein variant having substantially the same activity as AIM has a cytocidal effect on tumor cells by a new mechanism not involving complement. .
  • Apoptosis Inhibitor of Macrophage is a protein with a molecular weight of 40k that is specifically produced by differentiated and matured macrophages, and is known to consist of three scavenger receptor cysteine-rich (SRCR) domains. It has been.
  • the AIM used in this embodiment may be derived from a mammal, and examples of the mammal include mice, rats, hamsters, guinea pigs, rabbits, dogs, cats, horses, cows, sheep, pigs, A goat, a marmoset, a monkey, a human, etc. are mentioned, It is not limited to these.
  • a protein variant having substantially the same activity as AIM has, for example, 60% or more identity with the amino acid sequence of AIM, preferably 70% or more, and more preferably 80% or more. More preferably, the protein is 90% or more, particularly preferably 95% or more.
  • a protein variant having substantially the same activity as AIM is, for example, a protein comprising an amino acid sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence of AIM. Good.
  • the number of amino acids that may be deleted, substituted, or added is preferably 1 to 15, more preferably 1 to 10, and even more preferably 1 to 5.
  • the protein variant has substantially the same activity as AIM, that is, has a cytocidal effect on tumor cells.
  • the “cytocidal effect on tumor cells” means an effect of specifically killing tumor cells, for example, by promoting apoptosis.
  • tumor mainly indicates a malignant tumor (cancer), and infiltrates surrounding tissues in a cell population (tumor) that has grown autonomously and uncontrolled by gene mutation. Or a malignant neoplasm that causes metastasis.
  • cancer is used to represent a diagnosis name
  • cancer is used to represent a generic name of malignant neoplasm.
  • the type of tumor is differentiated by the cells that develop, "solid cancer", where tumor cells gather to form isolated lesions, and "humoral”, where tumor cells develop mainly in the blood due to abnormal hematopoietic tissue It is roughly divided into “cancer”.
  • solid cancer can be divided into malignant tumors derived from epithelial cells and other malignant tumors derived from non-epithelial cells.
  • examples of the solid cancer include breast tumors (eg, invasive ductal cancer, non-invasive ductal cancer, inflammatory breast cancer, etc.), prostate cancer, gastrointestinal tumors (eg, gastrointestinal stromal) Tumor, gastrointestinal adenocarcinoma), lung cancer (eg lung adenocarcinoma, lung squamous cell carcinoma, malignant mesothelioma), lymphoma (eg cutaneous lymphoma, intranasal lymphoma, digestive lymphoma, multicentric lymphoma) , Liver cancer (eg, hepatocellular carcinoma, hepatic carcinoid, extrahepatic bile duct cancer), kidney cancer (eg, renal cell carcinoma, nephroblastoma), gallbladder cancer, bile duct cancer, pancreatic cancer (eg, insulinoma) , Glucagonoma), ovarian tumor, uterine leiomyosarcoma, bladder cancer (eg transition
  • the liquid cancer includes acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), malignant lymphoma, multiple myeloma, and the like. It is not limited to these.
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • malignant lymphoma multiple myeloma, and the like. It is not limited to these.
  • the tumor to which the therapeutic agent for tumor of this embodiment is applied is not particularly limited as long as it is listed above, but among them, the therapeutic agent for tumor of this embodiment is for sarcoma. Are preferably used.
  • SEQ ID NO: 1 is the amino acid sequence of AIM in dogs. More specifically, as a protein variant having substantially the same activity as AIM, for example, the identity with the amino acid sequence shown in SEQ ID NO: 1 is 60% or more (preferably 70% or more, more preferably 80% or more, More preferably 90% or more, particularly preferably 95% or more) and having a cytocidal effect on tumor cells, derivatives thereof, or salts or esters thereof as active ingredients, etc. Is mentioned.
  • the AIM or a protein variant having substantially the same activity as the AIM may be composed of L-amino acids, D-amino acids, or a combination thereof.
  • L-amino acids are naturally occurring amino acids
  • D-amino acids are those in which the chirality of L-amino acid residues is reversed. It may also be chemically modified to increase the killing effect on the tumor cells or to optimize other physical properties. That is, the therapeutic agent for tumors of the present embodiment has the activity substantially equivalent to the AIM or the AIM together with or instead of the AIM or a protein variant having an activity substantially equivalent to the AIM.
  • guide_body of the protein variant which has this may be included.
  • the therapeutic agent for tumors of the present embodiment exerts a desired effect as long as it comes into contact with the cell membrane, it does not have to be permeable to cells.
  • the tumor therapeutic agent of the present embodiment has the AIM or a protein variant having substantially the same activity as the AIM, and / or a derivative of the AIM, or an activity substantially equivalent to the AIM.
