Targeting HER2-positive cancer cells with receptor-redirected anthrax protective antigen

• Published in: Molecular oncology Vol. 7; no. 3; pp. 440 - 451
• Main Authors: McCluskey, Andrew J., Olive, Andrew J., Starnbach, Michael N., Collier, R. John
• Format: Journal Article
• Language: English
• Published: United States Elsevier B.V 01-06-2013; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: Affibody; Anthrax; Anthrax toxin; Antibodies, Monoclonal, Humanized - pharmacology; Antigens; Antigens, Bacterial - administration & dosage; Antigens, Bacterial - genetics; Antigens, Bacterial - pharmacology; Apoptosis; Bacterial Toxins - administration & dosage; Bacterial Toxins - genetics; Bacterial Toxins - pharmacology; Binary toxin; Binding sites; Breast; Cancer; Cancer therapies; Cell death; Cell Death - drug effects; Cell Line, Tumor; Cell surface; Cell Survival - drug effects; Drug Delivery Systems; Drug Resistance, Neoplasm; Enzymes; Epidermal growth factor; ErbB Receptors - metabolism; ErbB-2 protein; Fusion protein; HER2/neu; Humans; Immunotoxin; Kinases; Ligands; Monoclonal antibodies; Neoplasms - drug therapy; Neoplasms - metabolism; Plasmids; Protective antigen; Proteins; Receptor, ErbB-2 - metabolism; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - pharmacology; Surface markers; Targeted cancer therapy; Trastuzumab; Tumor cells; Tumors; Immunotoxin; Anthrax toxin; Binary toxin; HER2/neu; Affibody
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2012.12.003

Targeted therapeutics have emerged in recent years as an attractive approach to treating various types of cancer. One approach is to modify a cytocidal protein toxin to direct its action to a specific population of cancer cells. We created a targeted toxin in which the receptor-binding and pore-forming moiety of anthrax toxin, termed Protective Antigen (PA), was modified to redirect its receptor specificity to HER2, a marker expressed at the surface of a significant fraction of breast and ovarian tumors. The resulting fusion protein (mPA-ZHER2) delivered cytocidal effectors specifically into HER2-positive tumor cells, including a trastuzumab-resistant line, causing death of the cells. No off-target killing of HER2-negative cells was observed, either with homogeneous populations or with mixtures of HER2-positive and HER2-negative cells. A mixture of mPA variants targeting different receptors mediated killing of cells bearing either receptor, without affecting cells devoid of these receptors. Anthrax toxin may serve as an effective platform for developing therapeutics to ablate cells bearing HER2 or other tumor-specific cell-surface markers.
► We created a protective antigen fusion that targets the HER2 receptor (mPA-ZHER2). ► mPA-ZHER2 delivered two cytocidal effectors into the cytosol of HER2-positive cells. ► Killing was specific for HER2-positive cells in homogeneous or mixed cell populations. ► A trastuzumab-resistant tumor cell line was killed by the HER2-targeted toxin. ► Redirected mPA variants can be combined to eliminate diverse tumor cell populations.