• Text in Japanese

2017-11-6
Publish Nature Medicine（2017） doi:10.1038/nm.4431

Osaka University study unveils new target for monoclonal antibody-based treatment of cancer

 Figure1.MMG49 CAR T cells target the activated conformation of integrin b7 expressed on MM cells (credit: Osaka University) Click to enlarge

In recent decades monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both solid tumors and blood cancers. Monoclonal antibodies (mAb), as the name implies, are antibodies that are made by clonal cells derived from a single parent cells and therefore share the identical amino acid sequences.

One of the leading technologies to emerge in mAb-based treatment is CAR-T, where CAR stands for “chimeric antigen receptor”, and T represents T cells, a type of white blood cells that have pivotal roles in immune defenses. CARs are produced by combining together the gene for an antibody that recognizes a tumor antigen with the gene for a receptor that resides on the surface of the T cells; insert this new gene into a T cell and it will be precisely targeted at the tumor.

Theoretically, new antigens – molecules capable of inducing an immune response to produce an antibody – that arise from cancer-specific mutations of cell-surface proteins are excellent targets. However, mAb therapy targeting such antigens is impractical because of these proteins’ vast diversity within and between individual tumors, which renders identifying new cancer-specific target antigens difficult.
However, such challenges have driven researchers centered at Japan’s Osaka University to think outside of the box; cancer-specific antigen formed by the modification of proteins during or after synthesis, such as glycosylation (attachment of sugar moieties to protein) or conformational changes, might have been missed in previous analyses. The team believed new antigen epitopes, which is the part of an antigen recognized by the immune cells, could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.

“We applied this strategy to identify novel therapeutic targets for multiple myeloma (MM), a cancer that forms in a type of white blood cell called a plasma cell,” explains Naoki Hosen, lead author of the study, which was recently published in Nature Medicine. “Despite advances in MM treatment, relapse remains common. As such, there is an ongoing need for new therapeutic approaches, including mAb-based therapies.”

The team screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β7, a cell-surface receptors that facilitate cell-extracellular matrix adhesion. MMG49 reacted to MM cells, but not other bone marrow cell types in MM patient samples. This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49. The resulting MMG49 CAR T was found to have anti-MM effects without damaging normal blood cells.
“Our results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM,” study coauthor Yukiko Matsunaga says. “Therefore it’s highly plausible that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific.

 Fig.2. Outline of CAR T cell therapy (credit: Osaka University) Click to enlarge

 Fig.3. Anti-myeloma activity of MMG49 CAR T cells (credit: Osaka University) Click to enlarge

The article, “The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy” was published in Nature Medicine at DOI:10.1038/nm.4431

Article:
“The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy” Journal: 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 Mugitani, Takafumi 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
DOI:10.1038/nm.4431

Authors:
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 Mugitani, Takafumi 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

Funder:
the Ministry of Education, Culture, Sports, Science and Technology of Japan / the Japan Agency for Medical
Research and Development AMED / JSPS KAKENHI / Japan Agency for Medical Research and Development

Summary:
Cancer-specific proteins have been identified for the development of monoclonal antibody (mA)-based therapies, but there remains a need to uncover new targets, especially in cancers that are prone to relapses, such as multiple myeloma (MM). A study centered at Osaka University successfully identified integrin β7 as a novel target. Specially designed immune T cells transduced with MMG49-derived chimeric antigen receptor for integrin β7 were found to have anti-MM effects without damaging normal blood cells.

Primary Keyword:Biology
Additional Keywords:Biochemistry, Cancer, Immunology, Molecular Biology