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  1. AU="Masahiro Yasunaga"
  2. AU="Westphal, Joachim"
  3. AU="Zhiqi, Huang"
  4. AU="Acevedo, A C"
  5. AU="García-Cenador, Begoña"
  6. AU="Wisecup, Ciara"
  7. AU="Scortti, Mariela"
  8. AU="Allen, David M."
  9. AU="Martínez, J Alfredo"

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  1. Artikel ; 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  Band 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.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2023-04-01T00:00:00Z
    Verlag Nature Portfolio
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; 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  Band 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 ...

    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.
    Schlagwörter T cell bispecific antibody ; T-BsAb ; pharmacokinetics ; T cell redirection ; mechanism of action ; drug development ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2021-11-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: Chemotherapy payload of anti-insoluble fibrin antibody-drug conjugate is released specifically upon binding to fibrin

    Hirobumi Fuchigami / Shino Manabe / Masahiro Yasunaga / Yasuhiro Matsumura

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Band 9

    Abstract: Abstract Cancer-induced blood coagulation in human tumour generates insoluble fibrin (IF)-rich cancer stroma in which uneven monoclonal antibody (mAb) distribution reduce the potential effectiveness of mAb-mediated treatments. Previously, we developed a ... ...

    Abstract Abstract Cancer-induced blood coagulation in human tumour generates insoluble fibrin (IF)-rich cancer stroma in which uneven monoclonal antibody (mAb) distribution reduce the potential effectiveness of mAb-mediated treatments. Previously, we developed a mAb that reacts only with IF and not with fibrinogen (FNG) or the fibrin degradation product (FDP). Although IF, FNG and FDP share same amino acid sequences, the mAb is hardly neutralised by FNG and FDP in circulation and accumulates in fibrin clots within tumour tissue. Here, we created an antibody drug conjugate (ADC) using the anti-IF mAb conjugated with a chemotherapy payload (IF-ADC). The conjugate contains a linker severed specifically by plasmin (PLM), which is activated only on binding to IF. Imaging mass spectrometry showed the substantial intratumour distribution of the payload following the IF-ADC injection into mice bearing IF-rich 5–11 xenografts derived from pancreatic tumours of LSL-Kras G12D/+; LSL-Trp53 R172H/+; Ptf1a-Cre (KPC) mice. IF-ADC treatment significantly extended the survival of the KPC mice. These data suggest that conjugating chemotherapy drugs to this IF-specific mAb could represent an effective means of treating stroma-rich tumours
    Schlagwörter Medicine ; R ; Science ; Q
    Sprache Englisch
    Erscheinungsdatum 2018-09-01T00:00:00Z
    Verlag Nature Publishing Group
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Protection from contamination by 211At, an enigmatic but promising alpha-particle-emitting radionuclide

    Kazunobu Ohnuki / Mitsuyoshi Yoshimoto / Hiromitsu Haba / Shino Manabe / Hiroki Takashima / Masahiro Yasunaga / Yasumasa Takenaka / Hirofumi Fujii

    EJNMMI Physics, Vol 9, Iss 1, Pp 1-

    2022  Band 8

    Abstract: Abstract Purpose 211At, a promising alpha-particle-emitting radionuclide, can easily volatilize and contaminate the environment. To safely manage this unique alpha-particle-emitting radionuclide, we investigated the permeability of four types of plastic ... ...

