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Nat Med. 2017 Dec;23(12):1436-1443. doi: 10.1038/nm.4431. Epub 2017 Nov 6.

The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy.

Author information

1
Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan.
2
Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
3
WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
4
Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan.
5
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6
Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan.
7
Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
8
Department of Hematology, Osaka General Hospital of West Japan Railway Company, Osaka, Japan.
9
Department of Hematology, Fuchu Hospital, Osaka, Japan.
10
Department of Hematology, Osaka City General Hospital, Osaka, Japan.
11
Department of Hematology and Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
12
Division of Immuno-Gene & Cell Therapy (Takara Bio), Jichi Medical University, Tochigi, Japan.
13
Institute of Medical Science, University of Tokyo, Tokyo, Japan.
14
Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
15
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
16
Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
17
Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
18
Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Japan.
19
Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan.

Abstract

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7 molecules. The MMG49 epitope, in the N-terminal region of the β7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.

PMID:
29106400
DOI:
10.1038/nm.4431
[Indexed for MEDLINE]

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