特任准教授　内田 宏昭

略歴

研究テーマ　業績

1994年　東京大学医学部医学科卒業
1994年　東京大学医学部附属病院第一外科　研修医
1995年　焼津市立総合病院外科　医員
1998年　東京大学医学部附属病院大腸肛門外科・血管外科　医員
2003年　東京大学大学院医学系研究科外科学専攻博士課程修了
2003年　日本学術振興会特別研究員
2004年　東京大学医科学研究所附属病院外科　助手
2005年　ピッツバーグ大学医学部分子遺伝学・生化学　Research Associate
2007年　ピッツバーグ大学医学部外科　Research Assistant Professor
2011年　東京薬科大学生命科学部腫瘍医科学研究室　准教授
2015年　東京大学医科学研究所先端医療研究センター臓器細胞工学分野　講師
2018年　東京大学医科学研究所がん生体分子治療社会連携研究部門　特任准教授
現在に至る

研究テーマ

略歴  業績
  • 受容体標的化改変を施した腫瘍溶解性ヘルペスウイルス（RR-oHSV）の開発

がんに対する新たな治療法として単純ヘルペスウイルス（HSV）を用いた腫瘍溶解性ウイルス療法が大きな期待を集めています。がん細胞だけに特異的に侵入し、静脈内投与可能な標的化改変ウイルスが開発できれば、原発巣のみならず全身の転移巣にも有効な治療法となり得ると考えられます。私たちのグループは、HSVにがん細胞表面抗原を認識する単鎖抗体を組み込むことにより、標的細胞のみに侵入可能な受容体標的化腫瘍溶解性HSV（Receptor-retargeted oncolytic HSV, RR-oHSV）の構築に成功しました。この新たなタイプの腫瘍溶解性ウイルスの臨床応用とそのさらなる改良のための基礎的研究を進めています。

  • がん特異的抗体の開発

ジフテリア毒素改変体（DT-3C）を結合させた抗体（イミュノトキシン）のがん細胞殺傷効果を指標とした独自の抗体スクリーニング法により、抗体薬物複合体（Antibody-drug conjugate, ADC）への応用に好適な抗体を樹立することに成功しました。さらに、RR-oHSVへの搭載に好適な抗体を選別するための抗体スクリーニング法を新たに考案し、抗体の樹立を進めています。私たちのグループの抗体スクリーニング法は、それぞれの治療薬の作動原理に即した直接的な選別法であることから、実用化を目指す上でのアドバンテージが高いことが期待されます。

