Top > Search of International Patents > MEDICINE COMPRISING MODULATOR OF ACTIVITY OF CD300a-EXPRESSING CELL ASSOCIATED WITH ALLERGIC DISEASE, CD300a GENE KNOCK-OUT MOUSE, AND USE OF MODULATOR OF ACTIVITY OF CD300a-EXPRESSING CELL

MEDICINE COMPRISING MODULATOR OF ACTIVITY OF CD300a-EXPRESSING CELL ASSOCIATED WITH ALLERGIC DISEASE, CD300a GENE KNOCK-OUT MOUSE, AND USE OF MODULATOR OF ACTIVITY OF CD300a-EXPRESSING CELL

Foreign code F150008173
Posted date Mar 19, 2015
Country WIPO
International application number 2013JP079890
International publication number WO 2014073529
Date of international filing Nov 5, 2013
Date of international publication May 15, 2014
Priority data
  • P2012-245816 (Nov 7, 2012) JP
Title MEDICINE COMPRISING MODULATOR OF ACTIVITY OF CD300a-EXPRESSING CELL ASSOCIATED WITH ALLERGIC DISEASE, CD300a GENE KNOCK-OUT MOUSE, AND USE OF MODULATOR OF ACTIVITY OF CD300a-EXPRESSING CELL
Abstract Provided are: a medicine for an allergic disease (e.g., atopic dermatitis, asthma); and a tool useful for the analysis of a clinical condition of an allergic disease. A medicine, which contains a substance capable of inhibiting the binding between CD300a and phosphatidyl serine and comprises, as an active ingredient, an activity modulator that can inhibit the inhibitory signal transduction of a myeloid cell capable of expressing CD300a, can be used for treating or preventing an allergic disease. A CD300a gene knock-out mouse can be used for analyzing a clinical condition of an allergic disease or screening for a candidate substance that can act as an active ingredient for a therapeutic or prophylactic agent for the allergic disease, as a model mouse that rarely develops the allergic disease when a substance capable of inducing the allergic disease is administered to the mouse.
Outline of related art and contending technology BACKGROUND ART
Host (human or animal body) the pathogen (bacteria, virus, parasite or the like) invasion, endogenous disease-body and the materials are produced, a site of pathogenic infestation or disease-material generated at the site of arterioles after temporarily contraction, expansion, to reach a hyperemia, a site of pathogenic infestation or disease-site material generated locally becomes slow blood flow such as inflammatory reaction may occur.
Then, leukocytes stuck to the vessel wall, immune system is configured to output various is released from cells by the action of, an ameba-like movement through the vessel wall to migrate. As , histamine, serotonin, lymphokines and the like are known. Histamine or serotonin production, mast cells release, plays a central role in inflammatory response is one of the lymphocytes. In addition, in the same manner as mast cells such as macrophages also produce TNF , release.
By the inflammatory response, such as leukocyte migration and is attracted to the pathogen, a pathogen antigen-antibody reaction with humoral immunity and cytotoxic T cells and so involved by cellular immunity, pathogen (clearance) and cleared from the body, is prevented from being spread. In this way, based on the acquired immune response and inflammatory response, in order to maintain homeostasis of the living body is of essential importance.
On the other hand, the inflammatory response, as described above and bio-defence, redness, heat, swelling, pain, dysfunction problems such as the signs, symptoms may indicate. As such a condition, specifically, allergic diseases, and various acute or chronic inflammation. In addition, immunological tolerance is not applied, self-immune occurs even in case the autoimmune disease, tissue injury occurs in the inflammatory response.
That is, preventing a disease associated with the inflammatory response, inflammatory response and trigger various pathogens killed by the antibiotic (antimicrobial agent) as such, to improve the immune function in vivo drug administration, before the excess inflammatory response enhancement, it is important to remove the pathogen.
On the other hand, improvement in a disease associated with inflammatory response, the treatment of, for example, inhibit the release of the such as, over-activated agents that reduce the immune function after administration of the (anti-inflammatory agent), is the result of inflammation can be known.
For example, Patent Document 1 is, as immune activity, various immune system cells as an antigen presenting cell activating function activation of dendritic cells is disclosed, specifically, isoleucine, leucine and valine 1 of at least one selected from a branched chain amino acid characterized in that the active ingredient according to the present invention.
Patent Document 2 is, as anti-inflammatory agents, peptides and pharmacologically SPARC (Secreted prоtein which is acidic and rich in cystein) carrier agent is disclosed.
However, responsible for the innate immune system cells (myeloid) system is on the cell membrane, referred to as a receptor molecule MAIR(Myeloid Associated Ig like Receptors) group is known to be expressed (non-patent document 1). Among these, also known as CD300a (other 'LMIR1', 'CLM-8' and may be called a) MAIR-I is, macrophages, mast cells, granulocytes (neutrophils), and expressed by dendritic cells, via a sequence ITIM(Immunoreceptor tyrosine-based inhibitory motif) of intracellular region associated with the phosphatase, inhibitory signals that are known to be inhibitory receptor (non-patent document 2) are. However, the ligand for a receptor is unknown, there has been a so-called orphan receptors.
Atopic dermatitis is, allergenic material enters the body (antigen), secreted from activated immune cells (interleukin 4, 13) material is made is a fibroblast stimulation, the surface of the skin keratinocytes' integrin ' another protein can be bonded to the cause can cause inflammation.
New by the binding of the integrin to a fibroblast proinflammatory agent is produced, even without the antigen to improved and continued and chronic. Experiment using mice, by an inhibitor of binding of the integrin to a fibroblast inhibition, does not take place any atopic dermatitis is shown (non-patent document 3).
Atopic dermatitis but it became clear that the main etiology, further elucidation of the disease state of atopic dermatitis and other inflammatory disease and analyzing the association, can be used in combination with an inhibitor of the medicament for atopic dermatitis and the like has been desired.
On the other hand, bronchial asthma and allergic reactions (Bronchial Asthma) or a bacterium, virus infection is a chronic inflammation of the bronchi which gave rise to the embodiment of the enhancement of airway hyperresponsiveness, airway constriction and is thus reversible, attack such as wheezing, coughing and interfering with the symptoms of a respiratory disease. Also, bronchial asthma, airway hyperresponsiveness, allergic constitution, it is assumed that a combination of environment occurs. To dictate the notification, apnea, recurrent symptoms such as chest tightness and cough in the form of expression, particularly night or early morning appears.
Many cells and cell components, particularly mast cells, eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells, plays a role in airway inflammation. Inflammation, plasma exudate, edema, smooth muscle hypertrophy, mucus and epithelial changes infarction (mucus plugging) the filler is associated with. In addition, inflammation may be, is present for the variety of stimuli causing an increase in the associated bronchial hyperresponsiveness.
Airway inflammation, airway smooth muscle atrophy, leading to rupture of small blood vessels and bronchial hyperresponsiveness. Of the airway reactivity is high and reacts, symptoms are more heavy, and continuously, the size of the lung function of the variation of greater than during the day. Bronchial airway inflammation is associated with the reactivity of the mechanism is unknown, and a useful tool in the elucidation of the pathophysiology of asthma, medical supplies and the like has been desired.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 CD300aとホスファチジルセリンの結合を阻害する物質を含有する、CD300aを発現するミエロイド系細胞の抑制性シグナル伝達を抑制するための活性調節剤を有効成分として含有することを特徴とする、アレルギー疾患を治療または予防するための医薬品。

