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Article ; Online: Antibody therapeutics and immunoregulation in cancer and autoimmune disease.

Yasunaga, Masahiro

2019 Volume 64, Page(s) 1–12

Abstract: Cancer and autoimmune disease are closely related, and many therapeutic antibodies are widely used in clinics for the treatment of both diseases. Among them, the anti-CD20 antibody has proven to be effective against both lymphoid malignancy and ... ...

Abstract	Cancer and autoimmune disease are closely related, and many therapeutic antibodies are widely used in clinics for the treatment of both diseases. Among them, the anti-CD20 antibody has proven to be effective against both lymphoid malignancy and autoimmune disease. Moreover, immune checkpoint blockade using the anti-PD1/PD-L1/CTLA4 antibody has improved the prognosis of patients with refractory solid tumors. At the same time, however, over-enhancement of immunoreaction can induce autoimmune reaction. Although anti-TNF antibody therapies represent a breakthrough in the treatment of autoimmune diseases, optimal management is required to control the serious associated issues, including development and progression of cancer, and it is becoming more and more important to control the immunoreaction. In addition, next-generation antibody therapeutics such as antibody-drug conjugates and bispecific antibodies, are anticipated to treat uncontrolled cancer and autoimmune disease. IL-7R signaling plays an important role in the development and progression of both lymphoid malignancy and autoimmune disease. In addition, abnormal homing activity and steroid resistance caused by IL-7R signaling may worsen prognosis. Therefore, anti-IL-7R targeting antibody therapies that enable suppression of such pathophysiological status have the potential to be beneficial for the treatment of both diseases. In this review, we discuss current antibody therapeutics in cancer and autoimmune disease, and describe a new therapeutic strategy for immunoregulation including IL-7R targeting antibodies.
MeSH term(s)	Animals ; Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents, Immunological/therapeutic use ; Autoimmune Diseases/complications ; Autoimmune Diseases/immunology ; Autoimmune Diseases/pathology ; Autoimmune Diseases/therapy ; Humans ; Immunotherapy ; Neoplasms/complications ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Receptors, Interleukin-7/antagonists & inhibitors ; Receptors, Interleukin-7/immunology
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents, Immunological ; Receptors, Interleukin-7
Language	English
Publishing date	2019-06-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2019.06.001
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Article ; Online: Expansion of mixed immune cells using CD3/CD161 co-stimulation for the treatment of cancer.

Tsumura, Ryo / Haruta, Miwa / Kuwano, Masataka / Yasunaga, Masahiro

Scientific reports

2023 Volume 13, Issue 1, Page(s) 6803

Abstract: Adoptive cell transfer (ACT) is a type of personalized immunotherapy in which expanded immune cells are administered to patients with cancer. However, single-cell populations, such as killer T cells, dendritic cells, natural killer (NK) cells, and NKT ( ... ...

Abstract	Adoptive cell transfer (ACT) is a type of personalized immunotherapy in which expanded immune cells are administered to patients with cancer. However, single-cell populations, such as killer T cells, dendritic cells, natural killer (NK) cells, and NKT (NKT) cells, have been generally used, and their effectiveness remains limited. Here, we established a novel culture method via CD3/CD161 co-stimulation and successfully expanded CD3
MeSH term(s)	Humans ; CD3 Complex ; CD8-Positive T-Lymphocytes ; Killer Cells, Natural ; Natural Killer T-Cells ; Neoplasms/therapy ; Neoplasms/metabolism ; T-Lymphocytes, Cytotoxic/metabolism ; NK Cell Lectin-Like Receptor Subfamily B/metabolism
Chemical Substances	CD3 Complex ; NK Cell Lectin-Like Receptor Subfamily B
Language	English
Publishing date	2023-04-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-33987-2
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Article ; Online: Chromatographic Analysis of the

Hiranyakorn, Methanee / Iwamoto, Shogo / Hoshinoo, Asako / Tsumura, Ryo / Takashima, Hiroki / Yasunaga, Masahiro / Manabe, Shino

ACS omega

2023 Volume 8, Issue 18, Page(s) 16513–16518

Abstract: ... ...

Abstract	N
Language	English
Publishing date	2023-04-28
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.3c02374
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Article ; Online: Expansion of mixed immune cells using CD3/CD161 co-stimulation for the treatment of cancer

Ryo Tsumura / Miwa Haruta / Masataka Kuwano / Masahiro Yasunaga

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 9

Abstract: Abstract Adoptive cell transfer (ACT) is a type of personalized immunotherapy in which expanded immune cells are administered to patients with cancer. However, single-cell populations, such as killer T cells, dendritic cells, natural killer (NK) cells, ... ...

