Inclusion of a Furin Cleavage Site Enhances Antitumor Efficacy against Colorectal Cancer Cells of Ribotoxin α-Sarcin- or RNase T1-Based Immunotoxins

Ruiz-de-la-Herrán, Javier; Tomé-Amat, Jaime; Lázaro-Gorines, Rodrigo; Gavilanes, José G.; Lacadena, Javier

doi:10.3390/toxins11100593

Cited by 10 publications

(17 citation statements)

References 87 publications

(140 reference statements)

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“…toxic proteins), DARPins are widely used in modern research [ 19 , 20 , 21 ]. Toxins of bacterial origin are widely used as cytotoxic component in anticancer therapy [ 21 , 22 , 23 , 24 , 25 ]. In this work we use ribonuclease Barnase (Bn) from Bacillus amyloliquefaciens [ 26 ] and Pseudomonas exotoxin A secreted by gram-negative bacteria Pseudomonas aeruginosa with removed or inactivated human B-cell recognition sites (LoPE) [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape

Шрамова

Прошкина

Shipunova

et al. 2020

Cancers

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We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The combined therapeutic effect is achieved owing to two highly toxic proteins – a low immunogenic variant of Pseudomonas aeruginosa exotoxin A and ribonuclease Barnase from Bacillus amyloliquefaciens. The delivery of toxins to cancer cells was carried out by targeting designed ankyrin repeat proteins (DARPins). We have shown that both target agents efficiently accumulate in the tumor. Simultaneous treatment of breast carcinoma-bearing mice with anti-EpCAM fusion toxin based on LoPE and HER2-specific liposomes loaded with Barnase leads to concurrent elimination of primary tumor and metastases. Monotherapy with anti-HER2- or anti-EpCAM-toxins did not produce a comparable effect on metastases. The proposed approach can be considered as a promising strategy for significant improvement of cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape

Шрамова

Прошкина

Shipunova

et al. 2020

Cancers

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“…Linkers and toxins that have the maximum efficacy in the conditions of the early endosome would be the logical choice. For example, Furin is a protease that is found in the early endosome and studies have shown that ADCs with a furin-cleavable linker in drug conjugates can enhance antitumor efficacy 38,39 . Incorporating the knowledge from this study can lead to highly effective VDC designs that maximize their anti-tumor efficacy tailored to each malignancy 38,39 .…”

Section: Discussionmentioning

confidence: 99%

Internalization and Trafficking of CSPG-Bound Recombinant VAR2CSA Lectins in Cancer Cells

Wang

Nelepcu

Hui

et al. 2021

Preprint

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Proteoglycans are proteins that are modified with glycosaminoglycan chains. Chondroitin sulfate proteoglycans (CSPGs) are currently being exploited as targets for drug-delivery in various cancer indications, however basic knowledge on how CSPGs are internalized in tumor cells is lacking. In this study we took advantage of a recombinant CSPG-binding lectin VAR2CSA (rVAR2) to track internalization and cell fate of CSPGs in tumor cells. We found that rVAR2 is internalized into cancer cells via multiple internalization mechanisms after initial docking on cell surface CSPGs. Regardless of the internalization pathway used, CSPG-bound rVAR2 was trafficked to the early endosomes in an energy-dependent manner but not further transported to the lysosomal compartment. Instead, internalized CSPG-bound rVAR2 proteins were secreted with exosomes to the extracellular environment in a strictly chondroitin sulfate-dependent manner. In summary, our work describes the cell fate of rVAR2 proteins in tumor cells after initial binding to CSPGs, which can be further used to inform development of rVAR2-drug conjugates and other therapeutics targeting CSPGs.

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“…For instance, the repeated systemic administration of VB6-845, an anti-EpCAM Fab linked to de-Bouganin plant ribotoxin, to 10 solid tumor patients did not result in the significant formation of ADAs [ 99 ]. Pre-clinical studies optimizing other low immunogenicity ribotoxins and RNase payloads, some of which are human-derived, are ongoing [ 100 , 101 ]. These payloads have not yet been utilized to target MSLN.…”

Section: Overcoming Challengesmentioning

confidence: 99%

Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors

Hagerty

Pegna

et al. 2020

Biomolecules

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Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox’s has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox’s. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.

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Inclusion of a Furin Cleavage Site Enhances Antitumor Efficacy against Colorectal Cancer Cells of Ribotoxin α-Sarcin- or RNase T1-Based Immunotoxins

Cited by 10 publications

References 87 publications

Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape

Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape

Internalization and Trafficking of CSPG-Bound Recombinant VAR2CSA Lectins in Cancer Cells

Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors

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