業績

略歴 研究テーマ
  1. Suzuki T, Uchida H*, Shibata T, Sasaki Y, Ikeda H, Hamada-Uematsu M, Hamasaki R, Okuda K, Yanagi S, Tahara H. (2021) Potent anti-tumor effects of receptor-retargeted syncytial oncolytic herpes simplex virus. Molecular Therapy Oncolytics. 22:265-276. *Corresponding author.
  2. Ikeda H, Uchida H*, Okubo Y, Shibata T, Sasaki Y, Suzuki T, Hamada-Uematsu M, Hamasaki R, Okuda K, Yamaguchi M, Kojima M, Tanaka M, Hamada H, Tahara H. (2021) Antibody screening system using a herpes simplex virus (HSV)-based probe to identify a novel target for receptor-retargeted oncolytic HSVs. Journal of Virology. 95:e01766-20. *Corresponding author.
  3. Okamoto H, Yoshimatsu Y, Tomizawa T, Kunita A, Takayama R, Morikawa T, Komura D, Takahashi K, Oshima T, Sato M, Komai M, Podyma-Inoue KA, Uchida H, Hamada H, Fujiu K, Ishikawa S, Fukayama M, Fukuhara T, Watabe T. (2019) Interleukin-13 receptor α2 is a novel marker and potential therapeutic target for human melanoma. Scientific Reports. 9:1281.
  4. Uchida H*, Hamada H, Nakano K, Kwon H, Tahara H, Cohen JB, Glorioso JC. (2018) Oncolytic herpes simplex virus vectors fully retargeted to tumor-associated antigens. Current Cancer Drug Targets. 18:162-170. *Corresponding author.
  5. Kanemura T, Miyata H, Makino T, Tanaka K, Sugimura K, Hamada-Uematsu M, Mizote Y, Uchida H, Miyazaki Y, Takahashi T, Kurokawa Y, Yamasaki M, Wada H, Nakajima K, Takiguchi S, Mori M, Doki Y, Tahara H. (2018) Immunoregulatory influence of abundant MFG-E8 expression by esophageal cancer treated with chemotherapy. Cancer Science. 109:3393-3402.
  6. Tanaka T, Uchida H. (2018) Inhibition of survivin by adenovirus vector enhanced paclitaxel-induced apoptosis in breast cancer cells. Anticancer Research. 38:4281-4288.
  7. Yamada S, Itai S, Furusawa Y, Sano M, Nakamura T, Yanaka M, Handa S, Hisamatsu K, Nakamura Y, Fukui M, Harada H, Mizuno T, Sakai Y, Ogasawara S, Murata T, Uchida H, Tahara H, Kaneko MK, Kato Y. (2018) Detection of tiger podoplanin using the anti-cat podoplanin monoclonal antibody PMab-52. Monoclonal Antibodies in Immunodiagnosis and Immunotherapy. 37:224-228.
  8. Yamada S, Kaneko MK, Itai S, Chang YW, Nakamura T, Yanaka M, Ogasawara S, Murata T, Uchida H, Tahara H, Harada H, Kato Y. (2018) Epitope mapping of monoclonal antibody PMab-48 against dog podoplanin. Monoclonal Antibodies in Immunodiagnosis and Immunotherapy. 37:162-165.
  9. Miyagawa Y, Verlengia G, Reinhart B, Han F, Uchida H, Zucchini S, Goins WF, Simonato M, Cohen JB, Glorioso JC. (2017) Deletion of the virion host shut-off gene enhances neuronal-selective transgene expression from an HSV vector lacking functional IE genes. Molecular Therapy Methods & Clinical Development. 6:79-90.
  10. Yamaguchi M, Hirai S, Sumi T, Tanaka Y, Tada M, Nishii Y, Hasegawa T, Uchida H, Yamada G, Watanabe A, Takahashi H, Sakuma Y. (2017) Angiotensin-converting enzyme 2 is a potential therapeutic target for EGFR-mutant lung adenocarcinoma. Biochemical and Biophysical Research Communications. 487:613-618.
  11. Kaneko MK, Abe S, Ogasawara S, Fujii Y, Yamada S, Murata T, Uchida H, Tahara H, Nishioka Y, Kato Y. (2017) Chimeric anti-human podoplanin antibody NZ-12 of lambda light chain exerts higher antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity compared with NZ-8 of kappa light chain. Monoclonal Antibodies in Immunodiagnosis and Immunotherapy. 36:25-29.
  12. Kato Y, Kunita A, Fukayama M, Abe S, Nishioka Y, Uchida H, Tahara H, Yamada S, Yanaka M, Nakamura T, Saidoh N, Yoshida K, Fujii Y, Honma R, Takagi M, Ogasawara S, Murata T, Kaneko MK. (2017) Antiglycopeptide mouse monoclonal antibody LpMab-21 exerts antitumor activity against human podoplanin through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Monoclonal Antibodies in Immunodiagnosis and Immunotherapy. 36:20-24.
  13. Okubo Y, Uchida H*, Wakata A, Suzuki T, Shibata T, Ikeda H, Yamaguchi M, Cohen JB, Glorioso JC, Tagaya M, Hamada H, Tahara H. (2016) Syncytial mutations do not impair the specificity of entry and spread of a glycoprotein D receptor-retargeted herpes simplex virus. Journal of Virology. 90:11096-11105. *Corresponding author.
