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Raxibacumab: Potential Role in the Treatment of Inhalational Anthrax

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Raxibacumab: Potential Role in the Treatment of Inhalational Anthrax Infection and Drug Resistance Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Raxibacumab: potential role in the treatment of inhalational anthrax Carlos E Kummerfeldt Abstract: Anthrax is a highly contagious and potentially fatal human disease caused by Bacillus Division of Pulmonary, Critical anthracis, an aerobic, Gram-positive, spore-forming rod-shaped bacterium with worldwide Care, Allergy and Sleep Medicine, distribution as a zoonotic infection in herbivore animals. Bioterrorist attacks with inhalational Medical University of South anthrax have prompted the development of more effective treatments. Antibodies against anthrax Carolina, Charleston, SC, USA toxin have been shown to decrease mortality in animal studies. Raxibacumab is a recombinant human monoclonal antibody developed against inhalational anthrax. The drug received approval after human studies showed its safety and animal studies demonstrated its efficacy for treatment as well as prophylaxis against inhalational anthrax. It works by preventing binding of the protec- tive antigen component of the anthrax toxin to its receptors in host cells, thereby blocking the For personal use only. toxin’s deleterious effects. Recently updated therapy guidelines for Bacillus anthracis recom- mend the use of antitoxin treatment. Raxibacumab is the first monoclonal antitoxin antibody made available that can be used with the antibiotics recommended for treatment of the disease. When exposure is suspected, raxibacumab should be given with anthrax vaccination to aug- ment immunity. Raxibacumab provides additional protection against inhalational anthrax via Video abstract a mechanism different from that of either antibiotics or active immunization. In combination with currently available and recommended therapies, raxibacumab should reduce the morbidity and mortality of inhalational anthrax. Keywords: anthrax, monoclonal antibody, protective antigen, raxibacumab Introduction Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 137.108.70.14 on 19-Jan-2020 In December 2012, the United States Food and Drug Administration (FDA) approved raxibacumab for treatment of and prophylaxis against inhalational anthrax.1 Its labeled uses are to treat inhalational anthrax in combination with appropriate antibacterial drugs, and for prophylaxis when alternative therapies are not appropriate or available.2 For its approval, the FDA granted fast track designation, priority review, orphan product Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: designation, and applied the Animal Efficacy Rule. Under this rule, medications are http://dvpr.es/1rmzddX given FDA approval based on efficacy findings from adequate and well controlled animal studies when it is not feasible or ethical to conduct studies in human subjects.3 Inhalational anthrax is a rare and lethal disease, so efficacy studies are unethical and prohibited in humans. Correspondence: Carlos E Kummerfeldt After the bioterrorist attacks of September 2001, which resulted in eleven confirmed Division of Pulmonary, Critical Care, cases of inhalational anthrax and five fatalities, the US government enacted new Allergy and Sleep Medicine, Medical University of South Carolina, 96 Jonathan rules and regulations to encourage pharmaceutical industry development of medical Lucas St, Suite 812-CSBMSC countermeasures against bioterrorist threats.4,5 The Project Bioshield Act was signed 630, Charleston, SC 29425-6300, USA Email [email protected] into law on July 2004 and provided funding for the development of raxibacumab. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2014:7 101–109 101 Dovepress © 2014 Kummerfeldt. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/IDR.S47305 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Kummerfeldt Dovepress Under Project Bioshield, the pharmaceutical company, The vegetative state is the replicating form that exists dur- Human Genome Sciences (GlaxoSmithKline, Research ing active infection. Herbivore mammals typically acquire Triangle Park, NC, USA) was awarded a contract to develop the infection after ingestion of spores, with transmission to and deliver human immune globulin against anthrax.5 The humans upon contact with contaminated animal products. reason for commissioning the development of passive Infection in humans results in four recognized