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Open AccessEditorial

Special Issue: Evaluation of the Antitumor Mechanism of Armed Antibodies

by Yoshikatsu Koga, Hiroki Takashima and Shigehiro Koganemaru

Pharmaceuticals 2023, 16(12), 1690; https://doi.org/10.3390/ph16121690 - 05 Dec 2023

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Abstract

This Special Issue focuses on the use of therapeutic antibodies in vitro, in vivo, and in clinical studies [...] Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

Research

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13 pages, 5397 KiB

Open AccessArticle

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

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

Pharmaceuticals 2022, 15(7), 837; https://doi.org/10.3390/ph15070837 - 06 Jul 2022

Cited by 2 | Viewed by 2224

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. [...] Read more.

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. Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

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14 pages, 36521 KiB

Open AccessArticle

Evaluation of Fluorescence Intensity and Antitumor Effect Using Real-Time Imaging in Photoimmunotherapy

by Kenji Takashima, Yoshikatsu Koga, Takahiro Anzai, Kayo Migita, Toru Yamaguchi, Akihiro Ishikawa, Shingo Sakashita, Masahiro Yasunaga and Tomonori Yano

Pharmaceuticals 2022, 15(2), 223; https://doi.org/10.3390/ph15020223 - 14 Feb 2022

Cited by 2 | Viewed by 1933

Abstract

Photoimmunotherapy (PIT) is a promising tumor-selective treatment method that uses light-absorbing dye-conjugated antibodies and light irradiation. It has been reported that IR700 fluorescence changes with light irradiation. The purpose of this study was to investigate the fluorescence intensity and antitumor effect of PIT [...] Read more.

Photoimmunotherapy (PIT) is a promising tumor-selective treatment method that uses light-absorbing dye-conjugated antibodies and light irradiation. It has been reported that IR700 fluorescence changes with light irradiation. The purpose of this study was to investigate the fluorescence intensity and antitumor effect of PIT using real-time fluorescence observation of tumors and predict the required irradiation dose. The near-infrared camera system LIGHTVISION was used to image IR700 during PIT treatment. IR700 showed a sharp decrease in fluorescence intensity in the early stage of treatment and almost reached a plateau at an irradiation dose of 40 J/cm. Cetuximab-PIT for A431 xenografts was performed at multiple doses from 0–100 J/cm. A significant antitumor effect was observed at 40 J/cm compared to no irradiation, and there was no significant difference between 40 J/cm and 100 J/cm. These results suggest that the rate of decay of the tumor fluorescence intensity correlates with the antitumor effect by real-time fluorescence imaging during PIT. In addition, when the fluorescence intensity of the tumor plateaued in real-time fluorescence imaging, it was assumed that the laser dose was necessary for treatment. Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

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17 pages, 35375 KiB

Open AccessArticle

Site-Specific Antibody Conjugation to Engineered Double Cysteine Residues

by Qun Zhou, Josephine Kyazike, Ekaterina Boudanova, Michael Drzyzga, Denise Honey, Robert Cost, Lihui Hou, Francis Duffieux, Marie-Priscille Brun, Anna Park and Huawei Qiu

Pharmaceuticals 2021, 14(7), 672; https://doi.org/10.3390/ph14070672 - 14 Jul 2021

Cited by 11 | Viewed by 5530

Abstract

Site-specific antibody conjugations generate homogeneous antibody-drug conjugates with high therapeutic index. However, there are limited examples for producing the site-specific conjugates with a drug-to-antibody ratio (DAR) greater than two, especially using engineered cysteines. Based on available Fc structures, we designed and introduced free [...] Read more.

Site-specific antibody conjugations generate homogeneous antibody-drug conjugates with high therapeutic index. However, there are limited examples for producing the site-specific conjugates with a drug-to-antibody ratio (DAR) greater than two, especially using engineered cysteines. Based on available Fc structures, we designed and introduced free cysteine residues into various antibody CH2 and CH3 regions to explore and expand this technology. The mutants were generated using site-directed mutagenesis with good yield and properties. Conjugation efficiency and selectivity were screened using PEGylation. The top single cysteine mutants were then selected and combined as double cysteine mutants for expression and further investigation. Thirty-six out of thirty-eight double cysteine mutants display comparable expression with low aggregation similar to the wild-type antibody. PEGylation screening identified seventeen double cysteine mutants with good conjugatability and high selectivity. PEGylation was demonstrated to be a valuable and efficient approach for quickly screening mutants for high selectivity as well as conjugation efficiency. Our work demonstrated the feasibility of generating antibody conjugates with a DAR greater than 3.4 and high site-selectivity using THIOMAB^TM method. The top single or double cysteine mutants identified can potentially be applied to site-specific antibody conjugation of cytotoxin or other therapeutic agents as a next generation conjugation strategy. Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

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13 pages, 2467 KiB

Open AccessArticle

Antibody–Drug Conjugate to Treat Meningiomas

by Kai Chen, Yingnan Si, Jianfa Ou, Jia-Shiung Guan, Seulhee Kim, Patrick Ernst, Ya Zhang, Lufang Zhou, Xiaosi Han and Xiaoguang (Margaret) Liu

Pharmaceuticals 2021, 14(5), 427; https://doi.org/10.3390/ph14050427 - 02 May 2021

Cited by 5 | Viewed by 3068

Abstract

Meningiomas are primary tumors of the central nervous system with high recurrence. It has been reported that somatostatin receptor 2 (SSTR2) is highly expressed in most meningiomas, but there is no effective targeted therapy approved to control meningiomas. This study aimed to develop [...] Read more.

