Human Genome Sciences, Inc. (HGSI) has announced that it has discovered and developed a human monoclonal antibody drug that is effective in protecting against anthrax in multiple experimental models in animals. A single dose of the new drug, ABthrax, increases survival significantly in both rabbit and nonhuman primate models of inhalational anthrax. Human Genome Sciences plans to develop ABthrax for use as a prophylactic and therapeutic drug to prevent and treat anthrax infections.
Currently, two options are available for the prevention or treatment of anthrax infections -- a vaccine and antibiotics. Both are essential to dealing with anthrax, but both have limitations. The anthrax vaccine takes several weeks following the first doses before immunity is initially established. The vaccine also requires multiple injections over a period of eighteen months, in addition to annual boosters, to maintain its protective effect. Antibiotics are effective in killing anthrax bacteria, but are not effective against the anthrax toxins once those toxins have been released into the blood. Antibiotics also may not be effective against antibiotic-resistant strains of anthrax.
In ABthrax (human monoclonal antibody to Bacillus anthracis protective antigen), Human Genome Sciences has discovered a third mechanism of defense against anthrax infections. In contrast to the anthrax vaccine, the protection afforded by a single dose of ABthrax would be immediate following the rapid achievement of appropriate blood levels of the antibody. In contrast to antibiotics, ABthrax acts against the lethal toxins produced by anthrax bacteria. It may also prevent and treat infections by antibiotic-resistant strains of anthrax.
Results from preclinical studies conducted to date demonstrate that a single dose of ABthrax administered prophylactically increases survival significantly in both rabbits and nonhuman primates exposed by inhaling lethal doses of anthrax spores. In both models, an absence of bacteria in the blood of all ABthrax-treated animals that survived was observed. The rabbit and nonhuman primate models of inhalation anthrax are regarded as relevant for the demonstration of the efficacy of therapeutic and prophylactic agents in treating or preventing anthrax infection. A single dose of ABthrax also fully protected rats against a lethal challenge with the anthrax toxins. Full results of these studies will be disclosed in upcoming scientific meetings and publications as appropriate.
Anthrax infection is caused by a spore-forming bacterium, Bacillus anthracis, which multiplies in the body and produces lethal toxins. Most anthrax fatalities are caused by the irreversible effects of the anthrax toxins. Research has shown that protective antigen is the key facilitator in the progression of anthrax infection at the cellular level. After protective antigen and the anthrax toxins are produced by the bacteria, protective antigen binds to the anthrax toxin receptor on cell surfaces and forms a protein-receptor complex that makes it possible for the anthrax toxins to enter the cells. ABthrax blocks the binding of protective antigen to cell surfaces and prevents the anthrax toxins from entering and killing the cells.
Human Genome Sciences plans to file an Investigational New Drug application in the near future, seeking clearance from the U.S. Food and Drug Administration (FDA) to begin clinical trials to evaluate the safety, tolerability, and pharmacology of ABthrax in healthy adults.
Under the Bioterrorism Act of 2002, the FDA specified the evidence required to demonstrate the efficacy of new drug and biological products used to counter biological agents, when traditional efficacy studies in humans are not feasible. According to the guidelines set forth in the Bioterrorism Act, successful studies in relevant animal models will be considered sufficient to establish efficacy for licensure and marketing approval. ABthrax is effective in preventing the lethal effects of anthrax infection in two relevant models, rabbits and nonhuman primates. According to the guidelines, human clinical trials will be required to establish safety, tolerability, and pharmacology, but not efficacy.
Craig A. Rosen, Ph.D., president, research and development, said, "Multiple in vivo and in vitro preclinical studies demonstrate that ABthrax specifically recognizes and neutralizes protective antigen. A single dose of ABthrax increases survival significantly in both rabbit and nonhuman primate models of inhalational anthrax. In both studies, we noted the absence of bacteria in the blood of all treated animals that survived, suggesting a sporicidal and/or bactericidal effect. Research has shown that protective antigen is a rational target of the toxin components that contribute to the pathogenesis of anthrax infection. By inhibiting protective antigen, the anthrax toxins are inhibited.
"We were able to make what we consider to be significant and rapid progress in the discovery and proof of efficacy of ABthrax as we have all of the relevant technology in house, including expertise in the creation of human monoclonal antibodies with desired medical properties, and antibody drug manufacturing capabilities. ABthrax used for preclinical and clinical studies is produced in our existing antibody manufacturing facilities."
David C. Stump, M.D., senior vice president, drug development, said, "The inhalational form of anthrax exposure is the most lethal. There are a limited number of prophylactic and therapeutic options available. The currently available anthrax vaccine requires multiple injections over a period of eighteen months, in addition to annual boosters, to maintain antibody levels. It takes several weeks following the first doses of the vaccine before immunity is initially established. By contrast, ABthrax confers effective protection against the lethal effects of anthrax infection immediately following the rapid achievement of appropriate blood levels of the antibody.
"Antibiotics are the current standard of care for post-exposure treatment of anthrax infection. While antibiotics are effective in controlling bacterial replication, they are not active against the lethal anthrax toxins produced by the bacteria. Based on our preclinical results to date, we believe that ABthrax has the potential to be used both prophylactically and therapeutically. For example, ABthrax may be used to protect rescuers entering a contaminated building, soldiers in an infected environment, or exposed individuals after an attack. In addition, post-exposure treatment may lessen the natural progression of anthrax infection and increase survival. ABthrax also may prevent and treat infections by antibiotic-resistant strains of anthrax. We look forward to exploring the safety, tolerability, and pharmacology of ABthrax in human studies."
William A. Haseltine, Ph.D., chairman and chief executive officer, said, "We believe that ABthrax demonstrates significant potential as a new prophylactic and therapeutic option in fighting anthrax infection. We intend to submit an Investigational New Drug application in the near future to initiate clinical trials to evaluate the safety and pharmacology of ABthrax in healthy adults.
"We hope, by applying our expertise in protein and antibody discovery and development, that Human Genome Sciences will be able to make an important contribution to our nation's biodefense initiative."
Human Genome Sciences is a company with the mission to treat and cure disease by bringing new gene-based drugs to patients.