Gene-Based Drug Targeting Immune Problems
Reaches Human Testing

Ron Winslow,
Staff Reporter

June 23, 2000 ROCKVILLE, MD; (The Wall Street Journal) -- Monday's much-anticipated announcement that scientists have deciphered the entire sequence of human genetic code is already being hailed as one of the most remarkable feats in human history. But even more practical advances are flowing from other genomic discoveries.

Friday, Human Genome Sciences Inc. expects to announce it has received Food and Drug Administration approval to begin human tests of a protein that is one of the body's primary natural weapons against infections. The compound, known as B-lymphocyte stimulator, or BLyS, is the fourth gene-based drug candidate developed by HGS to advance to human trials, expanding the company's early lead in the race to convert information from the human genome into new drugs. No other company has more than one such drug.

The news comes on the heels of Johnson & Johnson's recent disclosure that it is close to human tests of a gene-based drug that targets a brain receptor associated with memory and attention. It also reflects the impact of new robotic and other technology that is enabling drug companies to rapidly translate genomic data into potential new medicines.

BLyS, a long-sought protein that was subject of an intense hunt by several pharmaceuticals companies, appears to be particularly versatile. The initial trial will involve patients with deficient immune systems that leave them vulnerable to recurrent infections such as pneumonia, bronchitis, and sinusitis. But HGS hopes to soon launch additional studies to include certain cancers, patients undergoing chemotherapy and organ transplants, and perhaps older people whose immune systems have weakened with age.

"Genomics allowed us to find something that others couldn't find," says Dr. William Haseltine, Chief Executive Officer of HGS. "From one discovery, we think we will be able to treat a very broad array of diseases." There isn't any assurance, of course, that BLyS or any of the other three HGS proteins will pass muster in human trials and make it to the market. The majority of experimental medicines that enter clinical trials fail to clear the FDA; thus, plenty of young biotech companies have foundered after showing promise. While many scientists are hopeful that data from the human genome will help improve on that performance, that too remains a risky bet.

But how HGS discovered BLyS and moved it swiftly to human tests illustrates the power that genomic information holds for streamlining drug discovery. "From the time the gene was discovered to the time when it will go into the first patient, this has been incredibly fast," says Dhavalkumar Patel, a rheumatologist and immunologist at Duke University Medical Center in Durham, N.C., who is a consultant to HGS on the development of BLyS.

It also reflects how HGS, one of the first companies to focus solely on genomic information to spur new drug development, hopes to become a drug powerhouse in its own right as it competes against pharmaceutical-industry giants racing to develop their own gene-based medicines.

Genetic Pipeline

Gene-based drugs developed by Human Genome Sciences now in human testing:


Disease Target


Keratinocyte Growth Factor-2 (KGF-2)

Chronic wounds; ulcerative colitis, mucositis

Second stage human trials

Myeloid Progenitor Inhibitory Factor (MPIF)

Side effects of chemotherapy

Second stage human trials

Vascular Endothelial Growth Factor-2 (VEGF-2)--a

Obstructed arteries

Initial human trials--b

B Lymphocyte stimulator (BlyS)

Common variable immunodeficiency

Initial human trials

a--Licensed to Vascular Genetics Inc.

b--Trials currently suspended for regulatory issues

Advancing BLyS into human studies is the latest milestone to result from HGS's decision in the early 1990s to build a huge database of genes to use as a source code for drug development. At the time, Dr. Haseltine, previously an eminent researcher at Harvard Medical School, saw the potential of new gene-sleuthing technology to transform the search for both genes and new medicines.

But he and his scientific staff at HGS had little interest in sequencing DNA. That would require sifting through the 97 percent of genetic code regarded as "junk DNA" to get to the 3 percent that represent actual genes. Instead, the company used a revolutionary new technology that allowed researchers to skirt the junk and home in directly on genes.

By 1995, less than three years after HGS launched its effort, the company believed it had in its computers partial sequences of 95 percent of all human genes. This rich database, Dr. Haseltine says, helped give the company a head start in determining the actual functions of all genes -- the ultimate goal of the separate efforts by the public Human Genome Project and private companies such as Celera Genomics Group, which are expected to jointly announce a rough draft of the sequence of human DNA next week [Monday].

HGS decided it would focus on genes that produce natural growth factors acting as molecular switches that signal cells when to grow or stop growing, when to mature, when to die, when to move or stay put.

Many drug companies, such as SmithKline Beecham PLC, Pfizer Inc., Johnson & Johnson and Bristol-Myers Squibb Co., are racing to use the emerging DNA sequence data to find such switches Their goal is to create medicines that attack diseases by acting on these switches. But the strategy at HGS and several other biotech companies is to use the newfound genes and proteins they make as drugs themselves.

By 1997, HGS scientists had plucked from the company's database about 400 genes they believed make these molecular switches. One early area of interest was finding the proteins that play an important role in controlling B cells, a critical component of the immune system.

Aging and a variety of medical problems can leave people with a deficient supply of B cells, making them vulnerable to viruses, bacteria and other foreign invaders. Dr. Haseltine's strategy was to find new proteins that, when administered in the form of injectable drugs, would improve the body's own supply of these important cells. No one previously had found the protein or its gene responsible for stimulating production of B cells.

In an effort to find proteins that interact with B cells, HGS scientists performed a straightforward experiment: In test tubes, they mixed each of the 400 different proteins they uncovered with B cells to see if any of them would make the cells grow. One protein -- BLyS -- did activate the B cells, coaxing them into producing antibodies, the natural substances the immune system uses to fight off disease.

Next step: testing BLyS on hundreds of other types of cells to see if there were reactions, which would indicate the molecule could have serious side effects. There were no significant reactions, so the protein was tested in animals, where it bolstered production of B cells -- a critical step toward today's expected announcement about the start of human studies.

Meantime, the ability to use a protein to turn on B-cell production caused researchers to wonder what happens when people have too much BlyS. It turns out that recent animal studies suggest that overactive B cells are associated with autoimmune diseases such as lupus, multiple sclerosis, and rheumatoid arthritis. If the finding is confirmed in human studies, HGS already has developed an "anti-BLyS" molecule -- in essence, an antibody that would block production of B cells -- it hopes to be able to test in people. "We have ways to work on both ends of the B-cell," Dr. Haseltine says. "Basically you want to get things in the body back in balance."

During the past two years, the company has identified 10,000 more proteins from its database that it believes are growth factors with possible important medical applications. HGS has begun conducting thousands of experiments to determine their function and is storing the results in company computers for retrieval and further analysis. "Everything our body is doing, we know there is a growth factor that makes it happen," says Craig A. Rosen, HGS's Executive Vice President, Research and Development. "Genomics gives you the edge in choosing the right ones."

E-mail for Ron Winslow: .