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• 2004年

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  2007年

  札幌医科大学   医学部   分子医学研究部門  

• 1994年

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  1997年

  北海道大学   医学部   第2内科  

• 　

  -

  1988年

  Sho-oh Life Science   Clinical laboratory test technology school subject  

• 　

  -

  1988年

  湘央学園   臨床検査技術学科  

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• 札幌医科大学   医学博士

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• 2008年05月

  -

  継続中

  札幌医科大学   フロンティア医学研究所 分子医学部門   助教

  助教

• 1996年05月

  -

  2008年04月

  北海道赤十字血液センター   研究部  

• 1996年

  　

  　

  - Hokkaido Red Cross BLood Center  

• 1993年

  -

  1996年

  Kishimoto Clinical Laboratory  

• 1993年

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  1996年

  岸本医科学研究所 研究員  

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• 　

  　

  　

  Japanese Journal of Transfusion Medicine

• 　

  　

  　

  日本血液学会

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  日本癌学会

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  日本輸血学会

• 　

  　

  　

  Japanese Society of Hematology

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• ライフサイエンス   腫瘍診断、治療学  

• ライフサイエンス   細胞生物学  

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• 札幌医科大学   フロンティア医学研究所 分子医学部門   助教  

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• expansion

• 抗体薬剤(毒素)結合体（ADC）

• 抗体療法

• Mast cells

• Stem cells

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• A newly developed anti-Mucin 13 monoclonal antibody targets pancreatic ductal adenocarcinoma cells

  Yukari Nishii, Miki Yamaguchi, Yasutoshi Kimura, Tadashi Hasegawa, Hiroyuki Aburatani, Hiroaki Uchida, Koichi Hirata, Yuji Sakuma

  INTERNATIONAL JOURNAL OF ONCOLOGY ( SPANDIDOS PUBL LTD )  46 ( 4 ) 1781 - 1787  2015年04月  [査読有り]

  　概要を見る

  Pancreatic cancer is one of the most severe forms of malignancy. Patients with unresectable or metastatic pancreatic cancer usually receive chemotherapy that causes various adverse effects. Antibody-drug conjugates (ADCs), drugs developed by conjugating an anticancer agent to a monoclonal antibody (mAb), can alleviate the side effects of chemotherapy because ADCs selectively bind to cancer cells expressing a particular antigen. We recently developed the recombinant protein DT3C comprising diphtheria toxin (DT) lacking the receptor-binding domain but containing the Cl, C2, and C3 domains of Streptococcus protein G (3C). The mAb-DT3C conjugates can be used to select mAbs that are internalized by cells, because the conjugates decrease cell viability only when they are internalized by cells through Ab-antigen reactions. We developed a new mAb to be internalized by TCC-PAN2 cells, a pancreatic carcinoma cell line. The mAb, designated TCC56, recognized Mucin 13 (MUC13), while TCC56-DT3C conjugates induced cell death in TCC-PAN2 cells expressing MUC13. We found that MUC13 was expressed, at least partially, in all 40 pancreatic ductal carcinoma tissues and adjacent non-cancerous tissues analyzed. The expression levels of MUC13 in pancreatic cancer tissues were greater than those in normal tissues. Our findings suggest that MUC13 can be a target molecule for pancreatic cancer treatment. ADCs, including mAb TCC56, could be promising anticancer agents to alleviate the adverse effects of chemotherapy.

  DOI

• Pr1E11, a novel anti-TROP-2 antibody isolated by adenovirus-based antibody screening, recognizes a unique epitope

  Masahiro Ikeda, Miki Yamaguchi, Kazunori Kato, Kiminori Nakamura, Sagano Shiina, Takako Ichikawa-Ando, Hirofumi Misaka, Kensuke Myojo, Kazuyasu Nakamura, Yoshiyuki Sugimoto, Hirofumi Hamada

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE )  458 ( 4 ) 877 - 882  2015年03月  [査読有り]

  　概要を見る

  TROP-2 is a type I transmembrane glycoprotein that is highly expressed in various epithelial cancer cells, and its increased expression correlates with poor prognosis. Although several anti-TROP-2 antibodies have been described, they were found unsuitable for antitumor therapy use in vivo as naked antibodies. In this study, we established a novel anti-TROP-2 antibody, designated Pr1 E11, from mice immunized with primary prostate cancer cells. Antibody screening was based on the infection activity of Adv-LacZ-FZ33, which displays an immunoglobulin G binding domain in the adenoviral fiber protein. We found that Pr1 E11 specifically binds to TROP-2 with high affinity and recognizes diverse epithelial cancer cell lines and primary pancreatic cancer tissues. Epitope analysis using TROP-2 deletion mutants revealed that binding site of Pr1 E11 is a cysteine-rich domain, a unique epitope compared with other available anti-TROP-2 antibodies. In addition, Pr1 E11 exhibited low internalization activity, which may make it suitable for naked antibody therapeutics. Our results suggest that Pr1 E11 may stimulate different biological activities from other anti-TROP-2 antibodies based on its unique binding epitope, and is a potential candidate for naked antibody therapeutics for various epithelial cancer treatments. (C) 2015 Elsevier Inc. All rights reserved.