Meningiomas are primary tumors of the central nervous system with high recurrence. It has been reported that somatostatin receptor 2 (SSTR2) is highly expressed in most meningiomas, but there is no effective targeted therapy approved to control meningiomas. This study aimed to develop and evaluate an anti-SSTR2 antibody–drug conjugate (ADC) to target and treat meningiomas. The meningioma targeting, circulation stability, toxicity, and anti-tumor efficacy of SSTR2 ADC were evaluated using cell lines and/or an intracranial xenograft mouse model. The flow cytometry analysis showed that the anti-SSTR2 mAb had a high binding rate of >98% to meningioma CH157-MN cells but a low binding rate of <5% to the normal arachnoidal AC07 cells. The In Vivo Imaging System (IVIS) imaging demonstrated that the Cy5.5-labeled ADC targeted and accumulated in meningioma xenograft but not in normal organs. The pharmacokinetics study and histological analysis confirmed the stability and minimal toxicity. In vitro anti-cancer cytotoxicity indicated a high potency of ADC with an IC₅₀ value of <10 nM. In vivo anti-tumor efficacy showed that the anti-SSTR2 ADC with doses of 8 and 16 mg/kg body weight effectively inhibited tumor growth. This study demonstrated that the anti-SSTR2 ADC can target meningioma and reduce the tumor growth. Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

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Review

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27 pages, 1275 KiB

Open AccessReview

The Past, Present, and Future of Clinically Applied Chimeric Antigen Receptor-T-Cell Therapy

by Yuki Fujiwara, Toshiki Kato, Futoshi Hasegawa, Muha Sunahara and Yoshie Tsurumaki

Pharmaceuticals 2022, 15(2), 207; https://doi.org/10.3390/ph15020207 - 09 Feb 2022

Cited by 6 | Viewed by 5354

Abstract

Immunotherapy represents the fourth pillar of cancer therapy after surgery, chemotherapy, and radiation. Chimeric antigen receptor (CAR)-T-cell therapy is an artificial immune cell therapy applied in clinical practice and is currently indicated for hematological malignancies, with cluster of differentiation 19 (CD19) as its [...] Read more.

Immunotherapy represents the fourth pillar of cancer therapy after surgery, chemotherapy, and radiation. Chimeric antigen receptor (CAR)-T-cell therapy is an artificial immune cell therapy applied in clinical practice and is currently indicated for hematological malignancies, with cluster of differentiation 19 (CD19) as its target molecule. In this review, we discuss the past, present, and future of CAR-T-cell therapy. First, we summarize the various clinical trials that were conducted before the clinical application of CD19-targeted CAR-T-cell therapies began. Second, we discuss the accumulated real-world evidence and the barriers associated with applying clinical trials to clinical practices from the perspective of the quality and technical aspects. After providing an overview of all the moving parts involved in the production of CAR-T-cell products, we discuss the characteristics of immune cells (given that T cells are the raw materials for CAR-T-cell therapy) and elucidate the relationship between lifestyle, including diet and exercise, and immune cells. Finally, we briefly highlight future trends in the development of immune cell therapy. These advancements may help position CAR-T-cell therapy as a standard of care. Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

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24 pages, 830 KiB

Open AccessFeature PaperReview

T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity

by Daisuke Kamakura, Ryutaro Asano and Masahiro Yasunaga

Pharmaceuticals 2021, 14(11), 1172; https://doi.org/10.3390/ph14111172 - 17 Nov 2021

Cited by 13 | Viewed by 6513

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

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17 pages, 3197 KiB

Open AccessReview

Research and Clinical Landscape of Bispecific Antibodies for the Treatment of Solid Malignancies

by Gabriele Antonarelli, Federica Giugliano, Chiara Corti, Matteo Repetto, Paolo Tarantino and Giuseppe Curigliano

Pharmaceuticals 2021, 14(9), 884; https://doi.org/10.3390/ph14090884 - 31 Aug 2021

Cited by 18 | Viewed by 8345

Abstract

Solid tumors adopt multiple mechanisms to grow, evade immune responses, and to withstand therapeutic approaches. A major breakthrough in the armamentarium of anti-cancer agents has been the introduction of monoclonal antibodies (mAbs), able to inhibit aberrantly activated pathways and/or to unleash antigen (Ag)-specific [...] Read more.

Solid tumors adopt multiple mechanisms to grow, evade immune responses, and to withstand therapeutic approaches. A major breakthrough in the armamentarium of anti-cancer agents has been the introduction of monoclonal antibodies (mAbs), able to inhibit aberrantly activated pathways and/or to unleash antigen (Ag)-specific immune responses. Nonetheless, mAb-mediated targeted pressure often fails due to escape mechanisms, mainly Ag loss/downregulation, ultimately providing therapy resistance. Hence, in order to target multiple Ag at the same time, and to facilitate cancer-immune cells interactions, bispecific antibodies (bsAbs) have been developed and are being tested in clinical trials, yielding variable safety/efficacy results based on target selection and their structure. While in hematologic cancers the bsAb blinatumomab recently reached the Food and Drug Administration (FDA)-approval for B Cell Acute Lymphoblastic Leukemia, bsAbs use in solid tumors faces considerable challenges, such as target Ag selection, biodistribution, and the presence of an immune-suppressive tumor microenvironment (TME). This review will focus on the state-of-the art, the design, and the exploitation of bsAbs against solid malignancies, delineating their mechanisms of action, major pitfalls, and future directions. Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

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