Abstract	Abstract Adoptive cell transfer (ACT) is a type of personalized immunotherapy in which expanded immune cells are administered to patients with cancer. However, single-cell populations, such as killer T cells, dendritic cells, natural killer (NK) cells, and NKT (NKT) cells, have been generally used, and their effectiveness remains limited. Here, we established a novel culture method via CD3/CD161 co-stimulation and successfully expanded CD3+/CD4+ helper T cells, CD3+/CD8+ cytotoxic T cells (CTLs), CD3−/CD56+ NK cells, CD3+/CD1d+ NKT cells, CD3+/CD56+ NKT cells, CD3+/TCRγδ+ T cells, and CD3−/CD11c+/HLA-DR+ dendritic cells in peripheral blood mononuclear cells from healthy donors; their respective numbers were 155.5, 1132.5, 5.7, 117.0, 659.2, 325.6, and 6.8 times higher than those before expansion. These mixed immune cells showed strong cytotoxicity against cancer cell lines Capan-1 and SW480. Moreover, both CD3+/CD8+ CTLs and CD3+/CD56+ NKT cells killed tumor cells in cell contact-dependent and -independent manners via granzyme B and interferon-γ/TNF-α, respectively. Furthermore, the cytotoxicity of the mixed cells was significantly superior to that of CTLs or NKTs alone. A bet-hedging CTL-NKT circuitry is one potential mechanism underlying this cooperative cytotoxicity. Collectively, CD3/CD161 co-stimulation may be a promising culture method to expand multiple, distinct immune cell populations for the treatment of cancer.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The authors reply.

Ando, Takahiro / Kawashima, Masahiro / Jo, Taisuke / Yasunaga, Hideo / Nagase, Takahide

Critical care medicine

2021 Volume 49, Issue 4, Page(s) e466–e467

Language	English
Publishing date	2021-03-17
Publishing country	United States
Document type	Research Support, Non-U.S. Gov't ; Letter ; Comment
ZDB-ID	197890-1
ISSN	1530-0293 ; 0090-3493
ISSN (online)	1530-0293
ISSN	0090-3493
DOI	10.1097/CCM.0000000000004911
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Article ; Online: Perioperative Factors Aggravating Pharyngocutaneous Fistula After Total Laryngectomy: A Single-Center Retrospective Analysis Using the Clavien-Dindo Classification.

Haga, Yoshitaka / Yasunaga, Yoshichika / Araki, Jun / Nakao, Junichi / Mori, Hiroaki / Nakagawa, Masahiro / Mukaigawa, Takashi

Annals of plastic surgery

2023 Volume 91, Issue 1, Page(s) 84–89

Abstract: Background: Pharyngocutaneous fistula formation represents a major postoperative complication following total laryngectomy. We aimed to investigate the risk factors for pharyngocutaneous fistula development after total laryngectomy and to identify ... ...

Abstract	Background: Pharyngocutaneous fistula formation represents a major postoperative complication following total laryngectomy. We aimed to investigate the risk factors for pharyngocutaneous fistula development after total laryngectomy and to identify factors that lead to severe cases of pharyngocutaneous fistula. Methods: Patients who underwent total laryngectomy between January 2013 and February 2021 were included in the study and were divided into 2 groups: Those with and without pharyngocutaneous fistula. The severity of pharyngocutaneous fistula was graded using the Clavien-Dindo classification. Results: Patients with pharyngocutaneous fistula experienced longer operative time, greater intraoperative blood loss, greater decrease in perioperative hemoglobin level, and longer postoperative hospitalization. Unlike in lower-severity cases, patients with grade IIIb pharyngocutaneous fistula underwent preoperative radiotherapy or chemoradiotherapy; preoperative treatment was thus a risk factor for higher severity of pharyngocutaneous fistula (odds ratio, 35; P = 0.004). Conclusion: Salvage laryngectomy was found to be a predictor of severe pharyngocutaneous fistula development. Prolonged operative time, increased intraoperative blood loss, and decreased postoperative hemoglobin level were found to be predictors of postlaryngectomy pharyngocutaneous fistula formation.
MeSH term(s)	Humans ; Retrospective Studies ; Laryngectomy/adverse effects ; Blood Loss, Surgical ; Laryngeal Neoplasms/surgery ; Cutaneous Fistula/epidemiology ; Cutaneous Fistula/etiology ; Pharyngeal Diseases/etiology ; Pharyngeal Diseases/surgery ; Risk Factors ; Postoperative Complications/epidemiology ; Postoperative Complications/etiology ; Postoperative Complications/surgery ; Hemoglobins
Chemical Substances	Hemoglobins
Language	English
Publishing date	2023-07-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	423835-7
ISSN	1536-3708 ; 0148-7043
ISSN (online)	1536-3708
ISSN	0148-7043
DOI	10.1097/SAP.0000000000003627
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Article: T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity.

Kamakura, Daisuke / Asano, Ryutaro / Yasunaga, Masahiro

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 11

Abstract: As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with ...

