Targeting triple negative breast cancers with an antibody-toxin fusion protein directed to tumor-associated Epidermal Growth Factor Receptor

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Authors

• NC Simon
• A Antignani
• R Sarnovsky
• D FitzGerald

Abstract

Triple negative breast cancers (TNBC) are typically more aggressive and result in poorer outcomes than other breast cancers because treatment options are limited due to lack of hormone receptors or amplified HER2. Many TNBCs overexpress the epidermal growth factor receptor (EGFR) or manifest amplification of the EGFR gene, supporting EGFR as a therapeutic target. Using the single chain variable fragment (scFv) of the 806 monoclonal antibody that binds only to cells with overexpressed, misfolded, or mutant-variants of the EGFR, a recombinant immunotoxin was engineered through a gene fusion with truncated Pseudomonas aeruginosa Exotoxin A (806-PE38). 806-PE38 reduced the viability of multiple TNBC lines through inhibition of protein synthesis in a concentration-dependent manner, while not affecting cells with wild-type EGFR. Deletion of a catalytic residue, E553, from the toxin resulted in loss of cytotoxic activity, confirming the toxin’s ADP-ribosyltransferase activity as the mediator of cell death. Systemic treatments with 806-PE38 resulted in reduced tumor burdens and increased survival in two TNBC mouse xenograft models. These data support the development of the 806-PE38 immunotoxin as a therapeutic agent for the treatment of patients with EGFR-positive TNBC.

Scientific Focus Area: Cancer Biology

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