WO2006019187A1 - Remède pour une néphropathie - Google Patents

Remède pour une néphropathie Download PDF

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Publication number
WO2006019187A1
WO2006019187A1 PCT/JP2005/015384 JP2005015384W WO2006019187A1 WO 2006019187 A1 WO2006019187 A1 WO 2006019187A1 JP 2005015384 W JP2005015384 W JP 2005015384W WO 2006019187 A1 WO2006019187 A1 WO 2006019187A1
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WO
WIPO (PCT)
Prior art keywords
renal
ischemia
reperfusion
csf
kidney
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2005/015384
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English (en)
Japanese (ja)
Inventor
Eisei Noiri
Kousuke Negishi
Toshiro Fujita
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Kirin Brewery Co Ltd
University of Tokyo NUC
Original Assignee
Kirin Brewery Co Ltd
University of Tokyo NUC
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Priority to JP2006531961A priority Critical patent/JPWO2006019187A1/ja
Publication of WO2006019187A1 publication Critical patent/WO2006019187A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a therapeutic agent for ischemic hemorrhagic renal injury and renal injury associated with renal ischemia and reperfusion, which comprises granulocyte colony-stimulating factor (hereinafter abbreviated as G-CSF) as an active ingredient.
  • G-CSF granulocyte colony-stimulating factor
  • Renal insufficiency is a form of normal renal function due to renal dysfunction, that is, kidney failure
  • Renal failure is broadly divided into acute renal failure that usually develops within a few days, and chronic renal failure that lasts several months to several years and gradually leads to renal failure.
  • Some acute renal failure is reversible, and there are cases that can be cured and other cases that can be transferred to irreversibility.
  • blood purification therapy such as hemodialysis or abdominal B hemodialysis
  • Chronic renal failure is an irreversible and progressive disease that is subject to blood purification therapy when renal function declines markedly.
  • alternative therapies are unlikely to cause immediate death, there is a strong need for blood purification therapy that limits the lives and working hours of patients.
  • the number of dialysis patients exceeds 200,000 in Japan, and more than 10% of the population suffers from early kidney disease. Medical expenses account for 1 trillion yen of the total medical expenses of approximately 12 trillion yen. Therefore, control of progressive nephropathy is also eagerly desired from the medical and economic aspects.
  • causes of renal failure include circulatory and hemodynamic causes (eg, decreased blood flow to kidney tissue due to hypertension, arteriosclerosis, vasculitis, vascular hyperconstriction, excessive pressure load), inflammation 'immune Major causes (eg autoantibodies, immune globulin deposition, complement activation, infiltration of inflammatory cells), drug damage (eg direct renal tissue damage due to pile cancer drugs, antibiotics, contrast agents) are known.
  • hemodynamic causes eg, decreased blood flow to kidney tissue due to hypertension, arteriosclerosis, vasculitis, vascular hyperconstriction, excessive pressure load
  • inflammation 'immune Major causes eg autoantibodies, immune globulin deposition, complement activation, infiltration of inflammatory cells
  • drug damage eg direct renal tissue damage due to pile cancer drugs, antibiotics, contrast agents
  • Non-Patent Documents 2 and 3 it has been reported that ischemia is related to renal damage in chronic renal failure. In other words, if renal tissue damage due to ischemia can be controlled, it may be possible to treat various renal diseases or suppress the progression of renal failure.
  • kidney transplantation is applied in addition to blood purification therapy for the treatment of end-stage renal failure, in which the renal function is remarkably reduced.
  • Liver transplantation and cadaveric kidney transplantation are performed for kidney transplantation, but cadaveric kidney transplantation generally requires a longer time from the removal of the kidney from the donor until transplantation. Therefore, in cadaveric kidney transplantation, blood flow to the kidneys is interrupted after the death of the donor, causing the kidneys to become ischemic, resulting in damage to the kidney tissue due to ischemia.
  • an ischemia-reperfusion injury caused by reperfusion of blood into the kidney will also occur.
  • These ischemic injury or ischemia-reperfusion injury leads to a decrease in the survival rate of the kidney and a decrease in the expression of renal function immediately after transplantation (see Non-Patent Documents 4 and 5).
  • Non-patent Document 6 a therapeutic agent for renal diseases containing a colony-stimulating factor such as G-CSF as an active ingredient has been disclosed (Patent Document 1). However, only therapeutic effects on acute renal injury caused by ischemia-reperfusion have been confirmed here. Not.