Abstract	As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.
Language	English
Publishing date	2021-11-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14111172
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Article ; Online: T Cell Bispecific Antibodies

Daisuke Kamakura / Ryutaro Asano / Masahiro Yasunaga

Pharmaceuticals, Vol 14, Iss 1172, p

An Antibody-Based Delivery System for Inducing Antitumor Immunity

2021 Volume 1172

Abstract	As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.
Keywords	T cell bispecific antibody ; T-BsAb ; pharmacokinetics ; T cell redirection ; mechanism of action ; drug development ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	570
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: Identification of CD73 as the Antigen of an Antigen-Unknown Monoclonal Antibody Established by Exosome Immunization, and Its Antibody-Drug Conjugate Exerts an Antitumor Effect on Glioblastoma Cell Lines.

Anzai, Takahiro / Saijou, Shinji / Takashima, Hiroki / Hara, Misato / Hanaoka, Shingo / Matsumura, Yasuhiro / Yasunaga, Masahiro

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 7

Abstract: Development of antibodies against the native structure of membrane proteins with multiple transmembrane domains is challenging because it is difficult to prepare antigens with native structures. Previously, we successfully developed a monoclonal antibody ...

Abstract	Development of antibodies against the native structure of membrane proteins with multiple transmembrane domains is challenging because it is difficult to prepare antigens with native structures. Previously, we successfully developed a monoclonal antibody against multi-pass membrane protein TMEM180 by exosome immunization in rats. This approach yielded antibodies that recognized cancer-specific antigens on the exosome. In this study, we performed immunoprecipitation using magnetic beads to identify the antigen of one of the rat antibody clones, 0614, as CD73. We then converted antibody 0614 to human chimeric antibody 0614-5. Glioblastoma (GB) was the cancer type with the highest expression of CD73 in the tumor relative to healthy tissue. An antibody-drug conjugate (ADC) of 0614-5 exerted an antitumor effect on GB cell lines according to expression of CD73. The 0614-5-ADC has potential to be used to treat cancers with high CD73 expression. In addition, our strategy could be used to determine the antigen of any antibody produced by exosome immunization, which may allow the antibody to advance to new antibody therapies.
Language	English
Publishing date	2022-07-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15070837
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Article ; Online: Mechanism of action of a T cell-dependent bispecific antibody as a breakthrough immunotherapy against refractory colorectal cancer with an oncogenic mutation.

Kamakura, Daisuke / Asano, Ryutaro / Kawai, Hiroki / Yasunaga, Masahiro

Cancer immunology, immunotherapy : CII

2020 Volume 70, Issue 1, Page(s) 177–188

Abstract: T cell-dependent bispecific antibody (TDB)-induced T cell activation, which can eliminate tumor cells independent of MHC engagement, is expected to be a novel breakthrough immunotherapy against refractory cancer. However, the mechanism of action of TDBs ... ...

Abstract	T cell-dependent bispecific antibody (TDB)-induced T cell activation, which can eliminate tumor cells independent of MHC engagement, is expected to be a novel breakthrough immunotherapy against refractory cancer. However, the mechanism of action of TDBs has not been fully elucidated thus far. We focused on TDB-induced T cell-tumor cell contact as an important initial step in direct T cell-mediated tumor cell killing via transport of cytotoxic cell proteases (e.g., granzymes) with or without immunological synapse formation. Using an anti-EGFR/CD3 TDB, hEx3, we visualized and quantified T cell-tumor cell contact and demonstrated a correlation between the degree of cell contact and TDB efficacy. We also found that cytokines, including interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) secreted by activated T cells, damaged tumor cells in a cell contact-independent manner. Moreover, therapeutic experiences clearly indicated that hEx3, unlike conventional anti-EGFR antibodies, was effective against colorectal cancer (CRC) cells with mutant KRAS, BRAF, or PIK3CA. In a pharmacokinetic analysis, T cells spread gradually in accordance with the hEx3 distribution within tumor tissue. Accordingly, we propose that TDBs should have four action steps: 1st, passive targeting via size-dependent tumor accumulation; 2nd, active targeting via specific binding to tumor cells; 3rd, T cell redirection toward tumor cells; and 4th, TDB-induced cell contact-dependent (direct) or -independent (indirect) tumor cell killing. Finally, our TDB hEx3 may be a promising reagent against refractory CRC with an oncogenic mutation associated with a poor prognosis.
MeSH term(s)	Animals ; Antibodies, Bispecific/immunology ; Carcinogenesis/immunology ; Cell Line, Tumor ; Colorectal Neoplasms/immunology ; Colorectal Neoplasms/therapy ; Cytokines/immunology ; ErbB Receptors/immunology ; Female ; HCT116 Cells ; HT29 Cells ; Humans ; Immunotherapy/methods ; Interferon-gamma/immunology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mutation/immunology ; Prognosis ; T-Lymphocytes/immunology ; Tumor Necrosis Factor-alpha/immunology ; Xenograft Model Antitumor Assays/methods
Chemical Substances	Antibodies, Bispecific ; Cytokines ; Tumor Necrosis Factor-alpha ; Interferon-gamma (82115-62-6) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2020-07-14
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-020-02667-9
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