Abstract
Prostate cancer (PCa) is the second most common cancer in men, causing more than 300,000 deaths every year worldwide. Due to their superior cell-killing ability and the relative simplicity of their preparation, immunotoxin molecules have great potential in the clinical treatment of cancer, and several such molecules have been approved for clinical application. In this study, we adopted a relatively simple strategy based on a single-domain antibody (sdAb) and an improved Pseudomonas exotoxin A (PE) toxin (PE24X7) to prepare a safer immunotoxin against prostate-specific membrane antigen (PSMA) for PCa treatment. The designed anti-PSMA immunotoxin, JVM-PE24X7, was conveniently prepared in its soluble form in an Escherichia coli (E. coli) system, avoiding the complex renaturation process needed for immunotoxin preparation by the conventional strategy. The product was very stable and showed a very strong ability to bind the PSMA receptor. Cytotoxicity assays showed that this molecule at a very low concentration could kill PSMA-positive PCa cells, with an EC50 value (concentration at which the cell viability decreased by 50%) of 15.3 pM against PSMA-positive LNCaP cells. Moreover, this molecule showed very good killing selectivity between PSMA-positive and PSMA-negative cells, with a selection ratio of more than 300-fold. Animal studies showed that this molecule at a very low dosage (5 × 0.5 mg/kg once every three days) completely inhibited the growth of PCa tumors, and the maximum tolerable dose (MTD) was more than 15 mg/kg, indicating its very potent tumor-treatment ability and a wide therapeutic window. Use of the new PE toxin, PE24X7, as the effector moiety significantly reduced off-target toxicity and improved the therapeutic window of the immunotoxin. The above results demonstrate that the designed anti-PSMA immunotoxin, JVM-PE24X7, has good application value for the treatment of PCa.
Highlights
IntroductionProstate cancer (PCa), a prostatic epithelial malignant tumor, is the second most common cancer in men, accounting for more than one-fifth of newly diagnosed cancer cases in this population and causing more than 300,000 deaths every year worldwide [1]
Prostate cancer (PCa), a prostatic epithelial malignant tumor, is the second most common cancer in men, accounting for more than one-fifth of newly diagnosed cancer cases in this population and causing more than 300,000 deaths every year worldwide [1].Whereas primary PCa tumors can be managed quite successfully, there are no curative treatments for those in advanced stages, with 18% of PCa patients dying of this disease each year [2]
Construction of the expression plasmid for the anti-prostate-specific membrane antigen (PSMA) immunotoxin JVM-PE24X7 was based on the sequences of the anti-PSMA single-domain antibody (sdAb) JVM and the optimized Pseudomonas exotoxin A (PE) toxin
Summary
Prostate cancer (PCa), a prostatic epithelial malignant tumor, is the second most common cancer in men, accounting for more than one-fifth of newly diagnosed cancer cases in this population and causing more than 300,000 deaths every year worldwide [1]. Some studies have attempted to develop such molecules for the treatment of PCa, such as the immunotoxin A5-PE40, which showed therapeutic efficacy in animal tumor models [25], and the development of immunotoxins targeting PSMA is a new strategy to treat PCa. there are some limitations to the clinical application of immunotoxins prepared according to the conventional strategy in which a single-chain variable fragment of an antibody (scFv) or its disulfide-stabilized derivative (dsFv) is fused with the PE38 toxin. There are some limitations to the clinical application of immunotoxins prepared according to the conventional strategy in which a single-chain variable fragment of an antibody (scFv) or its disulfide-stabilized derivative (dsFv) is fused with the PE38 toxin These molecules have relatively high off-target toxicities and immunogenicity, and their relatively large molecular weights may reduce their ability to permeate solid tumors. We designed such a novel immunotoxin (JVM-PE24X7) and tested its potential in the treatment of PCa through detailed biochemical, cellular and animal experiments
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
