Immunotoxin and beyond—Past, Present and Future Perspectives

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Plant Toxins".

Deadline for manuscript submissions: closed (25 November 2022) | Viewed by 17430

Special Issue Editors


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Guest Editor
Ministry of Instruction University Research (MIUR), Monza (MB) 20900, Italy
Interests: cell biology; cancer therapy; ribosome-inactivating proteins; ligand toxin; drug targeting

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Guest Editor
Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
Interests: drug delivery; toxins; immune conjugates; cancer therapy; protein structure
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immunotoxins (ITxs) were born four decades ago (Nature. 1981 Mar 12;290(5802):145-6. doi: 10.1038/290145a0.), as whole bacterial or plant-derived toxin(s) conjugated to monoclonal antibodies, targeting specific antigens/receptors over-expressed at the surface of tumor cells. Compared to chemotherapy, targeted therapies show a much higher selectivity, thus helping to avoid some of the patients’ severe side-effects.

Antibodies’ target specificity/ internalization capability are key issues for the selective intracellular delivery of the toxin’s active domain. Bottlenecks have been identified, including among others avoiding cell surface recycling and degradation of the ITx, favoring toxin escape from the endomembrane system (endo-lysosomal for certain toxins or ER-Golgi retrograde transport route for other ones, to reach the cytosolic compartment) in order for them to exert their cytotoxic activity.

On the patient side, poor pharmacokinetics, vascular-leak syndrome, multi-drug resistance, and human anti-mouse antibody responses (HAMA) to both the antibody and toxin domains were tackled by switching to genetic engineering and combined recombinant approaches aiming to minimize these undesired side effects. In addition, several other novel combinatorial approaches are actively under investigation.

In a search for “immunotoxin” in PubMed, we obtained 7187 entries, 444 of which were published in the last couple of years, demonstrating that this is still a hot topic. Ligand toxins are broader ITx extensions which use targeting molecules other than antibody domains, and toxin gene delivery using nano-vector approaches, as well as novel co-adjuvant formulations, further broaden our toolbox.

In this Special Issue, we would like to invite authors to contribute regular research papers, reviews, and short communications in order to fully explore the ITx lessons from the past and indicate future paths towards innovative targeting systems to exploit the enormous potential of toxins. We would be delighted if women scientists and young investigators were willing to give their personal contribution to explore this “old” field with an emphasis on the future biomedical combined applications.

Dr. Maria Serena Fabbrini
Prof. Dr. Rodolfo Ippoliti
Guest Editors

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Keywords

  • plant- and bacterial-derived DNA toxin domains
  • combinatorial therapy
  • nanoparticle delivery
  • chimeric recombinant immunotoxins
  • phage-display antibody libraries
  • apoptosis
  • T-cell receptors
  • EGF receptors
  • suicide gene therapy
  • peptide-driven toxin

Published Papers (7 papers)

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Research

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19 pages, 6329 KiB  
Article
Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861
by Hossein Panjideh, Nicole Niesler, Alexander Weng and Hendrik Fuchs
Toxins 2022, 14(7), 478; https://doi.org/10.3390/toxins14070478 - 13 Jul 2022
Cited by 5 | Viewed by 2397 | Correction
Abstract
Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of [...] Read more.
Immunotoxins do not only bind to cancer-specific receptors to mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. The plant glycoside SO1861 was previously reported to enhance the endolysosomal escape of antibody-toxin conjugates in non-hematopoietic cells, thus increasing their cytotoxicity manifold. Here we tested this technology for the first time in a lymphoma in vivo model. First, the therapeutic CD20 antibody obinutuzumab was chemically conjugated to the ribosome-inactivating protein dianthin. The cytotoxicity of obinutuzumab-dianthin (ObiDi) was evaluated on human B-lymphocyte Burkitt’s lymphoma Raji cells and compared to human T-cell leukemia off-target Jurkat cells. When tested in combination with SO1861, the cytotoxicity for target cells was 131-fold greater than for off-target cells. In vivo imaging in a xenograft model of B-cell lymphoma in mice revealed that ObiDi/SO1861 efficiently prevents tumor growth (51.4% response rate) compared to the monotherapy with ObiDi (25.9%) and non-conjugated obinutuzumab (20.7%). The reduction of tumor volume and overall survival was also improved. Taken together, our results substantially contribute to the development of a combination therapy with SO1861 as a platform technology to enhance the efficacy of therapeutic antibody-toxin conjugates in lymphoma and leukemia. Full article
(This article belongs to the Special Issue Immunotoxin and beyond—Past, Present and Future Perspectives)
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Review

