A New Optimized Version of a Colorectal Cancer-Targeted Immunotoxin Based on a Non-Immunogenic Variant of the Ribotoxin α-Sarcin

Due to its incidence and mortality, cancer remains one of the main risks to human health and lifespans. In order to overcome this worldwide disease, immunotherapy and the therapeutic use of immunotoxins have arisen as promising approaches. However, the immunogenicity of foreign proteins limits the d...

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Bibliographic Details
Published in:Cancers 2023-02, Vol.15 (4), p.1114
Main Authors: Narbona, Javier, Gordo, Rubén G, Tomé-Amat, Jaime, Lacadena, Javier
Format: Article
Language:English
Subjects:
Antibodies
Antibody-toxin conjugates
Antigens
Antitumor activity
Cancer
Cancer therapies
Care and treatment
Cells
Colorectal cancer
Colorectal carcinoma
Cytosol
Cytotoxicity
Design
Drug targeting
Furin
Health aspects
Immune system
Immunogenicity
Immunotherapy
Immunotoxins
Mathematical optimization
Methods
Plasmids
Proteins
Sodium
Solid tumors
Tumors
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Summary:Due to its incidence and mortality, cancer remains one of the main risks to human health and lifespans. In order to overcome this worldwide disease, immunotherapy and the therapeutic use of immunotoxins have arisen as promising approaches. However, the immunogenicity of foreign proteins limits the dose of immunotoxins administered, thereby leading to a decrease in its therapeutic benefit. In this study, we designed two different variants of non-immunogenic immunotoxins (IMTXA33αSDI and IMTXA33furαSDI) based on a deimmunized variant of the ribotoxin α-sarcin. The inclusion of a furin cleavage site in IMTXA33furαSDI would allow a more efficient release of the toxic domain to the cytosol. Both immunotoxins were produced and purified in the yeast and later functionally characterized (both in vitro and in vivo), and immunogenicity assays were carried out. The results showed that both immunotoxins were functionally active and less immunogenic than the wild-type immunotoxin. In addition, IMTXA33furαSDI showed a more efficient antitumor effect (both in vitro and in vivo) due to the inclusion of the furin linker. These results constituted a step forward in the optimization of immunotoxins with low immunogenicity and enhanced antitumor activity, which can lead to potential better outcomes in cancer treatment.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers15041114