WO2012074043A1 - Agent thérapeutique pour des troubles neurologiques traumatiques - Google Patents

Agent thérapeutique pour des troubles neurologiques traumatiques Download PDF

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Publication number
WO2012074043A1
WO2012074043A1 PCT/JP2011/077782 JP2011077782W WO2012074043A1 WO 2012074043 A1 WO2012074043 A1 WO 2012074043A1 JP 2011077782 W JP2011077782 W JP 2011077782W WO 2012074043 A1 WO2012074043 A1 WO 2012074043A1
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Prior art keywords
brain
hmgb1
injury
monoclonal antibody
traumatic
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PCT/JP2011/077782
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English (en)
Japanese (ja)
Inventor
正洋 西堀
秀治 森
英夫 高橋
秀徳 和氣
克約 劉
勲 伊達
佑 大熊
靖子 友野
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国立大学法人 岡山大学
医療法人 創和会
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Priority to JP2012546930A priority Critical patent/JP6154135B2/ja
Publication of WO2012074043A1 publication Critical patent/WO2012074043A1/fr

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    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • the present invention relates to a drug for treating traumatic neuropathy, that is, brain injury, brain injury and / or spinal cord injury associated with brain surgery.
  • Brain trauma is also called traumatic brain injury (TBI).
  • TBI traumatic brain injury
  • a strong external force is applied to the head above the neck due to some kind of accident (for example, a traffic accident, a fall accident, a collision accident, a fall accident, etc.) This refers to a condition in which the brain itself has been injured and the brain itself has been damaged.
  • CHI closed head injury
  • OHI open head injury
  • Open head injury is a bullet. Or caused by something stuck.
  • An obstructive head injury is caused and caused by a sudden movement of the brain inside the skull during a sudden movement, for example by an accident as described above. The compression caused by such rapid movement damages nerve fibers and axons and destroys the nerve transmission pathway.
  • the spinal cord is the main pathway for transmitting information about the brain and other parts of the body.
  • a tube-like structure that extends downward from the base of the brain.
  • SCI Spinal Cord Injury
  • the strong external force applied to the spinal column damages nerve fibers and axons and destroys the nerve transmission pathway.
  • Patent Document 1 There is a disclosure of a brain injury protective agent and a brain tissue injury protective agent associated with head trauma or brain surgery (Patent Document 1).
  • Patent Document 1 is characterized by containing ( ⁇ ) -N, N′-ropyrenedinicotinamide (generic name: Nicaraben) or a pharmaceutically acceptable salt thereof as an active ingredient, and is related to the progress of brain damage.
  • ⁇ -N, N′-ropyrenedinicotinamide
  • Nicaraben a pharmaceutically acceptable salt thereof
  • Patent Document 2 discloses a method for treating hypoxic or ischemic stroke, comprising administering an NMDA receptor antagonist in combination with a thrombolytic agent to a patient in need of such treatment.
  • an NR2B subtype-selective N-methyl-D-aspartate (NMDA) receptor antagonist comprising: (a) a sodium channel antagonist; (b) a nitric oxide synthase (NOS) inhibitor; Glycine site antagonists; (d) potassium channel openers; (e) AMPA / kainic acid receptor antagonists; (f) calcium channel antagonists; (g) GABA-A receptor modulators (eg, GABA-A receptor agonists) Or (h) a method comprising administering in combination with an anti-inflammatory agent.
  • NMDA N-methyl-D-aspartate
  • TBI traumatic brain injury
  • SCI spinal cord injury
  • Patent Document 3 Another report discloses a method for suppressing or treating physiological damage caused by traumatic brain injury (TBI), spinal cord injury (SCI) or a related condition.
  • TBI traumatic brain injury
  • SCI spinal cord injury
  • Patent Document 3 Another report discloses a method for suppressing or treating physiological damage caused by traumatic brain injury (TBI), spinal cord injury (SCI) or a related condition.
  • TBI traumatic brain injury
  • SCI spinal cord injury
  • Patent Document 3 Another report discloses a method for suppressing or treating physiological damage caused by traumatic brain injury (TBI), spinal cord injury (SCI) or a related condition.
  • HMGB1 High Mobility Group Box 1: hereinafter referred to as “HMGB1” protein is a member of a non-histone chromatin-related protein family involved in DNA structure maintenance and transcriptional regulation. In recent years, it has been attracting attention as a new inflammatory marker, such as HMGB1 being released extracellularly due to cell necrosis, or active secretion being observed extracellularly by vascular inflammatory signal response.
