Novel antibodies beat bacterial toxins.

Novel Antibodies Beat Bacterial Toxins

An experimental drug that quenches microbial poisons can save the lives of patients with severe bacterial infections, new research indicates. If the findings convince the FDA to approve the compound later this year, as some physicians expect, the drug will become the first of a new family of medicines -- called human monoclonal antibodies -- to advance from the research arena into the clinic.

In the United States each year, as many as 300,000 people acquire severe blood infections from gram-negative bacteria. Many of these microbes, including the large-intestine inhabitant Escherichia coli, are normal tenants of the human body. But when an individual's immune system becomes suppressed (by disease or chemotherapy, for instance) or when protective tissue-barriers get breached (as in surgery), the otherwise benign organisms can enter the bloodstream and go on a rampage.

Most important, they secrete potent compounds called endotoxins, which trigger a cascade of life-threatening reactions in the body. Under the influence of endotoxins, pulse and respiratory rates increase, the coagulation system falters and kidneys begin to fail. The syndrome can progress rapidly to septic shock, in which blood pressure drops radically. About one-third of those diagnosed with this microbial poisoning, called gram-negative bacteremia, die from the infection despite massive doses of antibiotics, which kill the offending bacteria but leave the endotoxin intact.

The new drug, called HA-1A, consists of antibodies produced by laboratory-reared human cells isolated nearly a decade ago by researchers at Stanford University and the University of California, San Diego. The antibodies bind to endotoxins, inactivating them.

In its first large-scale human tests, HA-1A seems to have worked exactly as it should. The trial, described in the Feb. 14 NEW ENGLAND JOURNAL OF MEDICINE, involved more than three dozen U.S. and European medical centers and included 543 patients with various blood infections. All patients received standard antibiotic therapy. In addition, about half the patients received an intravenous infusion of HA-1A while the rest received a placebo infusion.

In the 200 patients with gram-negative bacteremia, infection-related mortality was 39 percent lower among those receiving HA-1A than among those on placebo. That's impressive, considering the severity of these patients' illness, comments Harry L. Malech, a bacterial disease specialist at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., who is familiar with the work. "The beauty of this study is that the product was helpful even after the bacteremia had progressed," he says. "This is a marvelous example of a drug whose performance in the clinic matches what we'd hoped for from theory."

The drug caused no significant side effects and, as expected, didn't help patients with blood infections due to microbes that don't secrete endotoxins.

In an editorial accompanying the report, Sheldon M. Wolff of the Tufts University School of Medicine in Boston cautions that the promising findings should be confirmed by additional studies. But he foresees a time when physicians may routinely treat gram-negative bacteremia not only be targeting the microbes with antibiotics but also by blocking the fatal effects of endotoxins with antibodies such as HA-1A and other novel compounds now under development.