Evaluation of the Antitumor Mechanism of Armed Antibodies: 2nd Edition

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

Deadline for manuscript submissions: closed (25 April 2025) | Viewed by 7384

Special Issue Editors


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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
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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

E-Mail Website
Guest Editor
Department of Strategic Programs, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Kashiwa, Japan
Interests: drug delivery system (DDS); antibody therapeutics; tumor microenvironments

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 the 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 to obtain target specific mAbs easily, the “missile therapy” or the “immunoconjugate” was developed for clinical use in the late 1980’s. In the 1990’s, 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 2000’s, these mAbs were again applied to the immunoconjugate, named the “antibody drug conjugate; ADC”. ADCs are categorized as the armed antibodies which means the antibodies have the “weapons”, and the antibodies are used for delivery carriers of the weapons, such as anticancer drugs and radioisotopes. As of November 2022, 12 ADCs and one radioimmunotherapy (RIT) drug are approved by 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), loncastuximab tesirine (CD19, PBD dimer; Zynlonta), tisotumab vedotin (TF, MMAE; Tivdak), mirvetuximab soravtansine (FRα, DM4; Elahere) 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 categorised 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 area for cancer therapeutics. In this Special Issue of Pharmaceuticals, original research, 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. Ryo Tsumura
Guest Editors

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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 (3 papers)

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Research

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14 pages, 7178 KiB  
Article
An Antagonist Antibody That Inhibits Cancer Cell Growth In Vitro through RACK1
by Ji Hoe Kim, Eun Ji Lee and Kyung Ho Han
Pharmaceuticals 2024, 17(10), 1303; https://doi.org/10.3390/ph17101303 - 30 Sep 2024
Cited by 1 | Viewed by 1251
Abstract
Background/Objectives: Our research introduces a novel screening method to identify antibodies that can suppress cell proliferation and induce apoptosis. Methods: By using an autocrine signaling system with lentivirus, we developed an antibody screening method based on FACS sorting assays and cell cycle analysis [...] Read more.
Background/Objectives: Our research introduces a novel screening method to identify antibodies that can suppress cell proliferation and induce apoptosis. Methods: By using an autocrine signaling system with lentivirus, we developed an antibody screening method based on FACS sorting assays and cell cycle analysis to inhibit tumor growth in vitro. This approach is particularly well suited for studying tumor suppressors. Inducing the G0 phase in tumor cells with specific antibodies may arrest their growth permanently or trigger apoptosis. The cell cycle is composed of tightly regulated phases for cell growth and division, with tumorigenesis or apoptosis occurring when these regulatory mechanisms fail. Results: In our study, we identified RACK1 as a key regulator of cancer cell growth. The H9 antibody against RACK1 selected from a human antibody library effectively suppressed cell proliferation by inhibiting RACK1 function. Conclusions: These findings suggest that RACK1 plays a crucial role in tumor cell cycling and could represent a novel therapeutic target for cancer treatment. Although RACK1 is recognized as a significant target protein in various tumors, no commercial therapeutic agents currently exist. Our results suggest that the H9 antibody could be a promising candidate for the development of novel cancer therapies. Full article
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14 pages, 3122 KiB  
Article
Real-Time Fluorescence Monitoring System for Optimal Light Dosage in Cancer Photoimmunotherapy
by Hideki Tanaka, Yoshikatsu Koga, Mayumi Sugahara, Hirobumi Fuchigami, Akihiro Ishikawa, Toru Yamaguchi, Akiko Banba, Takeshi Shinozaki, Kazuto Matsuura, Ryuichi Hayashi, Shingo Sakashita, Masahiro Yasunaga and Tomonori Yano
Pharmaceuticals 2024, 17(9), 1246; https://doi.org/10.3390/ph17091246 - 22 Sep 2024
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Abstract
Background/Objectives: Near-infrared photoimmunotherapy (NIR-PIT) was recently approved for the treatment of unresectable locally advanced or recurrent head and neck cancers in Japan; however, only one clinical dose has been validated in clinical trials, potentially resulting in excessive or insufficient dosing. Moreover, IRDye700X [...] Read more.
Background/Objectives: Near-infrared photoimmunotherapy (NIR-PIT) was recently approved for the treatment of unresectable locally advanced or recurrent head and neck cancers in Japan; however, only one clinical dose has been validated in clinical trials, potentially resulting in excessive or insufficient dosing. Moreover, IRDye700X (IR700) fluorescence intensity plateaus during treatment, indicating a particular threshold for the antitumor effects. Therefore, we investigated the NIR laser dose across varying tumor sizes and irradiation methods until the antitumor effects of the fluorescence decay rate plateaued. Methods: Mice were subcutaneously transplanted with A431 xenografts and categorized into control, clinical dose (cylindrical irradiation at 100 J/cm², frontal irradiation at 50 J/cm²), and evaluation groups. The rate of tumor IR700 fluorescence intensity decay to reach predefined rates (−0.05%/s or −0.2%/s) until the cessation of light irradiation was calculated using a real-time fluorescence imaging system. Results: The evaluation group exhibited antitumor effects comparable to those of the clinical dose group at a low irradiation dose. Similar results were observed across tumor sizes and irradiation methods. Conclusions: In conclusion, the optimal antitumor effect of NIR-PIT is achieved when the fluorescence decay rate reaches a plateau, indicating the potential to determine the appropriate dose for PIT using a real-time fluorescence monitoring system. Full article
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Review

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22 pages, 1556 KiB  
Review
Present Scenario and Future Landscape of Payloads for ADCs: Focus on DNA-Interacting Agents
by Barbara Valsasina, Paolo Orsini, Chiara Terenghi and Alberto Ocana
Pharmaceuticals 2024, 17(10), 1338; https://doi.org/10.3390/ph17101338 - 7 Oct 2024
Viewed by 3827
Abstract
ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors [...] Read more.
ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors has revitalized interest in the identification of novel agents overcoming present limitations in the field including narrow therapeutic window and chemoresistance. The success of DNA binders as payload for ADCs has been very limited, up to now, due, among other factors, to high hydrophobicity and planar chemical structures resulting in most cases in ADCs with a strong tendency to aggregate, poor plasma stability, and limited therapeutic index. Some of these molecules, however, continue to be of interest due to their favorable properties in terms of cytotoxic potency even in chemoresistant settings, bystander and immunogenic cell death effects, and known combinability with approved drugs. We critically evaluated several clinically tested ADCs containing DNA binders, focusing on payload physicochemical properties, cytotoxic potency, and obtained clinical results. Our analysis suggests that further exploration of certain chemical classes, specifically anthracyclines and duocarmycins, based on the optimization of physicochemical parameters, reduction of cytotoxic potency, and careful design of targeting molecules is warranted. This approach will possibly result in a novel generation of payloads overcoming the limitations of clinically validated ADCs. Full article
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