New Strategy For Broad Spectrum Anti-viral Drugs Developed

Bavituximab, an anti-viral drug developed by UT Southwestern Medical Center researchers, shows promise as a new strategy to fight viral diseases, including potential bioterrorism agents.
In a study appearing in the December issue of Nature Medicine, groups of guinea pigs infected with a virus similar to Lassa fever virus recovered from the fatal disease when treated with bavituximab alone or in combination with a common anti-viral medication. Bavituximab treatment also cured mice infected with cytomegalovirus, an opportunistic infection that afflicts transplant and AIDS patients.

Dr. Philip Thorpe, professor of pharmacology at UT Southwestern and senior author of the study, proposed that phosphatidylserine, a lipid molecule that is normally positioned on the internal surface of a cell, flips to the outside of the cell when the cell is infected by a virus. His laboratory developed bavituximab, which binds to phosphatidylserine on the infected cells. Dr. Thorpe, holder of the Serena S. Simmons Distinguished Chair in Cancer Immunopharmacology, predicted that this interaction would muster the body's immune cells to attack and destroy the infected cells before the virus has a chance to replicate.

"When injected into the bloodstream, bavituximab circulates in the body until it finds these inside-out lipids and then binds to them," said Dr. Thorpe. "In the case of virus infection, the binding raises a red flag to the body's immune system, forcing the deployment of defensive white blood cells to attack the infected cells."

In the study, half of the guinea pigs infected with a virus similar to the Lassa fever virus were cured when bavituximab was administered alone. This is the first report of a therapeutic treatment being effective against advanced Lassa-like fever infections in animals. Lassa fever is an endemic disease in portions of West Africa, where the Lassa virus is carried by rats. As a hemorrhagic fever virus, Lassa is listed as a Category A bioterrorism agent – the same class as the Ebola and Marburg viruses – by the Centers for Disease Control and Prevention.

In a second experiment, researchers administered both bavituximab and the anti-viral medication ribavirin. Ribavirin works by a different mechanism than bavituximab; it stops virus replication in the cell. With this combination therapy, 63 percent of guinea pigs survived.

Dr. Melina Soares, instructor of pharmacology at UT Southwestern and lead author of the Nature Medicine study, said, "As viruses mutate, they become more resistant to existing anti-viral drug therapies. Using bavituximab to attack a lipid target could prove to be a new and effective strategy for treating virus infections."

Dr. Thorpe said that because phosphatidylserine on virus-infected cells is host-derived and independent of the virus, drug-resistance should be less problematic.

"This approach reduces the ability of the virus to escape attack by a drug," he said. "Viruses often dodge drugs by mutating into a different form that the drug is ineffective against. Host cells are a more immutable target."

Bavituximab is currently in clinical trials to treat patients with hepatitis C. The trials have shown that treatment is safe for patients, and researchers are reporting a reduction in their blood-virus load.

UT Southwestern researchers have found that phosphatidylserine flipping occurs in cells infected with influenza, the herpes simplex virus and viruses in the families of the small pox and rabies viruses. Other researchers have shown that this also occurs in HIV.

"It could very well be that this is a generic feature of enveloped viruses," Dr. Soares said. "It could lead to a new, broad spectrum anti-viral treatment."

Peregrine Pharmaceuticals has exclusively licensed bavituximab from UT Southwestern and has a sponsored research agreement to develop the drug further. Dr. Thorpe is a consultant to and has an equity interest in the company.

The research was funded by the National Institutes of Health and Peregrine.

Cell Receptor Identified As Target For Anti-inflammatory Immune Response

Invading pathogens provoke a series of molecular heroics that, when successful, muster an army of antibodies to neutralize the threat. Like with any close-quarter combat, however, an aggressive immune response runs the risk of friendly fire accidents. For the last decade, immunologists have intensively studied mechanisms evolved by the immune system to avoid these accidents by shutting off the immune response once the invaders have been eliminated.
Now the discovery of a new role for a specialized cell receptor has revealed aspects of how the immune system prevents a harmful overreaction to a foreign threat. Researchers at The Rockefeller University found that a receptor known to shield HIV and Hepatitis C from an effective immune response is also essential to the therapeutic effects of a common anti-inflammatory drug, intravenous immunoglobulin (IVIG). The finding opens up new possibilities for developing drugs to suppress the inflammation caused by autoimmune diseases such as rheumatoid arthritis and lupus.

“I see the implications as quite immediate,” says Jeffrey Ravetch, Theresa and Eugene M. Lang Professor and head of Rockefeller’s Laboratory of Molecular Genetics and Immunology. “We can develop new classes of anti-inflammatory molecules that can exploit this pathway. These findings also explain why certain pathogens like the HIV virus and Hepatitis C have usurped this pathway with their own mechanisms for evading host response.”

The research further demystifies the workings of IVIG, which have baffled scientists for years. Essentially, IVIG is a very high dose of the same class of antibodies — immunoglobulin cells called IgG — that perpetrate autoimmune diseases in the first place. Ravetch and colleagues in his lab partially solved this paradox in earlier work that identified a single sugar molecule called sialic acid at the tail end of some IgG molecules. When present, the sugar gives IgG molecules anti-inflammatory activity. If absent, the IgG molecules lose their protective qualities and become pro-inflammatory agents. Building on that finding, Ravetch in April published research in Science explaining how to engineer a molecule of sialylated IgG that — when given to arthritic mice — was 30 times more effective than standard IVIG treatment.

The latest findings, to be published as Ravetch’s inaugural paper in the Proceedings of the National Academy of Sciences, pushes this research further to define a special cell receptor that is required for IVIG to work. In mice, this receptor — SIGN-R1 — is found in a group of cells in the spleen that regulate the immune response in part by recognizing that special sugar found on some IgG molecules. “This recognition of and binding with the sialylated IgG cells seems to be the first step that is triggered by IVIG to suppress inflammation,” Ravetch says.

Ravetch and his colleagues homed in on the spleen by breeding transgenic mice lacking in key types of immune cells, dosing them with IVIG, and measuring whether it protected them from an arthritis-inducing agent that they were then exposed to. They found that mice were not protected when certain types of immune cells common to the spleen were deleted. A series of biochemical tests on the different receptors within those cells identified SIGN-R1 as the one that bound specifically to the molecules that help along the anti-inflammation response, sialylated IgG.

The findings should apply to humans, too. Ravetch and his colleagues identified a receptor in human cells — DC-SIGN — that behaves exactly as the SIGN-R1 found in mice. In our case, the receptors are found on dendritic cells, a prominent cell-type of the human immune system.

Now that he knows both the protein and receptor that initiate the immune response, Ravetch wants to develop molecules that can regulate that response. He also wants to know what, exactly, the sialylated IgG causes to happen that ultimately leads to the anti-inflammatory response. “It’s exciting to have this new pathway to dissect,” Ravetch says