Development of antibody therapy targeting multiple myeloma-specific glyco-epitope

• Project/Area Number: 26461404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: Hosen Naoki 大阪大学, 医学系研究科, 寄附講座准教授 (10456923)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 多発性骨髄腫 / 多発性骨髄巣 / CAR T細胞 / 抗体療法

Outline of Final Research Achievements

In this study, we discovered that an antigen formed in CD98 heavy chain (hc) protein in cells undergoing endoplasmic reticulum (ER) stress could exert as a specific target for mAb therapy against multiple myeloma (MM). We first identified R8H283 as a mAb that specifically bound to MM cells after screening more than 10,000 anti-MM mAb clones. Although R8H283 specifically recognized CD98hc, which is expressed on most normal hematioietic cells, R8H283 binding to normal hematopoietic cells was not detected. After induction of endoplasmic reticulum (ER) stress, which is observed in most MM cells, by tunicamycin or thapsigargin, R8H283-negative hematopoietic cells expressed low molecular weight CD98hc and gained R8H283 reactivity. These results suggest that R8H283 reacted with CD98hc protein with altered modification under ER stress. Furthermore, R8H283 exhibited striking anti-MM effects in vitro and in vivo without damaging normal hematopoietic cells.

Research Products

• [Journal Article] Glycosylation Status of CD43 Protein Is Associated with Resistance of Leukemia Cells to CTL-Mediated Cytolysis. (2016)
  • Author(s): Hasegawa K, Tanaka S, Fujiki F, Morimoto S, Nakano K, Kinoshita H, Okumura A, Fujioka Y, Urakawa R, Nakajima H, Tatsumi N, Nakata J, Takashima S, Nishida S, Tsuboi A, Oka Y, Oji Y, Miyoshi E, Hirata T, Kumanogoh A, Sugiyama H, Hosen N.
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0152326-e0152326
  • DOI: 10.1371/journal.pone.0152326
  • Peer Reviewed / Open Access
• [Journal Article] The Wilms' tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression (2014)
  • Author(s): Wagner KD, Cherfils-Vicini J, Hosen N, Hohenstein P, Gilson E, Hastie ND, Michiels JF, Wagner N.
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 5852-5852
  • DOI: 10.1038/ncomms6852
  • Peer Reviewed
• [Presentation] Identification of multiple myeloma-specific antigens as immunotherapeutic targets (2016)
  • Author(s): Naoki Hosen1), Kana Hasegawa1), Yasutaka Aoyama5, Ichihara, Atsuko Mugitani, Takafumi Nakao6, Yamane, Manabe7, Akihiro Tsuboi2), Jun Nakata2), Sumiyuki Nishida3), Yoshihiro Oka4),Yusuke Oji1), Masayuki Hino8, Atsushi Kumanogoh3), Haruo Sugiyama4)
  • Organizer: 日本血液学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県、横浜市）
  • Year and Date: 2016-10-14