    Abstract Abstract Purpose 211At, a promising alpha-particle-emitting radionuclide, can easily volatilize and contaminate the environment. To safely manage this unique alpha-particle-emitting radionuclide, we investigated the permeability of four types of plastic films and two types of rubber gloves against 211At and identified suitable materials that prevent contamination by 211At. Methods Four types of plastic films, polyethylene, polyvinylidene chloride, polyvinyl chloride, and a laminated film, and two types of rubber gloves, latex and nitrile, were examined. Small pieces of filter paper were covered with these materials, and a drop containing 100 kBq of 211At was placed on them. The radioactivity of the pieces of filter paper under the materials was evaluated by measuring counts using a gamma counter and obtaining autoradiograms 3.5 h later. These experiments were also performed using 225Ac, 125I, 111In, 201Tl, and 99mTc. Results 211At solution easily penetrated polyethylene, polyvinyl chloride, and latex rubber. Similar results were obtained for 125I, while other radionuclides did not penetrate films or gloves. These results suggest that halogenic radionuclides under anionic conditions are likely to penetrate plastic films and rubber gloves. Conclusion Our evaluation revealed that, when 211At solution is used, the protection by polyvinylidene chloride, a laminated film, or nitrile rubber would be more effective than that by polyethylene, polyvinyl chloride, or latex rubber.
    Schlagwörter 211At ; Alpha-particle-emitting radionuclide ; Protection ; Volatility ; Plastic film ; Rubber sheet ; Medical physics. Medical radiology. Nuclear medicine ; R895-920
    Thema/Rubrik (Code) 620
    Sprache Englisch
    Erscheinungsdatum 2022-06-01T00:00:00Z
    Verlag SpringerOpen
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: The natural sulfoglycolipid derivative SQAP improves the therapeutic efficacy of tissue factor-targeted radioimmunotherapy in the stroma-rich pancreatic cancer model BxPC-3

    Yoichi Takakusagi / Aya Sugyo / Atsushi B. Tsuji / Hitomi Sudo / Masahiro Yasunaga / Yasuhiro Matsumura / Fumio Sugawara / Kengo Sakaguchi / Tatsuya Higashi

    Translational Oncology, Vol 15, Iss 1, Pp 101285- (2022)

    2022  

    Abstract: α-Sulfoquinovosylacyl-1,3-propanediol (SQAP) is a semi-synthetic derivative of natural sulfoglycolipid that sensitizes tumors to external-beam radiotherapy. How SQAP affects internal radiotherapy, however, is not known. Here, we investigated the effects ... ...

    Abstract α-Sulfoquinovosylacyl-1,3-propanediol (SQAP) is a semi-synthetic derivative of natural sulfoglycolipid that sensitizes tumors to external-beam radiotherapy. How SQAP affects internal radiotherapy, however, is not known. Here, we investigated the effects of SQAP for radioimmunotherapy (RIT) targeting tissue factor (TF) in a stroma-rich refractory pancreatic cancer mouse model, BxPC-3. A low dose of SQAP (2 mg/kg) increased tumor uptake of the 111In-labeled anti-TF antibody 1849, indicating increased tumor perfusion. The addition of SQAP enhanced the growth-inhibitory effect of 90Y-labeled 1849 without leading to severe body weight changes, allowing for the dose of 90Y-labeled 1849 to be reduced to half that when used alone. Histologic analysis revealed few necrotic and apoptotic cells, but Ki-67–positive proliferating cells and increased vascular formation were detected. These results suggest that the addition of a low dose of SQAP may improve the therapeutic efficacy of TF-targeted RIT by increasing tumor perfusion, even for stroma-rich refractory pancreatic cancer.
    Schlagwörter Refractory cancer ; Molecular radiotherapy ; Therapeutic nuclear medicine ; Radionuclide ; Neoangiogenesis ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2022-01-01T00:00:00Z
    Verlag Elsevier
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: Immunoregulation by IL-7R-targeting antibody-drug conjugates

    Masahiro Yasunaga / Shino Manabe / Yasuhiro Matsumura

    Scientific Reports, Vol 7, Iss 1, Pp 1-

    overcoming steroid-resistance in cancer and autoimmune disease

    2017  Band 14

    Abstract: Abstract Steroid-resistance is a common complication in the treatment of malignancies and autoimmune diseases. IL-7/IL-7R signaling, which regulates lymphocyte growth and survival, has been implicated in the development of malignancies and autoimmune ... ...

    Abstract Abstract Steroid-resistance is a common complication in the treatment of malignancies and autoimmune diseases. IL-7/IL-7R signaling, which regulates lymphocyte growth and survival, has been implicated in the development of malignancies and autoimmune diseases. However, the biological significance of IL-7/IL-7R signaling in steroid treatment is poorly understood. Here, we identified a novel relationship between IL-7R signaling and steroid-resistance, and showed that an anti-IL-7R antibody conjugated with SN-38 (A7R-ADC-SN-38) has strong anti-tumor effects against both parental and steroid-resistant malignant cells. Furthermore, inflammation in the mouse autoimmune arthritis model was suppressed to greater extent by A7R-ADC conjugated to MMAE than by A7R-ADC-SN-38. Given that an increased proportion of IL-7R-positive cells is a common mechanism underlying the pathogenesis of autoimmunity, we found that specific depletion of this cell population abrogated the progression of disease. This suggests that the cytotoxicity and immunosuppressive capacity of A7R-ADC could be modulated to treat specific malignancies or autoimmune diseases through the introduction of different payloads, and represents a novel alternative to steroid therapy.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2017-09-01T00:00:00Z
    Verlag Nature Publishing Group
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel: Influence of the dissociation rate constant on the intra-tumor distribution of antibody-drug conjugate against tissue factor

