Investigators at Hospital for Special Surgery have identified two new targets for drugs aimed at controlling lupus. If companies are able to develop drugs that hone in on these targets, patients may be able to control their disease with few side effects.

“The study identifies very good therapeutic targets, and what needs to be done is identify better candidate drugs,” said Lionel Ivashkiv, M.D., director of Basic Research at Hospital for Special Surgery in New York City. He led the study, which was published online in Nature Immunology and will appear in print in February.

Because abnormally high levels of interferon-alpha can lead to lupus, researchers have developed drugs that block interferon. These drugs, however, have immunosuppressive side effects that can leave patients vulnerable to various illnesses and infections, some of which can be deadly. Currently, these drugs are being tested in clinical trials. If researchers are able to develop drugs for the newly identified drug targets, patients may be able to avoid these immunosuppressive effects.

Interferons have two major functions. First, they protect against viruses and second, they regulate immune responses, strengthening immune responses and playing a role in autoimmunity. Different proteins, called STATs, mediate the two functions of IFN. STAT1 mediates the autoimmune and inflammatory functions, and STAT2 mediates the virus protection function. “What we were interested in understanding is how you can regulate the balance between activating the inflammatory effects and the antiviral effects,” Dr. Ivashkiv said. “We thought if we could control the functions of the interferons, that would lead to new therapeutic approaches where you could block specifically some of their functions, but not others.”

The investigators discovered that calcium specifically increases activation of STAT1 by interferons, and thus turned their attention to calcium. The researchers tested whether two kinase enzymes in the calcium-signaling pathway, CAMK and Pyk2, could be manipulated to control STAT1. In studies involving mice, the investigators showed that blocking these calcium-signaling pathways with a drug called KN-93 regulated the amount of STAT1, but not STAT2 activation.

“What we found was that these kinases that are regulated by calcium actually regulate the strength of activation of STAT1 by the interferons, but they do not regulate the strength of activation of STAT2,” said Dr. Ivashkiv. “The idea was if you block these signaling pathways, would you block the STAT1 part, which controls the inflammatory/deleterious effects and preserve the antiviral part. We tested that in an animal model of lupus and we were able to show, in vivo, that you can suppress STAT1 activation by inhibiting the calcium-dependent kinases.”

The researchers say that their work has identified a new therapeutic approach for attacking lupus. “What the companies are trying to develop are, basically, antibodies against the interferons. The concern there is that if you block the interferon completely, patients may become very immunosuppressed and unable to handle viral infections,” Dr. Ivashkiv said. “Our idea is that if you block these calcium pathways, you could block the deleterious effects of the interferon, but maintain the antiviral effects.”

Lupus is an autoimmune disease that can affect various parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain. Inflammation, considered the primary feature of lupus, is characterized by pain, heat, redness, swelling and loss of function. In most people, the disease affects only a few organs and symptoms are mild, but in others, the disease can cause serious and even life-threatening problems. According to the Lupus Foundation of America, an estimated 16,000 Americans develop lupus each year.

Wellcome Trust researchers have identified a key gene involved in the disease Lupus, which affects around 50,000 people in the UK, mostly women. The lead researcher behind the study has called for more patients to volunteer DNA samples to enable them to further study the underlying causes of the disease.

Lupus – or Systemic Lupus Erythematosus (SLE) – is an autoimmune disease which frequently causes skin rash, joint pains and malaise, but can also lead to inflammation of the kidneys and other internal organs. The risk of death in SLE is increased fivefold over that of the general population. However, because the symptoms are often non-specific, diagnosing the condition can be difficult. There is currently no cure for the disease, which can be triggered by viral infections, sunlight, trauma or stress, as well as puberty and childbirth.

In research published online recently in the journal Nature Genetics, Professor Tim Vyse from Imperial College London, and colleagues in the US and Canada, have identified a new genetic variant, OX40L, which increases the risk of developing Lupus. The variant, which is carried by one in six people in the UK, increases the risk of developing the disease by 50% per copy.

“Lupus can be a very serious condition, but because its symptoms are often similar to those of other illnesses, it can be difficult and take time to diagnose,” says Professor Vyse, a Wellcome Trust Senior Fellow from Imperial College. “Although it appears to have a number of environmental triggers, we are now beginning to get a clearer picture of the role that genetics also plays in the disease.”

OX40L is a gene that is important in several different types of cells in the immune system. The work, carried out by members of Prof Vyse’s laboratory, shows that the genetic variants in the OX40L gene that amplify the risk of lupus do so by increasing the amount of OX40L present on the surface of lymphocytes, which are key components of the immune system. They are currently studying exactly how this increases the risk of SLE.

“As well as causing problems with diagnosis, Lupus’s many symptoms make it difficult to work out which are key to the disease,” he says. “Identifying a specific gene will enable us to see at a molecular level what is behind Lupus and develop treatments targeted at inhibiting or blocking the action of those genes.”

