WO1997004806A1 - Medicament pour troubles neurologiques - Google Patents

Medicament pour troubles neurologiques Download PDF

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Publication number
WO1997004806A1
WO1997004806A1 PCT/JP1996/002080 JP9602080W WO9704806A1 WO 1997004806 A1 WO1997004806 A1 WO 1997004806A1 JP 9602080 W JP9602080 W JP 9602080W WO 9704806 A1 WO9704806 A1 WO 9704806A1
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WO
WIPO (PCT)
Prior art keywords
selectin
antibody
spinal cord
therapeutic agent
leukocytes
Prior art date
Application number
PCT/JP1996/002080
Other languages
English (en)
Japanese (ja)
Inventor
Kenji Okajima
Yuji Taoka
Original Assignee
Sumitomo Pharmaceuticals Company, Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sumitomo Pharmaceuticals Company, Limited filed Critical Sumitomo Pharmaceuticals Company, Limited
Priority to BR9703605-6A priority Critical patent/BR9703605A/pt
Publication of WO1997004806A1 publication Critical patent/WO1997004806A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • C07K16/2854—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72 against selectins, e.g. CD62
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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 neuropathy. Specifically, the present invention relates to a therapeutic agent for neuropathy containing a P-selectin binding inhibitor as an active ingredient.
  • Leukocytes have the function of treating foreign matter that has entered from outside the body, and usually remove foreign matter. In addition, when an organization is damaged, it gathers at the site of the injury and contributes to tissue repair
  • I CAM-2, VCAM-1 etc. bind to adhesion molecules LFA-1, Mac-1 and VLA-4 on leukocytes, etc., and have stronger adhesion of leukocytes to vascular endothelial cells Sir.
  • Leukocytes further react with other factors and pass between vascular endothelial cells and migrate to inflamed tissues. Leukocytes migrating out of the blood vessels release reactive oxygen species and proteases.
  • inflammation is exacerbated by damaging self-tissues.
  • leukocytes accumulated at the site of inflammation are activated and release proteolytic enzymes stored in the cells or produce active oxygen.These proteolytic enzymes and active oxygen are used for decomposing and processing foreign substances.
  • tissue cells are also oxidized and damaged, thereby exacerbating inflammation.
  • Anti-P-selectin antibody does not ameliorate symptoms of lung injury induced by cobra venom factor-induced complement activity and inflammatory models such as myocardial, auricular, intestinal or systemic blood reperfusion.
  • Known (Ayumi of Medicine, 12 36 (1995)) o Japanese clinical study, 52 vol. 11, 2995 (1994) discloses that selectin between leukocytes and vascular endothelium is mediated in cerebral ischemia-reperfusion injury. by means of an adhesive function, hypothesis force that the white blood cells infiltrate the brain disorders straining cause?
  • Steroid drugs such as dexamethasone and methylprednisolone were administered for spinal cord injury, but the effect was not yet confirmed (“Actual spinal cord injury” Akazu Takashi et al., Pp. 5-6, Nankodo (1991)).
  • a P-selectin binding inhibitor can treat a neurological disorder and treat a motor dysfunction based on the disorder.
  • An object of the present invention is to find an agent for preventing neuropathy and motor dysfunction based on neuropathy.
  • H is ffl.
  • FIG. 1 shows the effect of the anti-P-selectin antibody PB1.3 on rat motor dysfunction due to spinal cord compression. Each value represents the mean and standard deviation. In addition, * indicates that the significance level is statistically significant (Mann-Whitney U test) at less than 5%.
  • FIG. 2 shows the effect of the anti-P-selectin antibody PB1.3 on the increase of MPO activity in rat spinal cord tissue by spinal cord compression. Each value represents the mean and standard deviation. * Indicates statistical significance (Student's t-test) with a significance level of less than 5%.
  • the present inventors have conducted intensive studies to improve tissue disorders and motor dysfunction in neuropathy.As a result, the inflammatory pathology of nerves caused by neuropathy depends on the interaction between leukocytes and vascular endothelial cells.
  • the role of P-selectin which plays a role in the adhesion of leukocytes to vascular endothelial cells, is controlled by P-selectin binding inhibitor. Reached.
  • the present invention (1) a therapeutic agent for neuropathy comprising a P-selectin binding inhibitor as an active ingredient,
  • a therapeutic agent for motor dysfunction based on neuropathy comprising a P-selectin binding inhibitor as an active ingredient