    Tsumura, Ryo / Hiroki Takashima / Masahiro Yasunaga / Shino Manabe / Yasuhiro Matsumura / Yoshikatsu Koga

    Journal of controlled release. 2018 Aug. 28, v. 284

    2018  

    Abstract: Antibody-drug conjugates (ADCs) are currently considered to be promising agents for cancer therapy. However, especially in solid tumors, the uneven distribution of ADCs would decrease their efficacy in clinical studies. We suggest that in addition to ... ...

    Abstract Antibody-drug conjugates (ADCs) are currently considered to be promising agents for cancer therapy. However, especially in solid tumors, the uneven distribution of ADCs would decrease their efficacy in clinical studies. We suggest that in addition to optimizing ADC components, such as the linker structure and anticancer agent, it is necessary to consider the distribution of the ADC within tumor tissue. In this study, we established three kinds of anti–tissue factor (TF) ADCs: 1849ADC with a low kd, 444ADC with an intermediate kd, and 1084ADC with a high kd. All three of the anti-TF ADCs exhibited almost the same in vitro cytotoxicity and pharmacological and biochemical characteristics, although the binding kinetics parameters differed. In vivo, all ADCs exerted equivalent antitumor effects against small BxPC3 tumors. However, on larger BxPC3 tumors, 1084ADC (higher kd) exerted higher antitumor activity than 1849ADC (lower kd). Furthermore, immunofluorescence staining indicated that 1084ADC was distributed throughout the whole tumor, whereas 1849ADC was mainly localized close to tumor vessels. We conclude that the ADC with a higher kd increased the antitumor effect of because it penetrated and distributed evenly throughout the entire solid tumor. These findings highlight the importance of the kd of a mAb in ADC design.
    Schlagwörter antineoplastic activity ; antineoplastic agents ; clinical trials ; cytotoxicity ; dissociation ; fluorescent antibody technique ; neoplasms ; staining ; therapeutics
    Sprache Englisch
    Erscheinungsverlauf 2018-0828
    Umfang p. 49-56.
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2018.06.016
    Datenquelle NAL Katalog (AGRICOLA)

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  8. Artikel ; Online: Stabilization of an 211At-Labeled Antibody with Sodium Ascorbate

    Shino Manabe / Hiroki Takashima / Kazunobu Ohnuki / Yoshikatsu Koga / Ryo Tsumura / Nozomi Iwata / Yang Wang / Takuya Yokokita / Yukiko Komori / Sachiko Usuda / Daiki Mori / Hiromitsu Haba / Hirofumi Fujii / Masahiro Yasunaga / Yasuhiro Matsumura

    ACS Omega, Vol 6, Iss 23, Pp 14887-

    2021  Band 14895

    Schlagwörter Chemistry ; QD1-999
    Sprache Englisch
    Erscheinungsdatum 2021-05-01T00:00:00Z
    Verlag American Chemical Society
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  9. Artikel ; Online: Mass spectrometry imaging for early discovery and development of cancer drugs

    Masahiro Yasunaga / Shino Manabe / Masaru Furuta / Koretsugu Ogata / Yoshikatsu Koga / Hiroki Takashima / Toshirou Nishida / Yasuhiro Matsumura

    AIMS Medical Science, Vol 5, Iss 2, Pp 162-

    2018  Band 180

    Abstract: A drug delivery system (DDS) is a method for delivering a drug to its site of action in the body, with the goal of achieving therapeutic benefits while reducing adverse effects. Pharmacokinetics (PK) and pharmacodynamics (PD) studies have been conducted ... ...