  14. Shibata T, Uchida H*, Shiroyama T, Okubo Y, Suzuki T, Ikeda H, Yamaguchi M, Miyagawa Y, Fukuhara T, Cohen JB, Glorioso JC, Watabe T, Hamada H, Tahara H. (2016) Development of an oncolytic HSV vector fully retargeted specifically to cellular EpCAM for virus entry and cell-to-cell spread. Gene Therapy. 23:479-488. *Corresponding author.
  15. Miyagawa Y, Marino P, Verlengia G, Uchida H, Goins WF, Yokota S, Geller DA, Yoshida O, Mester J, Cohen JB, Glorioso JC. (2015) Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity. Proceedings of the National Academy of Sciences of the United States of America. 112:E1632-1641.
  16. Mazzacurati L, Marzulli M, Reinhart B, Miyagawa Y, Uchida H, Goins WF, Li A, Kaur B, Caligiuri M, Cripe T, Chiocca EA, Amankulor N, Cohen JB, Glorioso JC, Grandi P. (2015) Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. Molecular Therapy. 23:99-107.
  17. Nishii Y, Yamaguchi M, Kimura Y, Hasegawa T, Aburatani H, Uchida H, Hirata K, Sakuma Y. (2015) A newly developed anti-Mucin 13 monoclonal antibody targets pancreatic ductal adenocarcinoma cells. International Journal of Oncology. 46:1781-1787.
  18. Yamamoto Y, Hiraoka N, Goto N, Rin Y, Miura K, Narumi K, Uchida H, Tagawa M, Aoki K. (2014) A targeting ligand enhances infectivity and cytotoxicity of an oncolytic adenovirus in human pancreatic cancer tissues. Journal of Control Release. 192:284-293.
  19. Yamamoto Y, Goto N, Miura K, Narumi K, Ohnami S, Uchida H, Miura Y, Yamamoto M, Aoki K. (2014) Development of a novel efficient method to construct an adenovirus library displaying random peptides on the fiber knob. Molecular Pharmaceutics. 11:1069-1074.
  20. Yamaguchi M, Nishii Y, Nakamura K, Aoki H, Hirai S, Uchida H, Sakuma Y, Hamada H. (2014) Development of a sensitive screening method for selecting monoclonal antibodies to be internalized by cells. Biochemical and Biophysical Research Communications. 454:600-603.
  21. Uchida H, Marzulli M, Nakano K, Goins WF, Chan J, Hong CS, Mazzacurati L, Yoo JY, Haseley A, Nakashima H, Baek H, Kwon H, Kumagai I, Kuroki M, Kaur B, Chiocca EA, Grandi P, Cohen JB, Glorioso JC. (2013) Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Molecular Therapy. 21:561-569.
  22. Uchida H, Chan J, Shrivastava I, Reinhart B, Grandi P, Glorioso JC, Cohen JB. (2013) Novel mutations in gB and gH circumvent the requirement for known gD receptors in HSV-1 entry and cell-to-cell spread. Journal of Virology. 87:1430-1442.
  23. Wang PY, Currier MA, Hansford L, Kaplan D, Chiocca EA, Uchida H, Goins WF, Cohen JB, Glorioso JC, Kuppevelt TH, Mo X, Cripe TP. (2013) Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV. Gene Therapy. 20:761-769.
  24. Baek H, Uchida H, Jun K, Kim JH, Kuroki M, Cohen JB, Glorioso JC, Kwon H. (2011) Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells. Molecular Therapy. 19:507-514.
  25. Uchida H, Chan J, Goins WF, Grandi P, Kumagai I, Cohen JB, Glorioso JC. (2010) A double mutation in glycoprotein gB compensates for ineffective gD-dependent initiation of herpes simplex virus type 1 infection. Journal of Virology. 84:12200-12209.
  26. Frampton AR Jr, Uchida H, von Einem J, Goins WF, Grandi P, Cohen JB, Osterrieder N, Glorioso JC. (2010) Equine herpesvirus type 1 (EHV-1) utilizes microtubules, dynein, and ROCK1 to productively infect cells. Veterinary Microbiology. 141:12-21.
  27. Uchida H, Shah WA, Ozuer A, Frampton AR Jr, Goins WF, Grandi P, Cohen JB, Glorioso JC. (2009) Generation of HVEM-restricted HSV-1 mutant viruses: Resistance of HVEM-expressing cells and identification of mutations that rescue nectin-1 recognition. Journal of Virology. 83:2951-2961.
  28. Katsu M, Koyama H, Maekawa H, Kurihara H, Uchida H, Hamada H. (2009) Ex vivo gene delivery of ephrin-B2 induces development of functional collateral vessels in a rabbit model of hind limb ischemia. Journal of Vascular Surgery. 49:192-198.
  29. Tomihara K, Kato K, Masuta Y, Nakamura K, Uchida H, Sasaki K, Tanaka T, Huang J, Hiratsuka H, Hamada H. (2008) Gene transfer of CD40-ligand to dendritic cells stimulates interferon-gamma production to induce growth arrest and apoptosis of tumor cells. Gene Therapy. 15:203-213.
  30. Kobune M, Kato J, Kawano Y, Sasaki K, Uchida H, Takada K, Takahashi S, Takimoto R, Niitsu Y. (2008) Adenoviral vector-mediated transfer of the Indian hedgehog gene modulates lymphomyelopoiesis in vivo. Stem Cells. 26:534-542.