  • Non-Patent Document 1 P Li ss et al., “Kidney International J (USA) 1998, 53rd pp. 698-702
  • Non-Patent Document 2 M Nangaku; “Intern Med.” 2004, 43rd, pp. 9-17
  • Non-patent literature 3 KU Eckardt et al., “Blood Purification” (Switzerland) 2003, 21st pp. 253-257
  • Non-patent literature 4 D St Peter Shawn et al. , “The Lancet
  • Non-Patent Document 5 A Aikawa, “Kidney and Dialysis” (Japan) 2000, 49th Tsuji, No 3 Special Issue, pp. 472-477
  • Patent Document 1 International Publication W0 2005/034986 Disclosure of Invention
  • novel drugs that have a protective effect against ischemia or ischemia-reperfusion injury can be expected to treat various renal diseases or suppress the progression of renal failure.
  • ischemia or ischemia-reperfusion injury at the time of kidney transplantation, it is possible to increase transplant opportunities and reduce initial renal function decline, resulting in an increase in the number of transplants and a higher success rate.
  • securing peritubular blood flow necessary to maintain nephron function in the transplanted graft is considered to be directly involved in increasing the survival rate of the transplanted kidney. It is no exaggeration to say that this is a final common pathway that is generally related to the pathology of chronic kidney injury.
  • G-CSF has been clinically applied as a drug that increases neutrophils, it is not known to have a protective effect against damage caused by ischemia or ischemia-reperfusion in the kidney.
  • the drug-induced renal failure model as described above does not necessarily reflect renal damage caused by ischemia or renal damage associated with ischemia-reperfusion, and the effects on such renal damage are completely unknown. Met.
  • the present inventors examined whether or not the renal function is improved in a rat model reflecting renal injury caused by ischemia and ischemia-reperfusion. In the renal failure stage, administration of G-CSF was performed. It was confirmed that renal function was improved. Further, G-CSF has been found to reduce tissue damage in a folic acid-induced chronic kidney injury model, and the present invention has been completed.
  • the present invention provides a prophylactic or therapeutic agent for ischemia-related renal injury or renal injury associated with renal ischemia-reperfusion, comprising granulocyte colony stimulating factor as an active ingredient.
  • the preferred renal disorder is chronic renal disorder.
  • chronic kidney injury means at least renal interstitial fibrosis and chronic ischemia. It refers to the state of presenting either.
  • chronic kidney injury as used herein also includes progressive kidney injury in the process of progression from acute kidney injury to chronic kidney injury.
  • Chronic ischemia is a condition characterized by, for example, a decrease in the peritubular vascular network, and is detected using an anti-CD31 (PECAM) antibody.
  • PECAM anti-CD31
  • the present invention further comprises administering the prophylactic or therapeutic agent of the present invention to a patient having ischemia-related renal injury or renal injury associated with renal ischemia-reperfusion, wherein the renal injury is prevented or treated.
  • the prophylactic or therapeutic agent of the present invention to a patient having ischemia-related renal injury or renal injury associated with renal ischemia-reperfusion, wherein the renal injury is prevented or treated.
  • Figure 1 shows the histological evaluation of renal interstitial fibrosis.
  • the original picture (Original picture) shows an original photograph in which the fibrosis portion is stained blue with Masson / Trichrome staining.
  • the analysis picture (Analyzed picture) shows the figure analyzed by image analysis software.
  • G-CSF Granulocyte colony-stimulating factor
  • neutrophil progenitor cells acts on neutrophil progenitor cells, promotes their differentiation and proliferation, promotes the release of mature neutrophils from the bone marrow, and promotes neutrophil function Therefore, it is a protein that has already been clinically applied as a therapeutic agent for neutropenia after cancer chemotherapy and promoting the increase in the number of neutrophils after hematopoietic stem cell transplantation.
  • it since it has the effect of mobilizing hematopoietic stem cells in bone marrow into peripheral blood, it is also clinically applied as a mobilization agent for peripheral blood of hematopoietic stem cells when collecting allogeneic and autologous peripheral blood stem cells.
  • the inventors have surprisingly found that G-CSF improves renal function in a rat renal injury model with renal ischemia-reperfusion and a mouse renal failure model with folic acid.
  • the left renal artery is clipped under general anesthesia for 45 minutes. After removing the right kidney immediately before removing the clip, remove the clip and reperfuse the left kidney. In addition, it is considered that removing the right kidney immediately before reperfusion makes it easier to directly grasp the degree of reperfusion injury in the ischemic kidney as the transition of renal function.
