We have shown that a plant-produced recombinant protein derived from a human anthrax toxin receptor protein and human IgG (an immunoadhesin), neutralizes anthrax lethal toxin in cell culture assays. In this project we will show the effectiveness of this immunoadhesin in vivo, both against purified toxin and in an animal model of pulmonary anthrax (infection with Ames spores). The immunoadhesin can be produced at low cost in plants in almost unlimited supply, defined specificity and reproducible titer. Existing active vaccines against anthrax toxin require multiple administrations for effective, but delayed, immunization and are not therapeutic for B. anthracis infected patients. An effective immunoadhesin-based anti-toxin strategy would provide three major benefits: (1) immediate, but temporary immunity to anthrax toxin for first responders, military personnel, and civilians under acute threat of exposure to the pathogen;(2) therapeutic effect, possibly in conjunction with antibiotics administration, to more effectively treat cases of anthrax infection;and (3) non-interference with subsequent, and possibly concurrent, immunization with an anthrax vaccine. Planet Biotechnology has produced antibodies and immunoadhesins in transgenic plants and advanced them into clinical trials. If we achieve the aims in this Phase II proposal, we will submit an Investigational New Drug application to the FDA for this protein. The following aims support the overall goal: 1. Make improvements to the already active immunoadhesin to increase activity in a cell-based assay for Lethal Toxin neutralization and enhance yield in transgenic tobacco. 2. Determine antitoxin activity of the immunoadhesin in animal models of anthrax infection, and examine the effect of glycosylation. 3. Produce immunoadhesin for animal safety studies from greenhouse-grown tobacco lines under cGMP. 4. Examine the pharmacokinetics and toxicology of plant-produced immunoadhesin in rats and dogs. Relevance of this research to public health: Spores of Bacillus anthracis, a Class I bioterror agent, are easy to produce using unsophisticated techniques. Inhalation of these spores causes deadly pulmonary Anthrax. This research may lead to an inexpensive, safe and effective treatment for Anthrax infection.
| Wycoff, Keith L; Belle, Archana; Deppe, Dorothee et al. (2011) Recombinant anthrax toxin receptor-Fc fusion proteins produced in plants protect rabbits against inhalational anthrax. Antimicrob Agents Chemother 55:132-9 |
