Anthrax fusion protein therapy of cancer

Abstract

Most patients with cancer are treated with chemotherapy but die from progressive disease or toxicities of therapy. Current chemotherapy regimens primarily use cytotoxic drugs which damage cell DNA or impair cell proliferation in both malignant and normal tissues. After several treatment courses, the patients' tumor cells often overexpress multi-drug resistance genes which prevent further tumor cytoreduction. Novel agents which can kill such resistant tumor cells are needed. One such class of agents are targeted peptide toxins. Targeted peptide toxins consist of peptide toxins covalently linked to tumor selective peptide ligands. These molecules bind tumor cell surface receptors, internalize, and facilitate transfer of the toxin catalytic domains to the cytosol. Once in the cytosol, the enzyme activity leads to cell death. A number of plant, bacterial and fungal toxins have been used, and clinical trials with several of these have produced complete remissions in chemoresistant neoplasms. Nevertheless, there is a continuing need for novel targeted toxins. Many patients have pre-existing antibodies against the currently clinically used toxins and many toxins are inactive when used for myeloid malignancies where internalized proteins are rapidly routed and degraded in lysosomes. Anthrax toxins are the cytotoxic components of Bacillus anthracis. While the bacteria has been the source of serious illness, deaths and global anxieties related to past or future bioterrorism, the isolated toxins do not pose public health hazards. In fact, toxin treated patients will likely develop protective antibodies. Anthrax toxin is an excellent choice for tumor cell surface targeting. Other than U.S. military personnel immunized during the Gulf War, most people lack pre-existing antibodies. This may change in the future due to threats of additional terrorist acts, but for the present few patients will have antibodies to anthrax proteins. The separate subunits for binding, translocation and cell killing facilitate genetic engineering to yield tumor-specific cell killing. The toxins are more potent than most of the other peptide toxins and may yield highly efficacious targeted molecules. This essay will review anthrax toxin structure-function, preliminary experiments with re-targeted anthrax toxin and potential designs for new ligand-anthrax therapeutics.