  • the above model is representative of the pathophysiology of renal damage due to ischemia and reperfusion, and is acute renal failure that shows an increase in serum creatine concentration and urea nitrogen concentration that peak at about 24 hours after reperfusion.
  • G-CSF reduces tissue damage in a model of chronic renal damage caused by folic acid.
  • G-CSF proved to be effective in the above model is used for acute renal failure, chronic renal failure, various types of nephritis, kidney transplantation, etc. in which renal tissue damage due to ischemia or ischemia-reperfusion is involved it can.
  • G-CSF is administered prophylactically to prevent the onset or to prevent progression after onset.
  • “preventively” means preventing transition from non-chronic symptoms such as acute symptoms and nephritis to chronic symptoms.
  • a particularly preferred G-CGF that can be used in the present invention is human G-CGF.
  • human G-CSF include, for example, human G-CSF activity (ie, neutrophil-increasing activity) represented by the amino acid sequence of SEQ ID NOs: 1 to 3, preferably the amino acid sequence of SEQ ID NO: 1.
  • a polypeptide having ischemia-related or renal ischemia-related renal prophylaxis or therapeutic activity or a glycoprotein having a sugar chain attached thereto.
  • G-CSF derivatives having G-CSF activity in which a part of the amino acid sequence of the same sequence is modified are also included in G-CSF in the present invention.
  • Such a G-CSF derivative preferably has 90% or more, more preferably 95% or more identity with the amino acid sequence represented by SEQ ID NO: 1 or 2.
  • a polypeptide comprising an amino acid sequence having Such modifications can be performed, for example, by known site-directed mutagenesis methods (including methods utilizing polymerase chain reaction (PCR)) (eg, Ausubel et al., Current Protocols in Molecular Biology, John Wiley). and Sons, USA). Modifications include conservative amino acid substitutions. That is, such a substitution is a substitution between amino acids having electrically or structurally similar properties, for example, between basic amino acids, between acidic amino acids, between hydrophobic amino acids, or between polar amino acids. Amino acid substitution at
  • G-CSFs include those derived from nature and those obtained by gene recombination, but those obtained by gene recombination are preferred.
  • examples of host cells include E. coli and mammalian cells (C127, CH0, BHK, COS ⁇ HEK293 cells, etc.). Details of these production methods are disclosed in, for example, JP-A 63-500636, JP-A 62-236497, JP-A 62-236488, JP-A 63-267292, etc. Yes.
  • a particularly preferable water-soluble polymer is polyethylene glycol, for example, polyethylene glycol having a molecular weight of about 2,000 to 100,000, preferably about 6,000 to 25,000.
  • PEG PEGylation
  • amino-terminal amino groups of G-CSF and / or ⁇ -amino groups of lysine residues have amino groups such as acyl groups and aldehyde groups.
  • PEGylated G-CSF sold by Amgen as Neulasta (registered trademark).
  • the G-CSF chain modification such as the structure of the sugar chain, the addition or deletion of the chain, or albumin, This includes proteins fused with vitamin B12 or immunoglobulin.
  • the G-CSF sugar chain variant is composed of the amino acid sequence of G-CSF and the Asn-X-Thr / Ser sequence.
  • X is an amino acid other than Pro.
  • Such additions and deletions can be easily performed using, for example, site-directed mutagenesis using Au (Ausubel et al., Supra).
  • the fusion protein is synthesized by synthesizing DNA that encodes G-CSF encoding DNA and DNA encoding the protein to be fused, using a general gene recombination technique.
  • the fusion DNA can be obtained by a technique including inserting the fusion DNA into an appropriate vector below, introducing the vector into an appropriate host cell, and expressing the fusion DNA.
  • the prophylactic or therapeutic agent for ischemia-related nephropathy and nephropathy associated with renal ischemia-reperfusion is a pharmaceutical composition comprising alone or a pharmaceutically acceptable carrier, excipient, stabilizer and the like. Can be administered to patients.
  • the present invention also provides administration of the above pharmaceutical composition to a patient having ischemia-related nephropathy and renal ischemia associated with renal ischemia and one reperfusion, for preventing or treating the nephropathy.
  • a patient having ischemia-related nephropathy and renal ischemia associated with renal ischemia and one reperfusion for preventing or treating the nephropathy.
  • Such a pharmaceutical composition can take the form of sustained-release preparations such as injection preparations, oral preparations, transmucosal administration preparations, etc., and can use any form commonly used in the art. S, especially injectable preparations are preferred.