  • a salt of the AIM, or a salt or ester of a protein variant having substantially the same activity as the AIM, and / or a derivative of the AIM, or the A salt or ester of a derivative of a protein variant having substantially the same activity as AIM may be included.
  • the salt is preferably a pharmaceutically physiologically acceptable acid addition salt or basic salt.
  • Acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid; acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid And salts with organic acids such as benzoic acid, methanesulfonic acid, and benzenesulfonic acid.
  • Examples of the basic salt include salts with inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and magnesium hydroxide; salts with organic bases such as caffeine, piperidine, trimethylamine and pyridine. .
  • ester for example, a conventional pharmaceutically acceptable one in the carboxyl group in the case of having a carboxyl group is preferable. Specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, etc.
  • esters with lower alkyl groups include esters with lower alkyl groups; esters with lower alkyl groups such as allyl groups and 2-butenyl groups; esters with lower alkoxy lower alkyl groups such as methoxymethyl groups, 2-methoxyethyl groups and 2-ethoxyethyl groups Can be mentioned.
  • the lower alkyl group means an alkyl group having 1 to 6 carbon atoms.
  • the tumor therapeutic agent of the present embodiment may contain, as other components, for example, a buffer solution such as PBS or Tris-HCl; an additive such as sodium azide or glycerol.
  • a buffer solution such as PBS or Tris-HCl
  • an additive such as sodium azide or glycerol.
  • a method for treating a tumor can be provided by using the above-described tumor therapeutic agent.
  • the tumor include those similar to those exemplified above.
  • the subject of treatment is not limited, and includes mammals including human or non-human animals. Examples of mammals include the same as those exemplified above.
  • the AIM used in the tumor therapeutic agent of the present embodiment may be naturally derived, or may be obtained by artificial chemical synthesis.
  • AIM derived from a natural product may be obtained directly from a body fluid sample (eg, blood sample), tissue, or cell derived from a non-human mammal by known recovery and purification methods, or known genetic recombination.
  • the gene encoding the peptide may be incorporated into various expression vectors or the like, introduced into cells and expressed, and then obtained by known recovery and purification methods.
  • kits such as reagent kits PROTEIOSTM (manufactured by Toyobo), TNTTM System (manufactured by Promega), PG-MateTM (manufactured by Toyobo) and RTS (manufactured by Roche Diagnostics), etc. are used.
  • the AIM may be produced by a conventional cell-free protein synthesis system and may be obtained by a known recovery method and purification method, and is not limited.
  • AIM by chemical synthesis can be obtained using a known protein synthesis method.
  • Examples of the synthesis method include an azide method, an acid chloride method, an acid anhydride method, a mixed acid anhydride method, a DCC method, an active ester method, a carboimidazole method, and a redox method.
  • the solid phase synthesis method and the liquid phase synthesis method can be applied to the synthesis.
  • a commercially available protein synthesizer may be used.
  • AIM can be purified by combining known purification methods such as chromatography.
  • the AIM synthesis method can be prepared by the following method. First, a host is transformed with an expression vector containing a nucleic acid encoding AIM. Subsequently, the host is cultured to express AIM. Conditions such as medium composition, culture temperature, time, addition of inducer, etc. can be determined by those skilled in the art according to known methods so that transformants grow and AIM is efficiently produced. For example, when an antibiotic resistance gene is incorporated into an expression vector as a selection marker, a transformant can be selected by adding an antibiotic to the medium. Subsequently, AIM is obtained by purifying AIM expressed by the host by an appropriate method.
  • the dosage of the tumor therapeutic agent of this embodiment takes into account the age, sex, weight, symptoms, treatment method, administration method, treatment time, etc. of the test animal (various mammals including human or non-human animals). Adjust as appropriate. For example, when AIM or a protein variant having substantially the same activity as that of AIM is intravenously injected with an injection, the local concentration of AIM in a single administration is determined by AIM in a healthy subject. It is preferable to administer the blood concentration to be twice or more of the blood concentration, that is, 200 ⁇ M or more, more preferably 200 ⁇ M or more and 200 mM or less, and more preferably 2 mM or more and 20 mM or less. Particularly preferred.
  • the tumor therapeutic agent of this embodiment can confirm the death of tumor cells 30 minutes after administration, preferably 4 hours to 48 hours, more preferably 8 hours to 30 hours, Preferably, 95% or more of tumor cells can be killed in 12 hours or more and 24 hours or less.
  • the tumor therapeutic agent of this embodiment can kill tumor cells more rapidly than conventional anticancer agents, and further, this rapid cell killing effect does not depend on the mechanism through conventional complement. This is probably due to a new mechanism.
  • the number of administration is preferably 1 to several times per week.