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19 pages, 1855 KiB  
Review
Streptavidin-Saporin: Converting Biotinylated Materials into Targeted Toxins
by Leonardo R. Ancheta, Patrick A. Shramm, Raschel Bouajram, Denise Higgins and Douglas A. Lappi
Toxins 2023, 15(3), 181; https://doi.org/10.3390/toxins15030181 - 27 Feb 2023
Cited by 2 | Viewed by 1821
Abstract
Streptavidin-Saporin can be considered a type of ‘secondary’ targeted toxin. The scientific community has taken advantage of this conjugate in clever and fruitful ways using many kinds of biotinylated targeting agents to send saporin into a cell selected for elimination. Saporin is a [...] Read more.
Streptavidin-Saporin can be considered a type of ‘secondary’ targeted toxin. The scientific community has taken advantage of this conjugate in clever and fruitful ways using many kinds of biotinylated targeting agents to send saporin into a cell selected for elimination. Saporin is a ribosome-inactivating protein that causes inhibition of protein synthesis and cell death when delivered inside a cell. Streptavidin-Saporin, mixed with biotinylated molecules to cell surface markers, results in powerful conjugates that are used both in vitro and in vivo for behavior and disease research. Streptavidin-Saporin harnesses the ‘Molecular Surgery’ capability of saporin, creating a modular arsenal of targeted toxins used in applications ranging from the screening of potential therapeutics to behavioral studies and animal models. The reagent has become a well-published and validated resource in academia and industry. The ease of use and diverse functionality of Streptavidin-Saporin continues to have a significant impact on the life science industry. Full article
(This article belongs to the Special Issue Immunotoxin and beyond—Past, Present and Future Perspectives)
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21 pages, 2099 KiB  
Review
From Immunotoxins to Suicide Toxin Delivery Approaches: Is There a Clinical Opportunity?
by Matteo Ardini, Riccardo Vago, Maria Serena Fabbrini and Rodolfo Ippoliti
Toxins 2022, 14(9), 579; https://doi.org/10.3390/toxins14090579 - 23 Aug 2022
Cited by 5 | Viewed by 2123
Abstract
Suicide gene therapy is a relatively novel form of cancer therapy in which a gene coding for enzymes or protein toxins is delivered through targeting systems such as vesicles, nanoparticles, peptide or lipidic co-adjuvants. The use of toxin genes is particularly interesting since [...] Read more.
Suicide gene therapy is a relatively novel form of cancer therapy in which a gene coding for enzymes or protein toxins is delivered through targeting systems such as vesicles, nanoparticles, peptide or lipidic co-adjuvants. The use of toxin genes is particularly interesting since their catalytic activity can induce cell death, damaging in most cases the translation machinery (ribosomes or protein factors involved in protein synthesis) of quiescent or proliferating cells. Thus, toxin gene delivery appears to be a promising tool in fighting cancer. In this review we will give an overview, describing some of the bacterial and plant enzymes studied so far for their delivery and controlled expression in tumor models. Full article
(This article belongs to the Special Issue Immunotoxin and beyond—Past, Present and Future Perspectives)
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19 pages, 353 KiB  
Review
Plant-Derived Type I Ribosome Inactivating Protein-Based Targeted Toxins: A Review of the Clinical Experience
by David J. Flavell and Sopsamorn U. Flavell
Toxins 2022, 14(8), 563; https://doi.org/10.3390/toxins14080563 - 18 Aug 2022
Cited by 4 | Viewed by 1389
Abstract
Targeted toxins (TT) for cancer treatment are a class of hybrid biologic comprised of a targeting domain coupled chemically or genetically to a proteinaceous toxin payload. The targeting domain of the TT recognises and binds to a defined target molecule on the cancer [...] Read more.
Targeted toxins (TT) for cancer treatment are a class of hybrid biologic comprised of a targeting domain coupled chemically or genetically to a proteinaceous toxin payload. The targeting domain of the TT recognises and binds to a defined target molecule on the cancer cell surface, thereby delivering the toxin that is then required to internalise to an appropriate intracellular compartment in order to kill the target cancer cell. Toxins from several different sources have been investigated over the years, and the two TTs that have so far been licensed for clinical use in humans; both utilise bacterial toxins. Relatively few clinical studies have, however, been undertaken with TTs that utilise single-chain type I ribosome inactivating proteins (RIPs). This paper reviews the clinical experience that has so far been obtained for a range of TTs based on five different type I RIPs and concludes that the majority studied in early phase trials show significant clinical activity that justifies further clinical investigation. A range of practical issues relating to the further clinical development of TT’s are also covered briefly together with some suggested solutions to outstanding problems. Full article
