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.
Highlights
Cancer is the leading cause of death in developed countries and the second cause of death in developing countries [1, 2]
This review aims to highlight advances in applications of Pseudomonas exotoxin A (PE) protein and its derivatives for the production of ITs and their use in targeted cancer therapy
In a phase III clinical trial (CTI: NCT00076986), the efficacy of administration of CB via convectionenhanced delivery (CED) was compared with an approved treatment (Gliadel wafers containing 7.7 mg of carmustine) in adults with recurrent glioblastoma multiforme (GBM)
Summary
Cancer is the leading cause of death in developed countries and the second cause of death in developing countries [1, 2]. The aim of targeted therapy is to inhibit the proliferation of cancer cells either by delivery of growth inhibitory molecules or cytolethal agents to cancer cells or by controlled expression of cytolethal proteins via the use of a cancer-specific promoter [9] In the former strategy, tumor-specific receptors, which are not, or are much less, expressed on normal cells are targeted by a monoclonal antibody, or an antibody fragment, which blocks ligand–receptor interaction and intracellular signaling [10]. The antibody/ antibody fragment or the ligand can be fused to a protein toxin to kill the targeted cancer cell Such chimeric molecules are called immunotoxins (ITs) [11]. PE is one of the most potent bacterial toxins and is the most toxic virulence factor of the pathogenic bacterium Pseudomonas aeruginosa
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