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

Naoki Hosen, Yukiko Matsunaga, Kana Hasegawa, Hiroshi Matsuno, Yuki Nakamura, Mio Makita, Kouki Watanabe, Mikako Yoshida, Kei Satoh, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Jun Nakata, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Masahiro Manabe, Hiroyoshi Ichihara, Yasutaka Aoyama, Atsuko MugitaniTakafumi Nakao, Masayuki Hino, Ryosuke Uchibori, Keiya Ozawa, Yoshihiro Baba, Seitaro Terakura, Naoki Wada, Eiichi Morii, Junichi Nishimura, Kiyoshi Takeda, Yusuke Oji, Haruo Sugiyama, Junichi Takagi, Atsushi Kumanogoh

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 β77 molecules. The MMG49 epitope, in the N-terminal region of the β77 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β77 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β77 + 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.

Original languageEnglish
Pages (from-to)1436-1443
Number of pages8
JournalNature medicine
Volume23
Issue number12
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Antigen Receptors
Cell- and Tissue-Based Therapy
T-Cell Antigen Receptor
Multiple Myeloma
Integrins
Conformations
Monoclonal Antibodies
Immunotherapy
T-cells
Lymphocytes
Proteome
Surface Antigens
Epitopes
Transcriptome
Chemical activation
Neoplasms
Clone Cells
Molecules
T-Lymphocytes
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hosen, N., Matsunaga, Y., Hasegawa, K., Matsuno, H., Nakamura, Y., Makita, M., ... Kumanogoh, A. (2017). The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy. Nature medicine, 23(12), 1436-1443. https://doi.org/10.1038/nm.4431

The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy. / Hosen, Naoki; Matsunaga, Yukiko; Hasegawa, Kana; Matsuno, Hiroshi; Nakamura, Yuki; Makita, Mio; Watanabe, Kouki; Yoshida, Mikako; Satoh, Kei; Morimoto, Soyoko; Fujiki, Fumihiro; Nakajima, Hiroko; Nakata, Jun; Nishida, Sumiyuki; Tsuboi, Akihiro; Oka, Yoshihiro; Manabe, Masahiro; Ichihara, Hiroyoshi; Aoyama, Yasutaka; Mugitani, Atsuko; Nakao, Takafumi; Hino, Masayuki; Uchibori, Ryosuke; Ozawa, Keiya; Baba, Yoshihiro; Terakura, Seitaro; Wada, Naoki; Morii, Eiichi; Nishimura, Junichi; Takeda, Kiyoshi; Oji, Yusuke; Sugiyama, Haruo; Takagi, Junichi; Kumanogoh, Atsushi.

In: Nature medicine, Vol. 23, No. 12, 01.01.2017, p. 1436-1443.