  • HMGB1 is a protein having homology with 99% or more amino acid sequences from rodents to humans.
  • HMGB1 is also present in normal cells, the blood level is increased by stimulation with LPS (lipopolysaccharide), an endotoxin released in sepsis (systemic inflammatory response syndrome), resulting in final tissue damage .
  • LPS lipopolysaccharide
  • endotoxin released in sepsis systemic inflammatory response syndrome
  • final tissue damage resulting in final tissue damage .
  • drugs containing anti-HMGB1 monoclonal antibody against HMGB1 as active ingredients include cerebral vasospasm inhibitor (Patent Document 4) and cerebral infarction inhibitor (Patent Document 5) have already been patented, but accompany brain injury and brain surgery. There is no disclosure of agents for treating brain injury and / or spinal cord injury.
  • An object of the present invention is to provide a novel drug for treating traumatic neuropathy, that is, brain injury, brain injury and / or spinal cord injury associated with brain surgery.
  • the inventors of the present invention have made extensive studies in order to solve the above problems and examined the relationship between the physical external force on the brain and HMGB1.
  • HMGB1 is present in the nucleus of brain neurons, injury It was confirmed for the first time that HMGB1 was released out of the nucleus of the nerve cell in the tissue at or near the site where the blood was received.
  • HMGB1 was released out of the nucleus of the nerve cell in the tissue at or near the site where the blood was received.
  • it was found that by capturing HMGB1 released outside the nucleus of nerve cells it was possible to improve movement disorders caused by brain trauma, brain injury and / or spinal cord injury associated with brain surgery, and completed the present invention. .
  • this invention consists of the following.
  • a therapeutic agent for traumatic neuropathy comprising an anti-HMGB1 monoclonal antibody as an active ingredient.
  • 2. The therapeutic agent for traumatic neuropathy according to item 1 above, wherein the traumatic neuropathy is brain injury, brain injury associated with brain surgery, and / or spinal cord injury. 3.
  • 4. The therapeutic agent for traumatic neuropathy according to any one of items 1 to 3, wherein the anti-HMGB1 monoclonal antibody is administered at 0.2 to 5 mg / kg per dose. 5.
  • a method for treating traumatic neuropathy comprising using the therapeutic agent for traumatic neuropathy according to any one of 1 to 5 above.
  • the therapeutic agent for traumatic neuropathy characterized by comprising the anti-HMGB1 monoclonal antibody of the present invention as an active ingredient showed excellent effects both in behavior and histology in a percussion injury model rat.
  • the therapeutic agent for traumatic neuropathy of the present invention is extremely useful as a therapeutic agent for traumatic neuropathy that has not been particularly effective until now.
  • Example 2 It is a figure which shows the outline
  • Example 2 It is a figure which shows the rotarod test result at the time of administering an anti-HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 2-1 (A) It is a figure which shows the cylinder test result at the time of administering an anti-HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 2-1 (B) It is a photograph figure which shows the structure
  • Example 2-2 (A) It is the photograph which confirmed distribution of HMGB1 in the site
  • Example 2-2 (B) It is the photograph figure which confirmed distribution of HMGB1 in the site
  • Example 2-2 (B) It is the photograph which confirmed the distribution of HMGB1 around the site
  • Experimental example 2-2 (B) It is the figure which confirmed the amount of leakage of Evans blue about the brain of a percussion injury model.
  • Example 2-3 It is a figure which shows the rotarod test result 24 hours after administering anti- HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 3 It is a figure which shows the rotarod test result in 3 hours after administering anti- HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 3 It is a figure which shows the rotarod test result in the 6th hour after administering anti- HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 3 It is a figure which shows the rotarod test result in the time series after administration of an anti- HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 3 It is a figure which shows the cylinder test result 24 hours after administering anti- HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 4 It is a figure which shows the cylinder test result in the 3rd hour after administering anti- HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 4) It is a figure which shows the cylinder test result in the 6th hour after administration of an anti- HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 4 It is a figure which shows the cylinder test result in the time series after administration of an anti- HMGB1 monoclonal antibody with respect to a percussion injury model.
  • Example 4 It is a figure which shows the sample preparation method for performing HMGB1 western blotting in the brain of a percussion injury model.
  • Example 5 It is a photograph figure which shows the HMGB1 western blotting result in the brain of a percussion injury model.
  • Example 5 It is a figure which shows the HMGB1 western blotting result in the brain of a percussion injury model. (Example 5)
  • the therapeutic agent for traumatic neuropathy of the present invention comprises an anti-HMGB1 monoclonal antibody as an active ingredient.
