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

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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.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, University of Minnesota, 210 Delaware Street Southeast, Minneapolis, MN, 55455, USA

    Nate N. Waldron & Phillip R. Dougherty

  2. Department of Pathology, University of Nevada School of Medicine, Manville Medical Building, Reno, NV, 89557, USA

    Sanford H. Barsky

  3. Department of Therapeutic Radiology-Radiation Oncology, Section on Molecular Cancer Therapeutics, University of Minnesota Masonic Cancer Center, 425 East River Parkway, Minneapolis, MN, 55455, USA

    Daniel A. Vallera

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  1. Nate N. Waldron
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  2. Sanford H. Barsky
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  4. Daniel A. Vallera
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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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  • DOI: https://doi.org/10.1007/s11523-013-0290-9

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