[請求項2]
 前記CD300aとホスファチジルセリンの結合を阻害する物質がホスファチジルセリン結合性物質である、請求項1に記載の医薬品。

[請求項3]
 前記ホスファチジルセリン結合性物質が、MFG-E8、MFG-E8変異体(D89E MFG-E8)、T細胞免疫グロブリン、可溶型TIM-1、可溶型TIM-4、可溶型スタビリンおよび可溶型インテグリンαvβ3からなる群から選択される少なくとも1種類である、請求項2に記載の医薬品。

[請求項4]
 前記CD300aとホスファチジルセリンの結合を阻害する物質がCD300a結合性物質である、請求項1に記載の医薬品。

[請求項5]
 前記CD300a結合性物質が、配列番号3で表されるアミノ酸配列または当該アミノ酸配列に対して1,2,3,4または5個のアミノ酸の置換、付加、挿入または欠失を有するアミノ酸配列からなるH鎖可変領域と、配列番号4で表されるアミノ酸配列または当該アミノ酸配列に対して1,2,3,4または5個のアミノ酸の置換、付加、挿入または欠失を有するアミノ酸配列からなるL鎖可変領域とを有する、抗ヒトCD300a抗体である、請求項4に記載の医薬品。

[請求項6]
 前記CD300a結合性物質が、配列番号1で表されるアミノ酸配列または当該アミノ酸配列に対して1,2,3,4または5個のアミノ酸の置換、付加、挿入または欠失を有するアミノ酸配列からなるH鎖可変領域と、配列番号2で表されるアミノ酸配列または当該アミノ酸配列に対して1,2,3,4または5個のアミノ酸の置換、付加、挿入または欠失を有するアミノ酸配列からなるL鎖可変領域とを有する、抗マウスCD300a抗体である、請求項4に記載の医薬品。

[請求項7]
 前記アレルギー疾患が、アトピー性皮膚炎または喘息である、請求項1~6のいずれかに記載の医薬品。

[請求項8]
 アレルギー疾患について、病態解析を行うための、またはその治療薬もしくは予防薬の有効成分となりうる候補物質をスクリーニングするための、CD300a遺伝子欠損マウスの使用であって、
 前記CD300a遺伝子欠損マウスを、アレルギー疾患を誘導させる物質を投与したときにアレルギー疾患を誘発しにくいモデルマウスとして使用することを特徴とする、CD300a遺伝子欠損マウスの使用。

[請求項9]
 アレルギー疾患について、病態解析を行う際、またはその治療薬もしくは予防薬の有効成分となりうる候補物質をスクリーニングする際の、比較解析用のツールとしての、
 CD300aとホスファチジルセリンの結合を亢進する物質を含有する、CD300aを発現するミエロイド系細胞の抑制性シグナル伝達を亢進するための活性調節剤の使用。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • UNIVERSITY OF TSUKUBA
  • Inventor
  • SHIBUYA, Akira
  • ODA, Chigusa
  • KANKANAM GAMAGE, Udayanga Sanath
  • MIKI, Haruka
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN TD TG
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