Research output: Contribution to journalArticle

Hosen, N, Matsunaga, Y, Hasegawa, K, Matsuno, H, Nakamura, Y, Makita, M, Watanabe, K, Yoshida, M, Satoh, K, Morimoto, S, Fujiki, F, Nakajima, H, Nakata, J, Nishida, S, Tsuboi, A, Oka, Y, Manabe, M, Ichihara, H, Aoyama, Y, Mugitani, A, Nakao, T, Hino, M, Uchibori, R, Ozawa, K, Baba, Y, Terakura, S, Wada, N, Morii, E, Nishimura, J, Takeda, K, Oji, Y, Sugiyama, H, Takagi, J & Kumanogoh, A 2017, 'The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy', Nature medicine, vol. 23, no. 12, pp. 1436-1443. https://doi.org/10.1038/nm.4431
Hosen N, Matsunaga Y, Hasegawa K, Matsuno H, Nakamura Y, Makita M et al. The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy. Nature medicine. 2017 Jan 1;23(12):1436-1443. https://doi.org/10.1038/nm.4431
Hosen, Naoki ; Matsunaga, Yukiko ; Hasegawa, Kana ; Matsuno, Hiroshi ; Nakamura, Yuki ; Makita, Mio ; Watanabe, Kouki ; Yoshida, Mikako ; Satoh, Kei ; Morimoto, Soyoko ; Fujiki, Fumihiro ; Nakajima, Hiroko ; Nakata, Jun ; Nishida, Sumiyuki ; Tsuboi, Akihiro ; Oka, Yoshihiro ; Manabe, Masahiro ; Ichihara, Hiroyoshi ; Aoyama, Yasutaka ; Mugitani, Atsuko ; Nakao, Takafumi ; Hino, Masayuki ; Uchibori, Ryosuke ; Ozawa, Keiya ; Baba, Yoshihiro ; Terakura, Seitaro ; Wada, Naoki ; Morii, Eiichi ; Nishimura, Junichi ; Takeda, Kiyoshi ; Oji, Yusuke ; Sugiyama, Haruo ; Takagi, Junichi ; Kumanogoh, Atsushi. / The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy. In: Nature medicine. 2017 ; Vol. 23, No. 12. pp. 1436-1443.
@article{6edb3337dcfb425db435949ef0573da4,
title = "The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy",
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 β77 molecules. The MMG49 epitope, in the N-terminal region of the β77 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β77 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β77 + 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.",
author = "Naoki Hosen and Yukiko Matsunaga and Kana Hasegawa and Hiroshi Matsuno and Yuki Nakamura and Mio Makita and Kouki Watanabe and Mikako Yoshida and Kei Satoh and Soyoko Morimoto and Fumihiro Fujiki and Hiroko Nakajima and Jun Nakata and Sumiyuki Nishida and Akihiro Tsuboi and Yoshihiro Oka and Masahiro Manabe and Hiroyoshi Ichihara and Yasutaka Aoyama and Atsuko Mugitani and Takafumi Nakao and Masayuki Hino and Ryosuke Uchibori and Keiya Ozawa and Yoshihiro Baba and Seitaro Terakura and Naoki Wada and Eiichi Morii and Junichi Nishimura and Kiyoshi Takeda and Yusuke Oji and Haruo Sugiyama and Junichi Takagi and Atsushi Kumanogoh",
year = "2017",
month = "1",
day = "1",
doi = "10.1038/nm.4431",
language = "English",
volume = "23",
pages = "1436--1443",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy

AU - Hosen, Naoki

AU - Matsunaga, Yukiko

AU - Hasegawa, Kana

AU - Matsuno, Hiroshi

AU - Nakamura, Yuki

AU - Makita, Mio

AU - Watanabe, Kouki

AU - Yoshida, Mikako

AU - Satoh, Kei

AU - Morimoto, Soyoko

AU - Fujiki, Fumihiro

AU - Nakajima, Hiroko

AU - Nakata, Jun

AU - Nishida, Sumiyuki

AU - Tsuboi, Akihiro

AU - Oka, Yoshihiro

AU - Manabe, Masahiro

AU - Ichihara, Hiroyoshi

AU - Aoyama, Yasutaka

AU - Mugitani, Atsuko

AU - Nakao, Takafumi

AU - Hino, Masayuki

AU - Uchibori, Ryosuke

AU - Ozawa, Keiya

AU - Baba, Yoshihiro

AU - Terakura, Seitaro

AU - Wada, Naoki

AU - Morii, Eiichi

AU - Nishimura, Junichi

AU - Takeda, Kiyoshi

AU - Oji, Yusuke

AU - Sugiyama, Haruo

AU - Takagi, Junichi

AU - Kumanogoh, Atsushi

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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 β77 molecules. The MMG49 epitope, in the N-terminal region of the β77 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β77 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β77 + 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.

AB - 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 β77 molecules. The MMG49 epitope, in the N-terminal region of the β77 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β77 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β77 + 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.

UR - http://www.scopus.com/inward/record.url?scp=85039047406&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039047406&partnerID=8YFLogxK

U2 - 10.1038/nm.4431

DO - 10.1038/nm.4431

M3 - Article

C2 - 29106400

AN - SCOPUS:85039047406

VL - 23

SP - 1436

EP - 1443

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 12

ER -