Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

Abstract

Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.

Comparison of CD3e Antibody and CD3e-sZAP Immunotoxin Treatment in Mice Identifies sZAP as the Main Driver of Vascular Leakage

“…Immunotoxins (ITs) and antibody therapies have been developed to treat various diseases, including cancers, infectious diseases, autoimmune diseases, and organ transplant [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. A major side effect limiting the clinical application of ITs and some antibody therapies has been vascular leak syndrome (VLS) [ 8 , 11 , 12 , 13 ].…”

A Novel CXCR4-Targeted Diphtheria Toxin Nanoparticle Inhibits Invasion and Metastatic Dissemination in a Head and Neck Squamous Cell Carcinoma Mouse Model

“…Different immunotoxins, such as VB4-845 and SS1P, both including the Pseudomonas aeruginosa exotoxin fused to anti-EpCAM or mesothelin targeting moieties, have undergone clinical trials for the treatment of HNSCC. However, none of them has yet reached the market, due to immunogenicity, off-target toxicity concerns, and a lack of antitumor effect due to poor tumor uptake [40,41]. By contrast, our T22-based nanotoxin presents interesting features, including efficient single-step production and purification in recombinant bacteria, easy production scale-up, biocompatibility, and a lack of off-target toxicity [19].…”

Pseudomonas aeruginosa in Cancer Therapy: Current Knowledge, Challenges and Future Perspectives

“…The naming of the truncated PE used in construction of the recombinant immunotoxins is usually based on their molecular weight. PE38 and PE40, two truncated forms of PE (38 kDa and 40 kDa, respectively), are most commonly used for immunotoxin construction, and both of them lack the receptor-binding domain (I) ( 119 ). Furthermore, as a foreign protein, the immunogenicity of immunotoxins is able to induce production of anti-drug antibodies in host, which neutralize and decrease the efficiency of the immunotoxins ( 82 ).…”