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Antibody Based Delivery of Toxins and Other Active Molecules for...
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Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 20927

Special Issue Editor

Dr. Letizia Polito

E-Mail Website
Guest Editor
Department of Medical and Surgical Sciences -DIMEC, Alma Mater Studiorum, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy
Interests: immunotoxin; immunoconjugate; immunotargeting; plant toxins; ribosome-inactivating proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

More than one century ago, Paul Ehrlich postulated the “magic bullet concept”: drugs able to selectively act on target cells. Today, inspired by this idea, one of the most promising research approaches is based on the linking of pharmacologically active molecules to carriers, mainly antibodies, for selective delivery to target cells. These hybrid conjugates are primarily applied to research in the field of cancer therapy.

The clinical use of radio- and chemotherapeutic agents has evident antitumor effects, but also limitations (considerable side-effects due to lack of selectivity for tumor cells, development of drug resistance, and occurrence of secondary malignancies). As a consequence, the study and development of alternative therapies, such as immunotherapy, was deeply stimulated in order to find therapies with greater specificity for transformed cells and less nonspecific toxicity. Immunotherapy is based on characteristics (the recognition of specific membrane targets) that are completely independent from the parameters on which chemotherapy and radiotherapy are based. This allows for differential toxicity and results in a lack of superimposition of side-effects and unimpaired cytotoxicity towards cell clones resistant to chemotherapy and radiotherapy.

Various immunotherapeutic approaches are focused on the identification of specific antigens on the surface of cancer cells. An essential requirement for this approach is that the target molecule is confined to the cell population to be destroyed, or at least that it is not present on stem cells or other cell types essential for organism survival. Antibodies are the most utilized carriers due to their stability in blood and avidity and affinity for their target antigen. Many different molecules have been exploited as toxic moieties; the most studied are drugs, radionuclides, toxins, and human enzymes.

Thus, the scope of this Special Issue is to give readers a comprehensive overview on the pharmacological potential of immunoconjugates, both as single agents and in combination strategies. Research articles, reviews, and mini-reviews are welcome. I aim to collect studies, both in vitro and in vivo, concerning the development and the characterization of new conjugates, the evaluation of their antitumor effects, their pharmacological properties, and the pathogenetic mechanisms of the damage induced by these molecules.

Dr. Letizia Polito
Guest Editor

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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antibody 
  • Bacterial toxins 
  • Cancer therapy 
  • Drug delivery 
  • Immunoconjugates 
  • Immunotoxins 
  • Immunotherapy 
  • Immunotargeting 
  • Nanodelivery 
  • Plant toxins 
  • Ribosome-inactivating proteins 
  • Toxin

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Published Papers (6 papers)

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Editorial

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3 pages, 185 KiB  
Editorial
Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy
by Letizia Polito
Biomedicines 2022, 10(2), 267; https://doi.org/10.3390/biomedicines10020267 - 26 Jan 2022
Cited by 1 | Viewed by 2449
Abstract
The use of radio- and chemotherapeutic agents in cancer therapy have demonstrated evident antitumor effects, but also limitations (remarkable side-effects due to lack of selectivity for tumor cells, development of drug resistance, and occurrence of secondary malignancies) [...] Full article
(This article belongs to the Special Issue Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy)