Prof Vyse’s group and other scientists have previously discovered two other genes implicated in Lupus. IRF5 is a gene involved in regulating interferons, of which there appears to be an overabundance in Lupus. Interferons are natural proteins produced by the cells of the immune system in response to challenges by pathogens such as viruses, bacteria and tumour cells. The role of the second of the previously-discovered genes, FCGR3B, in Lupus is unclear.

Professor Vyse is very grateful to everyone who has provided DNA samples for these studies, but stresses the importance of more DNA samples from volunteers and calls for more patients to provide samples. The OX40L gene was identified by studying approximately 1.400 people with Lupus, and other members of their families in the UK and the US.

“Without DNA samples from people with Lupus, we would be unable to study the disease,” he says. “Despite the disease being relatively common, DNA samples are in short supply. I would encourage patients to discuss with their GP or consultant about providing a blood sample to help further our understanding.”

In a paper appearing online in the December issue of The European Journal of Immunology (Vol. 37, Issue 12), Dynavax scientists report the results of studies made possible under a grant from the Alliance for Lupus Research (ALR). In the article entitled, “Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms”, the data show that Dynavax’s proprietary IRS 954, a specific inhibitor of two Toll-like receptors, TLR7 and TLR9, can prevent progression of disease when injected in the lupus prone (NZBxNZW)F1 mice. The authors observed a significant reduction of serum levels of nucleic acid specific autoantibodies, the hallmark of systemic lupus erythematosus. IRS 954 treatment also resulted in decreased proteinuria, glomerulonephritis and end-organ damage and increased survival, compared to untreated mice.

According to Robert L. Coffman, Ph.D., Vice President and Chief Scientific Officer, “These results show that the previously reported ability of IRS 954 to block IFN-alpha translates into reduced symptoms in an animal model of lupus. The data support our hypothesis that blocking both TLR7 and TLR9 in B cells and in human plasmacytoid dendritic cells is a promising new approach for the treatment of lupus. The ability of IRS 954 to specifically intervene in the inappropriate immune signaling cascade that leads to autoimmunity may have application for other autoimmune diseases as well.”

IRS 954 represents a novel class of oligonucleotides, named immunoregulatory sequences (IRS), that specifically inhibit the TLR-induced inflammatory response implicated in disease progression in lupus. In 2005, the Alliance for Lupus Research awarded to Dynavax a $500,000 grant to explore new treatment approaches for systemic lupus erythematosus based on the company’s novel IRS technology. The grant was the first time ALR had provided funding to a private company.

About Dynavax

Dynavax Technologies Corporation discovers, develops, and intends to commercialize innovative TLR9 agonist-based products to treat and prevent infectious diseases, allergies, cancer, and chronic inflammatory diseases using versatile, proprietary approaches that alter immune system responses in highly specific ways. Our TLR9 agonists are based on immunostimulatory sequences, or ISS, which are short DNA sequences that enhance the ability of the immune system to fight disease and control chronic inflammation. Our product candidates include: HEPLISAVTM, a hepatitis B vaccine in Phase 3 partnered with Merck & Co. Inc.; TOLAMBATM, a ragweed allergy immunotherapy in Phase 2; a therapy for non-Hodgkin’s lymphoma (NHL) in Phase 2 and for metastatic colorectal cancer in Phase 1; and a therapy for hepatitis B also in Phase 1. Our preclinical asthma and COPD program is partnered with AstraZeneca. The National Institutes of Health (NIH) partially funds our preclinical work on a vaccine for influenza. Symphony Dynamo, Inc. (SDI) funds our colorectal cancer trials and our preclinical hepatitis C therapeutic program, and Deerfield Management has committed funding for our allergy programs. While Deerfield, NIH and SDI provide program support, Dynavax has retained rights to seek strategic partners for future development and commercialization. For more information, please visit http://www.dynavax.com.

This press release contains forward-looking statements that are subject to a number of risks and uncertainties, including statements about the potential for our IRS as an approach for the treatment of lupus and multiple autoimmune diseases. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in our business, including difficulties or delays in research and development and other risks detailed in the “Risk Factors” section of our Quarterly Report on Form 10-Q. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available.

The Lupus Research Institute (LRI) strategy of backing innovative investigations into systemic lupus, the autoimmune disease, has now yielded an unprecedented $30 million in large-scale funding from the National Institutes of Health and other government and private sources, an independent progress report has determined.

To date, 36 scientists have completed their novel research grants from the 7-year-old LRI — an Institute investment of $9 million. A remarkable 61% of these investigators have now turned their innovative hypotheses into confirmed discoveries, winning $30 million in large-scale grants to advance new scientific approaches to how and why lupus occurs, and what can be done to prevent and treat it.

