Engineering radiolabeled antibody fragments for enhanced tumor to kidney ratio

• Project/Area Number: 25713045
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Radiation science
• Research Institution: Chiba University
• Principal Investigator: Uehara Tomoya 千葉大学, 薬学研究科(研究院), 准教授 (10323403)
• Co-Investigator(Renkei-kenkyūsha): HANAOKA Hirofumi 群馬大学, 大学院医学研究科, 准教授 (50361390)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥25,090,000 (Direct Cost: ¥19,300,000、Indirect Cost: ¥5,790,000); Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2014: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2013: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
• Keywords: PET / 治療 / 腎臓 / 標識薬剤 / SPECT / ガリウム / 内照射治療

Outline of Final Research Achievements

The renal localization of radiolabeled antibody fragments is a limitation of clear target imaging and radiothearpy. Herein, we describe a strategy using a 67Ga-labeling reagent for antibody fragments that liberates 67Ga-NOTA-Methionine (NOTA-Met) by the action of renal brush border enzymes to reduce renal radioactivity levels. A 67Ga-labeled Fab fragments of anti-c-kit IgG using this labeling agentl resulted in significantly lower renal radioactivity levels and clearer tumor images than those of 67Ga-labeled Fabs using conventional methods. This strategy and radiolabeling reagent would also be applicable for engineered antibody fragments and also considerable influence on the development of new diagnostic and therapeutic engineered antibody fragments.

Research Products

• [Journal Article] 67/68Ga-labeling Agent that Liberates 67/68Ga-NOTA-methionine by Lysosomal Proteolysiso of Parental Low Molecular Weight Polypeptides to Reduce Renal Radioactivity Levels (2014)
  • Author(s): Tomoya Uehara, Takemi Rokugawa, Mai Kinoshita, Aouki Nemoto, Guerra Gomez Fransisco Lazaro, Hirofumi Hanaoka, and Yasushi Arano
  • Journal Title: Bioconjugate Chem. Volume: 25 Issue: 11 Pages: 2038-2045
  • DOI: 10.1021/bc5004058
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 放射性ガリウム標識抗体フラグメントの非特異的腎集積を低減させる標識薬剤の開発 (2016)
  • Author(s): 上原知也、横山幹、鈴木博元、荒野泰
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 東京
  • Year and Date: 2016-03-27
• [Presentation] 標的への集積向上を目的とした放射性ガリウム化合物の新規設計 (2015)
  • Author(s): 上原知也
  • Organizer: 第15回放射性医薬品・画像診断薬研究会
  • Place of Presentation: 京都
  • Year and Date: 2015-09-12
• [Presentation] 腎放射活性の低減を目的とする低分子ﾎﾟﾘペプチドGa標識薬剤に関する基礎的研究 (2014)
  • Author(s): 上原知也,横山幹,趙天会,花岡宏史,荒野泰
  • Organizer: 第５４回日本核医学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-11-06 – 2014-11-08
• [Presentation] SPECT装置を用いたｲﾒｰｼﾞﾝｸﾞとそのプローブ開発 (2014)
  • Author(s): 上原知也
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-04
  • Invited
• [Presentation] A novel chemical design of Ga-67/68 labeled probes based on chelation-madiated multivalency to enhance target accumulation (2014)
  • Author(s): Tomoya Uehara, Yasushi Arano
  • Organizer: International seminar on pharmaceutical science and technology2014
  • Place of Presentation: Bandung, Indonesia
  • Year and Date: 2014-09-16 – 2014-09-19
  • Invited
• [Presentation] A-Ga-68-labeling reagent liberating Ga--58-NOTA-conjugated methionine from low molecular weight polypeptides in lysosomes for low renal radioactivity levels (2013)
  • Author(s): Tomoya Uehara,Mai Kinoshita, Takemi Rokugawa, Guerra Gomez Fransicsco L, Hirofumi Hanaoka, Yasushi Arano
  • Organizer: The 20 th International Symposium on Radiopharmaceutical Sciences
  • Place of Presentation: Jeju (Korea)
• [Presentation] 腎放射活性の低減を目的とした放射性ガリウム標識RGDペプチドの開発 (2013)
  • Author(s): 趙 天会，上原知也，根本創紀，花岡宏史，荒野 泰
  • Organizer: 第１３回放射性医薬品・画像診断研究会
  • Place of Presentation: 京都
• [Patent(Industrial Property Rights)] 放射性標識薬剤 (2016)
  • Inventor(s): 荒野泰 上原知也
  • Industrial Property Rights Holder: 荒野泰 上原知也
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-038836
  • Filing Date: 2016-03-01