    Abstract A drug delivery system (DDS) is a method for delivering a drug to its site of action in the body, with the goal of achieving therapeutic benefits while reducing adverse effects. Pharmacokinetics (PK) and pharmacodynamics (PD) studies have been conducted to evaluate drug delivery, but these approaches are rarely used in the early stages of drug discovery and development. We demonstrated that the tumor stromal barrier inhibits drug distribution within tumor tissue, especially in refractory cancers such as pancreatic cancer. This poses an obstacle to the discovery of new drugs, and is difficult to overcome using conventional in vitro drug discovery methods. In addition, we are also developing new DDS drugs and antibody-drug conjugates (ADCs). These agents act via four steps: Systemic circulation, the enhanced permeability and retention (EPR) effect, penetration within the tumor tissue, and action on cells including controlled drug release. Most of these activities can be evaluated by conventional biological or pharmacological assays. However, it is difficult to examine drug distribution and controlled drug release within targeted tissues. Recent advances in mass spectrometry imaging (MSI) allow examining drug delivery much more conveniently with the off-labeling. A mass microscope, a new type of matrix-associated laser desorption/ionization (MALDI)-MSI analyzer, is a microscope coupled with an atmospheric MALDI and quadruple ion trap time-of-flight (TOF) mass spectrometer, and can provide imaging data with enhanced resolution and high sensitivity. Using a mass microscope, we succeeded in visualizing the EPR effect of a polymeric micelle drug and controlled drug release by an ADC. Currently, we are developing a new drug imaging method using electrospray ionization (ESI)-MSI. Here, we review the use of MSI in early stages of drug discovery and development, as well as our related recent work.
    Schlagwörter drug discovery and development ; molecular imaging ; mass spectrometry imaging (MSI) ; drug delivery system (DDS) ; antibody-drug conjugate (ADC) ; MALDI (matrix-associated laser desorption/ionization) ; electrospray ionization (ESI) ; mass microscope ; Medicine (General) ; R5-920
    Thema/Rubrik (Code) 500 ; 610
    Sprache Englisch
    Erscheinungsdatum 2018-04-01T00:00:00Z
    Verlag American Institute of Mathematical Sciences
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  10. Artikel ; Online: Development of Antibody–Drug Conjugates Using DDS and Molecular Imaging

    Masahiro Yasunaga / Shino Manabe / Atsushi Tsuji / Masaru Furuta / Koretsugu Ogata / Yoshikatsu Koga / Tsuneo Saga / Yasuhiro Matsumura

    Bioengineering, Vol 4, Iss 3, p

    2017  Band 78

    Abstract: Antibody-drug conjugate (ADC), as a next generation of antibody therapeutics, is a combination of an antibody and a drug connected via a specialized linker. ADC has four action steps: systemic circulation, the enhanced permeability and retention (EPR) ... ...

    Abstract Antibody-drug conjugate (ADC), as a next generation of antibody therapeutics, is a combination of an antibody and a drug connected via a specialized linker. ADC has four action steps: systemic circulation, the enhanced permeability and retention (EPR) effect, penetration within the tumor tissue, and action on cells, such as through drug delivery system (DDS) drugs. An antibody with a size of about 10 nm has the same capacity for passive targeting as some DDS carriers, depending on the EPR effect. In addition, some antibodies are capable of active targeting. A linker is stable in the bloodstream but should release drugs efficiently in the tumor cells or their microenvironment. Thus, the linker technology is actually a typical controlled release technology in DDS. Here, we focused on molecular imaging. Fluorescent and positron emission tomography (PET) imaging is useful for the visualization and evaluation of antibody delivery in terms of passive and active targeting in the systemic circulation and in tumors. To evaluate the controlled release of the ADC in the targeted area, a mass spectrometry imaging (MSI) with a mass microscope, to visualize the drug released from ADC, was used. As a result, we succeeded in confirming the significant anti-tumor activity of anti-fibrin, or anti-tissue factor-ADC, in preclinical settings by using DDS and molecular imaging.
    Schlagwörter ADC (antibody-drug conjugate) ; DDS (drug delivery system) ; molecular imaging ; antibody delivery ; controlled release ; PET (positron emission tomography) ; MSI (mass spectrometry imaging) ; Technology ; T ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 500
    Sprache Englisch
    Erscheinungsdatum 2017-09-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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