  • P-selectin binding inhibitor is an anti-P-selectin antibody, P-selectin ligand or derivative thereof, P-selectin ligand-specific antibody, P-selectin or a fragment thereof, or P-selectin A therapeutic agent described in (1) or (3) above, which is a biosynthesis inhibitor of the ligand, or
  • Neuropathy includes neuropathy involving leukocytes and the like, for example, spinal cord injury, neuropathy after ischemia-reperfusion, inflammatory central nervous disorder, and the like.
  • Spinal cord injuries include traumatic spinal cord injury, spinal degenerative diseases (spondylosis, etc.), spinal inflammatory diseases (spondylitis, rheumatoid arthritis, etc.), tumors (spinal cord tumors, spinal tumors, etc.), vascular diseases (spinal cord hemorrhage, Myelitis (arachnoiditis, viral myelitis, bacterial myelitis, etc.), multiple sclerosis, amyotrophic lateral sclerosis, and the like.
  • the neuropathy after ischemia reperfusion includes a disorder after cerebral ischemia reperfusion due to cerebrovascular disorder, a disorder after spinal cord ischemia reperfusion and the like.
  • Spinal cord ischemia is performed, for example, in surgery for an aortic aneurysm.
  • Inflammatory central nervous system disorders include those caused by bacterial infection, viral infection, and the like.
  • “Motor dysfunction based on neuropathy” occurs based on neuropathy These include shock, respiratory paralysis, sensory paralysis, motor paralysis, loss of reflexes, and autonomic paralysis.
  • P-selectin binding inhibitor refers to a substance that inhibits the binding between P-selectin on vascular endothelial cells and a ligand on leukocytes.
  • Examples of the P-selectin binding inhibitor in the present invention include the following three types depending on the mode of inhibition.
  • Inhibitors of this type include, for example, anti-P-selectin antibodies, P-selectin ligands and derivatives thereof.
  • Inhibitors of this type include, for example, P-selectin ligand specific antibodies, P-selectin and fragments thereof.
  • particularly preferred are those that bind to P-selectin to inhibit binding to ligand on leukocytes.
  • Anti-P-selectin antibody refers to an immunoglobulin that recognizes P-selectin and selectively binds to P-selectin, thereby suppressing cell-cell adhesion.
  • This antibody may be a polyclonal antibody or a monoclonal antibody.
  • the origin of this antibody is not limited, and examples include an antibody of mouse or human origin, a chimeric antibody in which the-portions of both human and mouse antibodies are bound, or a humanized antibody.
  • P-selectin ligands and their derivatives include glycoproteins on the surface of leukocytes and the like, Glycolipids and their terminal structures, oligosaccharide slides, and their derivatives are also included.
  • oligosaccharides and derivatives thereof include sialyl Lewis X and sialyl Lewis X derivatives, Lewis X and Lewis X derivatives, sulfated saccharides, phosphorylated saccharides, sulfatides and the like (for example, Varki et al. Proc. Natul. Acad. USA 9L 7390 (1994), WO 94/26 6 6
  • glycoproteins examples include PSGL-1 (for example, Sako et al. Cel 75.179 (PSGL-1).
  • the antibody specific to the ligand of P-selectin means an antibody specific to the aforementioned ligand.
  • This antibody may be a polyclonal antibody or a monoclonal antibody.
  • the origin of the present antibody is not limited, and examples thereof include an antibody of mouse or human origin, a chimeric antibody in which a part of both human and mouse antibodies are bound, or a humanized antibody.
  • Specific examples include anti-Sialyl Lewis X antibody, anti-Sialyl Lewis a antibody, anti-Lewis X antibody, anti-Lewis a antibody and the like (for example, Fukushima et al. Cancer Res. 44, 5279 (1984), Shitara et al. Cancer Res. 4L 1267 (1987), Takada et al. Biochem. Biophys. Res. Commun. 179, 713.
  • P-selectin means membrane-bound P-selectin and soluble P-selectin.
  • the fragment of P-selectin means a partial peptide of P-selectin and the like, and examples thereof include peptides described in Japanese Patent Application Laid-Open No. 7-501828.
  • P-selectin and its fragments have the ability to inhibit the adhesion of P-selectin in vivo to cells. That is, since these P-selectins and fragments thereof bind to the above-mentioned ligands or derivatives thereof, the ability of P-selectin on vascular endothelial cells in vivo to inhibit further adhesion to the ligands or derivatives thereof is exerted.
  • the P-selectin ligand biosynthesis inhibitor means an inhibitor such as a glycosyltransferase used in the biosynthesis of the P-selectin ligand described above.