  • the anti-HMGB1 monoclonal antibody binds only to HMGB1 to be detoxified and does not act on other compounds. Therefore, it is thought that there is no possibility that a side effect will occur or very little.
  • the active ingredient is an anti-HMGB1 monoclonal antibody, whereas HMGB1 is present in the nerve cell nucleus in a healthy state, whereas with traumatic neuropathy, This is because it was confirmed for the first time that HMGB1 was released from the nucleus of the nerve cell to the cytoplasm and extracellular area around the injury site.
  • traumatic neuropathy refers to brain injury, brain damage associated with brain surgery, and / or spinal cord injury.
  • brain trauma is also called traumatic brain injury (TBI), which is a pathological condition in which a strong external force is applied from the neck to the upper head, resulting in injury and damage to the brain itself.
  • TBI traumatic brain injury
  • brain damage associated with brain surgery may inevitably damage the brain during, for example, tumor removal, hematoma removal, or other surgical operations in the brain region.
  • SCI Spinal cord injury
  • the brain injury and / or brain surgery associated with brain surgery in the present invention and / or Or spinal cord injury is referred to as traumatic neuropathy.
  • Preparation of anti-HMGB1 monoclonal antibody may be performed according to a conventional method. For example, mice, rats, etc. are immunized using commercially available HMGB1, and hybridomas are obtained by fusing the antibody-producing cells, spleen cells and myeloma cells. The hybridoma is cloned, and a clone producing an antibody specifically reacting with HMGB1 is screened. This clone may be cultured and the secreted monoclonal antibody may be purified.
  • the therapeutic form of traumatic neuropathy comprising the anti-HMGB1 monoclonal antibody of the present invention as an active ingredient is not particularly limited in its dosage form or administration form.
  • the anti-HMGB1 monoclonal antibody as an active ingredient it can be formulated as a solution, microemulsion, dispersion, liposome, or other suitable shape suitable for high drug concentrations.
  • the requisite amount of anti-HMGB1 monoclonal antibody can be prepared by incorporating in a suitable solvent, optionally with one or a combination of the components listed above, and then filter sterilizing.
  • the therapeutic agent for traumatic neuropathy of the present invention can be administered by various methods known in the art.
  • the administration form is not particularly limited, but it is preferably administered intravenously as an injection in consideration of the urgency for traumatic neuropathy.
  • an isotonic solution of plasma such as a physiological saline adjusted with pH or an aqueous glucose solution can be used.
  • the antibody is lyophilized with salts or the like, pure water, distilled water, sterilized water, or the like can also be used.
  • the concentration may be that of a normal antibody preparation, and can be 0.2 to 5 mg / mL.
  • the osmotic pressure of the injection must be equivalent to that of plasma.
  • the timing of administration of the therapeutic agent for traumatic neuropathy of the present invention is not particularly limited, but it is preferably as early as possible after traumatic nerve injury, specifically within 12 hours after injury, preferably within 3 hours, more preferably 1 Within hours, most preferably within 10 minutes.
  • the dose for humans can be 0.2-5 mg / kg, more preferably 0.2-2 mg / kg of anti-HMGB1 monoclonal antibody per dose.
  • the dosage of these drugs should be changed as appropriate according to the age and sex of the patient, the severity of the disease, and the like.
  • the therapeutic agent for traumatic neuropathy of the present invention can be administered multiple times or continuously.
  • the anti-HMGB1 monoclonal antibodies of the invention may be formulated and / or co-administered with one or more other therapeutic agents.
  • the present invention also extends to a method for treating traumatic neuropathy, which comprises using the therapeutic agent for traumatic neuropathy of the present invention.
  • Example 1 Preparation of anti-HMGB1 monoclonal antibody An anti-HMGB1 monoclonal antibody was prepared by the same method as described in Patent Document 4. Specifically, it is as follows.
  • Example 2 Action of anti-HMGB1 antibody on traumatic neuropathy model rat 1
  • a percussion injury preparation device (Dragonfly HPD-1700: Dragonfly) was used.
  • the percussion injured rat used was prepared.
  • Wistar male rats (weight: approx. 300 g) were anesthetized with barbiturate (30 mg / kg), about 3 mm posterior from the bregma (Bregma: intersection of coronary and sagittal sutures) of the rat's skull, about 3 to the right
  • a burr-hole was pierced using a special crusher for mm, and a cylindrical plastic was attached using instant adhesive and bone cement.
