Evaluation of Intravenous Anthrax Immune Globulin for Treatment of Inhalation Anthrax

Abstract

Bacillus anthracis toxins can be neutralized by antibodies against protective antigen (PA), a component of anthrax toxins. Anthrivig (human anthrax immunoglobulin), also known as AIGIV, derived from plasma of humans immunized with BioThrax (anthrax vaccine adsorbed), is under development for the treatment of toxemia following exposure to anthrax spores. The pharmacokinetics (PK) of AIGIV was assessed in naive animals and healthy human volunteers, and the efficacy of AIGIV was assessed in animals exposed via inhalation to aerosolized B. anthracis spores. In the clinical study, safety, tolerability, and PK were evaluated in three dose cohorts (3.5, 7.1, and 14.2 mg/kg of body weight of anti-PA IgG) with 30 volunteers per cohort. The elimination half-life of AIGIV in rabbits, nonhuman primates (NHPs), and humans following intravenous infusion was estimated to be approximately 4, 12, and 24 days, respectively, and dose proportionality was observed. In a time-based treatment study, AIGIV protected 89 to 100% of animals when administered 12 h postexposure; however, a lower survival rate of 39% was observed when animals were treated 24 h postexposure, underscoring the need for early intervention. In a separate set of studies, animals were treated on an individual basis upon detection of a clinical sign or biomarker of disease, namely, a significant increase in body temperature (SIBT) in rabbits and presence of PA in the serum of NHPs. In these trigger-based intervention studies, AIGIV induced up to 75% survival in rabbits depending on the dose and severity of toxemia at the time of treatment. In NHPs, up to 33% survival was observed in AIGIV-treated animals. (The clinical study has been registered at ClinicalTrials.gov under registration no. NCT00845650.)

The prophylactic effects of human IgG derived from sera containing high anti-PcrV titers against pneumonia-causingPseudomonas aeruginosa

“…Food and Drug Administration for treating inhalation anthrax in conjunction with antibiotics in 2015, is a human immune globulin that is used in combination with antibiotics to treat anthrax. [41][42][43] Human hepatitis B immunoglobulin products (Nabi-HB Ò , Biotest Pharmaceuticals Co, Boca Raton, FL, USA; HepaGam B Ò Emergent BioSolutions, Gaithersburg, MD, USA; HyperHEP B Ò , Grifols Therapeutics Inc. Research Triangle Park, NC, USA) provide passive immunization for individuals exposed to the hepatitis B virus as evidenced by a reduction in the attack rate of hepatitis B following their use. 37,44,45 These products, which contain antibodies to the hepatitis B surface antigen (anti-HBs), are prepared from plasma donated by individuals with high anti-HBs titers.…”

Efficacy and Safety of AVP-21D9, an Anthrax Monoclonal Antibody, in Animal Models and Humans

“…Several anti-PA antibody-based anthrax therapeutics have been shown to increase survival in animal models of inhalational anthrax. These countermeasures act by neutralizing anthrax toxins (9)(10)(11)(12)(13)22). Here, we present data on the safety and efficacy of the anti-PA antibody-based therapeutic, AVP-21D9, which also neutralizes anthrax toxins and therefore might control toxemia and disease progression in the event of delayed treatment following exposure to aerosolized anthrax spores.…”

“…However, any delay in initiating antimicrobial therapy may result in toxemia, which accounts for most of the morbidity and mortality associated with progressive inhalational anthrax disease (7,8). The use of anthrax antitoxins, such as AVP-21D9, has been investigated as a treatment against anthrax toxemia (9)(10)(11)(12)(13).…”

“…Rabbits and nonhuman primates (NHPs) are considered acceptable models of inhalational anthrax and are widely used for assessing the efficacy of anthrax countermeasures, such as vaccines and therapeutics (19,20,21). Polyclonal and monoclonal antibody-based therapeutics for anthrax (9)(10)(11)(12)(13)22) have been evaluated using these models. Here, we evaluated the therapeutic efficacy of AVP-21D9 in New Zealand White (NZW) rabbits and cynomolgus macaques exposed to aerosolized B. anthracis spores and subsequently treated upon detection of a clinical sign or biomarker of infection.…”

Revisiting the Concept of Targeting Only Bacillus anthracis Toxins as a Treatment for Anthrax

“…Raxibacumab is a recombinant, fully humanized, immunoglobulin G1() [IgG1()] monoclonal antibody (15). AIGIV is a human polyclonal antiserum produced from the plasma of persons immunized with AVA, which might have some direct effect on LF and EF (16). In its recent recommendations for the treatment of systemic anthrax, the CDC recommends combining one of these antitoxin antibodies with antibiotic treatment.…”