Targeting Receptors on Cancer Cells with Protein Toxins

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.

Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology

“…Despite the numerous breakthrough solutions in cancer treatment, the problem is still far from being solved. It is worth mentioning that only two toxin-based molecules, namely Diphtheria toxin-based DAB 389 IL2 and DAB 389 IL3 [ 191 , 192 ], have been approved in late-stage clinical evaluation. Recently, a PE-based immunotoxin Moxetumomab Pasudotox (Lumoxiti), targeting CD22, has been approved for the treatment of patients with hairy cell leukemia [ 53 ].…”

The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities

“…Another class of targeted cytotoxic approaches is represented by recombinant immuno- and ligand-targeted toxins (IT and LT) [ 168 , 169 , 170 , 171 , 172 ]. In these fusion constructs, the tumor-targeting moiety—the receptor-binding antibody/antibody fragment or endogenous ligand—is armed with the catalytic domain of highly potent cytotoxic products, usually microbial or plant protein toxins, to achieve selective tumor potency and thus the killing of designated target cells [ 168 , 170 , 171 ]. Indeed, the construct is devised to replace the cell-binding domain of the toxin with the tumor-targeting vehicle to dictate the desired binding specificity [ 168 ].…”

“…In these fusion constructs, the tumor-targeting moiety—the receptor-binding antibody/antibody fragment or endogenous ligand—is armed with the catalytic domain of highly potent cytotoxic products, usually microbial or plant protein toxins, to achieve selective tumor potency and thus the killing of designated target cells [ 168 , 170 , 171 ]. Indeed, the construct is devised to replace the cell-binding domain of the toxin with the tumor-targeting vehicle to dictate the desired binding specificity [ 168 ]. Toxin-induced cell death generally occurs via apoptosis through irreversible inhibition of protein synthesis after internalization and intracellular processing of the construct [ 168 , 170 , 171 ].…”

The Protein Toxins Ricin and Shiga Toxin as Tools to Explore Cellular Mechanisms of Internalization and Intracellular Transport

“…Importantly, protein toxins can be exploited in medicine [17][18][19][20]. Researchers are attempting to use protein toxins for the selective killing of cancer cells by making constructs containing at least the enzymatically active part of the toxin and either an antibody against epitopes on cancer cells or growth factors for which the corresponding receptors are expressed at a high level on the target cells.…”

“…Researchers are attempting to use protein toxins for the selective killing of cancer cells by making constructs containing at least the enzymatically active part of the toxin and either an antibody against epitopes on cancer cells or growth factors for which the corresponding receptors are expressed at a high level on the target cells. So far, some products containing the active part of diphtheria toxin and Pseudomonas exotoxin A have been approved for human use [19,21]. The neutral glycosphingolipid Gb3, which serves as the receptor for Shiga toxin, is mostly found on cancer cells [17,18].…”