HER2-specific recombinant immunotoxin 4D5scFv-PE40 passes through retrograde trafficking route and forces cells to enter apoptosis

Соколова, Е. А.; Guryev, Evgenii L.; Yudintsev, Andrey; Vodeneev, Vladimir; Deyev, Sergey M.; Balalaeva, Irina V.

doi:10.18632/oncotarget.15833

Cited by 22 publications

(22 citation statements)

References 52 publications

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“…Confocal microscopy images provided further evidence that the nucleus of MDBK cells infected with BoHV-1 was damaged after treatment with 1.00 μM BoScFv-PE38 ( Figure 5D ). These findings clearly indicated the internalization capability of BoScFv-PE38 via entrapment of BoHV-1 after binding to gD, which is similar to the antitumor immunotoxin 4D5scFv-PE40 reported earlier ( Sokolova et al, 2017 ).…”

Section: Discussionsupporting

confidence: 85%

“…Previous studies have shown that cytotoxicity to targeted cells induces apoptosis in virus-infected host cells or cancer cells ( Liu X.F. et al, 2016 ; Sokolova et al, 2017 ); specifically, high levels of ATP and ammonia are the major inducers of apoptosis ( Jin et al, 2017 ; Zhang et al, 2017 ). In our study, BoScFv-PE38 significantly increased the titers of ATP and ammonia in MDBK cells infected with BoHV-1 ( Figures 6A,B ), which implied that apoptosis was triggered in MDBK cells as a result of treatment with BoScFv-PE38 immunotoxin and the effect was dose-dependent ( Figures 6C,D ).…”

Section: Discussionmentioning

confidence: 99%

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Antiviral Immunotoxin Against Bovine herpesvirus-1: Targeted Inhibition of Viral Replication and Apoptosis of Infected Cell

Jiang

et al. 2018

Front. Microbiol.

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Bovine herpesvirus 1 (BoHV-1) is a highly contagious viral pathogen which causes infectious bovine rhinotracheitis in cattle worldwide. Currently, there is no antiviral prophylactic treatment available capable of mitigating the disease impact and facilitating recovery from latent infection. In this study, we have engineered a novel recombinant anti-BoHV-1 immunotoxin construct termed “BoScFv-PE38” that consists of a single-chain monoclonal antibody fragment (scFv) fused with an active domain of Pseudomonas exotoxin A as a toxic effector (PE38). The recombinant BoScFv-PE38 immunotoxin expressed in a prokaryotic expression system has specific binding affinity for BoHV-1 glycoprotein D (gD) with a dissociation constant (Kd) of 12.81 nM and for BoHV-1 virus particles with a Kd value of 97.63 nM. We demonstrate that the recombinant BoScFv-PE38 is internalized into MDBK cell compartments that inhibit BoHV-1 replication with a half-maximal inhibitory concentration (IC50) of 4.95 ± 0.33 nM and a selective index (SI) of 456 ± 31. Furthermore, the BoScFv-PE38 exerted a cytotoxic effect through the induction of ATP and ammonia, leading to apoptosis of BoHV-1-infected cells and the inhibition of BoHV-1 replication in MDBK cells. Collectively, we show that BoScFv-PE38 can potentially be employed as a therapeutic agent for the treatment of BoHV-1 infection.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Antiviral Immunotoxin Against Bovine herpesvirus-1: Targeted Inhibition of Viral Replication and Apoptosis of Infected Cell

Jiang

et al. 2018

Front. Microbiol.

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“…57 Tumor necrosis factor (TNF)-based immunotoxins were developed with antimelanoma antibody (scFvMEL), which showed cytotoxicity in nude mice. 58…”

Section: Cytokine Receptor As a Target And Ligand As A Targeting Moietymentioning

confidence: 99%

“…ErbB has higher expression levels in many tumors; ErbB2/ Her2 was targeted by ScFv (FRP5)-ETA for solid tumors. 58 It consists of an N-terminal ScFv, genetically linked to truncated PE. Epidermal growth factor receptor (EGFR) is another growth factor being used widely for solid tumors.…”

Section: Growth Factor Receptors As Targetsmentioning

confidence: 99%

Immunotoxins: Targeted Toxin Delivery for Cancer Therapy

Xin

Chen

Wang

et al. 2019

Pharmaceutical Fronts

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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.

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“…As the value of recombinant protein has increased, increasing attention has been paid to their production and purification. Some recombinant proteins have been used as drugs for treating human disease (Bera, Onda, Kreitman, & Pastan, ; Simon & FitzGerald, ; Sokolova et al, ) as well as to evaluate the efficacy and safety of these recombinant protein drugs; >95% purity is essential (Geng & Wang, ).…”

Section: Introductionmentioning

confidence: 99%

An efficient scheme for purification of a novel recombinant immunotoxin, rCCK8PE38, for anti‐tumour experiments

Zhang

et al. 2018

Biomedical Chromatography

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rCCK8PE38 is a novel immunotoxin that targets choleystokinin B receptor, which is over-expressed in some tumor tissues. Although we constructed a prokaryotic expression vector to express rCCK8PE38 in our laboratory, thorough purification was necessary to quantitatively assess its anti-tumor effect. In this study, we established a purification protocol to obtain rCCK8PE38 with high purity from E. coli. Three different types of chromatography, hydrophobic chromatography, ion exchange chromatography and size exclusion chromatography, were used in combination. The purification technological parameters of each chromatography type were optimized. The whole process of purification was arranged to minimize the purification steps and achieve purity and bioactivity. Finally, through this optimized scheme, we obtained a recombinant protein with a purity of >95%; then, the protein was stored at -80°C after lyophilization. The purified protein was used in a tumor inhibition experiment and was effective in killing tumor cells that over-expressed choleystokinin B receptor. The results of this study may provide some valuable information about protein purification and lay the foundation for further clinical experiments with rCCK8PE38.

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HER2-specific recombinant immunotoxin 4D5scFv-PE40 passes through retrograde trafficking route and forces cells to enter apoptosis

Cited by 22 publications

References 52 publications

Antiviral Immunotoxin Against Bovine herpesvirus-1: Targeted Inhibition of Viral Replication and Apoptosis of Infected Cell

Antiviral Immunotoxin Against Bovine herpesvirus-1: Targeted Inhibition of Viral Replication and Apoptosis of Infected Cell

Immunotoxins: Targeted Toxin Delivery for Cancer Therapy

An efficient scheme for purification of a novel recombinant immunotoxin, rCCK8PE38, for anti‐tumour experiments

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