Fully Human Anti-Anthrax Antibody Enlists Immune System to Neutralize Anthrax Toxin in Preclinical Studies
Tuesday October 11, 7:00 am ET
New preclinical study findings presented at Infectious Diseases Society of America annual meeting
PRINCETON, N.J. and ANNAPOLIS, Md., Oct. 11 /PRNewswire-FirstCall/ -- Medarex, Inc. (Nasdaq: MEDX - News) and PharmAthene, Inc., a privately held biotechnology company dedicated to the development of biodefense products, today announced preclinical study findings describing the activity of Valortim(TM) (MDX-1303) against anthrax infection. Valortim is a fully human antibody developed by Medarex's UltiMAb Human Antibody Development System® that targets the Bacillus anthracis protective antigen.
Details of these findings were presented in a Late Breaker Session oral presentation on Friday, October 7 and as a poster on Saturday, October 8 at the Infectious Diseases Society of American (IDSA) annual meeting held in San Francisco, Calif. The presentation is entitled "Valortim (MDX-1303): A Fully Human Anti-Anthrax Toxin MAb Provides Potent and Durable Protection by Mechanisms Similar to Vaccine Induced Immunity," and the abstract is posted on the IDSA web site (http://www.idsociety.org/).
The research presented at the IDSA meeting was conducted in order to better understand the high level of potency exhibited by Valortim in both prophylaxis and treatment preclinical studies. Valortim binds to the protective antigen (PA) component of anthrax toxin and appears to interfere with the normal formation or function of the anthrax toxin complex on macrophage and dendritic cells, which are believed to be critical cells in the natural defense of the immune system against anthrax and are prime targets of the anthrax toxin complex in causing disease. In addition to binding to PA, study results suggest that Valortim also interacts with a receptor on the surface of macrophage and dendritic cells known as the Fc receptor (FcR).
The three-way interaction between Valortim, anthrax PA, and FcR on macrophage and dendritic cells appears to result in an efficient and potent neutralization of the toxin complex, and this mechanism has not been previously described in studies of other known anthrax neutralizing antibodies. Importantly, the ability to take advantage of this FcR interaction is also found in the protective serum raised in individuals after vaccination with effective anthrax vaccines. These data suggest that the FcR interaction is a characteristic shared by Valortim and optimal natural immune responses raised by vaccination. The companies believe that the FcR interaction may contribute to Valortim's potency and durability of protection seen in the animal studies.
"We are very pleased with the progress of the development of Valortim as both a potential treatment and prophylaxis. We believe that due to its unique mechanism of action with regard to other antibodies, demonstrated efficacy in two animal models, and its potency in animal studies at the lowest dose reported, Valortim is the leading candidate for Project Bioshield procurement," said David P. Wright, President and CEO of PharmAthene.
"We believe that Valortim has significant potential efficacy because it takes advantage of a natural mechanism for augmenting the potency of antibodies to the anthrax toxin and protecting the macrophage and dendritic cells," said Dr. Israel Lowy, Medarex's Senior Director of Clinical Science and Infectious Disease. "These data may account for the ability of Valortim to protect non-human primates from lethal anthrax infection at the lowest doses of administered antibody that have been achieved, to the best of our knowledge, by any of the anthrax monoclonal antibodies in development."
About Valortim
Valortim (MDX-1303) is a fully human antibody designed to protect against inhalation anthrax, the most lethal form of illness in humans caused by the Bacillus anthracis bacterium. The investigational antibody is designed to target a protein component known as the anthrax protective antigen (PA) of the lethal toxin complex produced by the bacterium. The anthrax protective antigen is believed to initiate the onset of the illness by attaching to cells in the infected person, and then is believed to facilitate the entry of additional destructive toxins into the cells. Valortim is designed to target anthrax protective antigen and protect the cells from damage by the anthrax toxins.
In preclinical studies, Valortim both protected against infection and induced recovery and survival in animals exposed to lethal doses of inhalation anthrax spores. A recently performed study in non-human primates has demonstrated the potency of Valortim in this model using the potentially most clinically-useful intramuscular route of administration. In this study, the animals were challenged with a target aerosol dose of 200 times the median lethal dose of B. anthracis spores; 6 animals received no treatment, 6 animals received 1 mg/kg of Valortim intramuscularly, and 6 animals received 10 mg/kg of Valortim intramuscularly, all at the time of aerosol challenge. None of the animals were given antibiotics or other therapies. All control animals died within one week of the challenge; all treated animals in both dose groups were reported alive 60 days post-challenge. The effectiveness of doses even lower than 1 mg/kg may be studied in future preclinical research.
A first clinical study of the safety and pharmacokinetics of a single dose of Valortim given to human volunteers is planned to begin in the future, under an Investigational New Drug application recently allowed by the U.S. Food and Drug Administration to Medarex. Funding for the clinical trial, as well as for the experimental data reported at IDSA, have been provided in large part through two grants from the National Institute of Allergy and Infectious Disease, part of the National Institutes of Health, awarded to Medarex to both support the clinical development and to understand the mechanism of action of Valortim.
About Anthrax
According to the Centers for Disease Control and Prevention, anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Anthrax most commonly occurs in hoofed mammals and can also infect humans. Symptoms of disease vary depending on how the disease was contracted, but usually occur within seven days after exposure. The serious forms of human anthrax are inhalation anthrax, cutaneous anthrax, and intestinal anthrax. Initial symptoms of inhalation anthrax infection may resemble a common cold. After several days, the symptoms may progress to severe breathing problems and shock. Inhalation anthrax is often fatal, even with the use of antibiotics. |
