title: Targeting HER2-positive cancer cells with receptor-redirected anthrax protective antigen.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McCluskey
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Olive
authors.forename: Michael N
authors.initials: MN
authors.lastname: Starnbach
authors.forename: R John
authors.initials: RJ
authors.lastname: Collier
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab; C533351:affibody (ZHER2-342)2; C030325:anthrax toxin