  • Administration routes for injection preparations include subcutaneous administration, intravenous administration, intramuscular administration, intrarenal artery administration, and administration using a sustained-release gel, with subcutaneous administration and intravenous administration being particularly preferred.
  • the dose and frequency of administration of G-CSF can be determined according to the patient's condition, and are particularly limited. Although it is not, it is usually 0.1 to 200 g / kg / day, preferably 1 to 100 ig / kg / day, and can be administered for 1 to 7 days for Z weeks.
  • the preventive or therapeutic agent for ischemia-related nephropathy and renal ischemia associated with renal ischemia-reperfusion of the present invention is also a supplement such as physiological saline, mannitol, Ringer's solution, an angiotensin converting enzyme inhibitor, angi Conventional renal diseases such as otensin II receptor antagonists, antihypertensives, diuretics, antiplatelets, thrombolytics, antidiabetics, antihyperlipidemics, anti-inflammatorys, steroids and immunosuppressants Or complications associated with the underlying disease It can be used in combination with one or more drugs used for renal diseases, and can be administered simultaneously, separately, or as a pharmaceutical composition containing these in combination. These drugs, which are not effective alone for kidney disease,
  • kidney disease The therapeutic effect on kidney disease is confirmed by, for example, reducing serum creatinine levels and blood urea nitrogen levels, reducing urinary protein levels and albumin levels, and improving histological tubular damage score (See JD Conger et al., Kidney International 1994, 46th, ⁇ ⁇ 318; SP Kel leher et al., Kidney International Natal, 1987, 31st, p. 725).
  • the therapeutic agent for renal injury associated with renal ischemia and reperfusion according to the present invention can also be performed as an adjuvant therapy before treatment such as kidney transplantation.
  • the test is based on Bonferroni / Dunn test. Table 2 Blood urea nitrogen concentration before and after ischemia-reperfusion (mg / dL) Time after ischemia-reperfusion
  • the test is based on the Unpaired t-test.
  • the score in the sham operation group was 0.00.
  • serum creatinine concentration and blood urea nitrogen concentration increased due to renal ischemia and reperfusion, and decreased renal function. These increases were suppressed by CSF administration, and renal function was improved by G-CSF. Furthermore, it was shown that tubule damage 72 hours after renal ischemia and reperfusion was also improved by G-CSF.
  • the fibrosis region is blue-stained.
  • Masson / Trichrome stained specimens were analyzed using dedicated image analysis software, AIS (manufactured by Imaging Research) (10 specimens were examined for each specimen). Specifically, it shows the ratio of fibrosis to the entire image captured by the 20X objective lens (see Table 5).
  • AIS manufactured by Imaging Research
  • rhG-CSF50 ig / kg was subcutaneously administered every other day from day 7 (11 times in total) to the same folic acid administration model as above, and histological evaluation was performed by killing on day 28.
  • Table 6 shows the results of evaluation of interstitial fibrosis as described above.
  • the evaluation of the peritubular capillary network was immunostained with CD31 and analyzed by AIS, and was significantly maintained in the rhG-CSF group compared to the physiological saline group (see Table 8). . From the above, the effectiveness of G-CSF was demonstrated for chronic kidney injury.
  • Saline group Saline group
  • Renal failure model by folic acid administration 28 days after administration (2 groups, 2 animals each, 10 subjects each)
  • Renal failure model by folic acid administration 28 days after administration (2 groups, 2 animals each, 10 subjects each)
  • Renal failure model by folic acid administration 28 days after administration (2 groups, 2 animals each, 10 fields contrasted)
  • the present invention can provide a drug capable of preventing acute renal failure or improving the progression of chronic renal failure by alone or in combination with other existing drugs. Furthermore, this drug can be used to improve the engraftment rate at the time of kidney transplantation and increase the chance of transplantation.
  • SEQ ID NO: 1 Amino acid sequence containing a Met residue at position 1 with respect to natural human G-CSF.
  • SEQ ID NO: 3 with respect to native human G-CSF-containing Met residue at position 1, and Thr residue at position +1, Leu residue at position +3 in natural human G-CSF, +4
  • An amino acid sequence in which the Gly residue at the position, the Pro residue at the +5 position, and the Cys residue at the +17 position are substituted with Ala, Thr, Tyr, Arg and Ser, respectively.