  • TBI head percussion injury
  • the group was divided into 15 groups administered with anti-HMGB1 monoclonal antibody (see Example 1) and 15 groups administered with control antibody (anti-Keyhole-Limpet-hemocyanin (KLH) antibody: homemade).
  • the brain pressure was measured again 5 minutes after the generation of the TBI rat.
  • another operator administered 200 ⁇ g of drug (anti-HMGB1 antibody or anti-KLH antibody) from the tail vein 5 minutes later.
  • Example 2-1 Behavioral Evaluation The TBI rat prepared in Example 2 was subjected to behavioral evaluation. As behavioral evaluations, a rotarod test (for about 0-10 minutes) to observe coordinated movements and a cylinder test (for 3 minutes) to observe spontaneous movements of the upper limbs were performed immediately before head injury. And 24 hours after the injury.
  • TBI indicates the pressure applied to the dura mater at the time of TBI preparation
  • pre indicates the time (seconds) until the rat before TBI falls from the rod
  • post Similarly shows the time (seconds) until the rat after TBI falls from the rod.
  • FIG. 2 shows the results of comparing the post-TBI motility (post TBI / pre TBI) to the pre-TBI motility (time to fall from the rat rod).
  • the sham operation group (sham group) is the TBI rat production method shown in Example 2, which is in a state before impact from the brain dura mater, that is, about 3 mm from the bregma of the rat's skull, about 3 to the right side. A burr hole was drilled at 3 mm using a special burr, and a plastic tube was attached using instant adhesive and bone cement, and the skin was lightly sutured.
  • Example 2 Histological evaluation The TBI rat prepared in Example 2 was anesthetized with barbiturate (50 mg / kg) after measuring the brain pressure 24 hours after TBI preparation, and cardiac reflux was performed with paraformaldehyde. Fixation was performed and brain tissue was removed. Slices were prepared from paraffin-embedded brain tissue, histologically assessed for brain damage, and evaluated for HMGB1 dynamics during TBI.
  • HMGB1 was found in the neurocytoplasmic part but not in the nucleus. It was confirmed that HMGB1 is released outside the nucleus of nerve cells due to injury (FIG. 7).
  • Example 2-3 Evaluation of Cerebrovascular Permeability
  • Evans Blue (EB) was administered from the tail vein 3 hours after the injury was created, and blood was removed and perfused 3 hours later.
  • the amount of Evans blue that migrated into the brain was quantified.
  • Evans blue leakage was observed in the control group, but the leakage was significantly lower in the anti-HMGB1 monoclonal antibody administration group (FIG. 8).
  • Example 3 Effect of Anti-HMGB1 Monoclonal Antibody on Traumatic Neuropathy Model Rat
  • anti-HMGB1 monoclonal antibody was administered to a TBI rat prepared by the same method as in Example 2 as a traumatic neuropathy model rat. The effect at the time of administration was confirmed by behavioral evaluation (Rotorod test) as in Experimental Example 2-1.
  • Ten minutes after TBI anti-HMGB1 monoclonal antibody was intravenously administered at 200 ⁇ g from the tail vein.
  • an anti-KLH antibody anti-Keyhole Limpet hemocyanin (KLH) antibody: homemade
  • KLH anti-Keyhole Limpet hemocyanin
  • 0.5 ml of 0.9% physiological saline containing 10% glycerol was intravenously administered as a standard treatment method.
  • the sham group was also confirmed.
  • Behavioral evaluation was performed by rotarod test just before TBI and 3, 6 and 24 hours after TBI.
  • the rotarod test was performed in the same manner as in Experimental Example 2-1 (A), and the motility after preparation of the brain injury (post time to fall from the rod of the rat) for each time before the preparation of the brain injury (post) TBI / pre TBI) were compared (FIGS. 9-11).
  • the anti-HMGB1 monoclonal antibody administration group showed a behavioral improvement effect over time, and increased to the same extent as the sham group at 24 hours. Excellent motor ability was shown (FIG. 12).
  • Example 4 Effect of anti-HMGB1 monoclonal antibody on traumatic neuropathy model rat
  • anti-HMGB1 monoclonal antibody was applied to TBI rat prepared by the same method as in Example 2 as traumatic neuropathy model rat. The effect at the time of administration was confirmed by behavioral evaluation (cylinder test) in the same manner as in Experimental Example 2-1.
  • Ten minutes after TBI anti-HMGB1 monoclonal antibody was intravenously administered at 200 ⁇ g from the tail vein.