  31. Frampton AR Jr, Stolz DB, Uchida H, Goins WF, Cohen JB, Glorioso JC. (2007) Equine herpesvirus 1 enters cells by two different pathways, and infection requires the activation of the cellular kinase ROCK1. Journal of Virology. 81:10879-10889.
  32. Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Ishii K, Kobune M, Hirai S, Uchida H, Sasaki K, Ito Y, Kato K, Honmou O, Houkin K, Date I, Hamada H. (2005) Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Molecular Therapy. 11:96-104.
  33. Uchida H, Tanaka T, Sasaki K, Kato K, Dehari H, Ito Y, Kobune M, Miyagishi M, Taira K, Tahara H, Hamada H. (2004) Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Molecular Therapy. 10:162-171.
  34. Kobune M, Ito Y, Kawano Y, Sasaki K, Uchida H, Nakamura K, Dehari H, Chiba H, Takimoto R, Matsunaga T, Terui T, Kato J, Niitsu Y, Hamada H. (2004) Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID-b2m-/- repopulating cells. Blood. 104:1002-1009.
  35. Sako A, Kitayama J, Koyama H, Ueno H, Uchida H, Hamada H, Nagawa H. (2004) Transduction of soluble flt-1 gene to peritoneal mesothelial cells can effectively suppress peritoneal metastasis of gastric cancer. Cancer Research. 64:3624-3628.
  36. Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Kobune M, Hirai S, Uchida H, Sasaki K, Ito Y, Kato K, Honmou O, Houkin K, Date I, Hamada H. (2004) BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Molecular Therapy. 9:189-197.
  37. Uchida H, Kawamura YJ, Takegami K, Matsuda K, Watanabe T, Masaki T, Minami M, Muto T. (2004) Colon cancer complicated by vascular and intestinal anomaly. Hepatogastroenterology. 51:156-158.
  38. Huang J, Ito Y, Morikawa M, Uchida H, Kobune M, Sasaki K, Abe T, Hamada H. (2003) Bcl-xL gene transfer protects the heart against ischemia/reperfusion injury. Biochemical and Biophysical Research Communications. 311:64-70.
  39. Huang J, Ito Y, Kobune M, Sasaki K, Nakamura K, Dehari H, Takahashi K, Ikeda K, Uchida H, Kato K, Hamada H. (2003) Myocardial injection of CA promoter-based plasmid mediates efficient transgene expression in rat heart. Journal of Gene Medicine. 5:900-908.
  40. Takahashi K, Ito Y, Morikawa M, Kobune M, Huang J, Tsukamoto M, Sasaki K, Nakamura K, Dehari H, Ikeda K, Uchida H, Hirai S, Abe T, Hamada H. (2003) Adenoviral-delivered angiopoietin-1 reduces the infarction and attenuates the progression of cardiac dysfunction in the rat model of acute myocardial infarction. Molecular Therapy. 8:584-592.
  41. Kobune M, Kawano Y, Ito Y, Chiba H, Nakamura K, Tsuda H, Sasaki K, Dehari H, Uchida H, Honmou O, Takahashi S, Bizen A, Takimoto R, Matsunaga T, Kato J, Kato K, Houkin K, Niitsu Y, Hamada H. (2003) Telomerized human multipotent mesenchymal cells can differentiate into hematopoietic and cobblestone area-supporting cells. Experimental Hematology. 31:715-722.
  42. Uchida H, Shinoura N, Kitayama J, Watanabe T, Nagawa H, Hamada H. (2003) 5-Fluorouracil efficiently enhanced apoptosis induced by adenovirus-mediated transfer of caspase-8 in DLD-1 colon cancer cells. Journal of Gene Medicine. 5:287-299.
  43. Tsuda H, Wada T, Ito Y, Uchida H, Dehari H, Nakamura K, Sasaki K, Kobune M, Yamashita T, Hamada H. (2003) Efficient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector. Molecular Therapy. 7:354-365.
  44. Uchida H, Shinoura N, Kitayama J, Watanabe T, Nagawa H, Hamada H. (2002) Caspase-8 gene transduction augments radiation-induced apoptosis in DLD-1 cells. Biochemical and Biophysical Research Communications. 292:347-354.
  45. Nishimura S, Adachi M, Ishida T, Matsunaga T, Uchida H, Hamada H, Imai K. (2001) Adenovirus-mediated transfection of caspase-8 augments anoikis and inhibits peritoneal dissemination of human gastric carcinoma cells. Cancer Research. 61:7009-7014.
  46. Kawamura YJ, Uchida H, Watanabe T, Nagawa H. (2000) Early feeding after oncological colorectal surgery in Japanese patients. Journal of Gastroenterology. 35:524-527.
  47. Matsuda K, Watanabe T, Abo Y, Uchida H, Kawamura YJ, Masaki T, Muto T. (1999) Severe complications of ulcerative colitis after high-dose prednisolone and azathioprine treatment. Journal of Gastroenterology. 34:390-394.
  48. Matsuda K, Masaki T, Abo Y, Uchida H, Watanabe T, Muto T. (1999) Rapid growth of residual colonic tumor after incomplete mucosal resection. Journal of Gastroenterology. 34:260-263.