  • Examples of the dosage form include intraarterial injection, intravenous injection, subcutaneous injection, intramuscular injection, eye drop, nasal drop, ear drop, intrabronchial administration, oral administration, or transdermal absorption, among others. Intravenous injection is preferred.
  • Injectables can also be prepared as non-aqueous diluents (eg, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol), suspensions, or emulsions. Such sterilization of injections can be performed by blending filter sterilization with a filter, bactericides, and the like.
  • Injectables can be manufactured in the form of business preparation. That is, it can be used as a sterile solid composition by lyophilization, etc., and dissolved in distilled water for injection or other solvent before use.
  • composition for treatment of tumor comprises a therapeutically effective amount of the above-mentioned tumor therapeutic agent and a pharmaceutically acceptable carrier or diluent.
  • Pharmaceutically acceptable carriers or diluents include excipients, diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, flavoring agents. Agents, solubilizers, additives and the like.
  • pharmaceutical compositions in the form of injections, solutions, capsules, suspensions, emulsions, syrups and the like can be prepared.
  • a colloidal dispersion system can be used as the carrier.
  • the colloidal dispersion system is expected to have an effect of enhancing the in vivo stability of the peptide and an effect of enhancing the transferability of the peptide to a specific organ, tissue, or cell.
  • colloidal dispersion systems include polyethylene glycol, polymer composites, polymer aggregates, nanocapsules, microspheres, beads, oil-in-water emulsifiers, micelles, mixed micelles, and lipids including liposomes. Liposomes such as liposomes and artificial membranes that are effective in efficiently transporting peptides to specific organs, tissues, or cells are preferred.
  • Examples of the formulation in the pharmaceutical composition for treatment of tumor of this embodiment include those used orally as tablets, capsules, elixirs, and microcapsules with sugar coating as necessary. Or what is used parenterally in the form of a sterile solution with water or other pharmaceutically acceptable liquid, or an injection of suspension.
  • a pharmacologically acceptable carrier or diluent specifically, sterilized water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, preservative , And those formulated by mixing in a unit dosage form generally required for pharmaceutical practice, in appropriate combination with a binder and the like.
  • Additives that can be mixed into tablets and capsules include, for example, binders such as gelatin, corn starch, tragacanth gum, gum arabic, excipients such as crystalline cellulose, swelling such as corn starch, gelatin, and alginic acid Agents, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, red mono oil or cherry.
  • the above material can further contain a liquid carrier such as fats and oils.
  • Sterile compositions for injection can be formulated according to normal pharmaceutical practice using a vehicle such as distilled water for injection.
  • Aqueous solutions for injection include, for example, isotonic solutions containing physiological saline, glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol and sodium chloride.
  • Suitable solubilizers such as Alcohols, specifically ethanol, polyalcohols such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80 (TM), HCO-50 may be used in combination.
  • oily liquid examples include sesame oil and soybean oil, which may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizing agent.
  • oily liquid examples include sesame oil and soybean oil, which may be used in combination with benzyl benzoate or benzyl alcohol as a solubilizing agent.
  • buffer for example, phosphate buffer, sodium acetate buffer, a soothing agent, for example, procaine hydrochloride, stabilizer, for example, benzyl alcohol, phenol, antioxidant.
  • the prepared injection solution is usually filled into a suitable ampoule.
  • One aspect of the present invention also provides the above-described AIM for treating tumors, or protein variants having substantially the same activity as the AIM, derivatives thereof, or salts or esters thereof.
  • One aspect of the present invention also provides a therapeutically effective amount of the above-mentioned AIM, or a protein variant having substantially the same activity as the AIM, a derivative thereof, or a salt or ester thereof, and pharmaceutically Pharmaceutical compositions comprising an acceptable carrier or diluent are provided.
  • a therapeutic agent for tumors which comprises the above-described pharmaceutical composition for treating tumors.
  • Another aspect of the present invention is the use of the above-described AIM, or a protein variant having substantially the same activity as the AIM, a derivative thereof, or a salt or ester thereof for producing a therapeutic agent for tumors I will provide a.
  • Another aspect of the present invention is a patient in need of treatment with an effective amount of the above-mentioned AIM, or a protein variant having substantially the same activity as the AIM, a derivative thereof, or a salt or ester thereof.
  • a method of treating a tumor comprising administering to a tumor.
  • Examples of the tumor to which the above-described treatment method is applied include those similar to those exemplified in the above ⁇ Tumor therapeutic agent >>.
  • examples of animals to which the above-described treatment methods are applied include humans and non-human mammals.
  • Non-human mammals include, but are not limited to, mice, rats, hamsters, guinea pigs, rabbits, dogs, cats, horses, cows, sheep, pigs, goats, marmosets, monkeys, and the like.
