More MS news articles for October 2000

High Levels of BLyS Implicated In Lupus and Rheumatoid Arthritis Patients
 
Findings From Human Genome Sciences and Academic

Collaborators May Lead to Treatments for Autoimmune Diseases

ROCKVILLE, Md., Oct. 30 /PRNewswire/ -- Scientists from Human Genome Sciences, Inc. and two of their academic collaborators today presented findings indicating that higher than normal blood levels of B Lymphocyte Stimulator, known as BLyS, may play a crucial role in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The findings suggest that reducing these higher than normal BLyS levels may be an effective way to treat serious autoimmune diseases.

The HGS scientists and their collaborators presented the results of two studies on BLyS levels in blood from autoimmune patients at the Annual Scientific Meeting of the American College of Rheumatology in Philadelphia.

One study, conducted with Robert P. Kimberly, M.D., Tong Zhou, M.D., and their colleagues at the University of Alabama at Birmingham, AL., examined blood sera from 150 SLE patients.  The principal finding was that two separate groups of SLE patients had significantly higher levels of active BLyS in their blood than did healthy individuals.  BLyS levels were significantly higher in patients with higher levels of anti-dsDNA antibody, that attacks the patient's own DNA and is often elevated in SLE patients.

The second study was conducted with Gurtej S. Cheema, M.D., and William Stohl, M.D., Ph.D., of the University of Southern California. The authors examined sera from 185 patients with various systemic immune-based rheumatological diseases, including SLE, RA and other conditions. This study concluded that the amount of BLyS in the serum of patients with SLE, RA and other rheumatological diseases was significantly greater than the amount in normal individuals' serum.  BLyS levels were also significantly higher in patients with higher levels of imunoglobulin G, in SLE patients with higher levels of anti-dsDNA antibody and in RA patients with higher levels of rheumatoid factor, a type of antibody that is overabundant in many patients with that disease.

Previous studies have already established that mice genetically altered to over-produce BLyS develop a syndrome that resembles SLE. Together with this prior finding, the new research provides a rationale for believing that high levels of BLyS cause over-proliferation of antibody-producing B cells in patients with SLE and RA. Many studies have confirmed excessive levels of antibodies in these conditions, although which specific ones are associated with disease progression has yet to be determined.

Craig A. Rosen PhD, Executive Vice President, Research and Development at HGS, said, "The new studies provide a clear rationale that we should test the hypothesis that an anti-BLyS antibody may be an effective therapy for SLE and rheumatoid arthritis. This is an exciting finding."

HGS currently has an active pre-clinical program to develop therapeutic antibodies that may reduce levels of BLyS in patients with autoimmune conditions such as SLE and RA.  This program is an extension of an established collaboration with Cambridge Antibody Technology plc, of Melbourn, U.K.

Rheumatoid arthritis affects more than 2,500,000 patients in the U.S. and can lead to disability and, in severe cases, death.  Systemic lupus erythematosus patients, who number approximately 500,000 in the U.S., develop symptoms involving the functioning of the kidneys, inflammation of joints and skin rashes and may be life-threatening.

BLyS is a naturally occurring immune-system growth factor discovered by HGS. In the body, BLyS binds to receptors on immune-system cells known as B cells, which stimulate the cells to secrete antibodies. Both RA and SLE are characterized by abnormally high levels of various antibodies, including antibodies that attack constituents of the patient's body.

The findings reported today were the work of HGS scientists and two of their academic collaborators were presented at the Annual Scientific Meeting of the American College of Rheumatology, held in Philadelphia.  The posters were entitled:

A Role for B Lymphocyte Stimulator (BLyS) in Systemic Lupus Erythematosus.

Authors include: Jun Zhang, Ph.D.; Viktor Roschke, Ph.D.; Kevin P. Baker, Ph.D.; Zheng Wang, M.S.; Graciela S. Alarcon, Barri J. Fessler and Holly Bastian of Human Genome Sciences, Inc.; and, Robert P. Kimberly, M.D., and Tong Zhou, M.D., of the University of Alabama at Birmingham, Alabama.

Elevated Serum B Lymphocyte Stimulator (BLyS) Levels in Patients With Systemic Immune-based Rheumatological Diseases.  The authors include Viktor Roschke, Ph.D. and David M. Hilbert, Ph.D., of Human Genome Sciences, Inc.; and, Gurtej S. Cheema M.D. and William Stohl, M.D. Ph.D., of the University of Southern California, Los Angeles.

In a separate program, HGS is currently testing BLyS as a therapy in a clinical trial treating patients with common variable immunodeficiency (CVID), a disease characterized by inadequate production of antibodies.

Individuals interested in BLyS or clinical trials for CVID, SLE or RA are encouraged to contact Human Genome Sciences at (1-301) 309-8504, extension 3550, or via the Internet at www.hgsi.com.

Human Genome Sciences is a company with the mission to treat and cure disease by bringing new gene-based drugs to patients.

HGS and Human Genome Sciences are registered trademarks of Human Genome Sciences, Inc.  For additional information on Human Genome Sciences, Inc., visit the company's web site at www.hgsi.com.  Copies of HGS press releases are also available by fax 24 hours a day at no charge by calling 800-758-5804, ext. 121115.

