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Novel regulatory mechanism of human Toll-like receptor 4 function by the inhibitory monoclonal antibody

Research Project

Project/Area Number 24790112
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Drug development chemistry
Research InstitutionTohoku University (2013)
Saga University (2012)

Principal Investigator

TSUKAMOTO HIROKI  東北大学, 薬学研究科(研究院), 助教 (70423605)

Project Period (FY) 2012-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
KeywordsTLR4 / MD-2 / リポ多糖 / モノクローナル抗体 / 敗血症 / 抗体医薬 / 免疫学
Research Abstract

In this study, novel inhibitory monoclonal antibodies against human Toll-like receptor 4 (TLR4), which are potential leading antibodies for anti-sepsis antibody drugs, were developed. These antibodies inhibited the production of proinflammatory cytokines, the upregulation of costimulatory molecules and the activation of NF-kappaB in lipopolysaccharide (LPS)-stimulated cells such as human peripheral blood mononuclear cells. The inhibitory activities were mediated by novel mechanism that is the induction of inactive TLR4 oligomerization, the inhibition of LPS-induced TLR4 internalization, but not the inhibition of TLR4-LPS binding. In addition, the epitope to which the binding of antibody inhibits the TLR4 function was found on extracellular domain of TLR4 independently of MD-2. Identification and chracterization of this epitope may provide a promising drug discovery target sturucture for the development of anti-septic antibody drugs.

Report

(3 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • Research Products

    (31 results)

All 2014 2013 2012 Other

All Journal Article (11 results) (of which Peer Reviewed: 11 results) Presentation (14 results) (of which Invited: 2 results) Book (4 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] A validated quantitative liquid chromatography-tandem quadrupole mass spectrometry method for monitoring isotopologues to evaluate global modified cytosine ratios in genomic DNA2014

    • Author(s)
      Tsuji M, Matsunaga H, Jinno D, Tsukamoto H, Suzuki N, Tomioka Y
    • Journal Title

      J Chromatogr B Analyt Technol Biomed Life Sci

      Volume: 953-954 Pages: 38-47

    • DOI

      10.1016/j.jchromb.2014.01.050

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] An assay for alpha1,6-fucosyltransferase (FUT8) activity based on the HPLC separation of a reaction product with fluorescence detection.2013

    • Author(s)
      Ihara H, Tsukamoto H, Taniguchi N, Ikeda Y
    • Journal Title

      Methods Mol. Biol.

      Volume: 1022 Pages: 335-348

    • DOI

      10.1007/978-1-62703-465-4_25

    • ISBN
      9781627034647, 9781627034654
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] A Delicate Balance–CD73 generated adenosine limits the severity of graft vs. host disease, but also constrains the allogeneic graft vs. tumor effect2013

    • Author(s)
      Thompson LF, Tsukamoto H, Chernogorova P, Zeiser R
    • Journal Title

      OncoImmunology

      Volume: 2(1) Issue: 1 Pages: 22107-22107

    • DOI

      10.4161/onci.22107

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] MD-2-dependent human Toll-like receptor 4 monoclonal antibodies detect extracellular association of Toll-like receptor 4 with extrinsic soluble MD-2 on the cell surface.2013

    • Author(s)
      Tsukamoto H, Ihara H, Ito R, Ukai I, Suzuki N, Kimoto M, Tomioka Y, Ikeda Y
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 440 Issue: 1 Pages: 31-36

    • DOI

      10.1016/j.bbrc.2013.09.004

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Difucosylation of chitooligosaccharides by eukaryote and prokaryote alpha1,6-fucosyltransferases.2013

    • Author(s)
      Ihara H, Hanashima S, Tsukamoto H, Yamaguchi Y, Taniguchi N, Ikeda Y
    • Journal Title

      Biochim. Biophys. Acta

      Volume: 1830 Issue: 10 Pages: 4482-4490

    • DOI

      10.1016/j.bbagen.2013.05.013

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of antibody production in vivo by pre-stimulation of Toll-like receptor 4 before antigen priming is caused by defective B cell priming and not impairment in antigen presentation.2013

    • Author(s)
      Nurlaely Mida Rachmawati, Kenji Fukudome, Naoko Tsuneyoshi, Uleng Bahrun, Hiroki Tsukamoto, Tsutomu Yanagibashi, Yoshinori Nagai, Kiyoshi Takatsu, Shoichiro Ohta, and Masao Kimoto
    • Journal Title

      International Immunology

      Volume: 25 Issue: 2 Pages: 117-128

    • DOI

      10.1093/intimm/dxs096

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Reduced surface expression of TLR4 by a V254I point mutation accounts for the low lipopolysaccharide responder phenotype of BALB/c B cells.2013

    • Author(s)
      Tsukamoto H, Fukudome K, Takao S, Tsuneyoshi N, Ohta S, Nagai Y, Ihara H, Miyake K, Ikeda Y, Kimoto M
    • Journal Title

