Final preclinical development of an immunoadhesin therapy for inhalation anthrax

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Description (provided by the applicant): Inhalational anthrax, caused by inhaled Bacillus anthracis spores, has a ~50% fatality rate even when treated with antibiotics. Pathogenesis is mediated by two toxic non-covalent complexes - edema toxin and lethal toxin. An essential component of both complexes, protective antigen (PA), binds to the major mammalian receptor which mediates toxin lethality in vivo, capillary morphogenesis protein-2 (CMG2). We have produced a fusion of the extracellular domain of human CMG2 and human IgG Fc, using a tobacco expression system, and demonstrated its effectiveness in treating inhalational anthrax in rabbits, both prophylactically and therapeutically. Our recombinant protein, PBI-220, binds to PA, blocks it from binding to cell-surface CMG2 and thus blocks toxicity. Significantly, PBI-220 neutralizes engineered PA variants that are poorly neutralized by anti-PA monoclonal antibodies in an in vitro assay, making it potentially superior to other anthrax therapeutics under development. We are developing PBI-220 as a passive immunotherapy to complement the use of antibiotics during treatment of inhalational anthrax. We have already completed pilot toxicology studies of PBI-220 in rats and cynomolgus macaques, and are developing a cGMP manufacturing process. We are collaborating with researchers at the Galveston National Laboratory and the Tulane National Primate Research Center to evaluate the benefits of combining PBI-220 and antibiotic treatment in late stages of disease in rabbits and to evaluate PBI-220 as a treatment in a cynomolgus macaque model of inhalational anthrax. This grant will advance our Product Development Plan for PBI-220 by completing the manufacturing and pre-clinical animal studies required for preparing an Investigational New Drug (IND) application, thus enabling human safety trials. Grant objectives include: 1) Develop a quantitative assay for contaminating plant proteins, to assure a minimal level of these proteins in the drug product, as required for human therapeutics; 2) Conduct GLP safety studies in two animal species (rats and monkeys) with drug product of the same quality as will be used in the first human clinical trial; 3 Produce PBI-220 under cGMP for Phase 1 clinical trial(s); 4) Develop immunoassays for clinical sample analyses (quantification of drug and anti-drug antibodies) and 5) Complete required benchmarks for successful submission of an IND application to FDA.