Introduction

High titers of antibody to infectious bacteria and viruses can be used to both prevent and treat infectious diseases. In particular, antitoxins have been shown to be beneficial in several forms of severe acute infections such as diphtheria, rabies and anthrax. The recent use of active anthrax spores as a bioweapon, particularly in acts of terror, has renewed research efforts to develop potent, rapidly active means of prevention and treatment of anthrax after purposeful or accidental exposure. Several monoclonal antibodies to anthrax antigens have been developed as part of research efforts in bioterrorism, of which two are commercially available: raxibacumab (2012) and obiltoxaximab (2016). These two agents were approved for use based upon the so called “Animal Rule”, which allows FDA approval based upon efficacy as shown in animal models of severe infectious diseases and upon safety data developed in healthy volunteers. Both monoclonal antibodies have had limited use in humans, but neither has been associated with serum enzyme elevations or with instances of clinically apparent liver injury during the limited preclinical safety evaluation in healthy volunteers. Updated information on prevention and treatment of anthrax is available from the Centers for Disease Control and Prevention on their website: https://www.cdc.gov/anthrax/index.html.

Introduction

Obiltoxaximab is a chimeric monoclonal antibody to the protective antigen of B. anthracis that is used to prevent and treat inhalation anthrax. Obiltoxaximab has had limited use in humans, but has not been associated with serum enzyme elevations during therapy or with instances of clinically apparent liver injury.

Background

Obiltoxaximab (oh" bil tox ax i mab) is a human-mouse chimeric monoclonal antibody to the Bacillus anthrax protective antigen that is the major immunogenic antigen produced by the bacterial infection. The binding of obiltoxaximab to the anthrax protective antigen blocks the binding of the bacterial toxin to host cells. In several animal models of inhalation anthrax, obiltoxaximab ameliorated the course of the disease and, if given before the onset of signs and symptoms, prevented clinically apparent disease. Obiltoxaximab was approved for use in the United States in 2016 for the prevention and treatment of inhalation anthrax. The approval was based upon the efficacy of obiltoxaximab in animal models of anthrax and on data on safety and pharmacokinetics in healthy human volunteers. Human anthrax is exceedingly rare, but has occurred in the United States as a result of acts of terrorism. Obiltoxaximab is available in single use vials of 600 mg in 6 mL (100 mg/mL) under the brand name Anthim. The recommended dose is 16 mg/kg by slow (90 minute) intravenous infusion in adults and children above 40 kg in weight. Side effects were assessed in studies done in several hundred healthy adult volunteers. While described as “generally well tolerated” adverse events included headache, itching, rash, urticaria and local infusion and hypersensitivity reactions including anaphylaxis. Premedication with diphenhydramine (an antihistamine) is recommended.

Hepatotoxicity

In human volunteer studies, obiltoxaximab was associated with local infusion and general hypersensitivity reactions, but clinical laboratory results were said to be unchanged over time. There have been no reports of hepatotoxicity associated with administration of obiltoxaximab.

Likelihood score: E (unlikely cause of liver injury, but it has had very limited use in humans).

Mechanism of Injury

Obiltoxaximab is a monoclonal antibody and is unlikely to be inherently hepatotoxic. Recombinant proteins are often metabolized in the cells on which they act but are also metabolized in the liver, largely to small peptides and amino acids which may be reused to synthesize proteins and are unlikely to be toxic or immunogenic.

Drug Class: Antiinfective Agents, Antitoxins; Monoclonal Antibodies

Introduction

Raxibacumab is a human monoclonal antibody to the protective antigen of B. anthracis that is used to prevent and treat inhalation anthrax. Raxibacumab has had limited use in humans, but has not been associated with serum enzyme elevations during therapy or with instances of clinically apparent liver injury.

Background

Raxibacumab (rax" ee bak' ue mab) is a human monoclonal IgG1 antibody to the Bacillus anthrax protective antigen, a major component of the lethal toxin of anthrax. The binding of raxibacumab to the anthrax protective antigen blocks the binding of the bacterial toxin to host cells. In several animal models of inhalation anthrax, raxibacumab ameliorated the course of the disease and, if given before the onset of signs and symptoms, prevented clinically apparent disease. Raxibacumab was approved for use in the United States in 2012 for the prevention and treatment (combined with appropriate antibiotics) of inhalation anthrax. The approval was based upon the efficacy of raxibacumab in animal models of anthrax and on data on safety and pharmacokinetics in healthy human volunteers. Human anthrax is exceeding rare, but has occurred in the United States as a result of acts of terrorism. Raxibacumab is available in single use vials of 1700 mg in 34 mL (50 mg/mL) under the brand name Raxibacumab. The recommended dose is 40 mg/kg by slow (135 minute) intravenous infusion in adults and children above 40 kg in weight. Side effects were assessed in studies done in several hundred healthy adult volunteers. While described as “generally well tolerated” and similar in rate to that in placebo recipients, adverse events included rash, pain, somnolence, and local infusion and hypersensitivity reactions. Premedication with diphenhydramine (an antihistamine) is recommended.

Hepatotoxicity

In human volunteer studies, raxibacumab was associated with local infusion and general hypersensitivity reactions, but clinical laboratory results remained unchanged. There have been no reports of hepatotoxicity associated with administration of raxibacumab.

Likelihood score: E (unlikely cause of liver injury, but it has had very limited use in humans).

Mechanism of Injury

Raxibacumab is a human monoclonal antibody and is unlikely to be inherently hepatotoxic. Recombinant proteins are often metabolized in the cells on which they act but are also metabolized in the liver, largely to small peptides and amino acids which may be reused to synthesize proteins and are unlikely to be toxic or immunogenic.

Drug Class: Antiinfective Agents, Antitoxins; Monoclonal Antibodies