Her2-specific targeted toxin darpin-lope: Immunogenicity and antitumor effect on intraperitoneal ovarian cancer xenograft model
Sokolova E. A., Shilova O. N., Kiseleva D. V., Schulga A. A., Balalaeva I. V., Deev S. M.
International Journal of Molecular Sciences
Vol.20, Issue10, Num.2399
Опубликовано: 2019
Тип ресурса: Обзор
Аннотация:
High immunogenicity and systemic toxicity are the main obstacles limiting the clinical use of the therapeutic agents based on Pseudomonas aeruginosa exotoxin A. In this work, we studied the immunogenicity, general toxicity and antitumor effect of the targeted toxin DARPin-LoPE composed of HER2-specific DARPin and a low immunogenic exotoxin A fragment lacking immunodominant human B lymphocyte epitopes. The targeted toxin has been shown to effectively inhibit the growth of HER2-positive human ovarian carcinoma xenografts, while exhibiting low non-specific toxicity and side effects, such as vascular leak syndrome and liver tissue degradation, as well as low immunogenicity, as was shown by specific antibody titer. This represents prospects for its use as an agent for targeted therapy of HER2-positive tumors. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Ключевые слова:
DARPin; Far-red fluorescent protein; HER2; Immunogenicity; Ovarian carcinoma; Pseudomonas exotoxin A; Targeted therapy
alanine aminotransferase; antineoplastic agent; aspartate aminotransferase; darpin lope toxin; darpin pe40 toxin; epidermal growth factor receptor 2; epitope; Pseudomonas exotoxin; red fluorescent protein; unclassified drug; ANKRD23 protein, human; antineoplastic agent; bacterial toxin; epidermal growth factor receptor 2; epitope; ERBB2 protein, human; exotoxin; fusion protein; immunotoxin; muscle protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; nuclear protein; toxA protein, Pseudomonas aeruginosa; tumor marker; virulence factor; alanine aminotransferase blood level; animal cell; animal experiment; animal model; animal tissue; antibody titer; antineoplastic activity; aspartate aminotransferase blood level; B lymphocyte; cancer inhibition; cell viability; controlled study; drug cytotoxicity; female; gene overexpression; human; human cell; in vitro study; in vivo study; liver tissue; molecularly targeted therapy; mouse; nonhuman; ovarian carcinoma cel
Язык текста: Английский
ISSN: 1661-6596
Sokolova E. A.
Shilova O. N.
Kiseleva D. V.
Schulga A. A.
Balalaeva I. V. Irina Vladimirovna 1978-
Deev S. M. Sergej Mikhaylovich 1951-
Соколова Е. А.
Шилова О. Н.
Киселева Д. В.
Счулга А. А.
Балалаева И. В. Ирина Владимировна 1978-
Деев С. М. Сергей Михайлович 1951-
Her2-specific targeted toxin darpin-lope: Immunogenicity and antitumor effect on intraperitoneal ovarian cancer xenograft model
Текст визуальный непосредственный
International Journal of Molecular Sciences
Vol.20, Issue10 Num.2399
2019
Обзор
DARPin Far-red fluorescent protein HER2 Immunogenicity Ovarian carcinoma Pseudomonas exotoxin A Targeted therapy
alanine aminotransferase antineoplastic agent aspartate aminotransferase darpin lope toxin darpin pe40 toxin epidermal growth factor receptor 2 epitope Pseudomonas exotoxin red fluorescent protein unclassified drug ANKRD23 protein, human antineoplastic agent bacterial toxin epidermal growth factor receptor 2 epitope ERBB2 protein, human exotoxin fusion protein immunotoxin muscle protein nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase nuclear protein toxA protein, Pseudomonas aeruginosa tumor marker virulence factor alanine aminotransferase blood level animal cell animal experiment animal model animal tissue antibody titer antineoplastic activity aspartate aminotransferase blood level B lymphocyte cancer inhibition cell viability controlled study drug cytotoxicity female gene overexpression human human cell in vitro study in vivo study liver tissue molecularly targeted therapy mouse nonhuman ovarian carcinoma cel
High immunogenicity and systemic toxicity are the main obstacles limiting the clinical use of the therapeutic agents based on Pseudomonas aeruginosa exotoxin A. In this work, we studied the immunogenicity, general toxicity and antitumor effect of the targeted toxin DARPin-LoPE composed of HER2-specific DARPin and a low immunogenic exotoxin A fragment lacking immunodominant human B lymphocyte epitopes. The targeted toxin has been shown to effectively inhibit the growth of HER2-positive human ovarian carcinoma xenografts, while exhibiting low non-specific toxicity and side effects, such as vascular leak syndrome and liver tissue degradation, as well as low immunogenicity, as was shown by specific antibody titer. This represents prospects for its use as an agent for targeted therapy of HER2-positive tumors. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.