Bifunctional Toxin DARP-LoPE Based on the Her2-Specific Innovative Module of a Non-Immunoglobulin Scaffold as a Promising Agent for Theranostics

G. M. Proshkina, D. V. Kiseleva, O. N. Shilova, A. V. Ryabova, E. I. Shramova, O. A. Stremovskiy, S. M. Deyev

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

We have generated and characterized HER2-specific targeted toxin based on the low-immunogenic variant of Pseudomonas exotoxin A (LoPE), in which most of the human immunodominant B-cell epitopes have been inactivated. Nonimmunoglobulin DARPin-based HER2-specific protein was used as a targeting module for toxin delivery to the cellular target. Using confocal microscopy, it has been found that both domains in this hybrid toxin retained their functionality, i.e., the specific interaction with HER2 receptor, as well as the internalization and effective transport to ER typical of the wild-type Pseudomonas exotoxin A. The HER2-dependent cytotoxic effect correlated with receptor expression level at the cell surface, as shown in vitro using cell lines with different levels of HER2 expression. Due to the very high selective cytotoxicity against HER2-positive human tumor cells, as well as expected low immunogenicity, we believe that this new targeted toxin may be promising for future in vivo studies as a therapeutic agent for HER2-positive tumors.

Original languageEnglish
Pages (from-to)865-873
Number of pages9
JournalMolecular Biology
Volume51
Issue number6
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • DARPin
  • HER2
  • Pseudomonas exotoxin А
  • targeted therapy

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology

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