Immunotoxins: From Design to Clinical Application

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 34335

Special Issue Editor


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Guest Editor
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Interests: recombinant immunotoxins for hematologic malignancies (including hairy cell leukemia (HCL); development of new targeted treatments and combinations for HCL; assessment and eradication of HCL minimal residual disease)

Special Issue Information

Dear Colleagues,

Nearly 60 years ago, antibodies were first chemically connected to protein toxins to selectively target cancer cells. They were called immunotoxins since they were chimeric proteins containing an antibody produced by the immune system, and a protein toxin. Protein toxins are extremely potent since they function catalytically, inhibiting protein synthesis, leading to apoptotic cell death. Once connected to an antibody, they may bind to the target cell-surface, internalize, and kill the cells. Their high potency has led to decades of difficulties due to nontargeted toxicities like capillary leak syndrome, and specific targeting of tumor antigens unexpectantly on normal tissues. Other problems have included inactivation by the immune system targeting plant or bacterial sequences, and difficulties in production due to heterogeneity of chemical conjugation. During their development, several drugs were developed and approved containing antibodies conjugated to non-immunogenic chemical poisons like Auristatin and Mytansine. In recent decades, recombinant immunotoxins were successfully engineered containing less immunogenic antibody fragments, target diseases were identified with less potential for immunogenicity, and smaller immunotoxins with shorter half-lives caused less capillary leak. In the previous year, two recombinant immunotoxins were FDA-approved for specific indications. In the coming years, developmental strategies reviewed in this Special Issue are expected to lead to additional indications for these recombinant immunotoxins, and also to the approval of new molecules combining antibodies and protein toxins for the treatment of cancer.

Dr. Robert J. Kreitman
Guest Editor

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Keywords

  • Pseudomonas exotoxin
  • Diphtheria toxin
  • Anthrax toxin
  • Fv fragment
  • Immunoconjugate
  • Moxetumomab pasudotox
  • Tagraxofusp
  • CD22
  • CD123
  • CD19

Published Papers (8 papers)

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Editorial

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6 pages, 217 KiB  
Editorial
Immunotoxins: From Design to Clinical Application
by Robert J. Kreitman and Ira Pastan
Biomolecules 2021, 11(11), 1696; https://doi.org/10.3390/biom11111696 - 15 Nov 2021
Cited by 9 | Viewed by 1906
Abstract
The Special Issue of Biomolecules entitled “Immunotoxins, From Design to Clinical Application” contains seven reviews related to immunotoxins [...] Full article
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)

