Bifunctional Toxin darp-lope Based on the her2-Specific Innovative Module of a Non-Immunoglobulin Scaffold as a Promising Agent for Theranostics
We have generated and characterized HER2 specific targeted toxin based on the low-immunogenic variant of Pseudomonas exotoxin A (LoPE) in which most of human immunodominant B-cell epitopes were inactivated. Non-immunoglobulin DARPin-based HER2-specific protein was used as a targeting module for toxin delivery to the cellular target. By means of confocal microscopy it was found that both domains in this hybrid toxin retained their functionality - specific interaction with HER2 receptor, as well as internalization and effective transport to ER typical to 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 the HER2 expression. Due to very high selective cytotoxicity for 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.