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Abstract

Agent de prévention ou remède pour une néphropathie liée à l'ischémie et une néphropathie accompagnant une ischémie-reperfusion rénale lequel contient un facteur de stimulation de colonies de granulocytes (G-CSF) comme ingrédient actif. Ainsi, il devient possible de prévenir des néphropathies accompagnant l'ischémie ou l'ischémie-reperfusion, d'empêcher la progression de l'insuffisance rénale, de prévenir ou de traiter l'ischémie ou l'ischémie-reperfusion dans une transplantation de rein ou similaire et de diminuer les affections ischémiques chroniques d'un rein transplanté pour de cette manière conserver les fonctions rénales de celui-ci sur une longue durée.
PCT/JP2005/015384 2004-08-18 2005-08-18 Remède pour une néphropathie Ceased WO2006019187A1 (fr)

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JP2006531961A JPWO2006019187A1 (ja) 2004-08-18 2005-08-18 腎障害治療剤

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JP2004-238573 2004-08-18
JP2004238573 2004-08-18

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016152706A1 (fr) * 2015-03-20 2016-09-29 株式会社明治 Agent améliorant la fonction rénale
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
CN113425706A (zh) * 2021-08-12 2021-09-24 宫念樵 一种甲基丁香酚在制备减轻肾脏缺血再灌注损伤的药物中的应用
CN115245509A (zh) * 2021-12-27 2022-10-28 南京市儿童医院 一种3-苯基戊二酸衍生物小分子在制备防治缺血再灌注导致的慢性肾脏病药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022163A1 (fr) * 2000-09-13 2002-03-21 Chugai Seiyaku Kabushiki Kaisha Remedes contre des maladies ischemiques

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2002022163A1 (fr) * 2000-09-13 2002-03-21 Chugai Seiyaku Kabushiki Kaisha Remedes contre des maladies ischemiques

Non-Patent Citations (5)

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Title
AKIZAWA T. ET AL: "The Effects and Pharmacokinetics of shG-CSF in Patients with Chronic Renal Failure.", ARTIFICIAL ORGANS., vol. 19, no. 12, 1995, pages 1251 - 1257, XP002992027 *
KALE S. ET AL: "Bone marrow stem cells contribute to repair of the ischemically injured renal tubule.", THE JOURNAL OF CLINICAL INVESTIGATION., vol. 112, no. 1, 2003, pages 42 - 49, XP002992030 *
LIN F. ET AL: "Hematopoietic Stem Cells Contribute to the Regeneration of Renal Tubules After Renal Ischemia-Reperfusion Injury in Mice.", J AM SOC NEPHROL., vol. 14, 2003, pages 1188 - 1199, XP002992029 *
NISHIDA M. ET AL: "Effect og hematopoietic cytokines on renal function in cisplatin-induced ARF in mice.", BBRC., vol. 324, 2004, pages 341 - 347, XP004583807 *
ZHANG Y. TE AL: "Ischemia-reperfusion induces G-CSF gene expression by renal medullary thick ascending limb cells in vivo and in vitro.", AM PHYSIOL RENAL PHYSIOL., vol. 286, 20 January 2004 (2004-01-20), pages F1193 - F1201, XP002992028 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10531655B2 (en) 2011-12-02 2020-01-14 The Regents Of The University Of California Reperfusion protection solution and uses thereof
WO2016152706A1 (fr) * 2015-03-20 2016-09-29 株式会社明治 Agent améliorant la fonction rénale
JPWO2016152706A1 (ja) * 2015-03-20 2017-12-28 株式会社明治 腎機能改善剤
CN113425706A (zh) * 2021-08-12 2021-09-24 宫念樵 一种甲基丁香酚在制备减轻肾脏缺血再灌注损伤的药物中的应用
CN115245509A (zh) * 2021-12-27 2022-10-28 南京市儿童医院 一种3-苯基戊二酸衍生物小分子在制备防治缺血再灌注导致的慢性肾脏病药物中的应用
CN115245509B (zh) * 2021-12-27 2023-05-09 南京市儿童医院 一种3-苯基戊二酸衍生物小分子在制备防治缺血再灌注导致的慢性肾脏病药物中的应用

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