(This article belongs to the Special Issue Immunotoxin and beyond—Past, Present and Future Perspectives)
29 pages, 2945 KiB  
Review
Saporin as a Commercial Reagent: Its Uses and Unexpected Impacts in the Biological Sciences—Tools from the Plant Kingdom
by Leonardo R. Ancheta, Patrick A. Shramm, Raschel Bouajram, Denise Higgins and Douglas A. Lappi
Toxins 2022, 14(3), 184; https://doi.org/10.3390/toxins14030184 - 02 Mar 2022
Cited by 9 | Viewed by 3915
Abstract
Saporin is a ribosome-inactivating protein that can cause inhibition of protein synthesis and causes cell death when delivered inside a cell. Development of commercial Saporin results in a technology termed ‘molecular surgery’, with Saporin as the scalpel. Its low toxicity (it has no [...] Read more.
Saporin is a ribosome-inactivating protein that can cause inhibition of protein synthesis and causes cell death when delivered inside a cell. Development of commercial Saporin results in a technology termed ‘molecular surgery’, with Saporin as the scalpel. Its low toxicity (it has no efficient method of cell entry) and sturdy structure make Saporin a safe and simple molecule for many purposes. The most popular applications use experimental molecules that deliver Saporin via an add-on targeting molecule. These add-ons come in several forms: peptides, protein ligands, antibodies, even DNA fragments that mimic cell-binding ligands. Cells that do not express the targeted cell surface marker will not be affected. This review will highlight some newer efforts and discuss significant and unexpected impacts on science that molecular surgery has yielded over the last almost four decades. There are remarkable changes in fields such as the Neurosciences with models for Alzheimer’s Disease and epilepsy, and game-changing effects in the study of pain and itch. Many other uses are also discussed to record the wide-reaching impact of Saporin in research and drug development. Full article
(This article belongs to the Special Issue Immunotoxin and beyond—Past, Present and Future Perspectives)
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18 pages, 1690 KiB  
Review
Immunotoxins Immunotherapy against Hepatocellular Carcinoma: A Promising Prospect
by Mohammad Heiat, Hamid Hashemi Yeganeh, Seyed Moayed Alavian and Ehsan Rezaie
Toxins 2021, 13(10), 719; https://doi.org/10.3390/toxins13100719 - 11 Oct 2021
Cited by 11 | Viewed by 2934
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Therefore, fighting against such cancer is reasonable. Chemotherapy drugs are sometimes inefficient and often accompanied by undesirable side effects for patients. On the other hand, the emergence of chemoresistant HCC [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Therefore, fighting against such cancer is reasonable. Chemotherapy drugs are sometimes inefficient and often accompanied by undesirable side effects for patients. On the other hand, the emergence of chemoresistant HCC emphasizes the need for a new high-efficiency treatment strategy. Immunotoxins are armed and rigorous targeting agents that can purposefully kill cancer cells. Unlike traditional chemotherapeutics, immunotoxins because of targeted toxicity, insignificant cross-resistance, easy production, and other favorable properties can be ideal candidates against HCC. In this review, the characteristics of proper HCC-specific biomarkers for immunotoxin targeting were dissected. After that, the first to last immunotoxins developed for the treatment of liver cancer were discussed. So, by reviewing the strengths and weaknesses of these immunotoxins, we attempted to provide keynotes for designing an optimal immunotoxin against HCC. Full article
(This article belongs to the Special Issue Immunotoxin and beyond—Past, Present and Future Perspectives)
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Other

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2 pages, 474 KiB  
Correction
Correction: Panjideh et al. Improved Therapy of B-Cell Non-Hodgkin Lymphoma by Obinutuzumab-Dianthin Conjugates in Combination with the Endosomal Escape Enhancer SO1861. Toxins 2022, 14, 478
by Hossein Panjideh, Nicole Niesler, Alexander Weng and Hendrik Fuchs
Toxins 2022, 14(10), 703; https://doi.org/10.3390/toxins14100703 - 13 Oct 2022
Viewed by 1027
Abstract
The authors wish to make corrections to their paper [...] Full article
(This article belongs to the Special Issue Immunotoxin and beyond—Past, Present and Future Perspectives)
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