      J. Immunol.

      Volume: 190 Issue: 1 Pages: 195-204

    • DOI

      10.4049/jimmunol.1201047

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Delicate Balance: CD73-generated adenosine limits the severity of graft vs. host disease, but also constrains the allogeneic graft vs. tumor effect2013

    • Author(s)
      Thompson LF, Tsukamoto H, Chernogorova P, Zeiser R
    • Journal Title

      OncoImmunology

      Volume: 2

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Multiple potential regulatory sites of TLR4 activation induced by LPS as revealed by novel inhibitory human TLR4 mAbs.2012

    • Author(s)
      Tsukamoto H, Fukudome K, Takao S, Tsuneyoshi N, Ihara H, Ikeda Y, Kimoto M
    • Journal Title

      Int. Immunol.

      Volume: 24 Issue: 8 Pages: 495-506

    • DOI

      10.1093/intimm/dxs053

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Measurement of Peroxiredoxin-4 in Rat Tissues and Implication of Its Serum Levels as a Potential Marker for Hepatic Disease.2012

    • Author(s)
      Ritsu Ito
    • Journal Title

      Mol Med Report

      Volume: 6 Issue: 2 Pages: 379-384

    • DOI

      10.3892/mmr.2012.935

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease2012

    • Author(s)
      Tsukamoto H, Chernogorova P, Ayata K, Gerlach UV, Rughani A, Ritchey JW, Ganesan J, Follo M, Zeiser R, Thompson LF, Idzko M
    • Journal Title

      Blood

      Volume: 119(19) Issue: 19 Pages: 4554-4564

    • DOI

      10.1182/blood-2011-09-375899

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Presentation] 抗1-methyladenosine抗体反応性分子の同定を目的としたtRNA分子種の解析法に関する研究2014

    • Author(s)
      津久井佑梨、陣野大輔、三島英換、鈴木直人、塚本宏樹、三枝大輔、伊藤邦彦、阿部高明、富岡佳久
    • Organizer
      日本薬学会第134年会
    • Place of Presentation
      熊本
    • Year and Date
      2014-03-28
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] リコカルコンAのCOX-1活性抑制メカニズムの解明2014

    • Author(s)
      菅原大貴、田代匠、三枝大輔、塚本宏樹、奥田亜沙、小原祐太郎、鈴木直人、富岡佳久
    • Organizer
      日本薬学会第134年会
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] 新規腎障害マーカーとしての1-メチルアデノシンの検討2013

    • Author(s)
      陣野大輔、鈴木直人、津久井佑梨、三枝大輔、三島英換、鈴木千登世、塚本宏樹、阿部高明、富岡佳久
    • Organizer
      第52回日本薬学会東北支部大会
    • Place of Presentation
      仙台
    • Year and Date
      2013-10-20
    • Related Report
      2013 Final Research Report
  • [Presentation] LC/ESI‐MSを用いた血清胸腺因子(FTS)定量法の開発2013

    • Author(s)
      中曽根正皓、鈴木直人、金光祥臣、塚本宏樹、富岡佳久
    • Organizer
      第52回日本薬学会東北支部大会
    • Place of Presentation
      仙台
    • Year and Date
      2013-10-20
    • Related Report
      2013 Final Research Report
  • [Presentation] MD-2-dependent and lipopolysaccharide-induced conformation change-sensitive monoclonal antibodies detect extracellular association of human toll-like receptor 4 with soluble MD-2 on cell surface2013

    • Author(s)
      Tsukamoto H, Ukai I, Kimoto M
    • Organizer
      第42回日本免疫学会総会・学術集会
    • Place of Presentation
      千葉
    • Related Report
      2013 Final Research Report
  • [Presentation] MD-2-dependent and lipopolysaccharide-induced conformation change-sensitive monoclonal antibodies detect extracellular association of human toll-like receptor 4 with soluble MD-2 on cell surface2013

    • Author(s)
      Tsukamoto H, Ukai I, Kimoto M
    • Organizer
      第42回日本免疫学会総会・学術集会
    • Place of Presentation
      幕張メッセ(千葉)
    • Related Report
      2013 Annual Research Report
  • [Presentation] Reduced surface expression of TLR4 by a V254I point mutation may account for the low LPS responder phenotype of BALB/c B cells2012

    • Author(s)
      Tsukamoto H, Fukudome K, Takao S, Tsuneyoshi N, Ohta S, Nagai Y, Ihara H, Miyake K, Ikeda Y, Kimoto M
    • Organizer
      第85回日本生化学会大会
    • Place of Presentation
      福岡
    • Related Report
      2013 Final Research Report 2012 Research-status Report
  • [Presentation] Enzymatic synthesis of di-fucosylated chitooligosaccharide by human and rhizobiaα1,6-fucosyltransferases2012