  • Specific examples include inhibitors for sialyltransferase for transferring sialic acid to the oligosaccharide force receptor, and inhibitors for fucosyltransferase for transferring fucose.
  • a sialyltransferase inhibitor described in JP-A-5-247780, a fucosyltransferase inhibitor described in Chi-Huey Wong et al., J. Am. Chem. So 114, 7321 (1992), etc. Are mentioned.
  • the therapeutic agent of the present invention is administered parenterally, topically, orally, or transdermally, and can be administered in various unit dosage forms depending on the method of administration.
  • unit dosage forms suitable for oral administration include powders, tablets, pills, capsules and dragees.
  • the therapeutic agents of the present invention are administered intravenously.
  • the drug is dissolved or suspended in a pharmaceutically acceptable carrier, preferably an aqueous carrier.
  • a pharmaceutically acceptable carrier for example, water, buffered water, physiological saline and the like can be used.
  • the resulting aqueous solutions can be packaged as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration.
  • the therapeutic agent of the present invention may be a pharmaceutically acceptable adjuvant, such as a pH adjuster and buffer, a tonicity adjuster, an infiltrant, such as sodium acetate, as required for approximate physiological conditions. , Sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate and the like.
  • the therapeutic agent of the invention is administered to a patient already afflicted with a disease in an amount sufficient to cure or at least partially arrest the condition of the disease and its complications. It is.
  • the dosage of the therapeutic agent of the invention may vary, for example, depending on the particular active ingredient, the mode of administration, the degree of the disease to be treated, the overall health and condition of the patient and the power of the prescribing physician, generally a body weight of 70 kg.
  • the therapeutic agent of the present invention is in a range of about 0.5 ra to about 10,000 mg per day, and preferably, for a patient weighing 70 kg, the active ingredient of the present invention per day is about 5 ra.
  • the therapeutic agent of the present invention can also be used as a prophylactic agent. In prophylactic applications, the therapeutic agents of the invention are administered to patients who are susceptible to, or otherwise at risk of, a particular disease.
  • an anti-P-selectin binding inhibitor PB1.3 (the antibody described in WO9321956) was used as a P-selectin binding inhibitor to inhibit the binding of P-selectin. It is specifically explained that the agent is an effective therapeutic agent for spinal cord disorders and motor dysfunction caused by inflammatory response after spinal cord injury.
  • a control antibody or an anti-P-selectin antibody PB 1.3, 1.5 was administered to male Wistar rats weighing 270 to 350 g anesthetized by intraperitoneal administration of sodium pentobarbital, 45 mg / kg. mg Z kg was administered intravenously. Thirty minutes later, the back of the rat was incised to expose the spine, and the laminectomy of the first and second thoracic vertebrae was excised. After applying a 20 g weight to the dorsal surface of the dura for 20 minutes to give spinal cord injury, the wound was sutured. As a negative control, a non-spinal cord injury group with only laminectomy was established. Was. Twenty-four hours after the spinal cord injury, Tarlov showed hind limb motor function below.
  • mice were sacrificed 3 hours after spinal cord injury and neutrophil intragranular enzyme myelin peroxidase (MP0) was expressed in spinal cord tissue as an indicator of neutrophil accumulation in spinal cord tissue. Activity was measured.
  • MP0 neutrophil intragranular enzyme myelin peroxidase
  • Anti-P-selectin antibody PB1.3 markedly improved hind limb motor function, which was reduced by spinal cord injury.
  • MPO activity in spinal cord tissue was markedly increased by spinal cord injury, and anti-P-selectin antibody PB1.3 showed a significant inhibitory effect on this increase.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Neurosurgery (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Médicament conçu pour des troubles neurologiques, tels que des lésions spinales, des troubles neurologiques consécutifs au reflux ischémique et des troubles inflammatoires du système nerveux central, et contenant en tant qu'ingrédient actif un inhibiteur de fixation de P-sélectine, tel qu'un anticorps anti-P-sélectine.
PCT/JP1996/002080 1995-07-25 1996-07-25 Medicament pour troubles neurologiques WO1997004806A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
BR9703605-6A BR9703605A (pt) 1995-07-25 1996-07-25 Sistema de exibição de posição de terminal móvel

