Analysis of ADAM28 activity mechanism on the cell surface

• Project/Area Number: 15K08409
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: National Defense Medical College (2016-2017); Keio University (2015)
• Principal Investigator: Mochizuki Satsuki 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 外科学, 助教 (80365428)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ＡＤＡＭ２８ / 分子標的薬 / 肺癌 / 増殖 / 転移 / ADAM28 / 活性阻害 / 癌細胞増殖 / ADAM / 分子標的治療

Outline of Final Research Achievements

We developed a human neutralizing anti-ADAM28 antibody (211-14) from human combinatorial antibody library, and showed that it inhibits ADAM28 activity and IGF-I-induced carcinoma cell proliferation and migration, leading to elongation of survival rate of mice. In addition, combination therapy of antibody 211-14 and docetaxel more effectively improved the survival time than that of bevacizumab and docetaxel.
All these data suggest that our neutralizing antibody 211-14 may be a useful ADAM28 inhibitor for treatment of the non-small cell lung carcinoma patients in the future.

Research Products

• [Journal Article] Disentangling the prognostic heterogeneity of stage III colorectal cancer through histologic stromal categorization (2018)
  • Author(s): Ueno H, Sekine S, Oshiro T, Kanemitsu Y, Hamaguchi T, Shida D, Takashima A, Ishiguro M, Ito E, Hashiguchi Y, Kondo F, Shimazaki H, Mochizuki S, Kajiwara Y, Shinto E, Yamamoto J, Shimada Y
  • Journal Title: Surgery Volume: 163 Issue: 4 Pages: 777-783
  • DOI: 10.1016/j.surg.2017.09.007
  • Peer Reviewed / Open Access
• [Journal Article] ADAM9 is over-expressed in human ovarian clear cell carcinomas and suppresses cisplatin-induced cell death (2018)
  • Author(s): Ueno Mari、Shiomi Takayuki、Mochizuki Satsuki、Chijiiwa Miyuki、Shimoda Masayuki、Kanai Yae、Kataoka Fumio、Hirasawa Akira、Susumu Nobuyuki、Aoki Daisuke、Okada Yasunori
  • Journal Title: Cancer Science Volume: 109 Issue: 2 Pages: 471-482
  • DOI: 10.1111/cas.13469
  • Peer Reviewed / Open Access
• [Journal Article] The metalloproteinase ADAM28 promotes metabolic dysfunction in mice. (2017)
  • Author(s): Lakshini Herat, Caroline Rudnicka, Yasunori Okada, Satsuki Mochizuki, Markus Schlaich, Vance Matthews
  • Journal Title: International Journal of Molecular Sciences Volume: 印刷中 Issue: 4 Pages: 884-884
  • DOI: 10.3390/ijms18040884
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Desmoplastic Pattern at the Tumor Front Defines Poor-prognosis Subtypes of Colorectal Cancer (2017)
  • Author(s): Ueno H, Kanemitsu Y, Sekine S, Ishiguro M, Ito E, Hashiguchi Y, Kondo F, Shimazaki H, Mochizuki S, Kajiwara Y, Shinto E, Yamamoto J.
  • Journal Title: Am J Surg Pathol. Volume: 41 Issue: 11 Pages: 1506-1512
  • DOI: 10.1097/pas.0000000000000946
  • Peer Reviewed / Open Access
• [Journal Article] ADAM23 is down-regulated in side population and suppresses lung matastasis of lung carcinoma cells (2016)
  • Author(s): Masahide Ota, Satsuki Mochizuki, Masayuki Shimoda, Hitoshi Abe, Yuka Miyamae, Ken Ishii, Hiroshi Kimura and Yasunori Okada
  • Journal Title: Cancer Sci Volume: 107 Issue: 4 Pages: 433-443
  • DOI: 10.1111/cas.12895
  • Peer Reviewed
• [Journal Article] ADAM28 is expressed by epithelial cells in human normal tissues and protects from C1q-induced cell death (2016)
  • Author(s): Yuka Miyamae, *Satsuki Mochizuki, Masayuki Shimoda, Kentaro Ohara, Hitoshi Abe, Shuji Yamashita, Saiko Kazuno, Takashi Ohtsuka, Hiroki Ochiai, Yuko Kitagawa and Yasunori Okada
  • Journal Title: FEBS J. Volume: 283 Issue: 9 Pages: 1574
  • DOI: 10.1111/febs.13693
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Overexpression and knock-down studies highlight that a disintegrin and metalloproteinase 28 controls proliferation and migration in human prostate cancer. (2016)