Research

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16 pages, 5926 KiB  
Article
Nectin Cell Adhesion Molecule 4 (NECTIN4) Expression in Cutaneous Squamous Cell Carcinoma: A New Therapeutic Target?
by Yuka Tanaka, Maho Murata, Yoshinao Oda, Masutaka Furue and Takamichi Ito
Biomedicines 2021, 9(4), 355; https://doi.org/10.3390/biomedicines9040355 - 30 Mar 2021
Cited by 25 | Viewed by 3691
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, and its incidence is rising because of the aging population. Nectin cell adhesion molecule 4 (NECTIN4) is involved in the progression of tumors and has attracted interest as a potential therapeutic [...] Read more.
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, and its incidence is rising because of the aging population. Nectin cell adhesion molecule 4 (NECTIN4) is involved in the progression of tumors and has attracted interest as a potential therapeutic target. However, little is known about the expression and significance of NECTIN4 in cSCC. The aim of this study was to determine the expression and function of NECTIN4 in cSCC. Immunohistological NECTIN4 expression was investigated in tissues from 34 cSCC patients. Using an A431 human SCC cell line, the role of NECTIN4 in the regulation of cell–cell attachment and migration and proliferation was assessed. NECTIN4 was expressed in most cSCC tissues and on the plasma membrane of A431 cells. Silencing of NECTIN4 prevented cell–cell attachment and induced the expression migration-related molecules, leading to an increase in cell migration. Knockdown of NECTIN4 downregulated extracellular signal-regulated kinase signaling, decreased cyclin D1 expression, and inhibited cell proliferation. These results show that NECTIN4 is expressed in cSCC and functions in the regulation of cell–cell interactions, as well as in the migration and proliferation of SCC cells. NECTIN4-targeted therapy may serve as a novel and promising treatment for cSCC. Full article
(This article belongs to the Special Issue Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy)
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19 pages, 5384 KiB  
Article
The Effect of Small Molecule Pharmacological Agents on the Triterpenoid Saponin Induced Endolysosomal Escape of Saporin and a Saporin-Based Immunotoxin in Target Human Lymphoma Cells
by Harrison J. Wensley, Wendy S. Smith, Suzanne E. Holmes, Sopsamorn U. Flavell and David J. Flavell
Biomedicines 2021, 9(3), 300; https://doi.org/10.3390/biomedicines9030300 - 15 Mar 2021
Cited by 4 | Viewed by 2299
Abstract
Triterpenoid saponins augment the cytotoxicity of saporin based immunotoxins. It is postulated that this results from a saponin-mediated increase in the endolysosomal escape of the toxin to the cytosol, but this remains to be confirmed. To address this issue, we used a number [...] Read more.
Triterpenoid saponins augment the cytotoxicity of saporin based immunotoxins. It is postulated that this results from a saponin-mediated increase in the endolysosomal escape of the toxin to the cytosol, but this remains to be confirmed. To address this issue, we used a number of pharmacological inhibitors of endocytic processes as probes to investigate the role played by saponin in the endolysosomal escape of fluorescently labeled saporin and a saporin based immunotoxin targeted against CD38 on human lymphoma and leukemia cell lines. Endolysosomal escape of the toxin was measured by flow cytometric pulse shape analysis. These results were compared to the effects of the various inhibitors on the saponin-mediated augmentation of toxin and immunotoxin cytotoxicity. Inhibitors of clathrin-mediated endocytosis, micropinocytosis, and endosomal acidification abrogated the saponin-induced increase in the endolysosomal escape of the toxin into the cytosol, suggesting that these processes may be involved in the internalization of saponin to the same endolysosomal vesicle as the toxin. Alternatively, these processes may play a direct role in the mechanism by which saponin promotes toxin escape from the endolysosomal compartment to the cytosol. Correlation with the effects of these inhibitors on the augmentation of cytotoxicity provides additional evidence that endolysosomal escape is involved in driving augmentation. Full article
(This article belongs to the Special Issue Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy)
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Review

