Abstract
The anticancer strategy underlying the use of immunotoxins is as follows: the cancer-binding domain delivers the toxin to a cancer cell, after which the toxin enters and kills the cell. TGFα-PE38 is an immunotoxin comprising transforming growth factor alpha (TGFα), a natural ligand of epidermal growth factor receptor (EGFR), and a modified Pseudomonas exotoxin A (PE38) lacking N terminal cell-binding domain, a highly potent cytotoxic protein moiety. Tumor cells with high level of EGFR undergo apoptosis upon treatment with TGFα-PE38. However, clinical trials demonstrated that this immunotoxin delivered by an intracerebral infusion technique has only a limited inhibitory effect on intracranial tumors mainly due to inconsistent drug delivery. To circumvent this problem, we turned to tumor-seeking bacterial system. Here, we engineered Salmonella typhimurium to selectively express and release TGFα-PE38. Engineered bacteria were administered to mice implanted with mouse colon or breast tumor cells expressing high level of EGFR. We observed that controlled expression and release of TGFα-PE38 from intra-tumoral Salmonellae by either an engineered phage lysis system or by a bacterial membrane transport signal led to significant inhibition of solid tumor growth. These results demonstrated that delivery by tumor-seeking bacteria would greatly augment efficacy of immunotoxin in cancer therapeutics.
Highlights
Several recombinant immunotoxins developed to target malignant tumors are undergoing clinical trials [1, 2]
We observed that controlled expression and release of TGFα-PE38 from intra-tumoral Salmonellae by either an engineered phage lysis system or by a bacterial membrane transport signal led to significant inhibition of solid tumor growth
We reported that induction of a plasmid carrying a Salmonellae lysis system consisting of three genes from a Salmonella bacteriophage effectively lysed bacteria and released their contents [34]
Summary
Several recombinant immunotoxins developed to target malignant tumors are undergoing clinical trials [1, 2]. Immunotoxins comprise a cancer-binding moiety linked to a potent toxin lacking an intrinsic cell-binding domain. The cancer-binding moiety most often comprises part of a monoclonal antibody, cytokines or growth factors that interact with receptors highly expressed by cancer cells have been used. Many tumor cells express high levels of epidermal growth factor receptor (EGFR) [3]. A recombinant immunotoxin comprising TGFα and a modified Pseudomonas exotoxin A (PE38) derived from Pseudomonas aeruginosa was developed for treatment of EGFR-expressing malignant tumors, e.g. brain tumors [4, 5]. PE38, which lacks an intrinsic cell-binding domain, binds to EGFR-expressing cancer cells via the TGFα moiety within the recombinant toxin. A limited positive response was observed, mainly due to inconsistent drug delivery by this technique
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