Development of monoclonal antibodies therapy for cerebral infarction and cerebral edema

• Project/Area Number: 21590594
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Okayama University
• Principal Investigator: RYU Katsuyaku 岡山大学, 大学院・医歯薬学総合研究科, 助教 (40432637)
• Co-Investigator(Kenkyū-buntansha): NISHIBORI Masahiro 岡山大学, 大学院・医歯薬学総合研究科, 教授 (50135943) ; WAKE Hidenori 岡山大学, 大学院・医歯薬学総合研究科, 助教 (60570520) ; TAKAHASHI Hideo 岡山大学, 大学院・医歯薬学総合研究科, 准教授 (60335627)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 脳梗塞 / 脳浮腫 / 抗体医薬 / 血液脳関門 / 炎症 / HMGB1 / 抗体治療

Research Abstract

High mobility group box1(HMGB1) originally identified as an architectural nuclear protein exhibits an inflammatory cytokine-like activity in the extracellular space. We showed that treatment with anti-HMGB1 monoclonal antibody(mAb) remarkably ameliorated brain infarction and edema induced by 2-hours middle cerebral artery occlusion(MCAO) in rats, even when the mAb was administered after reperfusion. Our results indicated that anti-HMGB1 mAb efficiently inhibited the development of brain edema through the protection of blood-brain barrier(BBB) structure in the ischemic region.

