Journal
TARGETED ONCOLOGY
Volume 9, Issue 3, Pages 239-249Publisher
SPRINGER
DOI: 10.1007/s11523-013-0290-9
Keywords
Cancer stem cells; Targeted toxins; Immunotoxins; CD133; EpCAM; Head and neck squamous cell carcinoma
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Funding
- US Public Health Service - NCI [R01-CA36725]
- NIAID, DHHS
- Randy Shaver Foundation
- Atwater Cancer Drug Development Award
- CETI translational award from the University of Minnesota Masonic Cancer Center
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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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