  DOI

• Development of a sensitive screening method for selecting monoclonal antibodies to be internalized by cells

  Mild Yamaguchi, Yukari Nishii, Kiminori Nakamura, Haruka Aoki, Sachie Hirai, Hiroaki Uchida, Yuji Sakuma, Hirofumi Hamada

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE )  454 ( 4 ) 600 - 603  2014年11月  [査読有り]

  　概要を見る

  Antibody-drug conjugates (ADCs), drugs developed by conjugation of an anticancer agent to a monoclonal antibody (mAb), have lately attracted attention in cancer therapy because ADCs can directly bind cancer cells and kill them. Although mAbs for ADCs must be internalized by the target cells, few methods are available for screening mAbs for their ability to be internalized by cells. We have developed a recombinant protein, termed DT3C, which consists of diphtheria toxin (DT) lacking the receptor-binding domain but containing the Cl, C2, and C3 domains of Streptococcus protein G (3C). When a mAb-DT3C conjugate, which functions in vitro like an ADC, reduces the viability of cancer cells, the mAb being tested must have been internalized by the target cells. DT3C can thus be a tool to identify efficiently and easily mAbs that can be internalized by cells, thereby enhancing the development of promising ADCs. (C) 2014 Elsevier Inc. All rights reserved.

  DOI

• Bone Marrow Stromal Cell Line Promotes the Proliferation of Mast Cell Progenitors Derived from Cord Blood CD34(+) Cells under Serum-free Conditions with a Combination of Both Cell-cell Interaction and Soluble Factors

  Mitsuhiro Fujihara, Hiroshi Azuma, Hisami Ikeda, Miki Yamaguchi, Hirofumi Hamada

  ARTIFICIAL CELLS BLOOD SUBSTITUTES AND BIOTECHNOLOGY ( INFORMA HEALTHCARE )  39 ( 2 ) 51 - 58  2011年04月  [査読有り]

  　概要を見る

  A higher production of functional mast cells (MCs) can be generated by co-culturing cord blood-derived CD34(+) cells with a human bone marrow stromal cell line under serum-free conditions supplemented with stem cell factor and IL-6. We addressed the question of whether the higher proliferation of MCs in this co-culture system might be due to the higher proliferation of MC progenitors. The stromal cell line increased the cell numbers of MC progenitors derived from cord blood-derived CD34(+) cells, in a combination of cell-cell interactions between stromal cells and CD34(+) cells, and as yet unidentified soluble factors derived from stromal cells.

  DOI

• Elevated Ca²+ influx-inducing activity toward mast cells in pretransfusion sera from patients who developed transfusion-related adverse reactions.

  Azuma H, Yamaguchi M, Takahashi D, Fujihara M, Sato S, Kato T, Ikeda H

  Transfusion. 2009 Aug;49(8):1754-61. ( WILEY-BLACKWELL )  49 ( 8 ) 1754 - 1761  2009年08月  [査読有り]

  　概要を見る

  BACKGROUND: Type I allergic reactions such as urticaria-like manifestations constitute a large percentage of transfusion-related adverse events. Along with donor factors, patient factors might be involved in these reactions. Sera from some patients with chronic idiopathic urticaria show histamine-releasing activity (HRA). Sera from patients who develop Type I allergic reaction might possess HRA. STUDY DESIGN AND METHODS: Pretransfusion serum samples were collected. Mast cells were cultured from peripheral blood CD34+ cells and mixed with the serum samples. Cells with elevated intracytoplasmic Ca2+ concentrations were monitored using flow cytometry to evaluate Ca2+ influx-inducing activity (CaIA) in serum. The amount of histamine released into the supernatant was measured using an enzyme immunoassay kit to evaluate HRA. In some assays, cells were incubated with pertussis toxin (Ptx). RESULTS: CaIA values were higher (p < 0.05) in sera from patients with reactions (27.68 +/- 20.38 [n = 145]; range, 0.49-84.90) than in sera of patients without reactions (10.70 +/- 6.50 [n = 54]; range, 2.67-36.97) and control sera (9.67 +/- 5.88 [n = 107]; range, 1.11-25.68). No difference in CaIA was found between patients with (27.38 +/- 20.46 [n = 88]) and without (28.38 +/- 20.59 [n = 57]) skin manifestations. However, CaIA was higher (p < 0.05) in patients with pure urticaria (mean, 30.58 +/- 21.3 [n = 30]; range, 70.43-4.1) than in patients with fever alone (mean, 18.61 +/- 14.71 [n = 18]; range, 45.94-3.19). Levels of HRA were higher (p < 0.001) in CaIA-positive sera than in CaIA-negative sera. Both CaIA and HRA were blocked by Ptx. CONCLUSION: Elevated CaIA and HRA in pretransfusion sera might be attributable to adverse reactions, especially to urticaria-like manifestation. The Gi protein-coupled receptor complexes on mast cells and its ligand must be involved.

