Therapeutic Applications Of Exotoxins

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One of the most exciting areas of bacterial exotoxin research has been the development of strategies to use exotoxins in therapeutic disciplines. Some therapies use the native cytotoxic form of the exotoxin. Other therapies use either the A or B domain, which is conjugated to a heterologous binding component or to effector elements, respectively, to produce a chimeric molecule with directed properties.

Botulinum toxin and tetanus toxin (BT/TT) are each a single protein that is organized as an AB exotoxin. The amino terminus of BT/TT expresses endopepti-dase activity and constitutes the A domain, whereas the B domain possesses neuronal cell-specific receptor-binding activity. The specific association of the B domain with neuronal cells is responsible for the clinical manifestation of these neurotoxins. BT/TT appear to enter neuronal cells by receptor-mediated endocyto-sis and to deliver the A domain to the cytosol, where it catalyzes the endoproteolytic cleavage of host proteins that are involved in vesicle fusion. Studies have shown that botulinum toxin can be introduced into the muscles surrounding the eye to temporarily reduce muscle spasms associated with several clinical disorders.

Diphtheria toxin has been used as a carrier to stimulate an immune response against several epitopes. One epitope is polyribitolphosphate, a component of the polysaccharide capsule of Haemophilus influenzae type b

(Hib). Early attempts to elicit an effective immune response to purified Hib antigen resulted in the production of a T-cell-independent immune response that did not yield an effective memory. A noncatalytic mutant of diphtheria toxin, CRM197, has been used as a carrier for the Hib epitope. Immunization with the CRM197-Hib conjugate yielded a strong T-dependent immune response. Mass immunization with Hib conjugates has resulted in a dramatic reduction in the number of cases of Hib in the immunized population.

Due to their potency, the catalytic A domain of exo-toxins have been used in the construction of chimeric immunotoxins that are designed to target cancer cells. Early studies used conjugates that were composed of the A domain of the diphtheria toxin coupled to an antibody that recognized a cell surface-specific antigen. The A chain of the diphtheria toxin was used in the first generation of immunotoxins because it had been shown to possess impressive cytotoxic potential when introduced into the cytosol of eukaryotic cells. It was estimated that the introduction of a single molecule of the A chain of diphtheria toxin into the cytosol was sufficient to kill that cell. In cell culture, these chimera have proven to be both potent and antigen specific. Ongoing research involves the determination of clinical situations for the use of these chimeras in a therapeutic arena.

The B component of anthrax toxin, protective antigen (PA) and a truncated, non-cytotoxic form of one of its A components (LF) has recently been used to deliver epitopes into antigen presenting cells to elicit a cyto-toxic lymphocyte (CTL) response. Anthrax toxin is a tripartite toxin composed of three non-associated proteins. After binding to cells, PA is proteolytically processed and undergoes oligomerization to form a heptameric structure on the cell surface. Processed PA is able to bind either LF or edema factor (EF) and the AB complex undergoes receptor-mediated endocytosis in which acidification in the early endosome stimulates the translocation of the A domain into the cell cytosol. In the nontoxic anthrax delivery system, PA is added to antigen-presenting cells with a nontoxic LF-CTL epi-tope chimera used to deliver the epitope into the host cell for antigen presentation. One of the more attractive aspects of this CTL-epitope delivery system is that small amounts of PA are required to present antigen.

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