Review

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14 pages, 1692 KiB  
Review
Anti-BCMA Immunotoxins: Design, Production, and Preclinical Evaluation
by Tapan K. Bera
Biomolecules 2020, 10(10), 1387; https://doi.org/10.3390/biom10101387 - 29 Sep 2020
Cited by 6 | Viewed by 3929
Abstract
Multiple myeloma (MM) is a B-cell malignancy that is incurable for a majority of patients. B-cell maturation antigen (BCMA) is a lineage-restricted differentiation protein highly expressed in multiple myeloma cells but not in other normal tissues except normal plasma B cells. Due to [...] Read more.
Multiple myeloma (MM) is a B-cell malignancy that is incurable for a majority of patients. B-cell maturation antigen (BCMA) is a lineage-restricted differentiation protein highly expressed in multiple myeloma cells but not in other normal tissues except normal plasma B cells. Due to the restricted expression and being a cell surface membrane protein, BCMA is an ideal target for immunotherapy approaches in MM. Recombinant immunotoxins (RITs) are a novel class of protein therapeutics that are composed of the Fv or Fab portion of an antibody fused to a cytotoxic agent. RITs were produced by expressing plasmids encoding the components of the anti-BCMA RITs in E. coli followed by inclusion body preparation, solubilization, renaturation, and purification by column chromatography. The cytotoxic activity of RITs was tested in vitro by WST-8 assays using BCMA expressing cell lines and on cells isolated from MM patients. The in vivo efficacy of RITs was tested in a xenograft mouse model using BCMA expressing multiple myeloma cell lines. Anti-BCMA recombinant immunotoxins are very effective in killing myeloma cell lines and cells isolated from myeloma patients expressing BCMA. Two mouse models of myeloma showed that the anti-BCMA immunotoxins can produce a long-term complete response and warrant further preclinical development. Full article
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
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20 pages, 1085 KiB  
Review
Targeting Receptors on Cancer Cells with Protein Toxins
by Antonella Antignani, Eric Chun Hei Ho, Maria Teresa Bilotta, Rong Qiu, Robert Sarnvosky and David J. FitzGerald
Biomolecules 2020, 10(9), 1331; https://doi.org/10.3390/biom10091331 - 17 Sep 2020
Cited by 24 | Viewed by 4795
Abstract
Cancer cells frequently upregulate surface receptors that promote growth and survival. These receptors constitute valid targets for intervention. One strategy involves the delivery of toxic payloads with the goal of killing those cancer cells with high receptor levels. Delivery can be accomplished by [...] Read more.
Cancer cells frequently upregulate surface receptors that promote growth and survival. These receptors constitute valid targets for intervention. One strategy involves the delivery of toxic payloads with the goal of killing those cancer cells with high receptor levels. Delivery can be accomplished by attaching a toxic payload to either a receptor-binding antibody or a receptor-binding ligand. Generally, the cell-binding domain of the toxin is replaced with a ligand or antibody that dictates a new binding specificity. The advantage of this “immunotoxin” approach lies in the potency of these chimeric molecules for killing cancer cells. However, receptor expression on normal tissue represents a significant obstacle to therapeutic intervention. Full article
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
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19 pages, 877 KiB  
Review
Development of Recombinant Immunotoxins for Hairy Cell Leukemia
by Robert J. Kreitman and Ira Pastan
Biomolecules 2020, 10(8), 1140; https://doi.org/10.3390/biom10081140 - 3 Aug 2020
Cited by 19 | Viewed by 3157
Abstract
Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each course. [...] Read more.
Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each course. Targeted therapies directed to the BRAF V600E mutation and Bruton’s tyrosine kinase may be helpful, but rarely eradicate the minimal residual disease (MRD) which will eventually lead to relapse. Moxetumomab pasudotox (Moxe) is an anti-CD22 recombinant immunotoxin, which binds to CD22 on HCL cells and leads to apoptotic cell death after internalization and trafficking of the toxin to the cytosol. Phase I testing achieved a complete remission (CR) rate of 57% in relapsed/refractory HCL. Most CRs were without MRD and eradication of MRD correlated with prolonged CR duration. Patients were often MRD-free after five years. Important mild-moderate toxicities included capillary leak and hemolytic uremic syndromes which could be prevented and managed conservatively. A phase 3 trial met its endpoint of durable CR with acceptable toxicity, leading to FDA approval of Moxe for relapsed/refractory HCL, under the name Lumoxiti. Moxe combined with rituximab is currently being evaluated in relapsed/refractory HCL to improve the rate of MRD-free CR. Full article
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
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13 pages, 548 KiB  
Review
Mechanisms of Resistance to Immunotoxins Containing Pseudomonas Exotoxin A in Cancer Therapy
by Michael Dieffenbach and Ira Pastan
Biomolecules 2020, 10(7), 979; https://doi.org/10.3390/biom10070979 - 30 Jun 2020
Cited by 20 | Viewed by 7011
Abstract
Immunotoxins are a class of targeted cancer therapeutics in which a toxin such as Pseudomonas exotoxin A (PE) is linked to an antibody or cytokine to direct the toxin to a target on cancer cells. While a variety of PE-based immunotoxins have been [...] Read more.
