Immunotoxins: Targeted Toxin Delivery for Cancer Therapy

Abstract

Immunotoxins are proteins that consist of a protein toxin conjugated to a specific targeting moiety. The targeting moiety is usually an antibody or ligand, such as monoclonal antibody, antibody fragment, a cytokine, or a growth factor. The toxins usually come from plant toxins, bacterial toxins, or human-origin cytotoxic elements. Nearly all toxins work by enzymatically inhibiting protein synthesis. After binding to antigens or receptors on target cell surfaces, immunotoxins are internalized and translocated to the cytosol where they can kill the cells. Immunotoxins have demonstrated high cytotoxicity to cancer cells and to date two immunotoxins have been approved by U.S. Food and Drug Administration on the markets for the treatment of hematological tumors: Lumoxiti and Ontak. Many other molecules are under development or clinical trials for different forms of cancer. Although immunotoxins exhibit great potency in xenograft model systems and early clinical trials, there are obstacles that limit successful treatments, including immunogenicity, nonspecific toxicity, and poor penetration. However, efforts are underway to address these problems. In this review, we summarize immunotoxins currently in clinical trials for either hematological tumors or solid tumors, outline the design of immunotoxins utilizing variety of components, and discuss the prominent examples of redesigned immunotoxins with reduced immunogenicity and nonspecific toxicity, as well as the strategies in manufacturing immunotoxins. With further improvements, it is anticipated that immunotoxins will play an increasing role in cancer therapy.

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

“…However, recent studies have used other cancer-specific targeting molecules including natural or synthetic cell-penetrating peptides ( 26 , 27 ) as well as natural and mutated antimicrobial peptides ( 28 , 29 ). The toxic moiety has not deviated as much and has consisted of cytolethal proteins from plants, animals, fungi, or bacteria ( 30 ). Among the bacterial toxins, diphtheria toxin ( 9 , 31 , 32 ), Shiga toxin ( 33 ), Vibrio cholerae toxin ( 34 ), and PE ( 35 , 36 ) have been used for construction of ITs.…”

Plant-Derived Lectins as Potential Cancer Therapeutics and Diagnostic Tools

“…Such toxicity could be mitigated by fusing lectins to other proteins for targeted delivery. For example, immunotoxins were designed for selective delivery of a toxin to malignant cells by linking a toxic domain to a specific targeting moiety, e.g., an antibody, or the Fab, Fc, or single-chain variable fragments [130]. Ricin has been widely assessed for such purpose [131].…”

Engineered Bifunctional Proteins for Targeted Cancer Therapy: Prospects and Challenges

“…[ 88 ] The mode of fusing the toxin with the targeting moiety depends on the structural characteristics of the toxin. For example, the enzymatic and binding domains of Pseudomonas aeruginosa exotoxin A (PE) are located at the carboxy and amino termini, respectively, whereas those of Diphtheria toxin (DT) are located at the amino and carboxy termini, respectively; [ 97 ] thus the sequence of the constructed immunotoxins may differ. The targeting moieties of clinically investigated immunotoxins can be roughly divided into two types.…”

“…For example, scFv‐based immunotoxins were shown to have good treatment efficacy in several hematologic and solid tumors; however, owing to their low molecular weight, they are cleared faster. [ 97 ] Many such immunotoxins are currently in various stages of clinical trials. The most common structures of immunotoxins used in clinical practice are shown in Figure 1.…”

“…[ 98 ] Since plant‐ or bacterial‐derived toxins are foreign proteins, they may induce neutralizing antidrug antibodies, leading to the rapid clearance of immunotoxins and reducing therapeutic effects. [ 97 ] In recent years, various strategies have been developed to overcome the abovementioned limitations, such as using human cytotoxic proteins, modifying the structure of immunotoxins (PEGylation), and using it in combination with immunosuppressive drugs (elimination of human B‐cell and T‐cell epitopes in toxins). [ 88,97 ] Future studies need to focus on optimizing and exploring new immunotoxin constructs to reduce non‐specific toxicity and improve their treatment efficacy.…”