    • Author(s)
      Ihara H, Hanashima S, Tsukamoto H, Yamaguchi Y, Taniguchi N, Ikeda Y
    • Organizer
      第85回日本生化学会大会
    • Place of Presentation
      福岡
    • Related Report
      2013 Final Research Report
  • [Presentation] Inhibition of antibody production in vivo by pre-injection of agonistic anti-TLR4/MD-2 monoclonal antibody before antigen priming is caused not by impairment in antigen presentation but by defective B cell priming2012

    • Author(s)
      Rachmawati NM, Fukudome K, Tsuneyoshi N, Bahrun U, Tsukamoto H, Ohta S, Kimoto M
    • Organizer
      第41回日本免疫学会総会・学術集会
    • Place of Presentation
      神戸
    • Related Report
      2013 Final Research Report 2012 Research-status Report
  • [Presentation] Enzymatic synthesis of di-fucosylated chitooligosaccharide by human and rhizobia α1,6-fucosyltransferases2012

    • Author(s)
      Ihara H, Hanashima S, Tsukamoto H, Yamaguchi Y, Taniguchi N, Ikeda Y
    • Organizer
      第85回日本生化学会大会
    • Place of Presentation
      福岡
    • Related Report
      2012 Research-status Report
  • [Presentation] 新規腎障害マーカーとしての1-メチルアデノシンの検討

    • Author(s)
      陣野大輔、鈴木直人、津久井佑梨、三枝大輔、三島英換、鈴木千登世、塚本宏樹、阿部高明、富岡佳久
    • Organizer
      第52回日本薬学会東北支部大会
    • Place of Presentation
      東北大学(仙台)
    • Related Report
      2013 Annual Research Report
  • [Presentation] LC/ESI‐MS を用いた血清胸腺因子(FTS)定量法の開発

    • Author(s)
      中曽根正皓、鈴木直人、金光祥臣、塚本宏樹、富岡佳久
    • Organizer
      第52回日本薬学会東北支部大会
    • Place of Presentation
      東北大学(仙台)
    • Related Report
      2013 Annual Research Report
  • [Presentation] Graft‐versus‐host diseaseにおけるCD73と細胞外アデノシンの役割

    • Author(s)
      塚本宏樹
    • Organizer
      第12回医療薬学若手研究者セミナーシンポジスト
    • Place of Presentation
      東北大学(仙台)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 移植片対宿主病と移植片対腫瘍効果における細胞外アデノシン産生系の機能解析とその薬学的制御に関する研究

    • Author(s)
      塚本宏樹
    • Organizer
      東北薬学セミナー奨励賞受賞講演
    • Place of Presentation
      東北薬科大学(仙台)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Book] Handbook of Glycosyltransferases and Related Genes, Mannosyl (β-1,4-)-glycoproteinβ-1,4-N-acetylglucosaminyltransferase (MGAT3);β1,4-N-Acetylglucosaminyltransferase III (GnT-III, GlcNAc-T III)(Taniguchi N, Honke K, Fukuda M, Narimatsu H, Yamaguchi Y, Angata T, eds)2014

    • Author(s)
      Ikeda Y, Ihara H, Tsukamoto H, Gu J, Taniguchi N
    • Publisher
      Springer Japan (Tokyo, Japan)
    • Related Report
      2013 Final Research Report
  • [Book] Handbook of Glycosyltransferases and Related Genes(FUT8), Fucosyltransferase 8. GDP-fucose N-glycan coreα6-fucosyltransferase(Taniguchi N, Honke K, Fukuda M, Narimatsu H, Yamaguchi Y, Angata T, eds)2014

    • Author(s)
      Ihara H, Tsukamoto H, Gu J, Miyoshi E, Taniguchi N, Ikeda Y
    • Publisher
      Springer Japan (Tokyo, Japan)
    • Related Report
      2013 Final Research Report
  • [Book] Handbook of Glycosyltransferases and Related Genes, 2nd ed2014

    • Author(s)
      Ihara H, Tsukamoto H, Gu J, Miyoshi E, Taniguchi N, Ikeda Y
    • Total Pages
      1717
    • Publisher
      Springer Japan
    • Related Report
      2013 Annual Research Report
  • [Book] Handbook of Glycosyltransferases and Related Genes, 2nd ed2014

    • Author(s)
      Ikeda Y, Ihara H, Tsukamoto H, Gu J, Taniguchi N
    • Total Pages
      1717
    • Publisher
      Springer Japan
    • Related Report
      2013 Annual Research Report
  • [Patent(Industrial Property Rights)] 炎症治療用医薬組成物2012

    • Inventor(s)
      木本雅夫、塚本宏樹、福留健司、常吉直子
    • Industrial Property Rights Holder
      佐賀大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2012-06-15
    • Related Report
      2013 Final Research Report
  • [Patent(Industrial Property Rights)] 炎症治療用医薬組成物2012

    • Inventor(s)
      木本雅夫、塚本宏樹、福留健司、常吉直子
    • Industrial Property Rights Holder
      佐賀大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2012-06-15
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2023-03-16  

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