  DOI

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• Cytotoxic Difference of T Cells Expanded with Anti-CD3 Monoclonal Antibody in the Presence and Absence of Anti-CD28 Monoclonal Antibody.

  Stem Cells Dev.   13(3):315-22.  2004年

  　概要を見る

  2004 Jun.

  DOI

• Possible contribution of apoptosis-inducing factor (AIF) and reactive oxygen species (ROS) to UVB-induced caspaseindependent cell death in the T cell line Jurkat

  H Murahashi, H Azuma, N Zamzami, KJ Furuya, K Ikebuchi, M Yamaguchi, Y Yamada, N Sato, M Fujihara, G Kroemer, H Ikeda

  JOURNAL OF LEUKOCYTE BIOLOGY ( FEDERATION AMER SOC EXP BIOL )  73 ( 3 ) 399 - 406  2003年03月

  　概要を見る

  We analyzed the mechanism of UVB-induced cell death using the Jurkat T cell line. Apoptosis was assessed by measuring phosphatidylserine (PS) externalization, caspase activity, the decrease in mitochondrial membrane potential (DeltaPsim), nucleosomal DNA fragmentation, and morphological changes such as chromatin condensation. The mitochondrio-nuclear translocation of apoptosis-inducing factor (AIF) was evaluated by confocal laser microscopy. The cell death pattern of UVB-irradiated cells was similar to the Fas-induced cell death pattern. However, zVAD-fmk inhibited the nucleosomal fragmentation of DNA but not the externalization of PS, decrease in DeltaPsim, or mitochondrio-nuclear translocation of AIF. N-acetyl L-cysteine significantly inhibited the translocation of AIF induced by UVB. These results suggested that caspase-dependent and -independent pathways were involved in UVB-induced cell death in Jurkat cells, and the mitochondrio-nuclear translocation of AIF was associated with the latter pathway. In addition, reactive oxygen species generated by UVB might be involved in inducing the mitochondrio-nuclear translocation of AIF. J. Leukoc. Biol. 73:399-406; 2003.

  DOI

• Ｉｎ ｖｉｔｒｏにおけるヘモグロビン小胞体の血小板活性化に対する影響

  若本 志乃舞, 藤原 満博, 阿部 英樹, 山口 美樹, 武岡 真司, 土田 英俊, 東 寛, 池田 久實

  日本輸血学会雑誌 ( The Japan Society of Transfusion Medicine and Cell Therapy )  49(5) 653-659 ( 5 ) 653 - 659  2003年

  　概要を見る

  Hemoglobin vesicles (HbV), a type of liposome-encapsulated hemoglobin (LEH), have been recently developed as an artificial oxygen carrier. The efficacy of HbV has been demonstrated in the transfusion of HbV into rodent models of hemorrhagic shock. It is important to evaluate the compatibility of HbV with human blood cells. We examined the effects of HbV on human platelet activation in vitro by estimating the platelet release reaction and expression of platelet surface activation markers in the presence or absence of agonists. HbV concentration in the reaction volume was prepared at 20% or 40%. Preincubation of platelet-rich plasma (PRP) with HbV had no adverse effects on RANTES or serotonin release from platelets. Preincubation of whole blood with HbV also had no effects on exposure of P-selectin on platelets. However, binding of PAC-1, a monoclonal antibody that detects the activation-dependent conformational change of α_IIbβ₃ to platelets, was amplified by preincubation of whole blood with HbV in the presence of relatively low concentration of ADP. These results suggest that HbV enhances the binding of PAC-1 to platelets. The clinical meaning of this increased binding of PAC-1 needs to be addressed.

  DOI CiNii

• Ex vivo expansion of human umbilical cord hematopoietic progenitor cells using a coculture system with human telomerase catalytic subunit (hTERT)-transfected human stromal cells.

  Blood.   101: 532-540  2003年

  　概要を見る

  2003 Jan.

  DOI

• Thrombopoietin upregulates nucleolin mRNA and protein in thrombopoietin-dependent megakaryocytic cell line, UT-7,TPO.

  Mol Cell Biochem.   247(1-2):75-82.  2003年

  　概要を見る

  2003 May.

  DOI

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• 抗Trop-2抗体

  山口美樹, 加藤和則, 濱田洋文

  特許権

共同研究・競争的資金等の研究課題 【 表示 ／ 非表示 】

共同研究・競争的資金等の研究課題 【 表示 ／ 非表示 】

• がん特異性と腫瘍溶解能を増強した組み合えヘルペスウイルスによる治療法の開発

  研究期間:

  2014年04月

  -

  2016年03月

   

  山口 美樹

  担当区分： 研究代表者

• 高性能イミュノトキシンを用いた急性骨髄性白血病の標的化治療

  研究期間:

  2011年04月

  -

  2013年03月

   

  山口 美樹

  担当区分： 研究代表者

• The establishment of the efficient culture method of the Mast cells.

  研究期間:

  2003年

  -

  2008年

   

• 肥満細胞の効率的な培養法の確立

  研究期間:

  2003年

  -

  2008年