PMID- 17283154
OWN - NLM
STAT- MEDLINE
DCOM- 20070301
LR  - 20070206
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 3
DP  - 2007 Feb 1
TI  - A single-chain Fv diabody against human leukocyte antigen-A molecules 
      specifically induces myeloma cell death in the bone marrow environment.
PG  - 1184-92
AB  - Cross-linked human leukocyte antigen (HLA) class I molecules have been shown to 
      mediate cell death in neoplastic lymphoid cells. However, clinical application of 
      an anti-HLA class I antibody is limited by possible side effects due to 
      widespread expression of HLA class I molecules in normal tissues. To reduce the 
      unwanted Fc-mediated functions of the therapeutic antibody, we have developed a 
      recombinant single-chain Fv diabody (2D7-DB) specific to the alpha2 domain of 
      HLA-A. Here, we show that 2D7-DB specifically induces multiple myeloma cell death 
      in the bone marrow environment. Both multiple myeloma cell lines and primary 
      multiple myeloma cells expressed HLA-A at higher levels than normal myeloid 
      cells, lymphocytes, or hematopoietic stem cells. 2D7-DB rapidly induced Rho 
      activation and robust actin aggregation that led to caspase-independent death in 
      multiple myeloma cells. This cell death was completely blocked by Rho GTPase 
      inhibitors, suggesting that Rho-induced actin aggregation is crucial for 
      mediating multiple myeloma cell death. Conversely, 2D7-DB neither triggered 
      Rho-mediated actin aggregation nor induced cell death in normal bone marrow cells 
      despite the expression of HLA-A. Treatment with IFNs, melphalan, or bortezomib 
      enhanced multiple myeloma cell death induced by 2D7-DB. Furthermore, 
      administration of 2D7-DB resulted in significant tumor regression in a xenograft 
      model of human multiple myeloma. These results indicate that 2D7-DB acts on 
      multiple myeloma cells differently from other bone marrow cells and thus provide 
      the basis for a novel HLA class I-targeting therapy against multiple myeloma.
FAU - Sekimoto, Etsuko
AU  - Sekimoto E
AD  - Department of Medicine and Bioregulatory Sciences, The University of Tokushima 
      Graduate School of Health Biosciences, 3-18-15 Kuramoto, Tokushima 770-8503, 
      Japan.
FAU - Ozaki, Shuji
AU  - Ozaki S
FAU - Ohshima, Takashi
AU  - Ohshima T
FAU - Shibata, Hironobu
AU  - Shibata H
FAU - Hashimoto, Toshihiro
AU  - Hashimoto T
FAU - Abe, Masahiro
AU  - Abe M
FAU - Kimura, Naoki
AU  - Kimura N
FAU - Hattori, Kunihiro
AU  - Hattori K
FAU - Kawai, Shigeto
AU  - Kawai S
FAU - Kinoshita, Yasuko
AU  - Kinoshita Y
FAU - Yamada-Okabe, Hisafumi
AU  - Yamada-Okabe H
FAU - Tsuchiya, Masayuki
AU  - Tsuchiya M
FAU - Matsumoto, Toshio
AU  - Matsumoto T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Cytokines)
RN  - 0 (HLA-A Antigens)
RN  - 0 (Immunoglobulin Fragments)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells/immunology/pathology
MH  - Cell Death/immunology
MH  - Cell Line, Tumor
MH  - Cytokines/pharmacology
MH  - Enzyme Activation
MH  - HLA-A Antigens/biosynthesis/*immunology
MH  - Humans
MH  - Immunization, Passive/*methods
MH  - Immunoglobulin Fragments/*pharmacology
MH  - Jurkat Cells
MH  - Mice
MH  - Mice, SCID
MH  - Multiple Myeloma/enzymology/*immunology/pathology/*therapy
MH  - Xenograft Model Antitumor Assays
MH  - rho GTP-Binding Proteins/metabolism
EDAT- 2007/02/07 09:00
MHDA- 2007/03/03 09:00
CRDT- 2007/02/07 09:00
PHST- 2007/02/07 09:00 [pubmed]
PHST- 2007/03/03 09:00 [medline]
PHST- 2007/02/07 09:00 [entrez]
AID - 67/3/1184 [pii]
AID - 10.1158/0008-5472.CAN-06-2236 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Feb 1;67(3):1184-92. doi: 10.1158/0008-5472.CAN-06-2236.