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ABthrax takes advantage of new knowledge about anthrax to fight the bacteria’s lethal toxin.
A new drug designed to defend cells against the toxins produced by anthrax won Human Genome Systems a government contract worth at least $1.8 million last month. The company will supply the department of Health and Human Services with a sample of its drug, ABthrax (raxibacumab), for testing. The government then has a year to decide whether to purchase up to 100,000 doses of the drug under the BioShield Act, which would trigger the second phase of the contract.
Current antibiotic treatments seek to kill anthrax bacteria that germinate from inhaled spores before they reach the lymph nodes and spread infection. To supplement antibiotics, the new drug aims to prevent a later phase of infection, when toxins produced by anthrax bacteria enter cells and kill them, explained Jerry Parrott, Human Genome Sciences spokesman.
How the Infection Progresses
When anthrax spores are inhaled, macrophages (immune scavanger cells in the lungs) ingest the spores. Inside these cells, the dormant spores become active, sometimes called “vegetative,” bacteria, said Stephen Morse a professor of epidemiology at Columbia University and director of the school’s Center for Public Health Preparedness. The macrophage transports the germinating spore to the nearest lymph node, where it leaves the macrophage as an active bacteria and begins producing the toxin that kills cells.
Anthrax toxin is composed of three proteins, explained John Young a professor of infectious disease at the Salk Institute. One of these, called protective antigen (PA), binds to one of two anthrax receptors on the cell surface, and begins a process that brings the other two proteins into the cell interior, where they fatally disrupt cell functioning.
After PA binds to the receptor, an enzyme called furin cuts PA, Young said, forming a seven-part ring that will eventually transport toxic proteins into the cell. The other proteins that make up anthrax toxin, edema factor and lethal factor, attach to the ring. This complex enters the cell by merging with an endosome, a bubble-like cell structure whose membrane separates its contents from the rest of cell.
This interior of an endosome is acidic, which drives a reaction that turns the PA ring into a pore in the membrane of the endosome, Young explained. The edema factor and lethal factor move through the pore into the interior of the cell, where they disrupt normal functioning and eventually kill the cell.
Targeting Protective Antigen
ABthrax works by binding PA outside of the cell and blocking it from attaching to the anthrax receptors, Parrott explained. Because PA does not bind to the anthrax receptors, ABthrax prevents the reactions that allow lethal factor and edema factor to enter and kill the cell.
PA is the most common target of the latest approach to fighting anthrax infection, said Young, who is a co-founder of PharmAthene Inc., another company developing an anthrax treatment, PharmAthene and Medarex Inc., another biotech, are developing Valortim, a drug that binds PA to a second receptor, which prevents if from ushering edema factor and lethal factor into the cell.
If the government decides to go forward with phase two of the contract with Human Genome Sciences, the company will have to conduct an additional safety study and scale up its manufacturing process, Parrott said. Until then, the company is taking no action, Parrott said, since the government is the largest, if not the only, customer for the drug,
Days before the contract for ABthrax was awarded to Human Genome Sciences, a similar deal was made with Cangene Corp., according to company spokeswoman Jean Compton. The Canadian company manufactures Anthrax Immune Globulin, an injection of concentrated, purified anthrax antibodies distilled from the plasma of people who have received the anthrax vaccine and developed antibodies naturally.
AIG is a type of treatment known as a “hyperimmune.” It can be administered after or just before exposure and provide the recipient with the necessary antibodies to fight anthrax infection for approximately three weeks, Compton said. But it does not enable patients to develop antibodies on their own, like a traditional vaccine would.