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11 pages, 1754 KiB  
Review
Validity of Anti-PSMA ScFvD2B as a Theranostic Tool: A Narrative-Focused Review
by Barbara Frigerio, Elena Luison, Alessandro Desideri, Federico Iacovelli, Chiara Camisaschi, Ettore C. Seregni, Silvana Canevari and Mariangela Figini
Biomedicines 2021, 9(12), 1870; https://doi.org/10.3390/biomedicines9121870 - 10 Dec 2021
Cited by 4 | Viewed by 3020
Abstract
Prostate cancer (PCa) is the second leading cause of cancer among men, and its diagnosis and adequate staging are fundamental. Among the biomarkers identified in recent years for PCa management, prostate-specific-membrane-antigen (PSMA), physiologically expressed at a low level on healthy prostate and in [...] Read more.
Prostate cancer (PCa) is the second leading cause of cancer among men, and its diagnosis and adequate staging are fundamental. Among the biomarkers identified in recent years for PCa management, prostate-specific-membrane-antigen (PSMA), physiologically expressed at a low level on healthy prostate and in other normal tissues and highly overexpressed in PCa, represents a reliable marker ideal for imaging and therapy. The development of anti-PSMA antibodies, such as D2B, demonstrated slow clearance of intact antibodies compared with fragments resulting in low tumor-to-blood ratios; however, the modular structural and functional nature of antibodies allowed the generation of smaller fragments, such as scFvs. In this review of the anti-PSMA antibody fragment scFvD2B, we combined further characterization of its biomolecular and tissue cross-reactivity characteristics with a comprehensive summary of what has already been performed in preclinical models to evaluate imaging and therapeutic activities. A molecular dynamics study was performed, and ScFvD2B occupied a limited conformational space, characterized by low-energy conformational basins, confirming the high stability of the protein structure. In the cross-reactivity study, the weak/absent immunoreactivity in non-tumor tissues was comparable to the PSMA expression reported in the literature. Biodistribution studies and therapeutic treatments were conducted in different animal models obtained by subcutaneous or locoregional injection of PSMA-positive-versus-negative xenografts. The maximum tumor uptake was observed for 123I(SPECT), 124I(PET), and optical imaging, which avoids kidney accumulation (compared with radiometals) and leads to an optimal tumor-to-kidney and tumor-to-background ratios. Regarding its possible use in therapy, experimental data suggested a strong and specific antitumor activity, in vitro and in vivo, obtained using CAR-T or NK-92/CAR cells expressing scFvD2B. Based on presented/reviewed data, we consider that scFvD2B, due to its versatility and robustness, seems to: (i) overcome some problems observed in other studied scFvs, very often relatively unstable and prone to form aggregates; (ii) have sufficient tumor-to-background ratios for targeting and imaging PSMA-expressing cancer; (iii) significantly redirect immune killing cells to PSMA-positive tumors when inserted in second-generation CAR-T or NK-92/CAR cells. These data suggest that our product can be considered the right reagent to fill the gap that still exists in PCa diagnosis and treatment. Full article
(This article belongs to the Special Issue Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy)
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24 pages, 998 KiB  
Review
Antibody-Based Immunotoxins for Colorectal Cancer Therapy
by Laura Sanz, Raquel Ibáñez-Pérez, Patricia Guerrero-Ochoa, Javier Lacadena and Alberto Anel
Biomedicines 2021, 9(11), 1729; https://doi.org/10.3390/biomedicines9111729 - 19 Nov 2021
Cited by 15 | Viewed by 4406
Abstract
Monoclonal antibodies (mAbs) are included among the treatment options for advanced colorectal cancer (CRC). However, while these mAbs effectively target cancer cells, they may have limited clinical activity. A strategy to improve their therapeutic potential is arming them with a toxic payload. Immunotoxins [...] Read more.
Monoclonal antibodies (mAbs) are included among the treatment options for advanced colorectal cancer (CRC). However, while these mAbs effectively target cancer cells, they may have limited clinical activity. A strategy to improve their therapeutic potential is arming them with a toxic payload. Immunotoxins (ITX) combining the cell-killing ability of a toxin with the specificity of a mAb constitute a promising strategy for CRC therapy. However, several important challenges in optimizing ITX remain, including suboptimal pharmacokinetics and especially the immunogenicity of the toxin moiety. Nonetheless, ongoing research is working to solve these limitations and expand CRC patients’ therapeutic armory. In this review, we provide a comprehensive overview of targets and toxins employed in the design of ITX for CRC and highlight a wide selection of ITX tested in CRC patients as well as preclinical candidates. Full article
(This article belongs to the Special Issue Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy)
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17 pages, 786 KiB  
Review
Antibody Conjugates for Sarcoma Therapy: How Far along Are We?
by Letizia Polito, Giulia Calafato, Massimo Bortolotti, Cecilia Chiarelli Olivari, Stefania Maiello and Andrea Bolognesi
Biomedicines 2021, 9(8), 978; https://doi.org/10.3390/biomedicines9080978 - 8 Aug 2021
Cited by 16 | Viewed by 3859
Abstract
Sarcomas are one of the most difficult type of cancer to manage and treat because of their extremely heterogeneous molecular and morphological features. Despite the progress made over the years in the establishment of standard protocols for high and low grading/staging sarcoma patients, [...] Read more.
Sarcomas are one of the most difficult type of cancer to manage and treat because of their extremely heterogeneous molecular and morphological features. Despite the progress made over the years in the establishment of standard protocols for high and low grading/staging sarcoma patients, mostly with chemotherapy and/or radiotherapy, 50% of treated patients experience relapse episodes. Because of this, in the last 20 years, new therapeutic approaches for sarcoma treatment have been evaluated in preclinical and clinical studies. Among them, antibody-based therapies have been the most studied. Immunoconjugates consist of a carrier portion, frequently represented by an antibody, linked to a toxic moiety, i.e., a drug, toxin, or radionuclide. While the efficacy of immunoconjugates is well demonstrated in the therapy of hematological tumors and more recently also of epithelial ones, their potential as therapeutic agents against sarcomas is still not completely explored. In this paper, we summarize the results obtained with immunoconjugates targeting sarcoma surface antigens, considering both preclinical and clinical studies. To date, the encouraging results obtained in preclinical studies allowed nine immunoconjugates to enter clinical trials, demonstrating the validity of immunotherapy as a promising pharmacological tool also for sarcoma therapy. Full article
(This article belongs to the Special Issue Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy)
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