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/212418 1995-07-28
JP7212418A JPH0940582A (ja) 1995-07-28 1995-07-28 神経障害治療剤

Publications (1)

Publication Number Publication Date
WO1997004806A1 true WO1997004806A1 (fr) 1997-02-13

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PCT/JP1996/002080 WO1997004806A1 (fr) 1995-07-25 1996-07-25 Medicament pour troubles neurologiques

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JP (1) JPH0940582A (fr)
WO (1) WO1997004806A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010025179A (ko) * 2000-09-04 2001-04-06 김영우 유기성 폐기물을 먹이로 양식한 지렁이와 배설물인분변토에 함유되어있는 중금속의 제거방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05247078A (ja) * 1992-03-03 1993-09-24 Japan Tobacco Inc 糖化合物、シアル酸含有糖鎖類生合成阻害剤、その製造方法、並びに新規な中間体
WO1993021956A1 (fr) * 1992-05-05 1993-11-11 Cytel Corporation Anticorps contre la p-selectine et leurs emplois
WO1994026760A1 (fr) * 1993-05-14 1994-11-24 Cytel Corporation ANALOGUES DE SIALYLE Lex UTILES EN TANT QU'INHIBITEURS DE L'ADHESION CELLULAIRE
JPH07501828A (ja) * 1991-12-18 1995-02-23 セントコー，インコーポレイテッド セレクチン類で仲介される炎症のペプチド阻害剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07501828A (ja) * 1991-12-18 1995-02-23 セントコー，インコーポレイテッド セレクチン類で仲介される炎症のペプチド阻害剤
JPH05247078A (ja) * 1992-03-03 1993-09-24 Japan Tobacco Inc 糖化合物、シアル酸含有糖鎖類生合成阻害剤、その製造方法、並びに新規な中間体
WO1993021956A1 (fr) * 1992-05-05 1993-11-11 Cytel Corporation Anticorps contre la p-selectine et leurs emplois
WO1994026760A1 (fr) * 1993-05-14 1994-11-24 Cytel Corporation ANALOGUES DE SIALYLE Lex UTILES EN TANT QU'INHIBITEURS DE L'ADHESION CELLULAIRE

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BIOCHEM. BIOPHYS. RES. COMMUN., Vol. 179, No. 2 (1991), AKIKO TAKADA et al., "Adhesion of Human Cancer Cells to Vascular Endothelium Mediated by a Carbohydrate Antigen, Sialyl Lewis A", pp. 713-719. *
CANCER RES., Vol. 44 (1994), KIYOYASU FUKUSHIMA et al., "Characterization of Sialosylated Lewis x as a New Tumor-Associated Antigen", pp. 5279-5285. *
CANCER RES., Vol. 47 (1987), KENYA SHITARA et al., "Distribution of Lung Adenocarcinoma-Associated Antigens in Human Tissues and Sera Defined by Monoclonal Antibodies KM-52 and KM-93", pp. 1267-1272. *
CELL, Vol. 75 (1993), DIANNE SAKO et al., "Expression Cloning of a Functional Clycoprotein Ligand for P-Selectin", pp. 1179-1186. *
J. AM. CHEM. SOC., Vol. 114 (1992), CHI-HUEY WONG et al., "Specificity, Inhibition and Synthetic Utility of a Recombinant Human alpha-1,3-Fucosyltransferase", pp. 7231-7232. *
PROC. NATL. ACAD. SCI. U.S.A., Vol. 91 (1994), AJIT VARKI, "Selection Ligands", pp. 7390-7397. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010025179A (ko) * 2000-09-04 2001-04-06 김영우 유기성 폐기물을 먹이로 양식한 지렁이와 배설물인분변토에 함유되어있는 중금속의 제거방법

Also Published As

Publication number Publication date
JPH0940582A (ja) 1997-02-10

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