  • Author(s): Caroline Rudnicka, Satsuki Mochizuki,Yasunori Okada, Claire McLaughlin, Peter J. Leedman, Lisa Stuart, Michael Epis, Gerard Hoyne, Sherif Boulos, Liam Johnson, Markus Schlaich and Vance Matthews
  • Journal Title: Medicine (Baltimore) Volume: 95 Issue: 40 Pages: e5085-e5085
  • DOI: 10.1097/md.0000000000005085
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of human neutralizing antibody to ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2) (2016)
  • Author(s): Aya Shiraishi, Satsuki Mochizuki, Akira Miyakoshi, Kanehisa Kojoh and Yasunori Okada
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 469 Issue: 1 Pages: 62-29
  • DOI: 10.1016/j.bbrc.2015.11.072
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] ADAM28によるがん組織内微小環境因子代謝を介したがん細胞増殖・転移 (2017)
  • Author(s): 望月早月、下田将之、岡田保典、上野秀樹
  • Organizer: 第49回日本結合組織学会学術大会
  • Invited
• [Presentation] Regulation of tumor microenvironmentalfactors by ADAM28. (2017)
  • Author(s): Satsuki Mochizuki, Masayuki Shimoda, Yasunori Okada and Hideki Ueno
  • Organizer: Gordon Research Conference on Matrix Metalloprotienases
  • Int'l Joint Research / Invited
• [Presentation] メタロテアーゼADAM28を標的とした新規分子標的治療薬開発 (2017)
  • Author(s): 望月早月、下田将之、岡田保典、長谷和生、上野秀樹
  • Organizer: 第55回日本癌治療学会学術集会
• [Presentation] メタロプロテアーゼ(ADAMTS/ADAM)のヒト型抗体開発研究 (2016)
  • Author(s): 望月早月、下田雅之、宮越陽、古城周久、上野秀樹、岡田保典
  • Organizer: 第1回エラスチン・関連分子研究会学術集会
  • Place of Presentation: アルカディア市ヶ谷、東京
  • Year and Date: 2016-12-02
• [Presentation] ADAMTS/ADAMメタロプロテアーゼの機能解析とヒト型抗体開発研究 (2016)
  • Author(s): 望月早月、千々岩みゆき、下田将之、宮越陽、古城周久、岡田保典
  • Organizer: 第48回日本結合組織学会学術大会
  • Place of Presentation: 長崎大学医学部良順会館、長崎
  • Year and Date: 2016-06-24
  • Invited
• [Presentation] Selective inhibition of ADAM28 activity by human anti-ADAM28 antibody suppresses cancer cell proliferation and metastasis of non-small cell lung carcinoma cells (2016)
  • Author(s): Satsuki Mochizuki and Yasunori Okada
  • Organizer: KSBMB conference 2016
  • Place of Presentation: Coex Hall D1,Seoul, Korea
  • Year and Date: 2016-05-19
  • Int'l Joint Research / Invited
• [Presentation] アグリカナーゼ(ADAMTS4/5)を標的としたヒト型活性阻害抗体の開発 (2016)
  • Author(s): 望月早月
  • Organizer: 第29回日本軟骨代謝学会
  • Place of Presentation: 広島大学医学部広仁会館（広島県広島市）
  • Year and Date: 2016-02-19
• [Presentation] ADAM28 (a disintegrin and metalloproteinase 28): Prospective roles in cancer cell proliferation and progression, angiogenesis and epithelial cell maintenance (2016)
  • Author(s): Satsuki Mochizuki and Yasunori Okada
  • Organizer: 2016 TIDRC International Symposium
  • Place of Presentation: Ewha Womans University,Seoul, Korea
  • Int'l Joint Research / Invited
• [Presentation] Development of human anti-ADAM28 neutralizing antibodies and functional analysis of ADAM28 in the human normal tissues (2015)
  • Author(s): Satsuki Mochizuki
  • Organizer: Development of human anti-ADAM28 neutralizing antibodies and functional analysis of ADAM28 in the human normal tissues
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2015-08-23
  • Int'l Joint Research
• [Presentation] ADAM28 is expressed by epithelial cells in human normal tissues and protects from C1q-induced cell death. (2015)
  • Author(s): Satsuki Mochizuki
  • Organizer: Gordon Research Conference on Matrix Metalloprotienases
  • Place of Presentation: Newry, U.S.A
  • Year and Date: 2015-08-02
  • Int'l Joint Research / Invited
• [Presentation] CCN1(Cyr61)は関節軟骨プロテオグリカン分解に必須なADAMTS4の活性を阻害する (2015)
  • Author(s): 望月早月
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-30
• [Remarks] 防衛医科大学外科学（消化管外科）
  • URL: http://www.ndmc.ac.jp/med/subject/sh_med038syoukakangeka/