This announcement contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended.  The forward-looking statements are based on Human Genome Sciences' current intent, belief and expectations.

These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Actual results may differ materially from these forward-looking statements because of the company's unproven business model, dependence on new technologies, uncertainty as to clinical trial results, ability to develop and commercialize products, dependence on collaborators for services and revenue, substantial indebtedness, intense competition, uncertainty of patent and intellectual property protection, dependence on key management, uncertainty of regulation of products, dependence on key suppliers and other risks that may be described in the company's filings with the Securities and Exchange Commission.  Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of today's date.  Human Genome Sciences undertakes no obligation to update or revise the information contained in this announcement whether as a result of new information, future events or circumstances or otherwise.

B LYMPHOCYTE STIMULATOR

Background

In July 1999, Human Genome Sciences (HGS) reported the discovery of a novel human protein called B Lymphocyte Stimulator, or BLyS. (1) BLyS stimulates immune system cells called B cells to mature into plasma B cells, which produce antibodies (see Fig. 1). Plasma B cells and the antibodies they produce constitute a critical part of the body's defense against infections and cancer.

The discovery of BLyS may lead to therapies for several diseases that involve B cells, including immune deficiencies, autoimmune disease and B cell tumors. HGS' drug development teams are advancing several therapeutic concepts based on the discovery of BLyS: BLyS therapeutic protein, anti-BLyS, and radiolabeled BLyS.

How BLyS Works

BLyS is made by immune-cells called monocytes and macrophages. When monocytes and macrophages are activated, BLyS is released and binds to a receptor found only on B cells. B cells arise from stem cells that do not themselves produce antibodies. When BLyS binds to its receptor on B cells, they mature into antibody-secreting plasma B cells. As a result, the number of antibodies in the patient's plasma increases.

When antibodies recognize foreign molecules, immune-cells target the molecules for destruction. Without plasma B cells and antibodies, the body is largely unprotected against pathogens, and infectious disease may follow.

TURNING BLyS INTO TECHNOLOGY FOR FIGHTING HUMAN DISEASE

BLyS Antagonists for Autoimmune Disease and Cancer

Autoimmune Disease

The immune system has to distinguish the body's own cells and tissues from those of pathogens so that it can avoid attacking itself while maintaining a diverse repertoire of antibodies. Abnormalities in the induction or maintenance of self-tolerance-the process that prevents the immune system from attacking the body's own tissues-can lead to inflammatory immune responses developing against self-antigens and thus to autoimmune disease. B cells that produce antibodies that recognize parts of the normal body play an important role in many autoimmune diseases. Systemic lupus erythromatosis, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes, and some forms of asthma are all examples of autoimmune diseases.

HGS scientists are creating human monoclonal antibodies that bind to BLyS and inactivate the BLyS protein. It is already known that overproduction of BLyS in animals leads to a lupus-like disease. (4) Experiments in models of autoimmune disease suggest that such BLyS antagonists may reduce the body's ability to produce harmful self-reactive antibodies, with consequent benefits for patients.

B Cell Cancers

B cells are centrally involved in certain types of cancer, including non-Hodgkin's lymphoma, chronic lymphocytic leukemia and multiple myeloma. In these diseases, B cells become malignant and grow in an unregulated fashion.

Non-Hodgkin's lymphoma is the fifth-most-common type of cancer diagnosed in the U.S. each year. Chronic lymphocytic leukemia is the most common form of leukemia. Multiple myeloma is a deadly form of B cell cancer with a five-year survival rate of 28 per cent. New therapies are needed to improve survival rates and bring cures to more patients with these forms of cancer.

Radiolabelled BLyS

BLyS linked to radionucleotides have a potential application as therapy for B-cell malignancies. Such malignancies are responsive to radiation, and radiotherapy is an important part of the treatment plan for many patients with these diseases. A drug consisting of BLyS linked to a source of radiation would bind only to B cells, so low doses of radiation would be effective at killing such cells (see Fig. 4). HGS is working with The Dow Chemical Company to evaluate technologies that will allow a radioisotope to be linked to BLyS to create drugs that bind to and kill B-cells.

BLyS Therapeutic Protein for Immunodeficiency

Immunodeficiency disorders are a diverse group of conditions caused by one or more immune system defects. They are characterized by increased susceptibility to infections with consequent severe, acute, recurrent or chronic disease. Physicians recognize more than 70 different primary immunodeficiencies-ones that are caused by abnormalities in the development of immune system cells. Increased susceptibility to infections as a consequence of decreasing antibody output is common in people older than 70. Antibody deficits leading to increased incidence of serious infections also occur in cancer patients, and in immunosuppressed transplant recipients. The HGS BLyS Therapeutic Protein Program is developing BLyS protein as a therapeutic agent that may be valuable in the treatment of all of these groups.