“The LRI has been the leader in seeking and funding unproven but promising scientific hypotheses in lupus,” said Mark Shlomchik, MD, PhD, professor of Laboratory Medicine and Immunology at Yale University School of Medicine and a member of the LRI Scientific Advisory Board. “It’s because the LRI supported these innovative ideas in the first place that successful competition for scarce federal funding was possible.”

An estimated 1.5 million Americans, and millions more worldwide, have lupus. Many are young women in the prime of their lives. No one knows why lupus occurs, or how to prevent or cure it. There hasn’t been a new treatment approved for lupus in nearly 50 years, and existing medications are often toxic and can have debilitating effects.

LRI Breakthrough Discoveries in Lupus

Since its inception 7 years ago, the Institute has invested $22 million overall in cutting-edge lupus research, and current LRI-supported investigators are poised to capture similar large-scale awards. The Institute supports scientists from wide-ranging specialties who might otherwise not receive funds for their innovative and untested hypotheses in lupus.

In a brief time, LRI scientists have made breakthrough discoveries in such diverse fields as genetics, molecular science, cardiovascular disease, kidney disease, cognitive science, biomarkers, and pathways to autoimmune attack. Discoveries include:

* 20 potential lupus biomarkers — early predictors of disease and treatment effectiveness; six are now in clinical investigation and human testing.

* Genes that increase susceptibility to lupus

* Pathways that enable misguided antibodies to attack

* Molecules that determine control of the immune system

* Targets for new treatments

* Insights on how lupus damages organs — the heart, kidneys, brain, skin

“I’m grateful to the LRI for being brave enough to fund unusual work at an early stage of development,” said Philip Cohen, MD, of the University of Pennsylvania, who received an LRI research grant in 2001 and is continuing his investigations. “This initial funding was responsible for getting what is now a very large project off the ground.”

High urinary levels of certain molecules might have the potential to serve as biomarkers for a potentially life shortening kidney ailment caused by the autoimmune disease lupus, UT Southwestern Medical Center researchers have found.

“Our studies suggest a quartet of molecules may have potential diagnostic significance,” said Dr. Chandra Mohan, professor of internal medicine and senior author of a study available online at the Journal of Immunology.

“Given that early intervention in lupus nephritis is associated with better treatment outcome, it is imperative that disease activity in the kidney be diagnosed as early as possible.”

Lupus is a chronic autoimmune disease in which the immune system attacks the body’s cells and tissues. In a normal immune system, foreign intruders are recognized by special immune cells that produce antibodies. In patients with lupus, however, the antibodies created start to attack the body itself. When the antibodies attack the kidneys, nephritis occurs, often shortening a patient’s life expectancy.

Dr. Mohan and colleagues screened urine from mice with lupus nephritis for the presence of four compounds VCAM-1, P-selection, TNFR-1 and CXCL 16. Previous research had suggested that these molecules are elevated in animal models of antibody-mediated nephritis. Dr. Mohan and his research team determined that the mice harbored increased levels of all four molecules in the urine, particularly at the peak of their lupus associated kidney disease.

The most reliable method now available for monitoring renal disease in lupus patients is to measure the level of protein excreted in urine. As part of their study, the researchers also tested the urine of lupus patients and found that they not only had high protein levels in their urine, but also elevated levels of all four compounds.

“It would be very beneficial to detect the presence of nephritis early in order to administer therapies to stop the immune system from destroying the kidney,” said Dr. Mohan. “There is an urgent need for a biomarker that one could potentially use to predict the onset of nephritis. That is what we’re trying to discover with this research.”

Dr. Mohan said further studies are in progress to ascertain if checking these molecule levels might be more effective than monitoring protein levels to predict kidney disease in lupus patients.

“The ability to detect these molecules in urine could potentially have tremendous impact on clinical diagnostics. Not only is urine a convenient body fluid to procure; in some clinical settings it may be the only fluid available,” he said.

Some of the compounds might play a critical role in deciphering potential drug targets for therapeutic intervention. Although more research is needed, blocking one or more of these molecules might offer relief to patients suffering from lupus nephritis, Dr. Mohan said.

In humans, lupus can cause life-threatening damage not only to the kidneys, but also to the lungs, heart, central nervous system, joints, blood vessels and skin. It can be associated with severe fatigue, joint pain, skin rashes, hair loss and neurological problems. Although treatable symptomatically, there is currently no cure for the disease, which affects up to 1 million people in the U.S.

Other UT Southwestern researchers involved in the study were lead author Dr. Tianfu Wu, assistant instructor of internal medicine; Dr. Xin J. Zhou, professor of pathology; Hong Wang, research associate in pathology; Sergio Calixto, graduate student fellow; and Chun Xie, a former graduate student. Researchers from the Albert Einstein College of Medicine and Columbia University also contributed.

The research was funded by the National Institutes of Health, the Alliance for Lupus Research, the Arthritis Foundation, the Lupus Foundation of America, and the American College of Rheumatology Research and Education Foundation.