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Fighting Diseases With Designer Genes ; Biotech's Mice in Demand By Big Drug Firms

Posted on: Thursday, 28 October 2004, 15:00 CDT

For a small biopharmaceutical company that has yet to get a drug on the market, Medarex Inc. has been keeping some impressive company.

Top pharmaceutical and biotech companies, from Johnson & Johnson to Amgen Inc., are lining up to pay Medarex to use its genetically engineered mice as they seek to develop new, better drugs.

The doctored mice have the rare ability to produce human antibodies, which can help fight disease in people for months at a time just like natural antibodies.

Last month, the world's biggest drug company, Pfizer Inc., signed Medarex to a decade-long development deal that could bring up to $500 million and a stream of future royalties.

Pfizer, which has been unable to get any antibody drugs approved, will try to develop up to 50 using Medarex technology.

Already, about 20 experimental drugs using Medarex antibodies are in various stages of testing - about one-third by the 17-year-old Princeton-based company and the rest by its collaborators and licensing partners. Those 50 partners include Abbott Laboratories, Eli Lilly & Co., Novartis Pharmaceuticals and Schering-Plough Corp., along with biotech companies Celltech Group, Genmab A/S, Human Genome Sciences Inc., Immunex and MedImmune.

"There are so many opportunities with this technology that they go beyond what we can do on our own," said Donald Drakeman, company co-founder and chief executive officer.

"The point is to take advantage of all these possibilities for the benefit of medicine and for the benefit of our company."

Medarex, which has laboratories in Bloomsbury, and in Milpitas and Sunnyvale, Calif., was founded in 1987 specifically to do work on monoclonal antibodies, which are made by cloning cells that can make a single antibody over and over.

The company went public in 1991 and has raised about $1 billion to fund its research, but the early going was tough.

In 1997, Drakeman took a big gamble, spending about two-thirds of the company's capital to acquire biotech company GenPharm and its top scientist, Nils Lonberg, because they had figured out how to make the immune systems of mice produce human antibodies.

The "transgenic" mice, made from standard brown ones used in research labs around the world, are altered by inactivating two key genes and adding two human genes, said Lonberg, who is now scientific director of Medarex. That's done through "molecular biology tricks" on the cells of mouse embryos.

To get specific human antibodies for use in drug development, Lonberg's team injects the mice with cells or material from a tumor, infectious agent or other target.

"The mice respond with a human antibody response instead of a mouse antibody response," he said.

Medarex researchers then put the antibody-making cells from the mice into special nutrients inside a vessel much like a beer- brewing vat so they multiply. The company's collaborators use antibodies made from those cells for their own research, or sometimes have the mice shipped overnight to them once they have begun producing antibodies.

"Antibodies are going to be the major source of breakthroughs in treating cancer and other terrible diseases over the next decade," Drakeman predicts.

One breakthrough could come from his company's leading drug candidate, MDX-010, for melanoma in patients who have failed prior treatments and had the deadly skin cancer spread to internal organs.

The final stage of human testing began in September and the drug could be approved in 2006, biotech analyst Brian Rye of Janney Montgomery Scott LLC said recently. Medarex still owns full marketing rights to MDX-010, meaning it would receive all the revenues if the drug is approved.

"The success of the company is by no means dependent on the success of that drug," Rye added, because Medarex could earn royalties of a few percent of sales if any of the other drugs in testing are approved, he said.

Medarex also owns full rights to three other cancer drugs currently in human testing.

Rye said Medarex is well structured, has strong patent protection for its technology and has enough money to fund operations for at least three or four years. The company, with about 430 employees, had revenues of about $11 million and a net loss of $129 million last year.

Still, Rye said it's a safer bet for investors than many of its peers.

Since 1986, 17 antibody drugs have been approved in this country, mostly in the last six years. They include Erbitux for colorectal cancer - the drug involved in the Martha Stewart stock scandal - six other cancer drugs, Remicade and Humira for rheumatoid arthritis, three drugs for preventing organ transplant rejection and Xolair for asthma.

Dr. George Weiner, director of the Holden Comprehensive Cancer Center at the University of Iowa, said antibody drugs also have promise against infections, heart and blood vessel diseases, and various immune system disorders.

In 1976, when the first monoclonal antibody was discovered, scientists had high hopes, said Dr. Lee Nadler, a pioneer in the field and chairman of the Dana Farber Cancer Institute.

"Everybody thought cancer would be immediately cured because this was the magic bullet," recalled Nadler, the first researcher to test a monoclonal antibody on a person, in 1979.

But progress proved very difficult, because researchers were using mouse antibodies that weren't able to kill cancer cells and sometimes triggered bad immune reactions in patients.

The field started drying up from lack of investment but was revived in the '90s when scientists figured out how to make mice produce partially human antibodies, Nadler said, leading to medicines such as Herceptin for breast cancer and "miracle drug" Rituxan for non-Hodgkin's lymphoma.

Now Medarex and competitor Abgenix Inc. of Fremont, Calif., each have a way to make mice produce fully human antibodies for medicines, limiting immune reactions in patients and allowing drugs to stay active in the body for months like natural antibodies.

"Antibodies have become for companies today the mainstay of therapy," Nadler said.

Researchers have been discovering many new potential targets on cancer cells for antibody drugs, and some newer ones have a radioactive substance attached to help kill cancer, said Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society.

Lichtenfeld thinks doctors will eventually be able to use a person's genetic profile to develop the most effective drug for them.

"We're far from there right now," he said.

Among the problems with antibody drugs still to be solved, the doctors said, are difficulties in manufacturing the complicated drugs consistently and the possibility that normal cells share some features with cancer cells and also would be attacked.

While earlier antibody drugs were directed at specific targets, newer ones direct the body's immune system to go on the attack, so it could attack healthy cells as well as intended targets.

Also, antibody drugs must be injected or infused and are expensive.

"It's an exciting field, but it's got a long way to go," Lichtenfeld said.

Source: Record, The; Bergen County, N.J.

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