Research Products

• [Journal Article] Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats (2011)
  • Author(s): Zhang J, Takahashi HK, Liu K, Wake H, Liu R, Maruo T, Date I, Yoshino T, Ohtsuka A, Mori S, Nishibori M
  • Journal Title: Stroke Volume: 42(5) Pages: 1420-8
  • Peer Reviewed
• [Journal Article] High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoproteine-deficient mice (2011)
  • Author(s): Kanellakis P, Agrotis A, Kyaw TS, Koulis C, Ahrens I, Mori S, Takahashi HK, Liu K, Peter K, Nishibori M, Bobik A
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(2) Pages: 313-9
  • Peer Reviewed
• [Journal Article] Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats (2011)
  • Author(s): Zhang J.
  • Journal Title: Stroke Volume: 42(5) Pages: 1420-1428
  • Peer Reviewed
• [Journal Article] Reduction of the infarct size by simultaneous administration of L-histidine and diphenhydramine in ischaemic rat brains (2011)
  • Author(s): Adachi N.
  • Journal Title: Resuscitation Volume: 82(2) Pages: 219-2121
  • Peer Reviewed
• [Journal Article] High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein e-deficient mice (2011)
  • Author(s): Kanellakis P
  • Journal Title: Arterioscler Thromb Vase Biol Volume: 31(2) Pages: 313-319
  • Peer Reviewed
• [Journal Article] Anti-Sp100 antibody (2010)
  • Author(s): Mori S, Wake H, Liu K, Takahashi HK, Nishibori M
  • Journal Title: Nihon Rinsho Volume: 68 Suppl 6 Pages: 711-3
  • NAID: 40017181877
  • Peer Reviewed
• [Journal Article] Prostaglandin E2 inhibits advanced glycation end product induced adhesion molecule expression on monocytes, cytokine production, and lymphocyte proliferation during human mixed lymphocyte reaction (2010)
  • Author(s): Takahashi HK, Zhang J, Mori S, Liu K, Wake H, Liu R, Sadamori H, Matsuda H, Yagi T, Yoshino T, Nishibori M
  • Journal Title: J Pharmacol Exp Ther Volume: 34(3) Pages: 964-72
  • Peer Reviewed
• [Journal Article] Effect of nicotine on advanced glycation end product-induced immune response in humanmonocytes (2010)
  • Author(s): Takahashi HK, Liu K, Wake H, Mori S, Zhang J, Liu R, Yoshino T, Nishibori M
  • Journal Title: J Pharmacol Exp Ther Volume: 332(3) Pages: 1013-21
  • Peer Reviewed
• [Journal Article] Advanced glycation end products enhance monocyte activation during human mixedlymphocyte reaction (2010)
  • Author(s): Ohashi K, Takahashi HK, Mori S, Liu K, Wake H, Sadamori H, Matsuda H, Yagi T, Yoshino T, Nishibori M, Tanaka N
  • Journal Title: Clin Immunol Volume: 134(3) Pages: 345-53
  • Peer Reviewed
• [Journal Article] Beta2-adrenoceptor stimulation inhibits advanced glycation end products-induced adhesion molecule expression and cytokine production in human peripheral bloodmononuclear cells (2010)
  • Author(s): Takahashi HK, Mori S, Liu K, Wake H, Zhang J, Liu R, Yoshino T, Nishibori M
  • Journal Title: Eur J Pharmacol Volume: 627(1-3) Pages: 313-7
  • Peer Reviewed
• [Journal Article] Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression on monocytes, cytokine production, and lymphocyte proliferation during human mixed lymphocyte reaction. (2010)
  • Author(s): Takahashi HK.
  • Journal Title: J Pharmacol Exp Ther Volume: 334(3) Pages: 964-972
  • Peer Reviewed
• [Journal Article] Effect of nicotine on advanced glycation end product-induced immune response in human monocytes. (2010)
  • Author(s): Takahashi HK.
  • Journal Title: J Pharmacol Exp Ther. Volume: 332(3) Pages: 1012-1021
  • Peer Reviewed
• [Journal Article] Advanced glycation end products enhance monocyte activation during human mixed lymphocyte reaction. (2010)
  • Author(s): Ohashi K.
  • Journal Title: Clin Immunol Volume: 134(3) Pages: 345-353
  • Peer Reviewed
• [Journal Article] High mobility group box 1 complexed with heparin induced angiogenesis in a matrigelplug assay (2009)
  • Author(s): Wake H, Mori S, Liu K, Takahashi HK, Nishibori M
  • Journal Title: Acta Med Okayama Volume: 63(5) Pages: 249-62
  • NAID: 120002312983
  • Peer Reviewed
• [Journal Article] Histidine-rich glycoprotein inhibited high mobility group box 1 in complex with heparin-induced angiogenesis in matrigel plug assay (2009)
  • Author(s): Wake H, Mori S, Liu K, Takahashi HK, Nishibori M
  • Journal Title: Eur J Pharmacol Volume: 623(1-3) Pages: 89-95
  • Peer Reviewed
• [Journal Article] Establishment of in vitro binding assay of high mobility group box-1 and S100A12 to receptor for advanced glycation endproducts : heparin's effect on binding (2009)
  • Author(s): Liu R, Mori S, Wake H, Zhang J, Liu K, Izushi Y, Takahashi HK, Peng B, Nishibori M
  • Journal Title: Acta Med Okayama Volume: 63(4) Pages: 203-11
  • NAID: 120002312782
  • Peer Reviewed
• [Journal Article] Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression, cytokine production, and lymphocyte proliferation in human peripheral blood mononuclear cells (2009)
  • Author(s): Takahashi HK, Liu K, Wake H, Mori S, Zhang J, Liu R, Yoshino T, Nishibori M
  • Journal Title: J Pharmacol Exp Ther Volume: 331(2) Pages: 656-70
