[PubMed] [Google Scholar] 42

[PubMed] [Google Scholar] 42. combination adjunct therapy with that of an antibiotic alone in treating inhalational anthrax. Overall, the results from this study indicate that a subtherapeutic regimen consisting of an antibiotic in combination with an anti-PA MAb results in increased survival compared to the antibiotic alone and would provide an effective therapeutic strategy against symptomatic anthrax in nonvaccinated individuals. INTRODUCTION is usually a Gram-positive, TSHR endospore-forming bacterial rod (1 to 10 MMAD m) that causes the disease anthrax (1, 2). The most lethal route of exposure is usually via inhalation, and the disease is usually characterized by extensive bacteremia and toxemia which, without aggressive prophylaxis or intervention, results in MMAD a high mortality rate (3,C5). Symptoms of inhalational anthrax present as nonspecific to moderate flu-like symptoms until the onset of hypotension, shock, and sudden death (6,C8). Aerosolized is considered a serious biological threat, with potential use as a military or terrorist weapon (9, 10). Several countries are believed to have offensive biological weapons programs, and some impartial terrorist groups have suggested their intent to use biological weapons (11, 12). In a bioterrorism attack in the United States in September 2001, spores were sent in letters to several locations via the U.S. MMAD Postal Support and resulted in 22 confirmed or suspect cases of cutaneous or inhalational anthrax contamination and 5 deaths (13). The capsule and two exotoxins, lethal toxin (LT) and edema toxin (ET), produced by are thought to be primarily responsible for the symptoms and pathogenesis of contamination (14,C16). The two enzymatically active toxin components, lethal factor and edema factor, are synthesized from different genes, but both associate with protective antigen (PA), which is the cell-binding component for each (17, 18). The key role of PA in anthrax contamination and pathogenesis makes it a good target for therapeutic treatments (19, 20), as well as its use as a diagnostic biomarker for contamination (7, 8, 14, 21, 22). Prophylactic anthrax vaccination in the United States has been available to special populations for over 40 years, but the vaccine is not available to the general public except for postexposure prophylaxis scenarios (23). Also, vaccine administered after exposure will not be effective for the first 4 to 6 6 weeks postadministration (21, 22). Therefore, option therapeutic strategies in nonvaccinated individuals, especially for those already suffering from the onset of anthrax contamination, are critically needed (3, 6, 24). Once clinical symptoms are apparent, mortality is nearly 100% in untreated cases (5, 9, 25, 26). Early diagnosis and aggressive treatment improve the prognosis. In the bioterrorism attack via the U.S. Postal Support in 2001, of the first 10 cases of inhalational anthrax, 4 patients were symptomatic at the time of hospital admission, were given multiple therapeutics, including antibiotics, but still succumbed to MMAD disease (13, 27). This strongly suggests that antibiotics MMAD are unable to prevent a fatal outcome in humans once the disease has reached a phase involving toxin production (11). Treatment to inactivate the toxins has been shown to be beneficial (19, 21, 28,C30). Therefore, as recommended by the Centers for Disease and Control and Prevention (CDC) and shown with raxibacumab, the use of an antitoxin antibody in conjunction with antibiotic treatment could be an effective option therapy (24, 31). Elusys Therapeutics, Inc., has developed ETI-204, a monoclonal antibody (MAb) against PA. ETI-204 contains human constant region sequences and deimmunized murine variable region sequences generated from 1H (32), an affinity-enhanced recombinant scFv (single-chain variable fragment) derived from the murine MAb 14B7 (33, 34). 1H is known to bind to domain name 4 of PA, which is the domain responsible for the binding of PA to cell.