  • an anti-KLH antibody anti-Keyhole Limpet hemocyanin (KLH) antibody: homemade
  • the behavioral evaluation was performed by a cylinder test in the same manner as in Experimental Example 2-1 (B) at 3, 6 and 24 hours after TBI (FIGS. 13-15). As a result, in the anti-HMGB1 monoclonal antibody administration group, a behavioral improvement effect was observed over time after TBI (FIG. 16).
  • Example 5 HMGB1 in percussion-injured rats
  • TBI rats produced as traumatic neuropathy model rats by the same method as in Example 2 were evaluated by Western blotting for HMGB1 in tissues when anti-HMGB1 monoclonal antibody was administered.
  • 200 ⁇ g of anti-HMGB1 monoclonal antibody was intravenously administered via the tail vein 10 minutes after TBI.
  • an anti-KLH antibody anti-Keyhole Limpet hemocyanin (KLH) antibody: homemade
  • KLH Keyhole Limpet hemocyanin
  • 0.9 mL of physiological saline containing 10% glycerol was intravenously administered as a standard treatment method.
  • the cerebral cortex from the center of the injury to the anterior side was sampled at a size of 3 mm ⁇ 3 mm 24 hours after the injury.
  • the non-disturbed side was also sampled from a symmetrical position.
  • Cerebral cortical tissue was homogenized with 1 ml of RIPPA buffer (50 mM Tris-HCl, pH 8.0, 0.15 M NaCl, 0.1% SDS, 0.1% Triton X-100, 0.5% Sodium deoxycholate). After centrifugation at 10,000 ⁇ g for 20 minutes, the supernatant was electrophoresed on 12% polyacrylamide SDS-PAGE and transferred to a nitrocellulose membrane.
  • RIPPA buffer 50 mM Tris-HCl, pH 8.0, 0.15 M NaCl, 0.1% SDS, 0.1% Triton X-100, 0.5% Sodium deoxycholate
  • HMGB1 on the nitrocellulose membrane was detected by chemiluminescence using Western blotting with an HRP-labeled anti-HMGB1 rat monoclonal antibody (FIG. 17).
  • the anti-HMGB1 monoclonal antibody group and the glycerol administration group showed no difference in the presence of HMGB1 in the tissue between the TBI side and the non-injured side, but the anti-KLH antibody administration group showed no difference in the TBI side.
  • the HMGB1 band was thinner on the side. From this, it was confirmed that the anti-HMGB1 monoclonal antibody showed the same effect as the existing glycerol for the presence of HMGB1 in the cerebral cortex (FIGS. 18 and 19).
  • the therapeutic agent for traumatic neuropathy which comprises the anti-HMGB1 monoclonal antibody of the present invention as an active ingredient, is both behaviorally and histologically in percussion-injured rats. Excellent effect.
  • the present invention is extremely useful as a treatment for traumatic neuropathy that has not been particularly effective until now, especially for acute traumatic neuropathy.

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Abstract

L'invention concerne un nouveau médicament pour le traitement de troubles neurologiques traumatiques, à savoir, une lésion cérébrale traumatique ou une lésion cérébrale et/ou une lésion de la moelle épinière associée à une opération chirurgicale du cerveau. En tant que résultats d'études sur la relation entre une force physique externe appliquée sur le cerveau et HMGB1, il a été découvert pour la première fois que HMGB1, qui existait dans le noyau des cellules nerveuses à l'état normal, était libéré à l'extérieur du noyau des cellules nerveuses au niveau d'un site de lésion ou des tissus environnants. Sur la base de cette découverte, il a également été clarifié qu'une perturbation de la motilité provoquée par une lésion cérébrale traumatique ou une lésion cérébrale et/ou lésion de la moelle épinière associée à une opération chirurgicale du cerveau peut être améliorée par la capture de HMGB1 ayant été libéré hors du noyau des cellules nerveuses, permettant ainsi la mise en œuvre de la présente invention.