Primary Immunodeficiency: CVID

Common variable immunodeficiency (CVID) is a group of immunodeficiency syndromes in which B cell immunity is abnormal. Most patients have normal or near-normal numbers of circulating B cells, but the cells fail to differentiate into effective plasma B cells. As a result, patients have low or undetectable amounts of serum antibodies. The condition may result from insufficient stimulation of B cells rather than from a failure intrinsic to B cells. (2)

There are several thousand CVID patients in the United States and Europe. CVID occurs equally in both genders. Most patients experience acute, recurring bacterial infections, including pneumonia, bronchitis and sinusitis. (3) Current treatment involves regular administration of intravenous antibodies, which are prepared from pooled blood samples from thousands of individual donors.

BLyS protein may boost antibody levels in patients with CVID, as well as in other immunodeficiency conditions that effectively mimic CVID. HGS scientists have found in laboratory studies that BLyS boosts antibody production in B cells isolated from some CVID patients.

Older Patients

Patients older than 70 years suffer significantly more from infectious disease and die more frequently from infections than younger people. This is believed to be in large part a result of age-related declines in the effectiveness of the immune system. BLyS may be able to stimulate immune system function in elderly patients.

Cancer and Transplant Patients

Several types of cancer, including chronic lymphocytic leukemia and multiple myeloma, affect the immune system's ability to fight off infections by impairing antibody production. BLyS may help these patients fend off infectious disease.  Cancer therapies also damage the immune system. In some cases it may take years for the full antibody response to recover following cancer treatment. Treatment with BLyS after cancer therapy may speed recovery of a fully competent immune system.

Transplant recipients have to take immunosuppressive drugs that make them vulnerable to infections of all sorts. BLyS may be able to help such patients maintain an immune system that is capable of combating infectious disease.

Patients with Infectious Diseases

Many bacterial infections that are resistant to treatment with antibiotics are able to persist because of an inadequate immune response. BLyS may be able to improve immune defenses in such patients. In addition, it is possible that BLyS protein may be useful when combined with vaccines. Vaccines work, in part, by inducing the production of antibodies that recognize invading organisms. Used as a vaccine adjuvant, BLyS may enhance the effectiveness of a wide range of vaccine candidates by stimulating B cell production and so strengthening the immune response to the vaccine.

How BLyS Was Discovered

A Functional Proteomics Success Story  

HGS scientists discovered BLyS (B Lymphocyte Stimulator) via functional proteomics, the study of the natural function and medical use of proteins discovered by genomic technology.

For decades, scientists sought a biological signal that stimulates immune-cells called B cells to become plasma B cells, which produce antibodies. Because biological signals are often secreted proteins, HGS scientists were studying a group of about 400 human proteins in the HGS database whose DNA sequences suggested that they were secreted. Each protein was purified and tested for the ability to stimulate B cell growth. One protein, BLyS, had a powerful effect on B cells.

Just as important, BLyS lacked effects on other cells. In pre-clinical experiments, BLyS was found to increase the production of antibodies, immediately suggesting medical applications in the treatment of immunodeficiencies and possibly other conditions. The HGSI scientists published the BLyS research in Science magazine in July 1999. (1)

The HGS functional proteomics program currently examines the biological activity of 10,000 human secreted proteins in the search for those that may serve as useful drugs.  Human proteins identified through genomics may have medical properties superior to conventional small-molecule drugs, and may enter clinical trials more quickly, because less medicinal chemistry research is needed to turn them into product candidates. Human antibodies to human genes and proteins may prove to be important medicines, and HGS is pursuing medicines based on antibodies to BLyS through several collaborations.

Conclusions  

The discovery of BLyS, a long-sought key immune system regulator with multiple possible uses in medicine, exemplifies the power of genomics to find molecules with therapeutic potential. Standard biochemical techniques had failed to identify BLyS, but systematic screening of proteins produced by candidate human genes revealed its identity and its powerful influence on the immune system. Genomics and proteomics may yield many additional potent molecules with medical applications.

References:

  1. Paul A. Moore, Ornella Belvedere, Amy Orr, Krystyna Pieri, David W. LaFleur, Ping Feng, Daniel Soppet, Meghan Charters, Reiner Gentz, David Parmelee, Yuling Li, Olga Galperina, Judith Giri, Viktor Roschke, Bernardetta Nardelli, Jeffrey Carrell, Svetlana Sosnovtseva, Wilbert Greenfield, Steven M. Ruben, Henrik S. Olsen, James Fikes, and David M. Hilbert. BLyS: Member of the Tumor Necrosis Factor Family and B Lymphocyte Stimulator. Science, Vol. 285, Number 5425, 260-263. July 9, 1999.
  2. F. Rosen et. al. The Primary Immunodeficiencies, A Review Article. New England Journal of Medicine 333: 7, August 17, 1995.
  3. Immune Deficiency and Allied Disorders: Clinical Updates, Immune Deficiency Foundation Vol. II, Issue 1, July 1995.
  4. Mice transgenic for BAFF develop lymphocytic disorders along with  autoimmune manifestations. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, Tschopp J, and Browning JL. J Exp Med 1999 Dec 6; 190(11): 1697-1710.
SOURCE  Human Genome Sciences, Inc.

CO:  Human Genome Sciences, Inc.

ST:  Maryland

IN:  BIO MTC

SU:

10/30/2000 01:00 EST http://www.prnewswire.com