  • Peer Reviewed
• [Journal Article] Histamine inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes (2009)
  • Author(s): Wake H, Takahashi HK, Mori S, Liu K, Yoshino T, Nishibori M
  • Journal Title: J Pharmacol Exp Ther Volume: 330(3) Pages: 826-33
  • Peer Reviewed
• [Journal Article] Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells (2009)
  • Author(s): Takahashi HK, Mori S, Wake H, Liu K, Yoshino T, Ohashi K, Tanaka N, Shikata K, Makino H, Nishibori M
  • Journal Title: J Pharmacol Exp Ther Volume: 330(1) Pages: 89-98
  • Peer Reviewed
• [Journal Article] Therapeutic effect of anti-nucleokine monoclonal antibody on ischemic braininfarction (2009)
  • Author(s): Mori S, Liu K, Takahashi HK, Nishibori M
  • Journal Title: Yakugaku Zasshi Volume: 129(1) Pages: 25-31
  • NAID: 110007028557
  • Peer Reviewed
• [Journal Article] Therapeutic effect of anti-nucleokine monoclonal antibody on ischemic brain infarction (2009)
  • Author(s): Mori S, Liu K, Takahashi HK, Nishibori M.
  • Journal Title: Yakugaku Zasshi 129(1) Pages: 25-31
  • NAID: 110007028557
  • Peer Reviewed
• [Journal Article] Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. (2009)
  • Author(s): Takahashi HK, Mori S, Wake H, Liu K, Yoshino T, Ohashi K, Tanaka N, Shikata K, Makino H, Nishibori M.
  • Journal Title: J Pharmacol Exp Ther 330(1) Pages: 89-98
  • Peer Reviewed
• [Journal Article] Establishment of in vitro binding assay of high mobility group box-1 and S100A12 to receptor for advanced glycation endproducts : heparin's effect on binding. (2009)
  • Author(s): Liu R, Mori S, Wake H, Zhang J, Liu K, Izushi Y, Takahashi HK, Peng B, Nishibori M.
  • Journal Title: Acta Med Okayama. 63(4) Pages: 203-211
  • NAID: 120002312782
  • Peer Reviewed
• [Journal Article] Anti-High Mobility Group Box-1Antibody Therapy for Traumatic Brain Injury
  • Author(s): Okuma, Y
  • Journal Title: Annals of Neurology Volume: (in press)
• [Presentation] Tracking the Leakage of Albumin in BBB-disrupted ischemia (2012)
  • Author(s): 劉克約
  • Organizer: 第85回薬理学年会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2012-03-14
• [Presentation] 抗HMGB1抗体は脳虚血誘発性の血液-脳関門破綻を防ぐ (2011)
  • Author(s): 劉克約, 他
  • Organizer: 第119回日本薬理学会近畿部会
  • Place of Presentation: 愛知県産業労働センター
  • Year and Date: 2011-07-08
• [Presentation] 抗HMGB1抗体は脳虚血誘発性の血液-脳関門破綻を防ぐ (2011)
  • Author(s): 劉克約
  • Organizer: 第119回薬理学会近畿部会
  • Place of Presentation: 名古屋ウィンク愛知
  • Year and Date: 2011-07-08
• [Presentation] 脳虚血早期におけるHMGB1の動態 (2011)
  • Author(s): 劉克約, 他
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-03-22
• [Presentation] Protective effect of anti-HMGB1 antibody on the increase in BBB permeability in rat MCAO model (2011)
  • Author(s): 劉克約
  • Organizer: 第84回日本薬理学会
  • Place of Presentation: パシフィコ横浜会議センター
  • Year and Date: 2011-03-22
• [Presentation] ヒスチジンとジフェンヒドラミン併用による脳梗塞縮小効果 (2010)
  • Author(s): 劉克約, 他
  • Organizer: 第14回日本ヒスタミン学会
  • Place of Presentation: 神奈川川崎グランドホテル
  • Year and Date: 2010-10-24
• [Presentation] Anti-high mobility group box1 monoclonal antibody protects blood-brain barrier from ischemic insult in rat (2010)
  • Author(s): 劉克約, 他
  • Organizer: 14th International Congress Of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-26
• [Presentation] Anti-high mobility group boxl monoclonal antibody protects blood-brain barrier from ischemic insult in rats (2010)
  • Author(s): 劉克約
  • Organizer: 国際免疫学会
  • Place of Presentation: 神戸国際展示場
  • Year and Date: 2010-08-24
• [Presentation] Disruption of BBB in rat MCAO and a protective effect of anti-HMGB1 antibody (2010)
  • Author(s): 劉克約, 他
  • Organizer: 16th World Congress on Basic and Clinical Pharmacology
  • Place of Presentation: Bella Center Copenhagen, Denmark
  • Year and Date: 2010-07-19
• [Presentation] Disruption of BBB in rat MCAO and a protective effect of anti-HMGB1 antibody (2010)
  • Author(s): 劉克約
  • Organizer: 国際薬理学会
  • Place of Presentation: コペンハーゲン
  • Year and Date: 2010-07-19
• [Presentation] ラット中大脳動脈閉塞・再灌流モデルにおける抗HMGB1単クローン抗体の効果:脳血管透過性亢進に対する影響 (2010)
  • Author(s): 劉克約, 他
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2010-03-18
• [Presentation] ラット中大脳動脈閉塞・再灌流モデルにおける抗HMGB1単クローン抗体の効果 : 脳血管透過性亢進に対する影響 (2010)
  • Author(s): 劉克約
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2010-03-18
• [Patent(Industrial Property Rights)] 外傷性神経障害治療剤 (2010)
  • Inventor(s): 西堀正洋、森秀治、高橋英夫、和氣秀徳、劉克約、伊達勲、大熊佑、友野靖子
  • Industrial Property Rights Holder: 西堀正洋、森秀治、高橋英夫、和氣秀徳、劉克約、伊達勲、大熊佑、友野靖子
  • Industrial Property Number: 2010-270133
  • Filing Date: 2010-12-03
• [Patent(Industrial Property Rights)] RAGEとAGEの結合抑制剤のスクリーニング方法 (2010)
  • Inventor(s): 西堀正洋、森秀治、高橋英夫、和氣秀徳、劉克約
  • Industrial Property Rights Holder: 西堀正洋、森秀治、高橋英夫、和氣秀徳、劉克約
  • Industrial Property Number: 2010-214019
  • Filing Date: 2010-09-24
• [Patent(Industrial Property Rights)] アデローム動脈硬化抑制剤 (2009)
  • Inventor(s): 西堀正洋、森秀治、高橋英夫、友野靖子、足立尚登、劉克約
  • Industrial Property Rights Holder: 岡山大学
  • Industrial Property Number: 2009-223472
  • Filing Date: 2009-09-28