Production and characterization of a colon cancer-specific immunotoxin based on the fungal ribotoxin  -sarcin

Carreras-Sangrà, Nelson; Tomé-Amat, Jaime; Garcı́a-Ortega, Lucı́a; Batt, Carl A.; Oñaderra, Mercedes; Martínez‐del‐Pozo, Álvaro; Gavilanes, José G.; Lacadena, Javier

doi:10.1093/protein/gzs032

Cited by 33 publications

(76 citation statements)

References 77 publications

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“…Much later, more systematic analysis of fungal genomes revealed that ribotoxins were a more widespread group of proteins within the filamentous fungi than had been previously believed (Lin et al, 1995;Martínez-Ruiz et al, 1999b;Varga and Samson, 2008). All this exhaustive work dealing with the characterization of their mechanism of action at the molecular level has not only helped to understand the basis of their antitumoral action (Lacadena et al, 2007) but also has established the principles to transform some of them into engineered chimeras with potential therapeutic uses (Carreras-Sangrà et al, 2008, 2012.…”

Section: Discussionmentioning

confidence: 99%

Fungal extracellular ribotoxins as insecticidal agents

Olombrada¹,

Herrero-Galán²,

Tello³

et al. 2013

Insect Biochemistry and Molecular Biology

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Fungal ribotoxins were discovered almost 50 years ago as extracellular ribonucleases (RNases) with antitumoral properties. However, the biological function of these toxic proteins has remained elusive. The discovery of the ribotoxin HtA, produced by the invertebrates pathogen H. thompsonii, revived the old proposal that insecticidal activity would be their long searched function. Unfortunately, HtA is rather singular among all ribotoxins known in terms of sequence and structure similarities. Thus, it was intriguing to answer the question of whether HtA is just an exception or, on the contrary, the paradigmatic example of the ribotoxins function. The work presented uses HtA and -sarcin, the most representative member of the ribotoxins family, to show their strong toxic action against insect larvae and cells.

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Section: Discussionmentioning

confidence: 99%

Fungal extracellular ribotoxins as insecticidal agents

Olombrada¹,

Herrero-Galán²,

Tello³

et al. 2013

Insect Biochemistry and Molecular Biology

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“…New non-immunogenic toxin warheads need to be developed and tested in order to provide a new generation of targeted immunotoxins for the treatment of malignancies. α-Sarcin is a good candidate toxin warhead since it has been demonstrated to have potent anti-tumour activity both in vitro and in animal models of colorectal cancer (Carreras-Sangrà et al ., 2012; Tomé-Amat et al ., 2015a). In order to improve therapeutic utility, we sought to deimmunise α-sarcin by identifying T cell epitopes within the protein and then removing them by mutagenesis.…”

Section: Discussionmentioning

confidence: 99%

A deimmunised form of the ribotoxin, α-sarcin, lacking CD4⁺T cell epitopes and its use as an immunotoxin warhead

Jones

Hearn

Holgate

et al. 2016

Protein Engineering, Design and Selection

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Fungal ribotoxins that block protein synthesis can be useful warheads in the context of a targeted immunotoxin. α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus that functions by catalytically cleaving a single phosphodiester bond in the sarcin–ricin loop of the large ribosomal subunit, thus making the ribosome unrecognisable to elongation factors and leading to inhibition of protein synthesis. Peptide mapping using an ex vivo human T cell assay determined that α-sarcin contained two T cell epitopes; one in the N-terminal 20 amino acids and the other in the C-terminal 20 amino acids. Various mutations were tested individually within each epitope and then in combination to isolate deimmunised α-sarcin variants that had the desired properties of silencing T cell epitopes and retention of the ability to inhibit protein synthesis (equivalent to wild-type, WT α-sarcin). A deimmunised variant (D9T/Q142T) demonstrated a complete lack of T cell activation in in vitro whole protein human T cell assays using peripheral blood mononuclear cells from donors with diverse HLA allotypes. Generation of an immunotoxin by fusion of the D9T/Q142T variant to a single-chain Fv targeting Her2 demonstrated potent cell killing equivalent to a fusion protein comprising the WT α-sarcin. These results represent the first fungal ribotoxin to be deimmunised with the potential to construct a new generation of deimmunised immunotoxin therapeutics.

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“…An immunotoxin, prepared by conjugating the single-chain variable fragment (scFv) of the monoclonal antibody that targets glycoprotein A33 (GPA33, a colon-cancer marker) to α-sarcin, demonstrated specific toxicity toward GPA33-positive cancer cells (Carreras-Sangrà et al 2012). An α-sarcin immunotoxin IMTXA33αS when injected intraperitoneally undermined the growth of GPA33-positive human colon cancer xenografts in nude mice.…”

Section: Fungal Proteins and Peptides With Antitumor Activitymentioning

confidence: 99%

Fungal proteinaceous compounds with multiple biological activities

Cheung

Wong

et al. 2016

Appl Microbiol Biotechnol

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Fungi comprise organisms like molds, yeasts and mushrooms. They have been used as food or medicine for a long time. A large number of fungal proteins or peptides with diverse biological activities are considered as antibacterial, antifungal, antiviral and anticancer agents. They encompass proteases, ribosome inactivating proteins, defensins, hemolysins, lectins, laccases, ribonucleases, immunomodulatory proteins, and polysaccharopeptides. The target of the present review is to update the status of the various bioactivities of these fungal proteins and peptides and discuss their therapeutic potential.

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Production and characterization of a colon cancer-specific immunotoxin based on the fungal ribotoxin -sarcin

Cited by 33 publications

References 77 publications

Fungal extracellular ribotoxins as insecticidal agents

Fungal extracellular ribotoxins as insecticidal agents

A deimmunised form of the ribotoxin, α-sarcin, lacking CD4⁺T cell epitopes and its use as an immunotoxin warhead

Fungal proteinaceous compounds with multiple biological activities

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Production and characterization of a colon cancer-specific immunotoxin based on the fungal ribotoxin -sarcin

Cited by 33 publications

References 77 publications

Fungal extracellular ribotoxins as insecticidal agents

Fungal extracellular ribotoxins as insecticidal agents

A deimmunised form of the ribotoxin, α-sarcin, lacking CD4+T cell epitopes and its use as an immunotoxin warhead

Fungal proteinaceous compounds with multiple biological activities

Contact Info

Product

Resources

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A deimmunised form of the ribotoxin, α-sarcin, lacking CD4⁺T cell epitopes and its use as an immunotoxin warhead