Immunotoxins are a class of targeted cancer therapeutics in which a toxin such as Pseudomonas exotoxin A (PE) is linked to an antibody or cytokine to direct the toxin to a target on cancer cells. While a variety of PE-based immunotoxins have been developed and a few have demonstrated promising clinical and preclinical results, cancer cells frequently have or develop resistance to these immunotoxins. This review presents our current understanding of the mechanism of action of PE-based immunotoxins and discusses cellular mechanisms of resistance that interfere with various steps of the pathway. These steps include binding of the immunotoxin to the target antigen, internalization, intracellular processing and trafficking to reach the cytosol, inhibition of protein synthesis through ADP-ribosylation of elongation factor 2 (EF2), and induction of apoptosis. Combination therapies that increase immunotoxin action and overcome specific mechanisms of resistance are also reviewed. Full article
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
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18 pages, 1337 KiB  
Review
Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors
by Brendan L. Hagerty, Guillaume J. Pegna, Jian Xu, Chin-Hsien Tai and Christine Alewine
Biomolecules 2020, 10(7), 973; https://doi.org/10.3390/biom10070973 - 28 Jun 2020
Cited by 16 | Viewed by 4292
Abstract
Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable [...] Read more.
Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox’s has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox’s. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents. Full article
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
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13 pages, 1871 KiB  
Review
Bispecific Targeting of EGFR and Urokinase Receptor (uPAR) Using Ligand-Targeted Toxins in Solid Tumors
by Felix Oh, Jaime F. Modiano, Veronika Bachanova and Daniel A. Vallera
Biomolecules 2020, 10(6), 956; https://doi.org/10.3390/biom10060956 - 25 Jun 2020
Cited by 12 | Viewed by 2927
Abstract
Ligand-targeted toxins (LTTs) are bioengineered molecules which are composed of a targeting component linked to a toxin that induces cell death once the LTT binds its target. Bispecific targeting allows for the simultaneous targeting of two receptors. In this review, we mostly focus [...] Read more.
Ligand-targeted toxins (LTTs) are bioengineered molecules which are composed of a targeting component linked to a toxin that induces cell death once the LTT binds its target. Bispecific targeting allows for the simultaneous targeting of two receptors. In this review, we mostly focus on the epidermal growth factor receptor (EGFR) as a target. We discuss the development and testing of a bispecific LTT targeting EGFR and urokinase-type plasminogen activator receptor (uPAR) as two attractive targets implicated in tumor growth and in the regulation of the tumor microvasculature in solid tumors. In vitro and mouse xenograft studies have shown that EGFR-targeted bispecific angiotoxin (eBAT) is effective against human solid tumors. Canine studies have shown that eBAT is both safe and effective against canine hemangiosarcoma, which is physiologically similar to human angiosarcoma. Finding the appropriate dosing strategy and sequencing of eBAT administration, in combination with other therapeutics, are among important factors for future directions. Together, the data indicate that eBAT targets cancer stem cells, it may have a role in inhibiting human tumor vasculature, and its bispecific conformation may have a role in reducing toxicity in comparative oncologic trials in dogs. Full article
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
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16 pages, 772 KiB  
Review
Development of Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer: An Update
by Bryan D. Fleming and Mitchell Ho
Biomolecules 2020, 10(6), 934; https://doi.org/10.3390/biom10060934 - 20 Jun 2020
Cited by 11 | Viewed by 5702
Abstract
Hepatocellular carcinoma (HCC) accounts for most liver cancers and represents one of the deadliest cancers in the world. Despite the global demand for liver cancer treatments, there remain few options available. The U.S. Food and Drug Administration (FDA) recently approved Lumoxiti, a CD22-targeting [...] Read more.
Hepatocellular carcinoma (HCC) accounts for most liver cancers and represents one of the deadliest cancers in the world. Despite the global demand for liver cancer treatments, there remain few options available. The U.S. Food and Drug Administration (FDA) recently approved Lumoxiti, a CD22-targeting immunotoxin, as a treatment for patients with hairy cell leukemia. This approval helps to demonstrate the potential role that immunotoxins can play in the cancer therapeutics pipeline. However, concerns have been raised about the use of immunotoxins, including their high immunogenicity and short half-life, in particular for treating solid tumors such as liver cancer. This review provides an overview of recent efforts to develop a glypican-3 (GPC3) targeting immunotoxin for treating HCC, including strategies to deimmunize immunotoxins by removing B- or T-cell epitopes on the bacterial toxin and to improve the serum half-life of immunotoxins by incorporating an albumin binding domain. Full article
(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)
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