  • the non-human mammal to which the above-described treatment method is applied is preferably a dog.
  • Example 1 (1) Preparation of recombinant canine AIM (1-1) Production of HA-tagged canine AIM expression vector
  • SEQ ID NO: 2 is the nucleotide sequence of a nucleic acid encoding canine AIM.
  • the restriction enzyme sites of NotI and XhoI were respectively added to the 5 ′ end and the 3 ′ end. PCR product was obtained.
  • a restriction enzyme treatment with NotI and XhoI was performed on the pCAGGS vector (pCAGGS-Leader Sequence-HNX-HA), and a nucleic acid (SEQ ID NO: 2) encoding canine AIM was inserted to prepare a canine AIM expression vector.
  • the produced vector contains a cytomegalovirus enhancer, chicken ⁇ -actin promoter, rabbit ⁇ -globulin exon and intron, nucleic acid encoding HA polypeptide, and nucleic acid encoding canine AIM.
  • the number of cells after the culture was counted using Cell Counting Kit-8 (manufactured by Dojindo).
  • the cell viability at each concentration of recombinant AIM was calculated by setting the number of cells without recombinant AIM (0 M) in each cell type as 100%. The results are shown in FIG. In FIG. 1, the vertical axis indicates the number of viable cells (%), and the horizontal axis indicates the concentration of recombinant AIM.
  • a negative control a recombinant AIM-free addition was prepared, and as a positive control, 10 ng / mL vincristine sulfate (manufactured by Sigma) was prepared. Subsequently, after washing with PBS, the cells were recovered with 200 ⁇ L of cell lysate. Next, 4 ⁇ L of RNase A (20 mg / mL, manufactured by Qiagen) and 4 ⁇ L of proteinase K (20 mg / mL, manufactured by Qiagen) were added to the obtained cell lysate and allowed to stand at 50 ° C. for 30 minutes.
  • FIG. 2 qualitatively shows that DNA fragmentation (apoptosis) significantly increases in the recombinant AIM addition group.
  • remarkable DNA fragmentation was observed 30 minutes after the addition of recombinant AIM, suggesting that apoptosis was rapidly induced as compared with conventional anticancer agents.
  • Example 2 (1) Preparation of recombinant canine AIM Using the same method as in (1) of Example 1 except that HeLa cells were used instead of the canine histiocytic sarcoma cell line CHS-5 as cells to be transfected, HA-tagged dog AIM was prepared.
  • sensitivity is the result of evaluating other AIM sensitivities when the AIM sensitivity in DH82 and HeLa cells is moderate. Compared with DH82 and HeLa cells, cells with high cell viability have low AIM sensitivity, cells with similar cell viability have medium AIM sensitivity, and cells with low cell viability have AIM sensitivity. Was high.
  • various malignant tumors can be effectively treated.

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Abstract

La présente invention concerne un agent thérapeutique destiné à des tumeurs, lequel agent contient un inhibiteur de l'apoptose des macrophages (AIM) ou un variant de protéine ayant pratiquement la même activité que celle de l'AIM en tant qu'ingrédient actif et ne contient sensiblement aucun complément.
PCT/JP2016/065568 2015-05-28 2016-05-26 Agent thérapeutique destiné à des tumeurs et utilisation de celui-ci WO2016190387A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108535492A (zh) * 2018-03-27 2018-09-14 重庆医科大学 Aim作为生物标志物在诊断、预后或监测脓毒症中的用途
WO2024014463A1 (fr) * 2022-07-12 2024-01-18 徹 宮崎 Agent pour traiter ou prévenir des calculs rénaux

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2010140531A1 (fr) * 2009-06-01 2010-12-09 国立大学法人東京大学 Composition pharmaceutique, aliment ou boisson, et procédés pour ces produits
WO2013162021A1 (fr) * 2012-04-27 2013-10-31 大日本住友製薬株式会社 Agent prophylactique ou thérapeutique pour des maladies hépatiques

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2010140531A1 (fr) * 2009-06-01 2010-12-09 国立大学法人東京大学 Composition pharmaceutique, aliment ou boisson, et procédés pour ces produits
WO2013162021A1 (fr) * 2012-04-27 2013-10-31 大日本住友製薬株式会社 Agent prophylactique ou thérapeutique pour des maladies hépatiques

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108535492A (zh) * 2018-03-27 2018-09-14 重庆医科大学 Aim作为生物标志物在诊断、预后或监测脓毒症中的用途
CN108535492B (zh) * 2018-03-27 2019-02-12 重庆医科大学 Aim作为生物标志物在诊断、预后或监测脓毒症中的用途
WO2024014463A1 (fr) * 2022-07-12 2024-01-18 徹 宮崎 Agent pour traiter ou prévenir des calculs rénaux

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