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Review
. 2020 Sep 17;10(9):1331.
doi: 10.3390/biom10091331.

Targeting Receptors on Cancer Cells with Protein Toxins

Antonella Antignani  1 , Eric Chun Hei Ho  1 , Maria Teresa Bilotta  1 , Rong Qiu  1 , Robert Sarnvosky  1 , David J FitzGerald  1
Affiliations
Review

Targeting Receptors on Cancer Cells with Protein Toxins

Antonella Antignani et al. Biomolecules. .

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 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.

Keywords: cancer; diphtheria; immunotoxin; pseudomonas; receptor; ricin; toxin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immunotoxin and ligand toxin constructs. In examples 1 and 2, antibodies (blue) are joined with toxins (red) to form immunotoxins. Shown in example 1, a toxin is attached chemically to a full-length antibody. Example 2 is a genetic fusion between the single-chain Fv portion of an antibody and a toxin. In examples 3 and 4, the two most common ligand toxin constructs are shown. Example 3 shows a ligand toxin whereby the ligand (blue) is placed at the N-terminus of the construct, in place of pseudomonas exotoxin’s (PE’s) native binding domain. Example 4 shows the ligand at the C-terminus, replacing the native binding domain of diphtheria toxin (DT).
Figure 2
Figure 2
Anti-receptor targeting by immunotoxins and ligand toxins. A ligand toxin is shown interacting with a target receptor at the ligand-binding site. Similarly, an immunotoxin is shown binding the same receptor but at a distinct site. Following binding, internalization results in delivery to endosomes. In endosomes, toxins are processed (often by furin-like proteases) to separate the antibody or ligand from the toxin. After the processing step, some toxins such as DT translocate directly from endosomes (yellow arrow) to the cell cytosol while others traffic further into the cell to the endoplasmic reticulum where translocation is noted for pseudomonas exotoxin (PE) and some plant toxins (purple arrow). Once in the cytosol, toxins shut down protein synthesis.
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