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Pharmaceuticals
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Evaluation of the Antitumor Mechanism of Armed Antibodies
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Evaluation of the Antitumor Mechanism of Armed Antibodies

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 41714

Special Issue Editors

Dr. Yoshikatsu Koga

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Guest Editor
Department of Strategic Programs, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Kashiwa, Japan
Interests: early detection; drug delivery system (DDS); armed antibody; PDX model; co-clinical trial; cancer screening; organoids; exfoliated cancer cells
Special Issues, Collections and Topics in MDPI journals
Dr. Hiroki Takashima

E-Mail Website
Guest Editor
Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Kashiwa, Japan
Interests: drug delivery system (DDS); radioimmunotherapy (RIT); antibody conjugated nanoparticle; brain tumor
Special Issues, Collections and Topics in MDPI journals
Dr. Shigehiro Koganemaru

E-Mail Website
Guest Editor
Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
Interests: armed antibody; early clinical trial; translational research; mass spectrometry

Special Issue Information

Dear Colleagues,

More than 120 years ago, Paul Ehrlich had a dream of the “magic bullet” that would seek out and specifically attack pathogens. “Magic bullets” can identify their target molecules without harming the other normal tissues. This concept was also applied to cancer treatment, and the discovery of monoclonal antibody (mAb) producing hybridoma technology was developed. After this success in obtaining target-specific mAbs easily, the “missile therapy” or the “immunoconjugate” was developed for clinical use in the late 1980s. In the 1990s, antibody engineering technologies that allowed genetic modification of murine antibodies to produce chimeric mouse–human antibodies or humanized antibodies were developed, and these mAbs are less likely to be recognized by the host immune system as a foreign antigen and have half-lives similar to those of natural human IgG. From the late 2000s, these mAbs were again applied to the immunoconjugate, named the “antibody drug conjugate; ADC”. ADCs are categorized as armed antibodies, which means antibodies have the “weapons”, and antibodies are used for delivery carriers of the weapons, such as anticancer drugs and radioisotopes. As of August 2020, 9 ADCs and one radioimmunotherapy (RIT) drug have been approved by the FDA: gemtuzumab ozogamicin (CD33, calicheamicin; Mylotarg), brentuximab vedotin (CD30, MMAE; Adcetris), trastuzumab emtansine (HER2, DM1; Kadcyla), inotuzumab ozogamicin (CD22, calicheamicin; Besponsa), polatuzumab vedotin (CD79b, MMAE; Polivy), enfortumab vedotin (nectin-4, MMAE; Padcev), trastuzumab deruxtecan (HER2, exatecan derivative; Enhertu), sacituzumab govitecan (TROP-2, SN38; Trodelvy), belantamab mafodotin (CD269, MMAF; Blenrep), and Ibritumomab tiuxetan (CD20, Yttrium-90; Zevalin). Photoimmunotherapy (PIT) or antibody conjugated nanoparticles (micelles and liposomes) are listed as the armed antibodies which can deliver a photoactivating chemical or anticancer drug-incorporated nanoparticles to the cancer cells, respectively. Bispecific antibodies, especially T cell-engaging (bispecific) antibodies, are also categorized into armed antibodies which can infiltrate the T cells to the cancer tissue and connect T cells to cancer cells. Thus, armed antibodies are one of the most exciting areas for cancer therapeutics. In this Special Issue of Pharmaceuticals, original research, mini-review, and review articles regarding armed antibodies are invited. This Special Issue focuses on the therapeutic antibodies in vitro, in vivo, and clinical studies.

Dr. Yoshikatsu Koga
Dr. Hiroki Takashima
Dr. Shigehiro Koganemaru
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • Antibody Drug Conjugate (ADC)
  • Photoimmunotherapy (PIT)
  • Radioimmunotherapy (RIT)
  • antibody-conjugated nanoparticle
  • bispecific antibody
  • CAR-T cell therapy

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review

4 pages, 186 KiB  
Editorial
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 - 5 Dec 2023
Cited by 1 | Viewed by 1126
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  
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
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 - 6 Jul 2022
Cited by 2 | Viewed by 2787
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  
Article
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 4 | Viewed by 2379
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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Graphical abstract

17 pages, 35375 KiB  
Article
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 14 | Viewed by 6782
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 THIOMABTM 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  
Article
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 - 2 May 2021
Cited by 6 | Viewed by 3769
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  
Review
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 - 9 Feb 2022
Cited by 7 | Viewed by 6270
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  
Review
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 16 | Viewed by 7630
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  
Review
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 24 | Viewed by 9793
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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