forms immunity is that current recommendations for therapy and of the disease, depending on the route of entry, ie, cutane- exposure prophylaxis have limitations.6,7 ous, gastrointestinal, injection, and inhalational anthrax.13,14 Cutaneous anthrax is the most common and frequently Why is raxibacumab needed? resolves spontaneously. Initially, a painless or pruritic papule Current therapy guidelines recommend use of antibiotics appears, and is surrounded by edema. The papule progresses that are highly effective against Bacillus anthracis, but until to a vesicle, rupturing and creating an ulcer covered by a recently did not recommend administration of antitoxin ther- black eschar that sloughs 2–3 weeks later. Gastrointestinal apy. Patients die due to toxin-induced disease despite effective anthrax occurs after ingestion of contaminated meat. Spores antibiotic use that kills the bacteria.8 Toxin levels are highest germinate, resulting in oropharyngeal and gastrointestinal during initial presentation and decline with early antibiotic ulceration, followed by regional lymphadenopathy, edema, administration.9 The Anthrax Vaccine Adsorbed (BioThrax®; sepsis, necrosis, and perforation. Ascites can also occur. Emergent BioSolutions Inc., Rockville, MD, USA) licensed for Patients develop nausea, vomiting, bloody diarrhea, and use in the USA requires at least 4 weeks to develop sufficient ultimately pain resulting in an acute abdomen. Intravenous protective immunity.7 Exposed patients are at risk of disease or intramuscular drug use results in injectional anthrax despite receiving immunization, given the bacteria’s short where the typical black eschar is absent. Patients develop incubation period of at least 4 days after inhalation. Another subcutaneous lesions that lead to sepsis. Inhalational anthrax concern is adherence with the recommended 2-month oral occurs after inhaled spores are phagocytosed by alveolar antibiotic regimens against exposure prophylaxis. In a study macrophages that carry the spores to hilar and mediastinal For personal use only. of antibiotic adherence among postal workers in Washington lymph nodes where they germinate. Germination results in after the terrorist attacks of 2001, only 40% of those sampled hemorrhagic mediastinitis, bilateral hemorrhagic pleural reported full adherence, while another 18% had completely effusions, dyspnea, hypotension, shock, and death. Patients discontinued their prophylaxis.10 The US Centers for Disease initially present with influenza-like symptoms during the first Control and Prevention recently updated their guidelines in 4 days, but rapidly progress to respiratory failure.13,14 2014 and support the use of antitoxin therapy (either raxi- The anthrax genome is comprised of a single covalently bacumab or anthrax immune globulin) in combination with closed chromosome. It contains two virulent plasmids, pXO1 antimicrobial drug treatment in any patient for whom there is and pXO2, responsible for synthesizing the immunologi- a high level of clinical suspicion for inhalational anthrax. They cally inert capsule and the anthrax toxin, respectively.15 The acknowledge that optimal timing of antitoxin administration capsule is composed of poly-γ-D-glutamyl amino acids and 11 16,17 Infection and Drug Resistance downloaded from https://www.dovepress.com/ by 137.108.70.14 on 19-Jan-2020 remains unknown given the lack of data. protects the bacteria from phagocytosis. The anthrax Thus, passive immunity in the form of protective anti- toxin is composed of two binary combinations, each con- bodies has a role in treatment as well as post-exposure taining a common binding component known as protective prophylaxis against inhalational anthrax. This review dis- antigen (PA). The other two components, edema factor and cusses raxibacumab (Abthrax®, GlaxoSmithKline), the first lethal factor, are enzymes. PA combines with edema factor human monoclonal antibody approved for treatment and to form edema toxin, and in a similar way with lethal factor prophylaxis against inhalational anthrax. to form lethal toxin. PA is a protein that mediates binding to its receptors in the cell membrane of host cells. Binding to Pathophysiology of anthrax either a high-affinity or low-affinity receptor (ANTXR1/2) B. anthracis is a large rod-shaped, aerobic, Gram-positive, that may or may not require a coreceptor (LRP6) occurs, with spore-forming bacterium that exists in a spore or vegetative subsequent transformation of PA, resulting in pore formation state. The spore is
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