Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape
Researchers of the Laboratory of Molecular Immunology, IBCh RAS, in collaboration with Russian colleagues have shown that the strategy of targeting of anticancer toxins to two different surface antigens on the surface of a cancer cell is effective in the treatment of not only primary solid tumors, but also distant metastases.
Targeting therapy of solid tumors represents a great challenge because of heterogeneity of tumor-associated antigen expression. To overcome this obstacle the authors proposed a dual targeting therapy. Two tumor-associated antigens HER2 and EpCam which are known to widespread on cancer cells of epithelial origin were selected as targets. The combined therapeutics effect was achieved owing to two highly toxic proteins – a low immunogenic variant of Pseudomonas aeruginosa exotoxin A and ribonuclease Barnase from Bacillus amyloliquefaciens. Exotoxin was delivered to cancer cells as fusion protein with an anti-EpCAM-specific scaffold protein based on ankyrin repeats, while barnase was delivered in liposomes, the outer surface of which was modified with an anti-HER2-specific scaffold. The dual specific therapy of breast carcinoma-bearing mice using the designed preparations eliminates both the primary tumor and distant metastases. The mono-targeting therapy aimed at single tumor-associated antigen did not suppress metastases at all. The proposed approach can serve as a potential therapeutic strategy that surpasses mono-specific targeting strategies in the anti-cancer efficacy. Results of the research are published in Cancers.