A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma

Abstract

The discovery of chemoresistant cancer stem cells (CSCs) in carcinomas has created the need for therapies that specifically target these subpopulations of cells. Here, we characterized a bispecific targeted toxin that is composed of two antibody fragments and a catalytic protein toxin allowing it to bind two CSC markers on the same cell killing this resistant subpopulation. CD133 is a well-known CSC marker and has been successfully targeted and caused regression of head and neck squamous cell carcinoma (HNSCC) in vivo. To enable it to bind a broader range of CSCs, an anti-epithelial cell adhesion molecule (EpCAM) scFv was added to create dEpCAMCD133KDEL, a deimmunized bispecific targeted toxin on a single amino acid chain. This bispecific potently inhibited protein translation and proliferation in vitro in three different types of carcinoma. Furthermore, in a CSC spheroid model dEpCAMCD133KDEL eliminated Mary-X spheroids, an inflammatory breast carcinoma. Finally, this bispecific also caused tumor regression in an in vivo model of HNSCC. This represents the first bispecific CSC-targeted toxin and warrants further development as a possible therapy for carcinoma.

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Acknowledgments

This work was supported in part by the US Public Health Service Grant R01-CA36725 awarded by the NCI and the NIAID, DHHS, the Randy Shaver Foundation, the Atwater Cancer Drug Development Award, and a CETI translational award from the University of Minnesota Masonic Cancer Center.

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The authors declare that they have no conflict of interest.

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Correspondence to Daniel A. Vallera.

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Waldron, N.N., Barsky, S.H., Dougherty, P.R. et al. A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma. Targ Oncol 9, 239–249 (2014). https://doi.org/10.1007/s11523-013-0290-9

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Keywords

  • Cancer stem cells
  • Targeted toxins
  • Immunotoxins
  • CD133
  • EpCAM
  • Head and neck squamous cell carcinoma