PCT/JP2011/077782 2010-12-03 2011-12-01 Agent thérapeutique pour des troubles neurologiques traumatiques WO2012074043A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013183494A1 (fr) 2012-06-06 2013-12-12 国立大学法人 岡山大学 Agent thérapeutique, méthode de traitement et procédé d'essai pour des maladies associées à l'activation de granulocytes neutrophiles
WO2014115430A1 (fr) 2013-01-28 2014-07-31 株式会社イーベック Anticorps anti-hmgb1 humanisé, ou fragment de liaison d'antigène de celui-ci

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007527406A (ja) * 2003-09-11 2007-09-27 クリティカル セラピューティクス，インコーポレイテッド Ｈｍｇｂ１に対するモノクローナル抗体

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09241161A (ja) * 1996-03-08 1997-09-16 Nippon Shinyaku Co Ltd 医 薬
JPH10101560A (ja) * 1996-07-10 1998-04-21 Mitsubishi Chem Corp 神経変性疾患の予防または治療薬
JPH11101560A (ja) * 1997-09-30 1999-04-13 Sanden Corp オープンショーケース
AUPQ514600A0 (en) * 2000-01-18 2000-02-10 James Cook University Brain injury treatment
US20060083734A1 (en) * 2004-10-18 2006-04-20 Henrich Cheng Composition and method for repairing nerve damage and enhancing functional recovery of nerve
US7648718B2 (en) * 2005-01-25 2010-01-19 University-Industry Cooperation Group Of Kyung Hee University Composition comprising the extract of crude drug complex having neuroprotective activity for preventing and treating stroke and neurodegenerative diseases
JP2006206490A (ja) * 2005-01-27 2006-08-10 Univ Nihon 新規化合物及びそれを含む医薬組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007527406A (ja) * 2003-09-11 2007-09-27 クリティカル セラピューティクス，インコーポレイテッド Ｈｍｇｂ１に対するモノクローナル抗体

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
COHEN, M.J. ET AL.: "Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion", CRIT CARE, vol. 13, no. 6, 2009, pages R174 *
ESPOSITO, E. ET AL.: "Melatonin reduces stress- activated/mitogen-activated protein kinases in spinal cord injury", JOURNAL OF PINEAL RESEARCH, vol. 46, no. 1, 2009, pages 79 - 86 *
HIDEAKI NAKAJIMA ET AL.: "Sonsho Sekizui ni Okeru high mobility group box-1(HMGB-1) no Dotai to Yakuwari", THE JOURNAL OF THE JAPANESE ORTHOPAEDIC ASSOCIATION, vol. 84, no. 8, August 2010 (2010-08-01), pages S1050 *
HIROKI TANAKA ET AL.: "Shinkei Saibo Shogai ni yoru Glial Saibo Kasseika ni Okeru HMGB1 no Yakuwari", THE JAPANESE PHARMACOLOGICAL SOCIETY HOKUBUKAI PROGRAM SHOROKUSHU, vol. 61, September 2010 (2010-09-01), pages 14 *
KIGERL, K.A. ET AL.: "High mobility group box-1 (HMGB1) contributes to post-traumatic spinal cord inflammation", SOCIETY FOR NEUROSCIENCE, 40TH ANNUAL MEETING, November 2010 (2010-11-01), Retrieved from the Internet <URL:http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=d600f39e-b921-47fb-90a0-3aad1e86f30c&cKey=80ce8754-blb3-462a-81be-1e31619d0eff&mKey=o7bE5D5C83F-CE2D-4D71-9DD6-FC723lE090FB%7d> [retrieved on 20111221] *
KIKUCHI, K. ET AL.: "Musanso Muto Jokenka deno Shinkeiyo Saibo ni Okeru Minocycline no HMGB1 ni Taisuru Koka", THE JAPAN SOCIETY OF NEUROTRAUMATOLOGY PROGRAM SHOROKUSHU, vol. 33, March 2010 (2010-03-01), pages 56 *
TSUYOSHI MAEKAWA ET AL.: "Shinshu no Unmei Kettei Inshi HMGB1 o Bunshi Hyoteki to shita Kyumeiteki Chiryoho no Kaihatsu Kyukyu Tobu Gaisho Kanja ni Okeru Kecchu Zuiekichu HMGB1 no Dotai to Seimei Yogo", HEISEI 18 TO 20 NENDO SOGO KENKYU HOKOKUSHO, 2009, pages 35 - 44 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013183494A1 (fr) 2012-06-06 2013-12-12 国立大学法人 岡山大学 Agent thérapeutique, méthode de traitement et procédé d'essai pour des maladies associées à l'activation de granulocytes neutrophiles
WO2014115430A1 (fr) 2013-01-28 2014-07-31 株式会社イーベック Anticorps anti-hmgb1 humanisé, ou fragment de liaison d'antigène de celui-ci
US9550825B2 (en) 2013-01-28 2017-01-24 Evec Inc. Humanized anti-HMGB1 antibody or antigen-binding fragment thereof

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